Adeno-associated virus (AAV) vectors have favorable safety and durable transgene expression but are limited in oncology by insufficient tumor specificity and off-target expression. Tumor hypoxia and non-small cell lung cancer (NSCLC)-associated surface ligands offer complementary layers of biological selectivity for more precise gene delivery. This study proposes an NSCLC-directed, hypoxia-responsive AAV architecture that integrates MGS4-guided capsid targeting with dual hypoxia-responsive element (HRE)-gated promoters driving glutamine-modified C-X-C motif chemokine ligand 9-fragment crystallizable region fusion protein (Q-CXCL9-Fc) expression and baculoviral IAP repeat containing 5 (BIRC5)-linked mesothelin (MSLN) silencing. We conceptually designed an AAV vector that combines three layers of NSCLC selectivity: MGS4-guided capsid targeting, hypoxia-gated transcription, and tumor-active promoter control. The capsid displays the MGS4 peptide, isolated by phage display biopanning as a high-affinity ligand for the lung squamous cell carcinoma cell line HCC15 and later shown to internalize into a substantial fraction of NSCLC cell lines and bind a subset of human NSCLC biopsy samples, indicating activity across multiple NSCLC subtypes. The genome encodes Q-CXCL9-Fc under a 4× HRE-cytomegalovirus promoter to sustain C-X-C motif chemokine receptor 3-dependent T-cell recruitment and a miR-30-based short hairpin RNA targeting MSLN under a 4× HRE-BIRC5 promoter to inhibit tumor progression. This architecture is hypothesized to enrich AAV entry into NSCLC lesions via MGS4 while restricting Q-CXCL9-Fc secretion and MSLN silencing to hypoxic, BIRC5-active tumor regions, enabling synergistic enhancement of antitumor immunity and suppression of tumor-intrinsic pathways. The proposed multimodal, hypoxia-responsive AAV platform represents a conceptual precision oncology strategy that couples environmental sensing, tumor-specific transcription, and peptide-defined tropism within a single vector and could inform next-generation NSCLC-directed AAV systems.

The pathogenic role of MIR142 genetic abnormalities in the development of primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS) is unexplored. The objective of this study was to investigate the frequency, spectrum, and functional significance of mutations in the MIR142 gene in primary CNS DLBCL.

Direct Sanger sequencing of the MIR142 gene was performed in tumor tissue from 35 patients with primary DLBCL of the CNS. In silico prediction of microRNA (miRNA)–target interactions, enrichment analysis of target gene ontologies, and prediction of the secondary structure and minimum free energy of the miRNA hairpin were performed.

The mutation frequency was 37.1% (95% confidence interval: 23.2–53.7%). The vast majority of the identified single-nucleotide variants were located outside the regions encoding mature miRNA chains. In silico analysis showed that the n.29A>G mutation located in the seed sequence of miR-142-5p resulted in a significant reduction in the number of potential targets and alterations to the interaction spectrum. All single-nucleotide variants identified in the study patients caused a change in minimum free energy and affected the shape and length of the hairpin stem of pri-miRNA. The results indicate the fragility of the pri-miR-142 hairpin.

The frequency of gene mutations in primary DLBCL of the CNS significantly exceeds that reported for systemic DLBCL.

Alpha-1 antitrypsin deficiency (AATD) is an autosomal codominant genetic disorder caused by mutations in the SERPINA1 gene. It results in reduced circulating levels of alpha-1 antitrypsin (AAT), a serine proteinase inhibitor (PI) primarily produced by hepatocytes. The most common deficient alleles are PI*S and PI*Z, with PI*ZZ homozygotes having the most severe deficiency and highest risk for lung and liver disease. While AATD is well established as a cause of early-onset emphysema and liver cirrhosis, emerging evidence suggests a potential association with the formation of arterial aneurysms. The pathophysiological rationale for this association centers on protease-antiprotease imbalance and potential extracellular matrix degradation of elastin in arterial vessel walls. Several studies have reported increased frequencies of AATD alleles in patients with abdominal aortic aneurysms and intracranial aneurysms compared to the general population, with some demonstrating statistically significant associations. Additionally, patients with the PI*ZZ genotype have been shown to have larger aortic diameters, greater aortic stiffness, and reduced distensibility compared to controls. However, the evidence is inconsistent, as several large studies have failed to demonstrate significant associations between AATD and aneurysm formation. Overall, current evidence suggests an association of AATD with the development of arterial aneurysms. However, it is also clear that the presence of AATD alone is not sufficient to increase the risk of developing new-onset arterial aneurysms.

Amatoxin-containing mushroom poisoning causes fatal acute liver failure with >50% mortality despite maximal medical therapy. Interrupting the enterohepatic recirculation of amatoxins is a mechanistically rational but unproven therapeutic strategy. This study aimed to evaluate the efficacy and safety of biliary drainage (BD) in patients with pre-liver failure caused by amatoxin-containing mushroom poisoning.

In this prospective cohort study (ChiCTR2300073442), consecutive adults with amatoxin-induced pre-acute liver failure received standardized care (silibinin, N-acetylcysteine, dehydration). Patients undergoing percutaneous or endoscopic BD were compared to non-BD controls. The primary outcome was survival to hospital discharge.

Nine patients were enrolled (mean age: 63.3 ± 15.6 years; 44.4% female). All five patients who underwent BD (performed at a median of three days after ingestion) survived (100%), whereas only one of the four non-BD patients survived (25%; P = 0.048). BD initiated a rapid biochemical recovery: within 48 h, mean alanine and aspartate transaminase levels decreased by 67.6% and 91.6%, respectively, from their peak levels (P < 0.001), and the international normalized ratio decreased from 1.99 to 1.27 (P = 0.008). Non-survivors in the non-BD group progressed to multiorgan failure. Procedure-related complications (transient pancreatitis/amylasemia) occurred in three of the five BD patients but resolved with conservative management.

Timely BD was associated with 100% survival after amatoxin-induced pre-acute liver failure, contrasting sharply with 75% mortality in non-BD controls. The dramatic biochemical improvement after BD supports enterohepatic recirculation interruption as a mechanistic intervention. BD represents a potentially definitive, life-saving intervention for this lethal poisoning as a preliminary finding; larger, multicenter studies are required to confirm the observed association between BD and survival.

Mitochondrial DNA (mtDNA) variability, especially heteroplasmy, is believed to affect cellular immunobiogenesis, particularly in monocytes in metabolic syndrome (MetS). This study aimed to identify associations of monocytic mtDNA variability with its phenotypic indices, including cytokine secretion and gene expression, and cardiometabolic parameters in patients with MetS.

The cross-sectional study recruited 87 adult participants, including 34 healthy blood donors (Control group), 21 obese patients (Obesity group), and 32 MetS patients (MetS group). Blood biochemistry tests were performed on venous blood samples, and monocytes (CD14+ cells) were isolated. Monocyte mtDNA was analyzed by next-generation sequencing to identify low (5–10%) and intermediate (10–95%) heteroplasmy, and homoplasmy (≥95%). Expression of genes related to mitochondrial biogenesis, mitochondrial uncoupling, oxidative stress system, and NF-κB signaling was assessed by quantitative real-time polymerase chain reaction. Monocytes cultured with and without lipopolysaccharide for 24 h were analyzed by enzyme-linked immunosorbent assay to assess the cytokine secretion stimulation index.

Monocyte mtDNA showed low variability, but alternative homoplasmies were significantly more common. Intermediate and low heteroplasmy from the protein-coding locus correlated with stenosis (r = 0.396; 95% confidence interval (CI) 0.067–0.647) and low-density lipoprotein levels (r = −0.258; 95% CI −0.45 – −0.043). Intermediate heteroplasmy from the rRNA locus correlated with blood insulin levels (r = −0.228; 95% CI −0.424 – −0.019). D-loop low heteroplasmy correlated with fasting blood glucose (r = 0.275; 95% CI 0.062–0.464). Homoplasmies were associated with creatinine, blood urea nitrogen, and alkaline phosphatase. Intermediate heteroplasmy in mtDNA was associated with the monocyte cytokine secretion stimulation index (R2 = 0.156, P = 0.003). However, there was no significant association between mtDNA variability and the expression of the various genes.

Monocyte mtDNA shows relatively low variability. Low and Intermediate heteroplasmy are associated with cardiometabolic parameters, and intermediate heteroplasmy is associated with the monocyte cytokine secretion stimulation index.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a major global health concern and encompasses a spectrum ranging from hepatic steatosis and metabolic dysfunction-associated steatohepatitis to liver fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. Insulin resistance, the pathogenic cornerstone of MASLD, drives enhanced peripheral lipolysis and increased hepatic de novo lipogenesis, thereby overloading the liver with lipids and inducing steatosis. Subsequent lipotoxicity, inflammation, and gut microbiota dysbiosis further exacerbate disease progression. The gut microbiota and their metabolites communicate with the liver via the gut-liver axis, forming a complex signaling network that directly or indirectly modulates hepatic metabolism, systemic immune responses, oxidative stress, and intestinal barrier integrity. In this review, we synthesize evidence for the beneficial and detrimental effects of the major human gut microbial communities and their metabolites during the course of MASLD. We delineate how these gut-derived factors regulate hepatic function through an integrated tripartite “gut-liver axis–oxidative stress–metabolic reprogramming” mechanism. These insights may inform microbiome-based precision interventions and accelerate the development of therapeutic strategies targeting MASLD.

Hepatocellular carcinoma (HCC) remains one of the most fatal cancers, primarily due to late diagnosis and the lack of effective early biomarkers. Recent advances in multi-omics and liquid biopsy technologies hold promise for improving early detection, prognostication, and monitoring of HCC. Understanding the immune landscape of HCC through genetic and epigenetic signatures is essential for identifying therapeutic targets and improving immunotherapy outcomes. This review aims to present current findings on immune-related biomarkers, multi-omics strategies, and biomarker validation in HCC. It also aims to evaluate the role of liquid biopsy and gene signatures in predicting treatment responses, with a specific focus on their applications in immunotherapy. The goal is to provide a comprehensive framework for integrating these emerging tools into clinical practice. The integration of multi-omics approaches has led to the identification of robust gene signatures that predict HCC prognosis and response to immune checkpoint inhibitors. Liquid biopsy technologies, including circulating tumor DNA, provide non-invasive alternatives for monitoring tumor evolution and therapeutic responses. Despite promising results, challenges remain in clinical validation, particularly in cross-platform reproducibility and the interpretation of complex multi-omics data. While genetic biomarkers are rapidly advancing, their clinical application in personalized medicine remains hindered by technical and ethical challenges, such as data privacy, informed consent, and method standardization. The integration of multi-omics data and liquid biopsies offers a promising path toward real-time, personalized treatment and the development of universal prognostic signatures for HCC. However, successful clinical adoption depends on cross-disciplinary collaboration to standardize data protocols and overcome challenges regarding accuracy, reproducibility, and patient privacy.

Pancreatic cystic neoplasms (PCNs) are increasingly detected in clinical practice, yet substantial variability exists in imaging interpretation and reporting, which may affect clinical decision-making. This guideline was developed to standardize diagnostic imaging evaluation and reporting for PCNs. A multidisciplinary expert panel conducted literature search and critical appraisal of domestic and international evidence, identified key clinical questions, and formulated recommendations using the Grading of Recommendations Assessment, Development and Evaluation framework. A modified Delphi consensus process and external review were performed to ensure the robustness of the recommendations. A total of 21 key questions were addressed, covering essential aspects of imaging evaluation and reporting for PCNs, including the preferred imaging modality for suspected lesions; standardized measurement of cyst size and mural nodules and their clinical significance; definitions of cyst wall and septal thickening; optimal imaging approaches for assessing the relationship between cystic lesions and the main pancreatic duct; measurement and evaluation of main pancreatic duct diameter and dilation; imaging-based classification of intraductal papillary mucinous neoplasms and serous cystic neoplasms; assessment of ductal obstruction, calcification, hemorrhage, and pancreatitis-related changes; criteria for suspicious lymph nodes; differentiation of PCNs from pancreatic pseudocysts or retention cysts; and recommended imaging modalities and follow-up intervals. This guideline provides a structured and evidence-based framework for imaging evaluation and reporting of PCNs, which may improve the consistency and clarity of imaging reports and support clinical decision-making.

The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) family regulates fundamental processes in both innate and adaptive immunity. Aberrant NF-κB activation, whether through canonical or non-canonical signaling pathways, contributes to chronic inflammation, autoimmunity, allergy, and primary immunodeficiency/autoinflammatory syndromes, while also influencing host defense and tissue repair mechanisms. The present review aims to synthesize molecular architecture, upstream triggers, ubiquitin-centered relay systems, and the dynamic regulation of NF-κB activity. The major findings on the NF-κB signaling pathway encompass its dual molecular mechanisms (canonical and non-canonical), its central roles in immune and inflammatory responses, cell survival, and development, as well as its complex regulatory networks. We interpret NF-κB as a master integrator of diverse signals, essential for both acute and long-term physiological processes. Dysregulation of NF-κB underlies many diseases, and while it is a promising therapeutic target, its ubiquitous functions demand precise modulation to avoid adverse effects. In conclusion, the proper function of the NF-κB signaling pathway is essential for maintaining cellular homeostasis and immune defense; its dysregulation is linked to chronic inflammatory diseases, autoimmune disorders, and cancer, which underscores the pathway’s significance as a therapeutic target. Although it elucidates molecular processes and treatment options, experimental validation of emerging therapeutic concepts such as ubiquitin code editing and spatial immunology remains limited.