Protocadherins constitute the largest subgroup in the cadherin superfamily of cell adhesion molecules. Their major functions are poorly understood, although some are implicated in nervous system development. As tumorspecific promoter methylation is a marker for tumor suppressor genes (TSG), we searched for epigenetically inactivated TSGs using methylation-subtraction combined with pharmacologic demethylation, and identified the PCDH10 CpG island as a methylated sequence in nasopharyngeal carcinoma (NPC). PCDH10 is broadly expressed in all normal adult and fetal tissues including the epithelia, though at different levels. It resides at 4q28.3 -a region with hemizygous deletion detected by array-CGH in NPC cell lines; however, PCDH10 itself is not located within the deletion. In contrast, its transcriptional silencing and promoter methylation were frequently detected in multiple carcinoma cell lines in a biallelic way, including 12/12 nasopharyngeal, 13/16 esophageal, 3/4 breast, 5/5 colorectal, 3/4 cervical, 2/5 lung and 2/8 hepatocellular carcinoma cell lines, but not in any immortalized normal epithelial cell line. Aberrant methylation was further frequently detected in multiple primary carcinomas (82% in NPC, 42-51% for other carcinomas), but not normal tissues. The transcriptional silencing of PCDH10 could be reversed by pharmacologic demethylation with 5-aza-2 0 -deoxycytidine or genetic demethylation with double knockout of DNMT1 and DNMT3B, indicating a direct epigenetic mechanism. Ectopic expression of PCDH10 strongly suppressed tumor cell growth, migration, invasion and colony formation. Although the epigenetic and genetic disruptions of several classical cadherins as TSGs have been well documented in tumors, this is the first report that a widely expressed protocadherin can also function as a TSG that is frequently inactivated epigenetically in multiple carcinomas.
DNA methylation and histone modifications have emerged as key mechanisms in transcriptional regulation. The target of methylation-induced silencing 1 (TMS1) is a bipartite protein. Recent studies have indicated that methylation-associated silencing of TMS1 occurs in many cancers. However, whether and how TMS1 is regulated by epigenetic mechanisms in cancers remains unknown. In this study we showed that methylation of the TMS1 promoter occurred in five of six hepatocellular carcinoma (HCC) cell lines. TMS1 expression was reduced in four HCC cell lines and correlated with methylation status. Furthermore, the TMS1 promoter was completely methylated and mRNA expression was undetectable. TMS1 expression could be restored by 5-aza-2'-deoxycitidine (5-Aza-dC) (a DNA methyltransferase inhibitor) or trichostatin A (TSA) (a histone deacetylase inhibitor) alone and the promoter methylation was partially reversible. TSA was more efficient than 5-Aza-dC in inducing TMS1 expression, and the combination of 5-Aza-dC and TSA resulted in markedly synergistic reactivation of the gene and completely reversed promoter methylation. Interestingly, TMS1 promoter methylation-associated gene silencing was accompanied by histone H3 Lysine 9 (H3K9) hypoacetylation and trimethylation. 5-Aza-dC and/or TSA also had some effect on conversion of methylated to acetylated H3K9 in restoring TMS1. This conversion was dynamic at the TMS1 promoter and a decrease in H3K9 trimethylation preceded an increase in H3K9 acetylation after 5-Aza-dC and/or TSA treatment. Our results thus suggest that epigenetic inactivation of TMS1 expression is regulated by promoter hypermethylation and H3K9 modifications in a coordinated way.
Objective To study the effect of optical coherence tomography (OCT) scan circle displacement on retinal nerve fibre layer (RNFL) measurement errors using cubic spline models. Methods Forty-nine normal subjects were included in the analysis. In one randomly selected eye in each subject, RNFL thickness around the optic disc was measured by taking 16 circular scans of different sizes (scan radius ranged from 1 to 2.5 mm). The RNFL profile in each eye was constructed with a mathematical model using a smoothing spline approximation. Scan circle (diameter 3.4 mm) RNFL measurements (total average, superior, nasal, inferior, and temporal RNFL thicknesses) obtained from eight directions (superior, superonasal, nasal, inferonasal, inferior, inferotemporal, temporal, and superotemporal) displaced at different distances (0.1, 0.2, 0.3, 0.4, 0.5, 0.6, and 0.7 mm) from the disc centre were then computed by a computer program and compared to the 'reference standard' where the scan circle is centred at the optic disc. RNFL measurement error was calculated as the absolute of (RNFL thickness (displaced) -RNFL thickness (reference standard) ). Results The respective mean average, superior, nasal, inferior, and temporal RNFL measurement errors were 2.3±2.0, 4.9±4.5, 4.1±3.8, 6.2±7.6, and 3.8±3.5 lm upon 0.1 mm scan circle displacement, and 12.1±11.4, 27.8 ± 18.4, 21.7 ± 18.6, 34.8 ± 22.9, and 15.2 ± 10.7 lm upon 0.7 mm scan circle displacement. Significant differences of average and quadrant RNFL thicknesses were evident between centred and displaced scan circle measurements (all with Po0.001). RNFL measurement error increased in a monotonic fashion with increasing distance away from the disc and the change was directiondependent. Conclusions RNFL measurement error varies with the direction and distance of scan displacement. The superior and the inferior RNFL measurements are most vulnerable to scan displacement errors, whereas the average RNFL thickness is the least susceptible. Obtaining a well-centred scan is essential for reliable RNFL measurement in OCT.
Background There are considerable sex differences in patients with myocardial infarction (MI). However, the recent temporal trends in characteristics and outcomes in women vs. men, particularly in an Asian population, remain poorly understood. Purpose We aim to evaluate the sex differences in characteristics and outcomes, and how have these differences evolved over the past 2 decades in patients with MI. Methods From a well-validated territory-wide database in Hong Kong, we included patients with incident acute MI from 1999/01/01 to 2018/12/31. Outcomes of interest include, at 30 days, all-cause death, new-onset heart failure (HF), and ischaemic stroke. Trends in sex differences in baseline characteristics were evaluated using linear and Poisson regression, while differences in outcomes were evaluated using Cox proportional hazard model, adjusted with demographics, comorbidities, and baseline medications. A Fine-Gray model was used to evaluate HF and ischaemic stroke to account for competing risk, with all-cause death defined as competing event. Results A total of 130,218 patients (age 73.6±13.9 years, 40.0% female) were included. Women were older (79.5±11.7 vs. 69.6±13.8 years, P<0.001) and had a more pronounced increasing trend in age over time (interaction P<0.001). Women were also more comorbid overall (Charlson Comorbidity Index [CCI] 1.25 vs 0.85, age-adjusted P<0.001), but the rising trend in CCI over time was less pronounced than in men (interaction P<0.001) (Figure 1). Women had more baseline hypertension, diabetes, and severe renal disease than men (age-adjusted P<0.001), while the increasing trends in these comorbidities were all more pronounced in men than in women (all interaction P<0.001). Women were more likely to have ST-elevation overall (P<0.001). Although the crude 30-day mortality rate was higher in women (32.6% vs 23.9%), after adjustment for confounders, they had a lower risk of death (hazard ratio [HR] 0.97, 95% CI [0.96 to 0.99], P=0.003). There was no significant difference in the decreasing trend in 30-day mortality between both sexes (interaction P=0.787) (Figure 1). Women had a higher risk of developing HF (HR 1.04 [1.01 to 1.08], P=0.012) and ischemic stroke (HR 1.36 [1.24 to 1.48], P<0.001) in 30 days. Among patients aged ≤55 (N=15,324), women (N=2,161, 14.1%) had higher risks of all-cause death (HR 1.61 [1.40 to 1.85], P<0.001), HF (HR 1.64 [1.17 to 2.32], P=0.004), and ischemic stroke (HR 1.69 [1.14 to 2.51], P=0.010) in 30 days, even after adjustment for covariates. The excess mortality in women declined over time (interaction P=0.002). Conclusions Women MI patients were older and more comorbid compared to men, which contributed to the higher risk of death, HF, and ischemic stroke among women. Among young MI patients, the increased risk for adverse outcomes among women was particularly pronounced, though the sex differences in mortality reduced over time. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): The Shenzhen Key Medical DisciplineThe Sanming Project of HKU-SZH Cardiology
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