Although venous invasion (VI) is associated with distant metastasis and observed in >50% of pT2–4 colorectal cancers (CRCs), the role of VI in pT1 CRCs is not well-defined. Methods: Thirty-four surgically resected pT1 CRCs were reevaluated for 2-dimensional (2D) VI using hematoxylin and eosin (H&E)–stained slides with additional elastic and desmin immunohistochemical staining (cohort A). Additionally, 27 pT1 CRCs without knowing VI status were selected for 3-dimensional (3D) VI evaluation only (cohort B). All 61 cases (cohorts A and B) were studied in 3D using tissue clearing. Results: VI was detected more commonly in 3D (17/34, 50.0%) than in 2D H&E slide evaluation (9/34, 26.5%, p = .047). When VI was identified in 3D (27/61, 44.3%), the most common phase was that of intraluminal growth (22/27, 81.5%), followed by intravasation (7/27, 25.9%) and extravasation (5/27, 18.5%). E-cadherin expression was characterized in 3D in foci of VI and varied in each phase of invasion. Conclusions: All three phases were observed in VI of pT1 CRCs. The extravasation of neoplastic cells from foci of VI in pT1 CRC suggests that VI could be a route of intratumoral spreading in a subset of pT1 CRCs.

α-Melanocyte-stimulating hormone (α-MSH) is a key physiological inducer of melanogenesis and melanocyte activation. Reactive oxygen species (ROS) function as secondary messengers in intracellular signaling pathways that regulate α-MSH-mediated melanogenesis. However, the mechanism by which α-MSH induces ROS generation in melanocytes remains incompletely understood. Here, we investigated the sources and regulatory mechanisms of α-MSH-induced ROS in murine B16F10 and human MNT-1 melanoma cells. Confocal microscopy revealed that α-MSH predominantly stimulated cytosolic rather than mitochondrial ROS generation. Western blot analysis showed that α-MSH upregulated the expression of NADPH oxidases NOX1 and NOX4 at early time points, key enzymes involved in cytosolic ROS production. Pharmacological inhibition of NOX1/4 significantly reduced α-MSH-induced ROS levels and melanin content, accompanied by decreased phosphorylation of MITF, a melanogenic transcription factor. These findings indicate that α-MSH is a key physiological inducer of melanogenesis and melanocyte-related signaling in melanoma cells. Our study highlights NOX4, together with NOX1, as potential targets for anti-pigmentation strategies.

Background/Aims: Various expanded criteria (EC) for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) have been proposed to avoid the narrow nature of the Milan criteria (MC). To investigate which EC predicts more favorable outcomes in terms of overall survival (OS) and recurrence-free survival (RFS), we conducted a network meta-analysis (NMA). Methods: A database search was conducted on PubMed, Embase, and the Cochrane Library, to identify studies comparing OS and RFS between patients within the MC and those exceeding the MC but within the EC. Hazard ratios (HRs) were pooled using a random-effects NMA and validated in an in-house cohort of 1,008 LT recipients. Results: Among 22,466 articles identified, 35 studies with 45 pairwise comparisons were included in the NMA along with 8 different EC. The University of California San Francisco (HR, 1.43; 95% CI, 1.19–1.71), Up-to-Seven (HR, 1.50; 95% CI, 1.15–1.97), and Hangzhou criteria (HR, 1.69; 95% CI, 1.11–2.57) showed inferior OS to the MC. The MC ranked highest for both OS and RFS, followed by Metroticket 2.0 for OS and the Asan criteria for RFS. In the validation cohort, both Metroticket 2.0 and AFP model yielded more favorable HCC-specific mortality than other EC. Conclusions Several EC, of which those of Metroticket 2.0 were the best, yielded comparable outcomes to the MC. AFP-based EC such as Metroticket 2.0 and AFP model appeared to be useful in both the NMA and the validation cohort, suggesting a potential role in identifying selected low-risk patients beyond the MC.

Background: This study aimed to investigate the densitometric characteristics and qualitative bone status in patients with normocalcemic primary hyperparathyroidism (PHPT) compared with those in controls who were younger adults under 50 years. Methods: This retrospective study included 60 controls and 31 patients with PHPT who underwent dual energy X-ray absorptiometry (DXA) of the lumbar spine (LS), femoral neck (FN), and total hip (TH). Trabecular bone score (TBS) was derived from LS DXA images. Bone mineral density (BMD) values were assessed using Z-scores, and correlations between TBS, BMD, and laboratory parameters were examined. Results: The median ages of the control and PHPT groups were 41 and 42 years, respectively. The proportion of individuals classified as “below the expected range for age” based on Z-scores differed significantly between groups only when considering any site collectively. Median TBS was significantly lower in PHPT patients than in controls, even when BMD values at LS, FN, and TH fell within similar diagnostic categories. In controls, TBS and BMD demonstrated very low correlation coefficients. In contrast, PHPT patients showed a stronger correlation between TBS and femoral BMD, whereas the association between TBS and LS BMD was largely absent. Among laboratory markers, only serum intact parathyroid hormone was significantly negatively correlated with TBS. Conclusions Young adults with PHPT exhibit impaired bone quality despite relatively preserved BMD, suggesting early microarchitectural deterioration. These findings support the combined use of LS and femoral BMD with TBS for more accurate assessment of skeletal health in PHPT.

Objective: To evaluate the association between chronic kidney disease (CKD) stage and serum fPL in cats and characterize how renal biomarkers relate to fPL. Methods: This retrospective study evaluated medical records of cats presented to a secondary referral veterinary hospital between February 2024 and March 2025. Inclusion required same-day testing of complete blood count, serum biochemistry, blood gas analysis, urinalysis, serum fPL, and abdominal ultrasonography. CKD staging followed International Renal Interest Society guidelines using serum creatinine, urine specific gravity (USG), and ultrasonography. Nonparametric group comparisons were performed using the Kruskal– Wallis test, and associations between fPL and renal biomarkers were assessed using Spearman’s correlation. Results: fPL increased significantly with advancing CKD stage (p < 0.001). Furthermore, fPL was positively correlated with blood urea nitrogen (ρ = 0.516, p < 0.001), creatinine (ρ = 0.459, p < 0.001), and inorganic phosphorus (ρ = 0.312, p < 0.001). Additionally, fPL and USG exhibited an inverse correlation (ρ = −0.502, p < 0.001). Ionized calcium showed no correlation with fPL (ρ = 0.012, p = 0.898). Conclusions and Relevance: In this clinical cohort, higher CKD stage was associated with higher serum fPL. Because fPL alone is insufficient to diagnose pancreatitis and may increase with reduced renal function, mild-to-moderate fPL elevations in cats with CKD should be interpreted in the context of clinical signs and pancreatic imaging findings.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced malignant melanoma. This study examined the real-world efficacy of dacarbazine (dimethyl triazeno imidazole carboxamide, DTIC) in patients who had previously received pembrolizumab, based on the hypothesis that prior ICI treatment enhances the therapeutic response to subsequent chemotherapy. Methods: This retrospective study included 71 patients with histologically confirmed malignant melanoma treated at Kyungpook National University Chilgok Hospital (Daegu, Korea) between 2011 and 2023. The patients received DTIC for unresectable stage IIIC, IIID, or IV melanoma (American Joint Committee on Cancer, 8th edition). Results: Among the 71 patients, the median patient age was 64 years (range, 25–89 years). When categorized by melanoma subtype, 18 patients (25.4%) had acral melanoma, 40 (56.3%) had cutaneous melanoma, and 13 (18.3%) had mucosal melanoma. Sixteen of the DTIC-treated patients had not received pembrolizumab previously (DTIC-only group), while 55 had (pem-DTIC group). The median progression-free survival was 2.3 months in the DTIC-only group and 3.9 months in the pem-DTIC group (hazard ratio [HR], 0.246; 95% confidence interval [CI], 0.106–0.576; p=0.001). The median overall survival was 6.8 months in the DTIC-only group and 19.0 months in the pem-DTIC group (HR, 0.198; 95% CI, 0.068–0.574; p=0.003). The duration of response (DoR) was 4.64 months in the DTIC group and 8.11 months in the pem-DTIC group. Conclusion This study demonstrated that the DoR to DTIC was prolonged following ICI therapy (4.64 months vs. 8.11 months). This indicates that prior ICI treatment may enhance tumor sensitivity to chemotherapy, making DTIC a viable option for treating refractory, relapsed, or progressive melanoma.

Background: The heterogeneity of chronic kidney disease (CKD) and fragmented analysis methods hinder the precise identification of novel biomarkers. We addressed this challenge using two independent cohorts to integrate genomics and metabolomics, aiming to identify cause-specific biomarkers for CKD in the Korean population. Methods: A longitudinal genome-wide association study using the Cox proportional hazards model was conducted using the Ansan and Ansung cohort. To validate these genomic biomarkers and integrate them with plasma metabolomics biomarkers, we utilized a hospital-based biopsy cohort to identify cause-specific CKD biomarkers. Within the biopsy cohort, we analyzed four disease subsets, including type 2 diabetic kidney disease (DKD), hypertensive nephropathy (HN), immunoglobulin A nephropathy (IgAN), and membranous nephropathy (MN), and compared them with healthy individuals. Significant single nucleotide polymorphisms(SNPs) and metabolites for each CKD subset were identified through logistic regression and correlation-based network analyses. Subsequently, we analyzed the risk of disease progression associated with the identified pairs. Results: A total of 448 variants associated with CKD occurrence were identified, with significant differences in several genetic variants and metabolites observed among patients with DKD, HN, IgAN, and MN compared to healthy individuals. Among 36 SNP-metabolite pairs, those involing FOXB1 and ZFP42 were associated with DKD, whereas pairs involving MMRN1 and SYNJ2 were linked to MN. Notably, the rs1025170 variant in FOXB1 and tyrosine pair was correlated with DKD progression. Conclusion Integrating genomics and metabolomics across independent cohorts enables the discovery of cause-specific biomarkers for the occurrence and progression of CKD in the Korean population.

Background: Obesity is a well-known risk factor for chronic kidney disease and its progression. However, the impact of obesity on the renal function of the elderly population is uncertain. We investigated the association between obesity and renal outcomes in the elderly. Methods: We analyzed 130,504 participants from the Korean National Health Insurance Service-Senior cohort. Obesity was classified according to body mass index (BMI), sex-specific waist circumference (WC), and the presence of metabolic syndrome. The primary outcome was renal function decline, defined as a decline in the estimated glomerular filtration rate (eGFR) of at least 50% from baseline or new-onset end-stage renal disease. Results: During a follow-up period of 559,531.1 person-years (median, 4.3 years), 2,486 participants (19.0%; incidence rate of 4.44 per 1,000 person-years) showed renal function decline. A multivariate Cox proportional hazards model revealed that BMI/WC was not associated with renal function decline. However, the group with metabolic syndrome had a significantly increased risk of renal function decline compared to the group without metabolic syndrome (adjusted hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.13–1.36). Compared with the non-metabolic syndrome group, the adjusted HRs (95% CI) for participants with one through five components were 0.96 (0.84–1.11), 1.10 (0.96–1.27), 1.24 (1.06–1.45), 1.37 (1.12–1.66), and 1.99 (1.42–2.79), respectively (p for trend < 0.001). Conclusion In elderly Korean adults, metabolic syndrome and the number of its components were associated with a higher risk of renal function decline, but BMI or WC was not significant.

Objective: The aims of this study were to assess embryonic development using a time-lapse monitoring system based on cleavage timing and the use of vitrification and to investigate the correlation between miRNA-429 expression and embryonic development in both fresh and vitrified-thawed embryos. Methods: Mouse embryos at the 1-cell stage were collected and randomly divided into fresh and vitrified-thawed groups. The embryos were monitored and further subdivided into early and delayed cleavage based on the timing of the third cleavage event at 55 hours after human chorionic gonadotropin injection. miRNA-429 extracted from spent media or embryos cultured in vitro was analyzed by quantitative reverse transcription-polymerase chain reaction. Results: Early cleavage was associated with a significantly higher blastulation rate, regardless of cryopreservation status. Notably, among vitrified-thawed embryos, outgrowth was greater in those exhibiting early cleavage compared to those with delayed cleavage. Furthermore, miRNA-429 expression was elevated in embryos exhibiting delayed cleavage, but only within the cryopreserved group. Conclusion Based on these findings, we suggest that the timing of the third cleavage event may be more critical than the vitrification process itself, and evaluating miRNA-429 expression could serve as an alternative non-invasive selection tool for vitrified surplus embryos.

Background/Aims: Although metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) represent the updated nomenclature and diagnostic criteria for nonalcoholic fatty liver disease, studies comparing the prognostic implications of these conditions remain limited. This meta-analysis aimed to quantify the associations among MAFLD, MASLD, and long-term clinical outcomes. Methods: A comprehensive literature search was performed to identify cohort studies that assessed the association of MASLD and MAFLD with all-cause mortality, cause-specific (cardiovascular and cancer-related) mortality, and the incidence of cardiovascular disease in the PubMed, Embase, Web of Science, CINAHL, and CENTRAL databases from inception through October 31, 2024. Pooled hazard ratios (HRs) were calculated for relevant outcomes. Results: We identified 18 cohort studies, comprising 10,653,666 patients with MAFLD from 13 studies and 3,202,447 patients with MASLD from nine studies. MAFLD was significantly associated with an increased risk of overall mortality (pooled HR [95% confidence interval], 1.30 [1.16 to 1.47]) and cardiovascular mortality (1.31 [1.08 to 1.60]; both p<0.01), but not with cancer-related mortality (1.10 [0.97 to 1.24]; p=0.130). Conversely, MASLD was associated with a higher risk for all mortality outcomes: overall mortality (1.34 [1.12 to 1.61]), cardiovascular mortality (1.17 [1.07 to 1.27]), and cancer-related mortality (1.24 [1.19 to 1.29]; all p<0.01). The risk of cardiovascular disease was increased in patients with both MAFLD (1.48 [1.31 to 1.66]) and MASLD (1.33 [1.21 to 1.46]; both p<0.001). Conclusions MAFLD and MASLD were both associated with increased risks of mortality and cardiovascular outcomes. Notably, a significant association with cancer-related mortality was observed for MASLD, but not for MAFLD.