Despite the fact that inflammatory bowel disease (IBD) has still no recognised therapy, treatments which have proven at least mildly successful in improving IBD symptoms include anti-inflammatory drugs and monoclonal antibodies targeting pro-inflammatory cytokines. Resveratrol, a natural (poly)phenol found in grapes, red wine, grape juice and several species of berries, has been shown to prevent and ameliorate intestinal inflammation. Here, we discuss the role of resveratrol in the improvement of inflammatory disorders involving the intestinal mucosa. The present review covers three specific aspects of resveratrol in the framework of inflammation: (i) its content in food; (ii) its intestinal absorption and metabolism; and (iii) its anti-inflammatory effects in the intestinal mucosa in vitro and in the very few in vivo studies present to date. Actually, if several studies have shown that resveratrol may down-regulate mediators of intestinal immunity in rodent models, only two groups have performed intervention studies in human subjects using resveratrol as an agent to improve IBD conditions. The effects of resveratrol should be further investigated by conducting well-designed clinical trials, also taking into account different formulations for the delivery of the bioactive compound.

Lung, breast, colorectal, and prostate cancers are the most incident worldwide. Optimal population-based cancer screening methods remain an unmet need, since cancer detection at early stages increases the prospects of successful and curative treatment, leading to a lower incidence of recurrences. Moreover, the current parameters for cancer patients’ stratification have been associated with divergent outcomes. Therefore, new biomarkers that could aid in cancer detection and prognosis, preferably detected by minimally invasive methods are of major importance. Aberrant DNA methylation is an early event in cancer development and may be detected in circulating cell-free DNA (ccfDNA), constituting a valuable cancer biomarker. Furthermore, DNA methylation is a stable alteration that can be easily and rapidly quantified by methylation-specific PCR methods. Thus, the main goal of this review is to provide an overview of the most important studies that report methylation biomarkers for the detection and prognosis of the four major cancers after a critical analysis of the available literature. DNA methylation-based biomarkers show promise for cancer detection and management, with some studies describing a “PanCancer” detection approach for the simultaneous detection of several cancer types. Nonetheless, DNA methylation biomarkers still lack large-scale validation, precluding implementation in clinical practice.

Background: Breast (BrC), colorectal (CRC) and lung (LC) cancers are the three most common and deadly cancers in women. Cancer screening entails an increase in early stage disease detection but is hampered by high false-positive rates and overdiagnosis/overtreatment. Aberrant DNA methylation occurs early in cancer and may be detected in circulating cell-free DNA (ccfDNA), constituting a valuable biomarker and enabling non-invasive testing for cancer detection. We aimed to develop a ccfDNA methylation-based test for simultaneous detection of BrC, CRC and LC. Methods: CcfDNA from BrC, CRC and LC patients and asymptomatic controls were extracted from plasma, sodium-bisulfite modified and whole-genome amplified. APC, FOXA1, MGMT, RARβ2, RASSF1A, SCGB3A1, SEPT9, SHOX2 and SOX17 promoter methylation levels were determined by multiplex quantitative methylation-specific PCR. Associations between methylation and standard clinicopathological parameters were assessed. Biomarkers’ diagnostic performance was also evaluated. Results: A “PanCancer” panel (APC, FOXA1, RASSF1A) detected the three major cancers with 72% sensitivity and 74% specificity, whereas a “CancerType” panel (SCGB3A1, SEPT9 and SOX17) indicated the most likely cancer topography, with over 80% specificity, although with limited sensitivity. Conclusions: CcfDNA’s methylation assessment allows for simultaneous screening of BrC, CRC and LC, complementing current modalities, perfecting cancer suspects’ triage, increasing compliance and cost-effectiveness.

Background: Breast cancer (BrC) is the most frequent neoplasm in women. New biomarkers, including aberrant DNA methylation, may improve BrC management. Herein, we evaluated the detection and prognostic performance of seven genes’ promoter methylation (APC, BRCA1, CCND2, FOXA1, PSAT1, RASSF1A and SCGB3A1). Methods: Methylation levels were assessed in primary BrC tissues by quantitative methylation-specific polymerase chain reaction (QMSP) and in circulating cell-free DNA (ccfDNA) by multiplex QMSP from two independent cohorts of patients (Cohort #1, n = 137; and Cohort #2, n = 44). Receiver operating characteristic (ROC) curves were constructed, and log-rank test and Cox regression were performed to assess the prognostic value of genes’ methylation levels. Results: The gene-panel APC, FOXA1, RASSF1A, SCGB3A1 discriminated normal from cancerous tissue with high accuracy (95.55%). In multivariable analysis, high PSAT1-methylation levels [>percentile 75 (P75)] associated with longer disease-free survival, whereas higher FOXA1-methylation levels (>P75) associated with shorter disease-specific survival. The best performing panel in ccfDNA (APC, FOXA1 and RASSF1A) disclosed a sensitivity, specificity and accuracy over 70%. Conclusions: This approach enables BrC accurate diagnosis and prognostic stratification in tissue samples, and allows for early detection in liquid biopsies, thus suggesting a putative value for patient management.

BackgroundLung (LC), prostate (PCa) and colorectal (CRC) cancers are the most incident in males worldwide. Despite recent advances, optimal population-based cancer screening methods remain an unmet need. Due to its early onset, cancer specificity and accessibility in body fluids, aberrant DNA promoter methylation might be a valuable minimally invasive tool for early cancer detection. Herein, we aimed to develop a minimally invasive methylation-based test for simultaneous early detection of LC, PCa and CRC in males, using liquid biopsies.ResultsCirculating cell-free DNA was extracted from 102 LC, 121 PCa and 100 CRC patients and 136 asymptomatic donors’ plasma samples. Sodium-bisulfite modification and whole-genome amplification was performed. Promoter methylation levels of APCme, FOXA1me, GSTP1me, HOXD3me, RARβ2me, RASSF1Ame, SEPT9me and SOX17me were assessed by multiplex quantitative methylation-specific PCR.SEPT9me and SOX17me were the only biomarkers shared by all three cancer types, although they detected CRC with limited sensitivity. A “PanCancer” panel (FOXA1me, RARβ2me and RASSF1Ame) detected LC and PCa with 64% sensitivity and 70% specificity, complemented with “CancerType” panel (GSTP1me and SOX17me) which discriminated between LC and PCa with 93% specificity, but with modest sensitivity. Moreover, a HOXD3me and RASSF1Ame panel discriminated small cell lung carcinoma from non-small cell lung carcinoma with 75% sensitivity, 88% specificity, 6.5 LR+ and 0.28 LR–. An APCme and RASSF1Ame panel independently predicted disease-specific mortality in LC patients.ConclusionsWe concluded that a DNA methylation-based test in liquid biopsies might enable minimally invasive screening of LC and PCa, improving patient compliance and reducing healthcare costs. Moreover, it might assist in LC subtyping and prognostication.

Background: Lung cancer (LCa) is the most frequently diagnosed and lethal cancer worldwide. Histopathological subtyping, which has important therapeutic and prognostic implications, requires material collection through invasive procedures, which might be insufficient to enable definitive diagnosis. Aberrant DNA methylation is an early event in carcinogenesis, detectable in circulating cell-free DNA (ccfDNA). Herein, we aimed to assess methylation of selected genes in ccfDNA from LCa patients and determine its accuracy for tumor subtyping. Methods: Methylation levels of APC, HOXA9, RARβ2, and RASSF1A were assessed in three independent study groups (study group #1: 152 tissue samples; study group #2: 129 plasma samples; study group #3: 28 benign lesions of lung) using quantitative methylation-specific PCR. Associations between gene promoter methylation levels and LCa subtypes were evaluated using non-parametric tests. Receiver operating characteristic (ROC) curve analysis was performed. Results: In study group #2, HOXA9 and RASSF1A displayed higher methylation levels in small-cell lung cancer (SCLC) than in non-small-cell lung cancer (NSCLC). HOXA9 displayed high sensitivity (63.8%), whereas RASSF1A disclosed high specificity (96.2%) for SCLC detection in ccfDNA. Furthermore, HOXA9 methylation levels showed to be higher in squamous cell carcinoma in comparison with adenocarcinoma in study group #1. Conclusions: Methylation level assessments in ccfDNA may provide a minimally invasive procedure for LCa subtyping, complementing standard diagnostic procedures.

Bladder cancer (BC) is the tenth most frequent cancer worldwide and is associated with high mortality when diagnosed in its most aggressive form, which is not reverted by the current treatment options. Thus, the development of new therapeutic strategies, either alternative or complementary to the current ones, is of major importance. The disruption of normal epigenetic mechanisms, namely, DNA methylation, is a known early event in cancer development. Consequently, DNA methyltransferase (DNMT) inhibitors constitute a promising therapeutic target for the treatment of BC. Although these inhibitors, mainly nucleoside analogues such as 5-azacytidine (5-aza) and decitabine (DAC), cause re-expression of tumor suppressor genes, inhibition of tumor cell growth, and increased apoptosis in BC experimental models and clinical trials, they also show important drawbacks that prevent their use as a valuable option for the treatment of BC. However, their combination with chemotherapy and/or immune-checkpoint inhibitors could aid in their implementation in the clinical practice. Here, we provide a comprehensive review of the studies exploring the effects of DNA methylation inhibition using DNMTs inhibitors in BC, from in vitro and in vivo studies to clinical trials.

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