Catholic University of Korea

By inhibiting the conversion of lysophosphatidylcholine into lysophosphatidic acid, a process pivotal to tumor progression, the autotaxin (ATX) inhibitor PF-8380 offers a new anticancer therapeutic strategy, distinct from the action mechanism of sorafenib. This study explored the potential anticancer effects of the PF-8380 on hepatocellular carcinoma (HCC) cells, especially sorafenib-resistant strains. The investigation included both in vitro and in vivo experiments to evaluate the impact of PF-8380 treatment on epithelial-mesenchymal transition (EMT) and autophagy markers. An orthotopic HCC model served as the in vivo platform. PF-8380 showed a significant reduction in cell viability in both sorafenib-susceptible and resistant HCC cells. It effectively altered EMT by increasing E-cadherin and reducing Snail levels, and inhibited autophagy, as indicated by changes in LC3 and p62 markers. These effects were consistently observed in the orthotopic HCC mouse model, reinforcing PF-8380’s potential as a dual inhibitor of EMT and autophagy in HCC treatment. Our research indicates that PF-8380 could provide substantial therapeutic benefits in the treatment of HCC, even in cases resistant to sorafenib, primarily by suppressing both EMT and autophagy processes.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging global health concern with limited therapeutic options. Multivitamins, widely consumed dietary supplements, have been proposed to modulate oxidative stress and inflammation, potentially impacting MASLD progression. However, their efficacy in reducing mortality and other complications in MASLD remains unclear. Using data from the UK Biobank with 7 years of median follow-up period, this study assessed the association between multivitamin use and health outcomes, including all-cause mortality, liver-related mortality, cardio-cerebrovascular disease (CVD), and chronic kidney disease (CKD), in individuals with MASLD and those without steatotic liver disease. Inverse probability of treatment weighting (IPTW) was employed to adjust for confounders. Multivitamin users showed a significantly lower all-cause mortality risk in the MASLD cohort both before (HR: 0.88, 95% CI 0.81–0.95, P = 0.034) and after (HR: 0.94, 95% CI 0.88–1.00, P = 0.037) IPTW adjustment. Multivitamin use was also associated with the lower risk of CVD (HR: 0.72, 95% CI 0.68–0.76, P < 0.001) and CKD (HR: 0.73, 95% CI 0.67–0.81, P < 0.001) in the MASLD cohort. No significant reduction was found for liver-related mortality or liver cirrhosis incidence. These findings suggest that multivitamins might provide broader protective effects in populations with metabolic dysfunction. Further research is needed to clarify their role in liver-specific outcomes.

In vitro modeling of vascular diseases provides a useful platform for drug screening and mechanistic studies, by recapitulating the essential structures and physiological characteristics of the native tissue. Bioprinting is an emerging technique that offers high-resolution 3D capabilities, which have recently been employed in the modeling of various tissues and associated diseases. Blood vessels are composed of multiple layers of distinct cell types, and experience different mechanical conditions depending on the vessel type. The intimal layer, in particular, is directly exposed to such hemodynamic conditions inducing shear stress, which in turn influence vascular physiology. 3D bioprinting techniques have addressed the structural limitations of the previous vascular models, by incorporating supporting cells such as smooth muscle cells, geometrical properties such as dilation, curvature, or branching, or mechanical stimulation such as shear stress and pulsatile pressure. This paper presents a review of the physiology of blood vessels along with the pathophysiology of the target diseases including atherosclerosis, thrombosis, aneurysms, and tumor angiogenesis. Additionally, it discusses recent advances in fabricating in vitro 3D vascular disease models utilizing bioprinting techniques, while addressing the current challenges and future perspectives for the potential clinical translation into therapeutic interventions.

Purpose: Traditional methods, fine-needle aspiration cytology (FNAC) and washout thyroglobulin (Tg), do not always provide sufficient accuracy for diagnosing lymph node (LN) metastasis in thyroid cancer. This study aimed to validate the diagnostic performance of washout cytokeratin fragment 21-1 (CYFRA 21-1) as a complementary biomarker for diagnosing metastatic LNs in thyroid cancer and to explore its relationship with molecular analysis and distant metastasis. Patients and Methods: In this retrospective cohort study involving 230 LNs in 224 patients with PTC, FNAC, washout Tg, and CYFRA 21-1 levels were measured in suspicious LNs. The final LN outcomes were confirmed by surgical histology. Results: Among the 230 LNs, 145 (63.0%) were benign and 85 (37.0%) were metastatic. The optimal cut-off value for washout CYFRA 21-1 was established at 1.12 ng/mL (Area under curve AUC, 0.959; 95% confidence interval CI, 0.936-0.982) with sensitivity of 93.4% and specificity of 97.8%. The cut-off value for washout Tg was 12.61 ng/mL (AUC 0.832, 95% CI, 0.772-0.892). The diagnostic performance of CYFRA 21-1 remained consistent across the preoperative (1.14 ng/mL) and postoperative assessment (1.10 ng/mL). The combination of FNAC and washout CYFRA 21-1 showed high sensitivity (93.1%), specificity (95.6%), negative predictive value (95.3%), and diagnostic accuracy (94.6%) than FNAC with washout Tg. Washout CYFRA 21-1 level was associated with TERT mutations (odds ratio, OR 3.35, P<0.001), LN metastasis (OR 5.43, P=0.019), and distant metastasis (OR 4.27, P =0.019). Conclusions: Incorporating washout CYFRA 21-1 into the diagnostic process improves the accuracy of metastatic LN detection in thyroid cancer.

Objectives Implantable hearing devices, such as cochlear implants (CI) and bone conduction implants (BCI), are options for hearing rehabilitation in patients with asymmetric hearing loss (AHL) and single‐sided deafness (SSD). This study aimed to compare the effects of CI and BCI on tinnitus in AHL/SSD patients with tinnitus. Methods This retrospective study enrolled adult AHL/SSD patients with significant tinnitus who underwent CI or BCI placement between 2017 and 2023. Clinical characteristics, preoperative and postoperative audiologic test results, and tinnitus questionnaires (tinnitus handicap inventory, THI; visual analog scale, VAS) were collected and analyzed. Results Of 33 AHL/SSD patients with significant tinnitus (THI ≥ 18), 16 received CI and 17 BCI. In the CI group, all four VAS scores (loudness, awareness, annoyance, and effect on life) and THI scores significantly improved. In the BCI group, annoyance and effect on life categories of VAS and THI scores significantly improved, while VAS loudness and awareness remained similar. Linear mixed model analysis showed that the decrease in VAS loudness, awareness, and annoyance scores was significantly greater in the CI group compared to the BCI group. The CI group showed a significantly higher tinnitus cure rate (62.5.0%) compared with the BCI group (11.8%) at 6‐months postoperative. Conclusion Both CI and BCI effectively improved tinnitus in AHL/SSD patients with tinnitus. However, CI is considered the first‐line therapeutic option for tinnitus due to its stronger effect on tinnitus suppression as well as the higher cure rate in SSD/AHL patients with tinnitus. Level of Evidence 3

Janus kinase (JAK) inhibitors provide limited depth and durability of response in myelofibrosis. We evaluated pelabresib—a bromodomain and extraterminal domain (BET) inhibitor—plus ruxolitinib (a JAK inhibitor) compared with placebo plus ruxolitinib as first-line therapy. In this phase 3 study (MANIFEST-2), JAK inhibitor-naive patients with myelofibrosis were randomized 1:1 to pelabresib 125 mg once daily (QD; 50–175 mg QD permitted) for 14 days followed by a 7-day break (21-day cycle), or to placebo in combination with ruxolitinib 10 or 15 mg twice daily (BID; 5 mg QD–25 mg BID permitted). Primary endpoint was reduction in spleen volume of ≥35% from baseline at week 24. Key secondary endpoints were absolute change in total symptom score (TSS) and TSS50 response (≥50% reduction in TSS from baseline at week 24). The primary endpoint was met in 65.9% of patients randomized to pelabresib–ruxolitinib (n = 214) versus 35.2% to placebo–ruxolitinib (n = 216) (difference, 30.4%; 95% confidence interval (CI), 21.6, 39.3; P < 0.001). Absolute change in TSS was −15.99 versus −14.05 (difference, −1.94; 95% CI, −3.92, 0.04; P = 0.0545) and TSS50 was achieved in 52.3% versus 46.3% (difference, 6.0%; 95 CI, −3.5, 15.5) with pelabresib–ruxolitinib versus placebo–ruxolitinib. Exploratory analyses of proinflammatory cytokine amounts and bone marrow morphology showed greater improvement with the combination. Thrombocytopenia and anemia were the most common treatment-emergent adverse events, occurring in 52.8% (13.2% grade ≥3) versus 37.4% (6.1% grade ≥3) and 44.8% (23.1% grade ≥3) versus 55.1% (36.5% grade ≥3), respectively. Pelabresib in combination with ruxolitinib is well tolerated, improves signs of underlying myelofibrosis pathobiology and provides substantial clinical benefit over standard-of-care JAK inhibitor monotherapy. ClinicalTrials.gov identifier: NCT04603495.

Objective:Frankl (1963) introduced the concept of “meaning in life” (MIL) as essential for individuals’ stability, a view supported by Baumeister and Hippel (2020). This study suggests that MIL restoration follows a dynamic pattern after traumatic events. Method: We conducted a longitudinal study with 135 family members affected by the 2014 Sewol ferry disaster in South Korea, examining changes in MIL over 5 years (2015–2019). Utilizing the repeated-measures actor–partner interdependence model, we assessed the dynamic patterns of searching for MIL (SMIL) and presence of MIL (PMIL) from a dynamical systems perspective. Results: The analysis showed that PMIL and SMIL significantly predict their stability, indicating an attractor state for each type of MIL. Notably, survivor family members exhibited a pattern where SMIL stabilization enhanced PMIL in tandem with stability in PMIL, indicating increased MIL dynamism during active meaning restoration. Conclusions: These findings underscore MIL’s critical role in life stability after an adverse life event for the bereaved and the survivors’ family members. The dynamic interaction between SMIL and PMIL in family members who experienced a traumatic life event reveals more intricate dynamics in the meaning reconstruction process, highlighting MIL’s importance as a potential resilience mechanism against adversities.

Current European/US guidelines recommend that molecular testing in advanced non‐small cell lung cancer (aNSCLC) be performed using next‐generation sequencing (NGS). However, the global uptake of NGS is limited, largely owing to reimbursement constraints. We compared real‐world costs of NGS and single‐gene testing (SGT) in nonsquamous aNSCLC. This observational study was conducted across 10 pathology centers in 10 different countries worldwide. Biomarker data collected via structured questionnaires (1 January–31 December 2021) were used to feed micro‐costing analyses for three scenarios [‘Starting Point’ (SP; 2021–2022), ‘Current Practice’ (CP; 2023–2024), and ‘Future Horizons’ (FH; 2025–2028)] in both a real‐world model, comprising all biomarkers tested by each center, and a standardized model, comprising the same sets of biomarkers across centers. Testing costs (including retesting) encompassed personnel costs, consumables, equipment, and overheads. Overall, 4,491 patients with aNSCLC were evaluated. Mean per‐patient costs decreased for NGS relative to SGT over time, with real‐world model costs 18% lower for NGS than for SGT in the SP scenario, and 26% lower for NGS than for SGT in the CP scenario. Mean per‐biomarker costs also decreased over time for NGS relative to SGT. In the standardized model, the tipping point for the minimum number of biomarkers required for NGS to result in cost savings (per patient) was 10 and 12 in the SP and CP scenarios, respectively. Retesting had a negligible impact on cost analyses, and results were robust to variation in cost parameters. This study provides robust real‐world global evidence for cost savings with NGS‐based panels over SGT to evaluate predictive biomarkers in nonsquamous aNSCLC when the number of biomarkers to be tested exceeds 10. Widespread adoption of NGS may enable more efficient use of limited healthcare resources.

Objective: This study assessed the impact of the COVID-19 pandemic on the health status of self-employed workers by comparing their status before and during the pandemic, using nationwide data from the Korean Working Conditions Survey (KWCS). Methods: The final study included 16,620 and 14,342 self-employed participants in the 5th (2017) and 6th (2020-2021) surveys. Musculoskeletal symptoms, systemic fatigue, headache, and eye strain, as well as mental health status, such as anxiety, depression, and insomnia, were assessed using a structured questionnaire. Gender, age, education level, and income were adjusted for the multivariable logistic regression analysis to assess pre- and peri-pandemic changes in the health status based on working conditions. Results: Compared to the pre-pandemic period, all aspects of health status of self-employed individuals surveyed during the peri-pandemic period showed deterioration. Back pain increased 3.4 times (adjusted OR 3.44, 95% CI: 3.15–3.75) compared to the pre-pandemic period, followed by anxiety, which increased 2.1 times (adjusted OR 2.13, 95% CI: 1.79–2.54). For single-person businesses, the overall health status showed statistically significant deterioration, highlighting the heightened vulnerability of these groups during this period. Conclusions: This study confirmed that the physical and mental health status of self-employed individuals significantly deteriorated during the COVID-19 pandemic period compared to the pre-pandemic period. These findings suggest the need for government health protection policies for vulnerable groups, such as self-employed individuals, during future pandemics when social control measures are implemented.

We investigated the effect of differential blood pressure (BP) levels on future end-stage renal disease (ESRD) in patients with type 2 diabetes mellitus (T2DM) and established coronary artery disease with a previous record of percutaneous coronary intervention (PCI). Using health check-up data from the Korean National Health Insurance Service (2015–2016), we analyzed 80,187 T2DM patients with a history of PCI. Patients were categorized by BP levels measured: systolic BP < 120, 120–129 (reference), 130–139, 140–149, and ≥150 mmHg; diastolic BP < 70, 70–79 (reference), 80–89, and ≥90 mmHg. Incident ESRD, defined by disease codes and renal replacement therapy initiation, was the primary outcome. Multivariate Cox proportional hazard regression assessed adjusted hazard ratios (HRs) (95% confidence intervals) by BP group. Mean age was 67.7 years; 80.9% used antihypertensives. ESRD incidence was 1.70% (1,362 patients) over 4.7 years. After adjustment for confounding factors, the HR of ESRD patients significantly and sequentially increased in the higher BP groups. Similar trends were seen with pulse pressure (PP). Subgroup analysis showed stronger BP-ESRD association in < 65-year-olds compared to those aged ≥65 years. ESRD risk linearly increased with systolic BP and had a J-shaped association with diastolic BP, with the lowest risk at 68 mmHg. Elevated BP, including PP, correlated with ESRD risk in a dose‒response manner among T2DM patients with a previous record of PCI. Strict BP control is crucial for preventing ESRD in these high-risk patients.

Introduction Using a nationwide population-based cohort, we primarily investigated whether overall and site-specific cancer risk are increased in patients with acromegaly. Materials and methods The study included 2,382 patients with acromegaly and 11,910 controls aged above 20, from 2006 to 2016. Cox hazards regression analysis was used, adjusting for baseline covariates. To investigate the association between acromegaly and cancer risk, we conducted Cox proportional hazards regression analysis with adjustments for age, sex, hypertension, diabetes, and dyslipidemia, and stratified the analysis by age (<50 years, 50-64 years, ≥65 years), sex, and follow-up duration (<1 year, 1-4 years, ≥5 years). Results Among the 2,382 patients with acromegaly, overall cancer occurred in 244 (10.2%), while the 11,910 controls had 707 (5.9%) occurrences (HR: 1.90 (95% CI: 1.63-2.22). Patients with acromegaly had the highest relative risk for brain cancers with an HR of 6.80 (95% CI: 2.83-16.38) and significantly higher risk of lymphoma, thyroid cancer, multiple myeloma, pancreatic cancer, and colorectal cancer. Even five years after the diagnosis of acromegaly, patients continued to show a significantly higher incidence of cancer. The overall cancer risk, particularly for stomach cancer, was significantly higher in patients under the age of 50 compared to older patients. No significant difference was observed between sexes. Conclusions This nationwide longitudinal cohort study shows an increased risk of cancer in patients with acromegaly Active and long-term cancer screening is necessary in patients with acromegaly.

Mild head trauma often leads to long-term cognitive and neurological deficits. PLX3397, an inhibitor of colony-stimulating factor 1 receptor (CSF1R), offers promise as a therapeutic agent for traumatic brain injury (TBI) by targeting neuro-inflammation. Stem cell-based approaches are widely studied for neurological disorders. The objective of this study was to investigate therapeutic effect of intranasal administration of human neural crest-derived nasal turbinate stem cells (hNTSCs) on mild TBI in comparison with that of PLX3397. We developed a model of mice with repetitive and mild TBI following a weight-drop once a day for 5 days. PLX3397 (50 mg/kg, p. o.) was administered for 21 days. Intranasal administration of hNTSCs (1 × 106) was performed once. Iba1 + and GFAP + cells were increased in the cortex and hippocampus of TBI models. Iba1 + cells and GFAP + cells were remarkably decreased in PLX3397 or hNTSC-treated TBI models. Administration of PLX3397 attenuated the decrease in neurobehavioral activity. Similar effects were observed in a TBI model with a single dose of hNTSC. Intranasal administration of hNTSCs had a microglia-depleting effect. Administered hNTSCs were found around the cortex and hippocampus of TBI brains. This investigation may provide a promising path for therapeutic initiatives for repetitive and mild TBI.