Risk score predicts high‐grade prostate cancer in DNA‐methylation positive,histopathologically negative biopsies

BACKGROUND

Prostate cancer (PCa) diagnosis is challenging because efforts for effective, timely treatment of men with significant cancer typically result in over‐diagnosis and repeat biopsies. The presence or absence of epigenetic aberrations, more specifically DNA‐methylation of GSTP1, RASSF1, and APC in histopathologically negative prostate core biopsies has resulted in an increased negative predictive value (NPV) of ～90% and thus could lead to a reduction of unnecessary repeat biopsies. Here, it is investigated whether, in methylation‐positive men, DNA‐methylation intensities could help to identify those men harboring high‐grade (Gleason score ≥7) PCa, resulting in an improved positive predictive value.

METHODS

Two cohorts, consisting of men with histopathologically negative index biopsies, followed by a positive or negative repeat biopsy, were combined. EpiScore, a methylation intensity algorithm was developed in methylation‐positive men, using area under the curve of the receiver operating characteristic as metric for performance. Next, a risk score was developed combining EpiScore with traditional clinical risk factors to further improve the identification of high‐grade (Gleason Score ≥7) cancer.

RESULTS

Compared to other risk factors, detection of DNA‐methylation in histopathologically negative biopsies was the most significant and important predictor of high‐grade cancer, resulting in a NPV of 96%. In methylation‐positive men, EpiScore was significantly higher for those with high‐grade cancer detected upon repeat biopsy, compared to those with either no or low‐grade cancer. The risk score resulted in further improvement of patient risk stratification and was a significantly better predictor compared to currently used metrics as PSA and the prostate cancer prevention trial (PCPT) risk calculator (RC). A decision curve analysis indicated strong clinical utility for the risk score as decision‐making tool for repeat biopsy.

CONCLUSIONS

Low DNA‐methylation levels in PCa‐negative biopsies led to a NPV of 96% for high‐grade cancer. The risk score, comprising DNA‐methylation intensity and traditional clinical risk factors, improved the identification of men with high‐grade cancer, with a maximum avoidance of unnecessary repeat biopsies. This risk score resulted in better patient risk stratification and significantly outperformed current risk prediction models such as PCPTRC and PSA. The risk score could help to identify patients with histopathologically negative biopsies harboring high‐grade PCa. Prostate 76:1078–1087, 2016. © 2016 The Authors. The Prostate Published by Wiley Periodicals, Inc.     

CBP/P300介导的组蛋白H3K9乙酰化修饰对GATA4表达的影响

目的 明确GATA4在小鼠胚胎心脏发育过程中的时序表达,并阐明其组蛋白修饰调控机制.方法 选取胎龄11.5 d(E11.5)至新生0.5d胎鼠心脏,RT-PCR检测胎鼠心肌细胞中GATA4mRNA表达水平,CHIP-QPCR检测GATA4启动子区组蛋白H3K9ac水平及与CBP/P300的结合水平.用CBP30干预心肌祖细胞,RT-PCR检测心肌祖细胞在不同浓度CBP30(0.5、1、2、4μmol/L)干预不同时间点(6、12、24、36 h)后GATA4 mRNA表达水平,CHIP-QPCR检测心肌祖细胞中GATA4启动子区组蛋白H3 K9 ac水平及与CBP/P300的结合水平.结果 ①小鼠胚胎心脏发育过程中GATA4表达量,E14.5明显高于E11.5(P ＜0.05);CHIP结果显示E14.5 GATA4启动子区组蛋白H3 K9 ac水平高于E11.5(P ＜0.05);E14.5与CBP/P300的结合水平亦高于E11.5(P ＜0.05).②CBP30干预心肌祖细胞后,GATA4表达量较对照组明显降低(P＜0.05).CHIP结果显示CBP30组GATA4启动子区组蛋白H3K9ac水平及与CBP/P300的结合水平较对照组显著降低(P＜0.05).结论 CBP/P300可通过介导组蛋白H3 K9乙酰化修饰参与调控GATA4在小鼠胚胎心脏发育过程中的时序表达.     

The status of diabetic embryopathy

Diabetic embryopathy is a theoretical enigma and a clinical challenge. Both type 1 and type 2 diabetic pregnancy carry a significant risk for fetal maldevelopment, and the precise reasons for the diabetes-induced teratogenicity are not clearly identified. The experimental work in this field has revealed a partial, however complex, answer to the teratological question, and we will review some of the latest suggestions.     

Therapeutic targets for altering mitochondrial dysfunction associated with diabetic retinopathy

Introduction: Retinopathy remains as one of the most feared blinding complications of diabetes, and with the prevalence of this life-long disease escalating at an alarming rate, the incidence of retinopathy is also climbing. Although the cutting edge research has identified many molecular mechanisms associated with its development, the exact mechanism how diabetes damages the retina remains obscure, limiting therapeutic options for this devastating disease.

Areas covered: This review focuses on the central role of mitochondrial dysfunction/damage in the pathogenesis of diabetic retinopathy, and how damaged mitochondria initiates a self-perpetuating vicious cycles of free radicals. We have also reviewed how mitochondria could serve as a therapeutic target, and the challenges associated with the complex double mitochondrial membranes and a well-defined blood-retinal barrier for optimal pharmacologic/molecular approach to improve mitochondrial function.

Expert opinion: Mitochondrial dysfunction provides many therapeutic targets for ameliorating the development of diabetic retinopathy including their biogenesis, DNA damage and epigenetic modifications. New technology to enhance pharmaceuticals uptake inside the mitochondria, nanotechnology to deliver drugs to the retina, and maintenance of mitochondrial homeostasis via lifestyle changes and novel therapeutics to prevent epigenetic modifications, could serve as some of the welcoming avenues for a diabetic patient to target this sight-threatening disease.     

维生素D缺乏与儿童疾病表观遗传学研究

维生素D不仅对骨代谢有着经典的作用,同时在免疫、细胞增殖和分化中有重要的作用。最近的研究发现,孕期维生素D水平也可能通过表观遗传修饰影响到后代儿童期非骨骼系统疾病的易感性,如哮喘,自身免疫性疾病和神经精神疾病等。本文将综述维生素D缺乏与儿童疾病表观遗传学的研究进展。     

圆锥角膜病因学研究进展——遗传、环境刺激、表观遗传的相互作用

圆锥角膜是一种扩张性角膜疾病,以角膜中央变薄、向前凸出呈锥状为特征,可严重影响视力。圆锥角膜病因复杂,迄今为止尚未完全明确,可能是遗传、表观遗传和环境刺激之间相互作用的结果。本文旨在对近年来圆锥角膜病因学的研究进展进行综述,并对未来该领域的研究方向进行展望:阐明表观遗传学的调控路径可能是明确病因的关键;3D培养的体外模型可望为探索圆锥角膜病因和推进治疗提供依据。     

Resveratrol Based Oral Nutritional Supplement Produces Long-Term Beneficial Effects on Structure and Visual Function in Human Patients

Background: Longevinex^® (L/RV) is a low dose hormetic over-the-counter (OTC) oral resveratrol (RV) based matrix of red wine solids, vitamin D₃ and inositol hexaphosphate (IP6) with established bioavailability, safety, and short-term efficacy against the earliest signs of human atherosclerosis, murine cardiac reperfusion injury, clinical retinal neovascularization, and stem cell survival. We previously reported our short-term findings for dry and wet age-related macular degeneration (AMD) patients. Today we report long term (two to three year) clinical efficacy. Methods: We treated three patients including a patient with an AMD treatment resistant variant (polypoidal retinal vasculature disease). We evaluated two clinical measures of ocular structure (fundus autofluorescent imaging and spectral domain optical coherence extended depth choroidal imaging) and qualitatively appraised changes in macular pigment volume. We further evaluated three clinical measures of visual function (Snellen visual acuity, contrast sensitivity, and glare recovery to a cone photo-stress stimulus). Results: We observed broad bilateral improvements in ocular structure and function over a long time period, opposite to what might be expected due to aging and the natural progression of the patient’s pathophysiology. No side effects were observed. Conclusions: These three cases demonstrate that application of epigenetics has long-term efficacy against AMD retinal disease, when the retinal specialist has exhausted other therapeutic modalities.     

Known epigenetic biomarkers for prostate cancer detection and management: exploring the potential of blood-based liquid biopsies

Introduction: Although prostate cancer (PCa) stands as an important cause of cancer-related deaths, a sizeable proportion of diagnosed cases are clinically insignificant. Hence, novel and more specific biomarkers to identify clinically significant PCa are needed. Liquid biopsies offer the potential to accurately identify cancer markers, including PCa. Epigenetic biomarkers such as cell-free DNA and circulating RNAs have emerged as minimally invasive cancer markers.

Areas covered: Herein, we provide an overview of epigenetic biomarkers current state based on a comprehensive review of the relevant literature in blood-based liquid biopsies and challenges/limitations of this new and growing field of cancer biomarkers.

Expert opinion: The epigenetic-based biomarkers characteristics make them attractive to the clinics and their minimally invasive assessment are a promising opportunity for PCa detection/management. The main limitations are the lack of robust validation studies and integrated approaches. Future studies would benefit from a change in focus to a ‘selected PCa detection’.