Advances in biological sciences and technology have continuously reshaped the questions that researchers are able to address. Over the past several decades, developments in DNA sequencing, mass spectrometry, genome analysis, and omics technologies have transformed not only biomedical research itself, but also the interpretation of observations that previously remained unresolved because of technical limitations. This Editorial reflects on how evolving technologies allow long-standing scientific questions to be revisited across generations of research. Two examples illustrate this process. One concerns the structural re-analysis of a Streptomyces lectin first studied in the 1970s, whose molecular features could only later be clarified through advances in mass spectrometry and expanding genetic databases. The second involves a recent transcriptomic re-examination of ethanol-associated lifespan responses in Caenorhabditis elegans, where modern RNA-seq approaches provided pathway-level insights that were not technically accessible in earlier studies. Together, these examples highlight that scientific progress often emerges not only from asking new questions, but also from revisiting unresolved observations using new technologies and perspectives.

Cholangiocarcinoma (CCA) is a highly aggressive, molecularly heterogeneous biliary tract malignancy and the second most common primary liver cancer, and it has an increasing global incidence and persistently poor prognosis. Recent updates of international guidelines, including those from the NCCN, ESMO, EASL, CSCO, BSG, and Japanese societies, along with rapid advances in precision oncology, have substantially changed the clinical management of CCA. This review systematically compares current global guidelines, highlighting both areas of consensus and regional differences in epidemiology, risk factors, screening strategies, diagnostic approaches, pathological and molecular classification, staging systems, surgical indications, systemic therapy, and multidisciplinary management. This review also summarizes recent advances in molecular diagnostics, including next-generation sequencing, liquid biopsy, circulating tumor DNA, extracellular vesicles, artificial intelligence-assisted imaging, radiomics, and emerging prognostic biomarkers. The evolving roles of immune checkpoint inhibitors, molecularly targeted therapies against FGFR2, IDH1, HER2, BRAF, NTRK, and MSI-H/dMMR, liver transplantation, locoregional treatment, and conversion (translational) therapy are also discussed. Finally, this review addresses current challenges, including drug resistance, limited access to molecular testing, regional disparities in healthcare resources, and the lack of universally accepted screening strategies. By integrating updated guideline recommendations with the latest clinical evidence, this review provides a comprehensive reference for evidence-based clinical decision-making and future translational research in CCA.

Hepatocellular carcinoma (HCC) is governed by malignant progression and deterioration of the organ in which the cancer arises. Modern management has therefore outgrown static stage-to-treatment allocation. We define dynamic therapeutic opportunity as the time-varying set of clinically credible treatment options available to an individual patient, determined by hepatic reserve, oncological tractability, physiological reserve, prior therapeutic exposure, patient goals, and real-world deliverability. This framework does not replace validated staging systems or liver-function scores; it asks how each intervention changes the circumstances under which the next decision will be made. Evidence for curative-intent conversion remains dominated by selected cohorts, although the interim results of the randomized TALENTop trial provide the first prospective comparative signal supporting resection in a narrowly defined post-induction population. We review liver-sparing surgery, locoregional-systemic integration, conversion therapy, and modifiers such as frailty and metabolic dysfunction-associated steatotic liver disease. We then propose a trial architecture that complements tumor endpoints with hepatic decompensation, sustained ALBI deterioration, subsequent-treatment access, curative-intent transition, functional independence, and patient-reported outcomes. Modern HCC management should evaluate not only whether an intervention controls the present tumor but also whether it preserves, expands, or eliminates the patient's future set of clinically meaningful treatment options.

Portal vein tumor thrombus (PVTT) is a biologically aggressive and clinically heterogeneous form of hepatocellular carcinoma (HCC). Global guidelines generally classify macrovascular invasion as advanced disease and prioritize systemic therapy, whereas selected East Asian practice pathways incorporate hepatic arterial infusion chemotherapy (HAIC), radiotherapy, or resection. This review critically evaluates HAIC combined with an antiangiogenic agent and immune checkpoint inhibitor as a conversion strategy for HCC with PVTT. Randomized trials substantiate the efficacy of HAIC-based treatment in contrast to controls from the days of sorafenib but do not establish the incremental benefit of the contemporary triplet. Across prospective single-arm studies, RECIST 1.1 objective response rates ranged from approximately 36 to 77%, with higher estimates in some studies using mRECIST. Retrospective PVTT-focused comparisons also suggest longer progression-free and overall survival than with dual systemic therapy or HAIC alone, but these figures remain vulnerable to confounding by indication, heterogeneous regimens, inconsistent response criteria, and immortal-time bias related to surgery. Conversion should be defined as a prospectively documented transition from unresectable disease to an R0-resectable state with adequate liver reserve, not as radiological response alone. We propose an explicitly unvalidated multidisciplinary framework for candidate selection, reassessment, and perioperative management. Current evidence supports protocol-based use in clinical trials or experienced centers rather than routine global adoption. Randomized PVTT-stratified trials comparing the triplet to contemporary immunotherapy, with intention-to-treat reporting of resection and pathological response, are required.

Rare diseases impose a disproportionate clinical burden, and yet therapeutic progress is hindered by small cohorts, biological heterogeneity, and limited disease-specific options. Stem cell-derived extracellular vesicles (EVs), and especially exosome-enriched products, are emerging as adaptable cell-free therapeutics that preserve key paracrine activities of parent cells while offering improved controllability, engineering flexibility, and potentially lower acute immunogenicity than living-cell products. This review proposes a clinically driven bottleneck-to-mechanism framework for rare-disease translation, matching each disease class to its dominant pathological barrier, mechanism-relevant EV function, route-aware delivery strategy, and measurable potency endpoint. Using this framework, EVs may enable immune circuit rewiring in autoimmune disorders, neuroprotection and toxic-protein clearance in neurodegeneration, osteogenic and matrix-supportive repair in skeletal/connective tissue diseases, and metabolic rescue in lysosomal or mitochondrial disorders. We further highlight a key conceptual distinction between EVs as active biologics and EVs as engineered delivery vehicles. Successful translation will depend on integrating cargo design, surface targeting, biodistribution-aware administration, scalable manufacturing, and quality-by-design control, while anticipating repeat-dose pharmacokinetics/pharmacodynamics (PK/PD), immunogenicity, complement activation, procoagulant risk, impurity control, and off-target organ-accumulation challenges. Multi-omics and artificial intelligence may further refine target selection and precision engineering. Overall, stem cell-derived EVs constitute a versatile platform for treating rare diseases, but clinical success requires closer alignment among mechanism, disease specificity, product definition, and translational endpoints.

Antiretroviral therapy (ART) has transformed HIV infection into a manageable chronic condition, but pathological weight gain, adipose dysfunction, and persistent inflammation are increasingly prevalent among aging people with HIV (PWH). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GIP/GLP-1 RAs have emerged as transformative therapies, although PWH were underrepresented in pivotal trials. This review integrates randomized trials, observational cohorts, pharmacogenomic studies, and emerging mechanistic evidence within a framework of GLP-1-mediated immunometabolic reprogramming. HIV-specific trials demonstrate reductions in visceral adiposity, body weight, inflammatory biomarkers, and liver fat. Exploratory or preliminary studies suggest possible effects on gut epithelial integrity, immune-cell trafficking, lymphoid pyroptosis, and DNA-methylation aging measures; however, several of these findings remain conference-level, preprint, or post hoc evidence and require prospective validation. We also examine lean-mass loss, weight regain after discontinuation, pharmacogenomic variation, drug access, and research priorities. Overall, GLP-1 RAs are promising components of cardiometabolic care for PWH, but immunologic, gerotherapeutic, and HIV-reservoir applications should currently be considered hypothesis-generating.

Oncolytic adenovirus H101 has shown antitumor activity in hepatocellular carcinoma (HCC), but the molecular determinants of treatment response remain unclear. In this study, a Hepa1-6 subcutaneous tumor model was established in C57BL/6 mice and treated with intratumoral H101, followed by integrated transcriptomic and proteomic analyses to identify candidate genes associated with H101 response. PRXL2B was selected for further investigation using public multi-omics datasets, tissue microarray-based immunohistochemistry, in vitro functional assays, mechanistic analyses, and in vivo validation experiments. Integrated multi-omics analyses identified PRXL2B as a candidate gene downregulated after H101 treatment. Public datasets and tissue-based validation further showed that PRXL2B was upregulated in HCC tissues. In MHCC97H and HCCLM3 cells, PRXL2B knockdown inhibited proliferation, migration, and invasion, promoted apoptosis and cell-cycle arrest, and enhanced the antitumor effect of H101. Mechanistically, PRXL2B silencing reduced AKT phosphorylation and PD-L1 expression. In vivo, PRXL2B knockdown suppressed tumor growth, and the combination of PRXL2B knockdown and H101 produced the strongest antitumor effect. These findings indicate that PRXL2B promotes malignant phenotypes in HCC and may modulate H101 efficacy through the PI3K/AKT/PD-L1 axis. Targeting PRXL2B may therefore represent a potential strategy to enhance the therapeutic efficacy of oncolytic virus therapy in HCC.

Vascular instability, characterized by impaired pericyte coverage, is a hallmark of tumor progression. ATP6L is highly expressed in colorectal cancer (CRC) tissues and promotes tumor progression by enhancing the tumor microvasculature; however, its direct impact on vascular stability remains unclear. ATP6L expression, microvascular morphology, and pericyte coverage were analyzed by immunohistochemistry in a cohort of 179 CRC specimens, and the role of ATP6L in vascular stability was further investigated by modulating its expression both in vitro and in vivo. In vitro, MC38 and CT26 cells with ATP6L overexpression or knockdown were co-cultured with mouse vascular smooth muscle cells (MOVAS), and MOVAS proliferation, migration, and apoptosis were evaluated using EdU incorporation, transwell migration, and TUNEL staining assays, respectively. PDGFB secretion and PDGFRβ expression were assessed by ELISA, Western blotting, and immunofluorescence. Along the normal colorectal mucosa–adenoma–adenocarcinoma sequence, ATP6L upregulation was closely associated with progressive vascular instability, characterized by loss of pericyte coverage and increasing vascular morphological heterogeneity. Mechanistically, ATP6L overexpression promoted extracellular acidification, suppressed PDGFB secretion, and subsequently reduced PDGFRβ expression in pericytes, thereby impairing their recruitment and survival. Conversely, ATP6L knockdown attenuated extracellular acidification, restored PDGFB/PDGFRβ signaling, and rescued pericyte proliferation, migration, and survival. These findings identify ATP6L as a key mediator of perivascular dysfunction in CRC and demonstrate that ATP6L-induced extracellular acidification disrupts vascular stability by suppressing the PDGFB/PDGFRβ signaling axis and impairing pericyte function.

Postoperative complications remain major determinants of outcomes after hepatectomy for hepatocellular carcinoma (HCC), but whether complications that prolong hospitalization are also those that contribute most to mortality remains unclear. This multicentre cohort study included 1,883 patients undergoing curative-intent hepatectomy for HCC across seven tertiary centers. Postoperative complications were categorized by organ system, and adjusted population-attributable fractions (PAFs) were calculated to estimate their contributions to 90-day mortality and prolonged hospital stay. Multivariable Cox models were used to assess associations with overall survival and recurrence-free survival. A divergence between hospitalization burden and mortality burden was observed. Liver surgery-specific complications accounted for the largest population-level burden of prolonged hospitalization (PAF 11.0%) and 90-day mortality (PAF 10.0%). Cardiovascular complications were the leading non-liver contributor to 90-day mortality (PAF 9.4%), despite a smaller contribution to prolonged hospitalization (PAF 4.1%). Pulmonary complications, cardiovascular complications, renal complications, and glucose dysregulation were independently associated with worse overall survival, whereas no complication domain was independently associated with recurrence-free survival. These findings show that postoperative recovery burden and mortality burden are not interchangeable after hepatectomy. Liver surgery-specific complications dominated hospitalization burden, whereas cardiovascular complications represented an underrecognized non-liver contributor to early mortality and worse long-term survival. An integrated perioperative framework incorporating systematic cardiovascular risk assessment may improve risk prioritization after hepatectomy for HCC.

Previous studies have suggested that low to moderate alcohol exposure can extend Caenorhabditis elegans (C. elegans) lifespan, but early molecular mechanisms linking ethanol exposure to longevity have not been fully characterized. Here, we investigated how ethanol treatment affects transcriptional networks in L4-stage C. elegans by time-resolved RNA-seq. L4-stage C. elegans were exposed to 5% ethanol and time-resolved RNA-seq was performed after 1, 4, and 20 hours in solution cultures, followed by differential gene expression and KEGG pathway-based Gene Set Enrichment Analysis. At 1 hour, GSEA analysis showed significant enrichment of genes in the Longevity regulating pathway (worm) with elevated expression. Core-enrichment genes exhibited coordinated upregulation of redox-defense modules, including glutathione S-transferases (gst) and p38 MAPK components (pmk-2/pmk-3), consistent with upregulation of SKN-1/Nrf2-related stress-response genes. Detoxification (gpx and fmo families) and lipid-remodeling genes were enriched at 1 hour. By 4 hours, sod-3, a canonical DAF-16/FOXO target, was clearly upregulated, suggesting engagement of DAF-16-associated antioxidant responses, whereas Peroxisome and TGF-β signaling pathways were significantly downregulated. Together, these findings provide transcriptomic insights into a temporally structured longevity-associated response to ethanol exposure, in which early detoxification and antioxidant programs, together with membrane-lipid remodeling, are followed by DAF-16-associated gene induction and repression of peroxisome- and development-related signaling. These pathway-level changes highlight candidate biological processes potentially associated with ethanol-linked lifespan modulation in C. elegans.