Aberrant histone acetylation and dysregulated synaptic plasticity in cognitive impairment induced by a high-methionine diet.

Biliary tract cancer (BTC), a heterogeneous group of rare but highly aggressive malignancies, including intrahepatic, perihilar, distal cholangiocarcinoma, and gallbladder cancer, poses a significant challenge in global oncology., Despite advancements in therapeutic modalities, the five-year survival rate remains dismal, largely due to the asymptomatic nature of early-stage disease. Consequently, most patients are diagnosed at advanced stages, when curative surgical resection is no longer feasible. Current diagnostic protocols rely primarily on serum biomarkers such as carbohydrate antigen 19–9 (CA19-9), and various imaging modalities, including computed tomography (CT), magnetic resonance imaging (MRI), and magnetic resonance cholangiopancreatography (MRCP). However, CA19-9 exhibits suboptimal diagnostic performance: a meta-analysis of 31 studies reported a pooled sensitivity of 72% and specificity of 84% for cholangiocarcinoma, and sensitivity drops further to approximately 53% in non-PSC patients at the standard cut-off of 100 U/mL, while levels are markedly elevated in benign conditions such as PSC or obstructive jaundice, severely limiting its clinical utility. Furthermore, CT-based imaging demonstrates sensitivity of approximately 61% for CCA and is particularly prone to missed detection of lesions smaller than 10 mm. Although ERCP-guided brush cytology is routinely employed for biliary stricture evaluation, a meta-analysis reports a pooled sensitivity of only 45% (95% CI, 40–50%) for malignant biliary strictures, despite a near-perfect specificity of approximately 99%. Although tissue biopsy remains the gold standard, its clinical application is frequently hampered by the anatomical inaccessibility of the biliary tract, risk of tumor seeding, and inherent spatial heterogeneity of the tumor, which a single-needle biopsy cannot fully capture. Consequently, there is an urgent clinical mandate for the development of non-invasive, high-sensitivity diagnostic tools that can facilitate early detection and longitudinal monitoring. Liquid biopsy has emerged as a compelling diagnostic paradigm to overcome the limitations of traditional tissue biopsies. By analyzing tumor-derived components, such as circulating tumor cells, circulating tumor DNA, and extracellular vesicles (EVs), from easily accessible bodily fluids, liquid biopsy offers a minimally invasive method for capturing the dynamic genomic and proteomic profiles of a tumor in real time. Within the context of BTC, liquid biopsy is not limited to peripheral blood. Bile fluid, which is in direct contact with the tumor microenvironment, has recently gained attention as a superior source of biomarkers. This shift toward liquid biopsy facilitates not only early diagnosis but also the monitoring of treatment response and early detection of recurrence, paving the way for personalized precision oncology in BTC management., Among the various analytes used in liquid biopsy, exosomes and small extracellular vesicles ranging from 30 to 150 nm in diameter have emerged as exceptionally promising biomarkers. Secreted by almost all cell types, including malignant cells, exosomes carry a rich molecular cargo consisting of proteins, lipids, and various RNA species (eg, miRNA, lncRNA, and circRNA) that mirror the physiological and pathological states of their parental cells. Exosomes have several unique advantages over liquid biopsy components. First, the lipid bilayer structure protects the internal molecular cargo from degradation by exogenous RNases and proteases, thereby ensuring high stability even within proteolytically harsh environments, such as bile or blood. Second, cancer cells secrete exosomes at significantly higher rates than healthy cells, making them more abundant than CTCs during early-stage disease. Third, beyond being mere waste disposal vesicles, exosomes serve as critical mediators of intercellular communication and play a vital role in premetastatic niche formation and tumor immune evasion. Thus, decoding the exosomal signature provides a profound fingerprint of the biological behavior of a tumor, making it an ideal candidate for early BTC screening.,