Cholangiocarcinoma in Latin America: a multicentre observational study alerts on ethnic disparities in tumour presentation and outcomes.

Background: Cholangiocarcinoma (CCA) represents a global health challenge, with rising incidence and mortality rates. This study aimed to elucidate the clinical course and practices of CCA in Latin America.

Methods: This observational cohort study investigated individuals diagnosed with CCA between 2010 and 2023 at five referral centres across Latin America.

A functional genomic framework to elucidate novel causal metabolic dysfunction-associated fatty liver disease genes.

Background And Aims: Metabolic dysfunction-associated fatty liver disease (MASLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for MASLD have been hampered by the relative paucity of human data from gold standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using MASLD surrogate phenotypes have been used, but only a small number of loci have been identified to date.

Caspases compromise SLU7 and UPF1 stability and NMD activity during hepatocarcinogenesis.

Background & Aims: The homeostasis of the cellular transcriptome depends on transcription and splicing mechanisms. Moreover, the fidelity of gene expression, essential to preserve cellular identity and function is secured by different quality control mechanisms including nonsense-mediated RNA decay (NMD). In this context, alternative splicing is coupled to NMD, and several alterations in these mechanisms leading to the accumulation of aberrant gene isoforms are known to be involved in human disease including cancer.

Refinement of paramagnetic bead-based digestion protocol for automatic sample preparation using an artificial neural network.

Despite technological advances in the proteomics field, sample preparation still represents the main bottleneck in mass spectrometry (MS) analysis. Bead-based protein aggregation techniques have recently emerged as an efficient, reproducible, and high-throughput alternative for protein extraction and digestion. Here, a refined paramagnetic bead-based digestion protocol is described for Opentrons® OT-2 platform (OT-2) as a versatile, reproducible, and affordable alternative for the automatic sample preparation for MS analysis.

MCPIP1 Inhibits Hepatic Stellate Cell Activation in Autocrine and Paracrine Manners, Preventing Liver Fibrosis.

Background & Aims: Hepatic fibrosis is characterized by enhanced deposition of extracellular matrix (ECM), which results from the wound healing response to chronic, repeated injury of any etiology. Upon injury, hepatic stellate cells (HSCs) activate and secrete ECM proteins, forming scar tissue, which leads to liver dysfunction. Monocyte-chemoattractant protein-induced protein 1 (MCPIP1) possesses anti-inflammatory activity, and its overexpression reduces liver injury in septic mice.

Thyroid hormone receptor alpha modulates fibrogenesis in hepatic stellate cells.

Objective: Progressive hepatic fibrosis can be considered the final stage of chronic liver disease. Hepatic stellate cells (HSC) play a central role in liver fibrogenesis. Thyroid hormones (TH, e.

Lacking Immunotherapy Biomarkers for Biliary Tract Cancer: A Comprehensive Systematic Literature Review and Meta-Analysis.

Background: Immunotherapy has recently been incorporated into the spectrum of biliary tract cancer (BTC) treatment. The identification of predictive response biomarkers is essential in order to identify those patients who may benefit most from this novel treatment option. Here, we propose a systematic literature review and a meta-analysis of PD-1, PD-L1, and other immune-related biomarker expression levels in patients with BTC.

Serum identification of at-risk MASH: The metabolomics-advanced steatohepatitis fibrosis score (MASEF).

Background: Early identification of those with NAFLD activity score ≥ 4 and significant fibrosis (≥F2) or at-risk metabolic dysfunction-associated steatohepatitis (MASH) is a priority as these patients are at increased risk for disease progression and may benefit from therapies. We developed and validated a highly specific metabolomics-driven score to identify at-risk MASH.

Methods: We included derivation (n = 790) and validation (n = 565) cohorts from international tertiary centers.

In Vivo Hepatic Triglyceride Secretion Rate in Antisense Oligonucleotide (ASO)-Treated Mice.

The liver is a central organ in regulating the whole body metabolic homeostasis, and, among many other processes, it plays a crucial role in lipoprotein metabolism. The liver controls the secretion of very-low-density lipoproteins (VLDLs), particles specialized in the transport of liver lipids, mainly triglycerides (TGs), to the adipose tissue, heart, and muscle, among other tissues, providing fatty acids to be stored or to be used as an energy source. The analysis of this metabolic process provides relevant information about the crosstalk between the liver and other organs.

In Vivo Tissue Lipid Uptake in Antisense Oligonucleotide (ASO)-Treated Mice.

The prevalence of obesity has increased to pandemic levels over the past years. Associated comorbidities linked with the accumulation of lipids in different tissues and blood are responsible for the high mortality in these patients. The increased dietary lipid uptake contributes to these metabolic diseases.

Ceramide present in cholangiocarcinoma-derived extracellular vesicle induces a pro-inflammatory state in monocytes.

Cholangiocarcinoma (CCA) is a rare cancer characterized by a global increasing incidence. Extracellular vesicles (EV) contribute to many of the hallmarks of cancer through transfer of their cargo molecules. The sphingolipid (SPL) profile of intrahepatic CCA (iCCA)-derived EVs was characterized by liquid chromatography-tandem mass spectrometry analysis.

A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans.

Background And Aims: Cholestasis is characterized by intrahepatic accumulation of bile constituents, including bile acids (BAs), which promote liver damage. The apical sodium-dependent BA transporter (ASBT) plays an important role in BA reabsorption and signaling in ileum, bile ducts, and kidneys. Our aim was to investigate the pharmacokinetics and pharmacological activity of A3907, an oral and systemically available ASBT inhibitor in experimental mouse models of cholestasis.

Heterogeneity of Cholangiocarcinoma Immune Biology.

Cholangiocarcinomas (CCAs) are aggressive tumors arising along the biliary tract epithelium, whose incidence and mortality are increasing. CCAs are highly desmoplastic cancers characterized by a dense tumor microenvironment (TME), in which each single component plays a fundamental role in shaping CCA initiation, progression and resistance to therapies. The crosstalk between cancer cells and TME can affect the recruitment, infiltration and differentiation of immune cells.

Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinoma.

Background & Aims: Cholangiocarcinoma (CCA), heterogeneous biliary tumours with dismal prognosis, lacks accurate early diagnostic methods especially important for individuals at high-risk (i.e. those with primary sclerosing cholangitis [PSC]).

MicroRNA-27a-3p targets FoxO signalling to induce tumour-like phenotypes in bile duct cells.

Background & Aims: Cholangiocarcinoma (CCA) is a heterogeneous and lethal malignancy, the molecular origins of which remain poorly understood. MicroRNAs (miRs) target diverse signalling pathways, functioning as potent epigenetic regulators of transcriptional output. We aimed to characterise miRNome dysregulation in CCA, including its impact on transcriptome homeostasis and cell behaviour.

Combined Inhibition of Smoothened and the DNA Damage Checkpoint WEE1 Exerts Antitumor Activity in Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is characterized by resistance to chemotherapy and a poor prognosis. Therefore, treatments that can effectively suppress tumor growth are urgently needed. Aberrant activation of hedgehog (HH) signaling has been implicated in several cancers, including those of the hepatobiliary tract.

Aberrant fucosylation sustains the NOTCH and EGFR/NF-κB pathways and has a prognostic value in human intrahepatic cholangiocarcinoma.

Background And Aims: Intrahepatic cholangiocarcinoma (iCCA) is a lethal malignancy, with increasing incidence worldwide and limited therapeutic options. Aberrant protein glycosylation is a hallmark of cancer. Here, we thoroughly investigated the possible involvement of fucosylation in cholangiocarcinogenesis.

SLU7: A New Hub of Gene Expression Regulation-From Epigenetics to Protein Stability in Health and Disease.

SLU7 (Splicing factor synergistic lethal with U5 snRNA 7) was first identified as a splicing factor necessary for the correct selection of 3' splice sites, strongly impacting on the diversity of gene transcripts in a cell. More recent studies have uncovered new and non-redundant roles of SLU7 as an integrative hub of different levels of gene expression regulation, including epigenetic DNA remodeling, modulation of transcription and protein stability. Here we review those findings, the multiple factors and mechanisms implicated as well as the cellular functions affected.