表观遗传学与临床肾病

表观遗传学是研究不涉及DNA序列变化,表型却发生可遗传改变的一门不同于遗传学的学科,其异常可能影响疾病的发生发展。慢性肾脏疾病受到遗传因素和表观遗传修饰的双重影响。在一些临床肾脏疾病中,特别是一些特定基因的启动子区的甲基化水平异常可影响该基因的表达与失活,参与疾病的发生与发展。因此,通过对表观遗传学与临床肾脏疾病关系的研究,可为进一步认识和治疗某些临床肾脏疾病提供一种新的途径。     

Patient-reported Symptom Outcomes and Microsatellite Instability in Patients With Metastatic Colorectal Cancer

BackgroundThe survival of patients with metastatic colorectal cancer (mCRC) is influenced by the genetic and epigenetic changes that might influence the patient experience of symptom burden. Understanding the association of molecular changes with the symptom burden could help clinicians gain insight into the molecular basis of symptom burden and improve treatment tolerance. To date, no studies have compared the patient-reported symptom burden with these molecular subsets among patients with mCRC.Patients and MethodsWe recruited patients with mCRC that was refractory to ≥ 1 line of therapy who had been enrolled in the Assessment of Targeted Therapies Against Colorectal Cancer trial at The University of Texas MD Anderson Cancer Center. All patients completed a baseline gastrointestinal symptom inventory (MD Anderson Symptom Inventory, gastrointestinal). The symptom burden across key demographic variables and molecular changes, including CRC-associated mutations, microsatellite instability (MSI) status, and the CpG island methylator phenotype (CIMP) were compared using χ² tests. Association of the symptom burden with overall survival was examined using Cox regression models.ResultsPatients with an MSI-high (MSI-H) phenotype reported greater pain (odds ratio [OR], 3.06; 95% confidence interval [CI], 1.61-5.84), fatigue (OR, 2.78; 95% CI, 1.41-5.49), sleep (OR, 2.52; 95% CI, 1.32-4.08); and drowsiness (OR, 2.51; 95% CI, 1.32-4.78) compared with microsatellite stable patients. Patients with an MSI-H phenotype also had greater odds of overall symptom burden (OR, 2.48; 95% CI, 1.29-4.74) compared with microsatellite stable patients. The CIMP-high patients experienced greater odds of pain compared with the CIMP-negative patients (OR, 1.72; 95% CI, 1.06-2.80). A greater overall symptom burden was associated with poor overall survival (hazard ratio, 1.42; 95% CI, 0.98-2.06]), although the difference was not significant (P = .06).ConclusionCorrelation of MSI-H–associated tumor features with the symptom burden could help provide a better understanding of underlying mechanisms associated with our findings.     

Early exposure to food contaminants reshapes maturation of the human brain-gut-microbiota axis

Early childhood growth and development is conditioned by the consecutive events belonging to perinatal programming. This critical window of life will be very sensitive to any event altering programming of the main body functions.Programming of gut function, which is starting right after conception, relates to a very well-established series of cellular and molecular events associating all types of cells present in this organ, including neurons, endocrine and immune cells. At birth, this machinery continues to settle with the establishment of extra connection between enteric and other systemic systems and is partially under the control of gut microbiota activity, itself being under the densification and the diversification of microorganisms' population. As thus, any environmental factor interfering on this pre-established program may have a strong incidence on body functions. For all these reasons, pregnant women, fetuses and infants will be particularly susceptible to environmental factors and especially food contaminants. In this review, we will summarize the actual understanding of the consequences of repeated low-level exposure to major food contaminants on gut homeostasis settlement and on brain/gut axis communication considering the pivotal role played by the gut microbiota during the fetal and postnatal stages and the presumed consequences of these food toxicants on the individuals especially in relation with the risks of developing later in life non-communicable chronic diseases.     

PARP1: A potential biomarker for gastric cancer

Gastric cancer (GC) is the third leading cause of cancer mortality worldwide, with an overall 5-y survival rate of 25%. The majority of GCs are caused by infectious agents, including the bacterium Helicobacter pylori (H. pylori) and Epstein–Barr virus (EBV). Furthermore, inappropriate repair of DNA damage can also result in genomic instability, which has shown to be a key factor in carcinogenesis of different regions including gastric region. Present study was designed to explore the association between base excision repair pathway genes, PARP1 and APEX1 and gastric pathology and H. pylori infection. Two hundred gastric cancer tissue samples (114 H. pylori positive and 86 H. pylori negative) and adjacent uninvolved area taken as controls was used for expression analysis of BER pathway genes at mRNA level and protein levels using quantitative PCR (qPCR) and immunohistochemistry (IHC) respectively. Oxidative stress and DNA damage was also determined by measuring the level of antioxidant enzymes and comet assay respectively. Significant upregulation in PARP1 (p < 0.001) and APEX1 (p < 0.02) was observed in GC tissue samples compared to controls and this upregulation was more pronounced in H. pylori positive cases (HPGC) (PARP1, p < 0.02: APEX1, p < 0.04) than H. pylori negative cases (HNGC). Upregulation of BER pathway genes in HPGC was found correlated with smoking status (p < 0.0001), T stage (p < 0.01) and lymph node metastasis (p < 0.03). Moreover, immunohistochemical staining of BER pathway genes was found correlated with a number of clinicopathological characteristics such as tumor type (p < 0.03), tumor size (p < 0.01) and lymph node metastasis (p < 0.01). Expression levels of APEX1 and PARP1 gene also correlated with increased oxidative burden (p < 0.0001) and DNA damage (p < 0.001) in GC patients. Survival analysis showed that upregulation of PARP1 gene was associated with poor overall survival outcome of gastric cancer patients (HR = 2.04 (95% CI = 1.10–3.76; p < 0.02). Univariate and multivariate cox regression analysis showed the upregulated PARP1 gene (HR = 5.03; 95%CI (2.22–11.35); p = 0.0001), positive smoking status (HR = 3.58; 95%CI (1.67–7.65); p = 0.001), positive status for H pylori infection (HR = 4.38; 95%CI (1.82–10.56); p = 0.001) and advance N-stage (HR = 5.29; 95%CI (2.28–12.24); p = 0.0001) were independent prognostic factors for gastric cancer and may serve as a valuable biomarker for the diagnosis and progression of GC and can be helpful in developing individualized treatment strategies for treating GC.     

Epigenetic regulation of anterior segment diseases and potential therapeutics

In recent years, technological advances in sequencing have accelerated our understanding of epigenetics in ocular development and ophthalmic diseases. We now know that epigenetic modifications are necessary for normal ocular development and biological processes such as corneal wound healing and ocular surface repair, while aberrant epigenetic regulation underlies the pathogenesis of a wide range of ocular diseases, including cataracts and various diseases of the ocular surface. As the epigenetics of the eye is a constantly changing field of medicine, this comprehensive review focuses on innovations and scientific discoveries related to epigenetic control of anterior segment diseases that were published in the English literature in the past five years. These recent studies attempt to elucidate therapeutic targets for the anterior segment pathological processes. Already, recent studies have shown therapeutic potential in targeting epigenetic mechanisms of ocular diseases, and new epigenetic therapies are on the verge of being introduced to clinical practice. New drug targets can potentially emerge as we make further discoveries within this field.     

Neuroepigenetic impact on mentalizing in childhood

Mentalizing, or the ability to understand the mental states and intentions of others, is an essential social cognitive function that children learn and continue to cultivate into adolescence. While most typically developing children acquire sufficient mentalizing skills, individual differences in mentalizing persist throughout childhood and are likely influenced by a combination of cognitive functioning, the social environment, and biological factors. DNA methylation of the oxytocin receptor gene (OXTRm) impacts gene expression and is associated with increased brain activity in mentalizing regions during displays of animacy in healthy young adults. The establishment, fine-tuning, and implications of such associations in the context of broader social functioning remain unclear. Using a developmental neuroimaging epigenetic approach, we investigated the contributions of OXTRm to individual variability in brain function during animate motion perception in middle childhood. We find that higher levels of OXTRm are associated with increased neural responses in the left temporo-parietal junction and inferior frontal gyrus. We also find a positive association between neural activity in LTPJ and social skills. These findings provide evidence of epigenetic influence on the developing child brain and demonstrate that variability in neural social perception in childhood is multifaceted with contributions from individual social experience and the endogenous oxytocin system.     

Sex-Specific Regulation of Fear Memory by Targeted Epigenetic Editing of Cdk5

Background

Sex differences in the expression and prevalence of trauma- and stress-related disorders have led to a growing interest in the sex-specific molecular and epigenetic mechanisms underlying these diseases. Cyclin-dependent kinase 5 (CDK5) is known to underlie both fear memory and stress behavior in male mice. Given our recent finding that targeted histone acetylation of Cdk5 regulates stress responsivity in male mice, we hypothesized that such a mechanism may be functionally relevant in female mice as well.