Risultati per: L’alcool danneggia il DNA e aumenta il rischio di cancro.

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Background
The traditional neoadjuvant chemoradiotherapy (nCRT) combined with total mesorectal excision has been widely accepted as the standard treatment for patients with locally advanced rectal cancer (LARC). New strategies such as total neoadjuvant therapy (TNT) and neoadjuvant immunotherapy have shown great promise in certain patient populations. Currently, there is an urgent need to stratify patients before treatment to adopt the appropriate neoadjuvant strategies. Our previous study has shown that circulating tumour DNA (ctDNA) effectively reflects tumour burden and genetic characteristics and has significant predictive value for tumour recurrence, demonstrating great potential in guiding the choice of neoadjuvant strategies.

Methods and analysis
The CINTS-R trial is a multicentre, open-label, randomised controlled trial designed to evaluate the efficacy and safety of a ctDNA-guided neoadjuvant treatment strategy compared with conventional neoadjuvant therapy regime in patients with LARC. The trial will enrol 470 patients diagnosed with LARC (staged cT3-4N0 or cTanyN1-2) with tumours located ≤12 cm from the anal verge across seven centres in China. Patients will be randomly assigned in a 2:1 ratio to the experimental group or the control group. Patients in the experimental group will receive different intensities of neoadjuvant chemoradiotherapy (TNT or modified nCRT) or neoadjuvant immunotherapy based on the molecular features of the tumour, baseline ctDNA concentration and changes in ctDNA status early in treatment. Patients in the control group will receive modified nCRT. The primary endpoint is the 2-year disease-related treatment failure rate. The secondary endpoints include time to recurrence, 2-year overall survival, 2-year disease-free survival, clinical complete response (cCR) rate, near cCR rate and pathologically complete response rate, pathological tumour regression grade and quality of life.

Ethics and dissemination
This protocol has been approved by the ethics committee of Peking Union Medical College Hospital, with approval number I-23PJ157, and by the institutional review boards of all the participating centres. All data will be collected and stored in a specially designed database. The results of our trial will be disseminated through peer-reviewed publications and presented at national and international academic conferences.

Trial registration number
This trial is registered on ClinicalTrials.gov and the registration ID is NCT05601505.

This cohort study investigates the association between salivary DNA methylation and war exposure in Syrian refugee children and adolescents.

Stroke, Volume 56, Issue Suppl_1, Page ATP382-ATP382, February 1, 2025. Background:Moyamoya disease (MMD) is a chronic cerebrovascular disorder that can affect both children and adults. It is characterized by chronic and progressive narrowing of the cerebral arteries and the formation of fragile collateral blood vessels. The narrowed arteries can lead to lead to stroke and neurological dysfunctions. Considering that MMD is mostly sporadic and gene-environment interactions play an important in various diseases, we sought to investigate epigenetic modifications in MMD, focusing specifically on changes in DNA methylation magnitude and variability.Methods:We performed genome-wide DNA methylation using Illumina 850K Methylation EPIC BeadChip, in two racially distinct adult female cohorts: A Non-Asian cohort (13 MMD patients and 7 healthy controls) and an Asian cohort (14 MMD patients and 3 healthy controls). An additional external cohort with both sexes (females: 5 MMD patients and 5 healthy controls, males: 5 MMD patients and 5 healthy controls) was included for validation.Results:Our findings revealed subtle changes in the magnitude of DNA methylation, but a strikingly low DNA methylation variability between MMD patients and healthy controls across both female MMD cohorts. In the Non-Asian cohort, only 6 probes showed increased variability, compared to 647 probes that showed decreased variability. Similarly, in the Asian cohort, the MMD group also displayed a reduced methylation variability across all 2845 probes. Further analysis showed that these differentially variable probes are associated with genes involved in key biological processes such as methylation and transcription, DNA repair, cytoskeletal remodeling, natural killer cell signaling, cellular growth, and migration.Conclusions:These findings mark the first observation of low methylation variability in any disease, contrasting with the high variability observed in other disorders. This reduced methylation variability in MMD may impair patients’ adaptability to environmental changes, such as hemodynamic stress, thereby disrupting vascular homeostasis and contributing to MMD pathology. These findings offer new insights into the mechanisms of MMD and suggest potential avenues for treatment strategies.

Stroke, Volume 56, Issue Suppl_1, Page AWP30-AWP30, February 1, 2025. Introduction:Brain arteriovenous malformations (bAVMs) are vascular anomalies resulting from defective morphogenesis of blood vessels in the brain. Kirsten rat sarcoma virus (KRAS)somatic activating gene mutations have been identified in the majority of bAVMs using digital droplet PCR-based assays (ddPCR). Currently, bAVM somatic mutation genetic characterization requires sequencing surgically excised lesion DNA, but recent advancements have overcome some conventional biopsy limitations through sequencing cell-free DNA (cfDNA) which is directly released into the blood circulation from cell breakdown and turnover at the site of the lesion. Therefore, cfDNA released from the mutated bAVM tissue cells may be detectable in a peripheral blood sample, providing a non-invasive approach for somatic mutation screening.Hypothesis:We hypothesize that somaticKRAS G12Dmutations in bAVM patients can be detected using non-invasive cfDNA screening.Methods:We selected six bAVM patients whose surgically-resected bAVM lesions screened positive for somaticKRAS G12Dmutation using ddPCR and had contributed a peripheral blood sample for research within 2 months prior to surgery. For each patient, cfDNA was isolated from 1.0 mL of banked plasma using the Circulating cfDNA/RNA Isolation Kit (Qiagen). We used the ddPCRKRAS G12Dassay (Bio-Rad) to screen cfDNA samples for presence of the mutation. Samples were screened in duplicate using 8 uL and 4 uL of cfDNA eluate and assays included both positive controls (syntheticKRAS G12Doligo sequence (Integrated DNA Technologies)) and negative controls (no template and water). The variant allele frequency was estimated for each sample as the (target concentration)/(target + reference concentration).Results:Of the six bAVM cases, five screened positive forKRAS G12Dmutation in the cfDNA sample. TheKRAS G12DcfDNA variant allele frequency ranged from 0.20 – 0.54% for the five positive samples.Conclusions:We detected somaticKRAS G12Dmutations in bAVM patients using non-invasive cfDNA screening. While further studies are needed to validate these findings, these exciting results suggest that we may be able to perform non-invasiveKRASsomatic mutation screening using cfDNA in a greater number of bAVM cases (e.g., not just those undergoing surgery), which may be useful to clinically stratify bAVM patients and provide targeted therapies based on specific genetic defect.

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Il 25 Airc celebra 60 anni d’impegno, 141 milioni alla ricerca