👤 Byeonghyeon Lee

Obstructive sleep apnea (OSA) is characterized by recurrent intermittent hypoxia (IH) and has been increasingly associated with lung cancer incidence and mortality. However, how IH-related biological programs relate to immune remodeling, stemness-associated phenotypes, and therapeutic resistance in lung cancer remains incompletely understood. We integrated single-cell RNA sequencing data from IH-exposed murine lung tissues (GSE301350) with bulk transcriptomic datasets from TCGA-LUAD and GSE31210 to examine hypoxia-associated cellular and transcriptional patterns. Stemness was quantified using CytoTRACE and transcriptome-based stemness scoring, and its associations with immune infiltration, immune checkpoint expression, TIDE scores, predicted drug sensitivity, and immunotherapy response were evaluated. A stemness-based prognostic model was constructed using LASSO Cox regression and validated in independent cohorts. Single-cell analysis revealed marked immune remodeling under intermittent hypoxia (IH), including expansion of effector T cells, and monocytes/macrophages, populations alongside reduced B cells and dendritic cells. In human LUAD cohorts, stemness-high tumors were associated with mitochondrial and metabolic stress-related transcriptional programs, and increased expression of immune checkpoint genes (PD-1, PD-L1, CTLA4, LAG3). Elevated stemness scores correlated with higher TIDE scores, poorer overall survival, and reduced predicted responsiveness to immunotherapy. LASSO modeling identified a six-gene stemness signature (EIF5A, MELTF, SEMA3C, CPS1, TCN1, SELENOK), that consistently stratified patients into high- and low-risk groups across TCGA and GSE31210 cohorts. Multivariate Cox regression confirmed the risk score as an independent prognostic factor. Drug sensitivity analyses further suggested that stemness-high tumors may exhibit increased susceptibility to selected kinase inhibitors (Dasatinib, A-770041) and metabolic modulators (Phenformin, Salubrinal). OSA-associated IH is linked to stemness-associated transcriptional plasticity, immune suppression, and adverse clinical outcomes in lung cancer. The identified stemness-based gene signature provides a robust prognostic biomarker and highlights potential therapeutic vulnerabilities, supporting integrative strategies that combine stemness and immune -targeted approaches with immunotherapy in OSA-associated lung cancer. Show less

Keratin 17 (K17) is a stress-responsive intermediate filament protein that is upregulated in chronic skin diseases and in several carcinomas. We previously showed that K17 is induced in epidermal keratinocytes following exposure to DNA-damaging agents, promoting keratinocyte survival and chemically induced papilloma formation in mouse skin. Molecularly, K17 is recruited to the nucleus, where it impacts nuclear architecture, gene expression, and the DNA damage response (DDR). Here, we report on efforts to delineate K17-dependent processes during DDR by focusing on its interacting partners. Using mass spectrometry, we identified a network of K17-interacting Rho GTPase signaling proteins, including Rac1 and its activator Dock7. Biochemically, we confirmed that Rac1 and K17 interact directly in vitro and in A431 tumor keratinocytes, both at baseline and after ionizing radiation. We show that Show less

Osteomas are benign, slow-growing bony tumors that commonly develop in the craniofacial region; however, standardized diagnostic and treatment protocols remain limited. This study aimed to establish a systematic approach for the diagnosis, genetic evaluation, and surgical management of craniofacial osteomas, with emphasis on lesion distribution and gender prevalence. A retrospective review was conducted on 141 patients with craniofacial osteomas at Kyungpook National University Hospital between October 2011 and September 2025. All patients underwent clinical examinations and 3-dimensional computed tomography for diagnostic confirmation. Surgical excision was performed using direct, endoscopic, or bicoronal approaches based on lesion characteristics. Whole exome sequencing was performed in patients with multiple large osteomas to evaluate mutations in EXT1, EXT2, APC, MSH2, and MLH1 genes associated with Gardner syndrome. A total of 148 osteomas were identified. The frontal bone was the most common site (60.1%), followed by the parietal, mandibular, and occipital bones. Females accounted for 79.1% of cases. Genetic testing revealed no pathogenic variants related to Gardner syndrome, and no recurrences were observed during 6 months of follow-up. Craniofacial osteomas are benign, slow-growing lesions most frequently found in the frontal bone and are more prevalent among females. The integration of imaging-based diagnosis, tailored surgical techniques, and selective genetic testing allows for accurate evaluation, effective treatment, and favorable postoperative outcomes. Show less

Building on the identification of ABCB5 as a marker of limbal stem cells (LSCs), this study examines CD63, a newly identified molecule co-expressed with ABCB5 in limbal epithelial cells, to define its role in maintaining corneal epithelial cell identity. RNA sequencing (RNA-seq) was performed on flow cytometry-sorted Abcb5-positive and Abcb5-negative murine corneal epithelial cells. CD63 expression in human corneal tissue was assessed by immunostaining. CD63 was silenced in cultured human limbal epithelial cells using siRNA-mediated knockdown and resulting molecular and cellular changes were analyzed by qRT-PCR, flow cytometry, RNA-seq, Western blotting, and cell proliferation assays. RNA-seq analysis revealed increased expression of LSC markers, including Krt15, Krt6b, Fgfr1, Gpha2, Ifitm3, Ifitm1, and Cd63, and decreased expression of differentiation-associated markers, such as Krt12, Gja1, and Ovol1 in Abcb5-positive cells. Immunostaining of human corneal tissue demonstrated strong CD63 expression localized to the limbal region. Knockdown of CD63 in cultured human limbal epithelial cells resulted in reduced cell proliferation and significantly decreased expression of corneal epithelium-enriched genes, including KRT12, CLU, ALDH1A1, ALDH3A1, TGFBI, and MYEOV. Notably, CD63 knockdown led to an approximately 50% reduction in expression of PAX6, a key transcriptional regulator of corneal epithelial identity. CD63 is highly expressed in the human limbus and is required for maintaining cell proliferation and the expression of corneal epithelium-specific proteins, likely through regulation of PAX6. These findings establish CD63 as a functionally important component of limbal stem cell biology and a key contributor to corneal epithelial homeostasis. Show less

High-grade astrocytoma with piloid features (HGAP) has recently emerged as an aggressive glioma entity with distinct molecular alterations, yet its clinicogenomic distinction from pilocytic astrocytoma (PA) remains to be fully elucidated. This study aims to clarify the clinical, pathological, and genomic differences between pediatric PA, adult PA, and HGAP, and to provide evidence supporting the recognition of HGAP as a new, aggressive entity. We retrospectively analyzed 100 genetically and histopathologically confirmed PA cases (87 pediatric, 13 adult) and 25 HGAP cases (all > 19 years old) diagnosed at Seoul National University Hospital between 2015 and 2024. Next-generation sequencing using a brain tumor-specific gene panel and immunohistochemistry evaluation. Pediatric PAs (median age 7 years) were predominantly cerebellar (61%) and showed classic biphasic histology (72%) with frequent HGAP represents a clinically aggressive and molecularly distinct high-grade glioma, clearly separable from pediatric and adult PA. Its poor prognosis and unique genetic drivers justify its recognition as a new entity. Accurate molecular profiling is essential for diagnosis and management of these tumors, and the poor survival outcomes observed in HGAP highlight the need for further larger cohort studies to identify optimal therapeutic strategies. Show less

Long overshadowed by VEGF-A, vascular endothelial growth factor B (VEGF-B) has emerged as a critical regulator of vascular, metabolic, and immune cross-talk. Unlike the potent angiogenic factor VEGF-A, VEGF-B does not induce vascular leakage but modulates tissue-specific functions, including fatty acid transport, neuronal survival, and immunometabolism, through its receptors VEGFR1 and NRP1. Its roles are often paradoxical, suppressing angiogenesis in some cancers while promoting metastasis and immune evasion in others, highlighting its profoundly context-dependent nature of action. Recent discoveries, such as the identification of FGFR1 as a key receptor and the essential role of VEGF-B in T cell survival, have revitalized interest in its therapeutic potential. However, clinical translation remains challenging, as exemplified by the recent failure of the anti-VEGF-B antibody CSL346 in diabetic kidney disease, underscoring our incomplete understanding of VEGF-B biology. This review integrates cutting-edge insights into the diverse functions of VEGF-B, proposes a mechanistic framework for its complex signaling networks, and outlines a roadmap for developing precision therapies for metabolic, cardiovascular, neurodegenerative, and oncological diseases. We address the critical translational challenges to maximize the therapeutic benefits while preserving the crucial homeostatic functions of VEGF-B. Show less

Gynecologic carcinosarcoma is an uncommon but aggressive malignancy that frequently requires systemic therapy but therapeutic options are limited. Development of preclinical models is therefore important for therapeutic advancement. Carcinosarcoma tumor (6 uterine and 1 tubo-ovarian) from 7 surgical samples were implanted into immunocompromised mice for patient-derived xenograft (PDX) and/or cell line development. The histologic, immunophenotypic and genetic features were characterized. Based on the observed molecular profiles and targetable molecular alterations, in vivo studies were conducted to evaluate the efficacy of targeted therapy on tumor growth. We established 1 cell line and 6 PDX models which recapitulated the dominant phenotype of the respective parental tumors with preserved mesenchymal differentiation lineage in the sarcomatous component. Genomically, the PDX/cell line models preserved similar complex pattern of copy number alterations and similar mutation landscape when compared to the respective parental tumors. All 7 parental carcinosarcoma tumors and PDX/cell line models harbored pathogenic TP53 mutations. Moreover, we identified recurrent copy number gain/amplification involving several receptor tyrosine kinases (RTK), including amplification and protein over-expression of FGFR1. In vivo drug evaluation using a small molecule inhibitor (AZD4547) of FGFRs showed significant growth inhibition in the carcinosarcoma PDX tumor with the highest FGFR1 amplification and protein expression whereas AZD4547 showed no significant growth effects on carcinosarcoma lacking high level FGFR1 amplification, indicating oncogenic dependency on the amplified RTK pathway. These findings demonstrate the utility of patient-derived tumor models in the identification and the functional validation of potentially targetable molecular alterations in preclinical setting. Show less

A plethora of factors contribute to cognitive impairment in Alzheimer's disease (AD), including neuroinflammation, synaptic dysfunction and gene alteration. In search of transcription factors controlling dysregulated genes in AD, we identified that the histone demethylase PHF2 (KDM7C) was a top-ranking candidate. Significant upregulation of PHF2 was found in AD human postmortem tissues, iPSC-derived neurons from AD patients, and a familial AD mouse model (5xFAD). ChIP-seq analysis and quantitative PCR profiling with bidirectional manipulation of Phf2 revealed that Phf2 regulated many genes critically involved in inflammatory pathways and neurodegeneration, including Stat3, Nfkbia, Nfkb2, Tnfrsf1a, Fgfr1, IL6st, Notch2, and Csf1. Knockdown of Phf2 in 5xFAD mice reduced the expression of inflammatory genes, leading to the substantial reduction of microglia/astrocyte activation and the restoration of glutamatergic synaptic function. Behavioral studies showed that Phf2 knockdown in 5xFAD mice significantly improved performance in the Barnes maze test, indicating a mitigation of spatial memory deficits. Our findings have revealed the epigenetic enzyme PHF2 as a regulator of neuroinflammatory processes in AD, linking its activity to both gene expression and cognitive outcomes. It suggests that targeting PHF2 could be a novel therapeutic approach for AD and other brain disorders involving neuroinflammation. Show less

This study aimed to identify breast cancer-specific circulating tumor DNA (ctDNA) methylation markers that correspond to tissue DNA methylation. Using The Cancer Genome Atlas (TCGA) database, we selected breast cancer-specific DNA methylation markers. The methylation and expression patterns of candidate genes were analyzed in breast cancer cell lines and tissue samples. We also assessed the methylation status in ctDNA obtained from breast cancer patients and examined associations with the clinicopathological features. Among candidate genes with breast cancer-specific methylation patterns, USP44, ZNF454, and GPRC5B were selected. The methylation status and expression of selected genes varied by molecular subtype of cancer in the cell line. In tissue samples, expression of all three genes was generally lower in breast cancer than in controls. ctDNA methylation patterns showed no significant change before and after treatment for each candidate gene. Correlations between gene expression and DNA methylation status or clinicopathological characteristics in cancer tissues differed among genes. Further studies are needed for clinical application of liquid biopsy using methylation analysis for ctDNA according to individual characteristics for breast cancer. Show less

Pelvic radiation therapy is an essential treatment for several pelvic malignancies, but it can lead to radiation cystitis (RC), a severe progressive inflammatory bladder disorder lacking effective diagnosis and therapeutic options. RC evolves through acute, latent, and chronic phases, ultimately resulting in bladder fibrosis, vascular damage, and hematuria. Here, we characterize the molecular and immunological features associated with RC progression using a preclinical mouse model. Building on a prior analysis of the acute and chronic phases, we examined the previously unanalyzed latent phase and integrated transcriptomics, immune cell profiling, inflammatory protein measurements, and bladder function assessments across all stages. Acute radiation injury was marked by the strong activation of apoptotic pathways, whereas latent and chronic phases were dominated by inflammatory signaling with distinct cytokine and chemokine signatures. The persistent upregulation of Cdkn1a (P21) was consistent with sustained senescence-associated signaling, while reductions in IL-27 and shifts in the granulocyte-lymphocyte-enriched immune population during the latent phase were consistent with altered immune regulatory states. At chronic stages, increased SASP-associated proteins and matrix remodeling mediators coincided with bladder functional decline. Together, these findings support a model in which radiation-induced senescence, coupled with immune dysregulation during the latent phase, are coordinated features accompanying inflammation, tissue remodeling, and bladder dysfunction in RC. Show less

The non-high-density lipoprotein to high-density lipoprotein cholesterol ratio (NHHR) has emerged as a comprehensive lipid index reflecting the balance between atherogenic and anti-atherogenic lipoproteins. However, evidence on how different intensities and durations of physical activity (PA) influence NHHR remains scarce, particularly in aging populations. Data were obtained from China Health and Retirement Longitudinal Study. PA was self-reported and categorized as high- (HPA), moderate- (MPA), or low-intensity (LPA). Multivariable linear regression models assessed associations between PA and NHHR, with subgroup, sensitivity, and dose-response analyses further exploring robustness. Cox regression and mediation analyses examined the associations of PA and NHHR with 10-year all-cause mortality. Higher levels of total, moderate-, and high-intensity PA were significantly associated with lower NHHR. The results were generally consistent with a graded pattern, with lower NHHR observed at higher activity durations, particularly for moderate-to-vigorous activity. Exploratory mediation analyses suggested that NHHR may partially account for the inverse association between PA and mortality. This study adds large-scale, population-based evidence on the associations between different PA intensities and NHHR. Regular moderate-to-vigorous PA is associated with more favorable lipid profiles and lower mortality risk. These findings highlight NHHR as a valuable biomarker linking physical activity to cardiometabolic health and longevity in middle-aged and older adults. Show less

The effects of extruded flaxseed-pulse mixture (LinPRO-24) on growth performance, tissue fatty acid composition, carcass traits, and meat quality in broilers were investigated. A total of 540-day-old male 308 Ross chicks were placed in pens (30 chicks/pen) and allocated to three diets (n = 6) in a completely randomized design. The diets were: CON (basal corn-soybean meal diet); LPA (CON+2.5% LinPRO-24); and LPB (CON+ 5.0% LinPRO-24). Diets were isocaloric and isonitrogenous, formulated for starter (day 1-10), grower (day 11-24), and finisher (day 24-34). Feed intake and body weight (BW) were recorded daily, and mortalities as they occurred to calculate average daily gain (AWG) and FCR. On day 34, visceral organs, breast tissue, and leg tissue were sampled. The CON group exhibited higher overall BW, AWG, and AFI than LPB (P < 0.05). Breast and leg tissues of birds fed LPB had the highest concentration of Alpha-linolenic acid (ALA) and total ω-3 PUFA followed by LPA; both had a higher ALA concentration than the CON group (P < 0.05). Thus, the ω-6:ω-3 ratio in these tissues was lower for LPA and LPB groups (P < 0.05). Additionally, both LPA and LPB groups had lower Docosatetraenoic acid (DTA, C22:4 ω-6), higher Docosapentaenoic acid (DPA, C22:5 ω-3) and total PUFA content, resulting in a reduced SFA:PUFA ratio in leg tissue compared with the CON group (P < 0.05). However, LPB negatively affected the water-holding capacity (WHC) in breast meat compared with the CON and in leg tissue compared with LPA treatment (P < 0.05). Moreover, LPB increased muscle hardness and gumminess in the breast compared with the CON group (P < 0.05), thereby negatively affecting meat textural qualities. Overall, both LPA and LPB diets increased the ω-3 PUFA content in poultry meat, thereby reducing the ω-6:ω-3 ratio. However, the current study suggests that the use of LinPRO-24 at 2.5% may be more appropriate for improving the fatty acid profile of broiler meat without compromising production performance and meat quality. Show less

Mendelian randomization studies suggest a causal effect of lipoprotein(a) (Lp(a)) on atherosclerotic cardiovascular disease. Noncardiovascular effects (eg, diabetes risk) are inadequately investigated. In this noninterventional phenome-wide association study designed to better understand the potential causal role of Lp(a), direct causal phenotypic effects of exposure to Lp(a) were estimated. Also, the association between LPA null allele rs41272114 with type 2 diabetes was assessed, and ancestry-specific Lp(a) thresholds were determined. In the UK Biobank (n = 425,677 adults, 55% female), we studied 1,456 phenotypes spanning 18 classes using 4 ancestry-specific polygenic risk scores and false discovery rate multiple testing correction. Network deconvolution Mendelian randomization was leveraged to separate direct from indirect (ie, associations via mediating variables) causal phenotypic effects and account for confounding, reverse causation, and bidirectionality. Lp(a) was significantly associated with 80 phenotypes across 7 classes. Higher Lp(a) exposure had significant direct causal effects, independent of low-density lipoprotein cholesterol, on coronary artery disease (OR: 1.36; 95% CI: 1.21-1.54) and glycated hemoglobin (HbA1c; β = 0.099; 95% CI: 0.051-0.15) only. Very low Lp(a) exposure was not associated with type 2 diabetes (OR: 0.92; 95% CI: 0.64-1.31) or HbA1c (β = -0.016; 95% CI: -0.062 to 0.030). Among European and African ancestries, 86 (77th percentile) and 93 (59th percentile) nmol/L optimally discriminated myocardial infarction risk, respectively. Increasing Lp(a) exposure had direct, independent causal effects on coronary artery disease and HbA1c only; very low Lp(a) exposure is suggested to not be causally associated with type 2 diabetes. The optimal European and African ancestry threshold to stratify cardiovascular risk is comparable, and below 125/105 nmol/L in current U.S./European medical professional society guidelines. Show less

Lipoprotein(a) [Lp(a)] is a genetically determined lipoprotein that has been established as an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). Structurally composed of a low-density lipoprotein (LDL)-like particle covalently linked to apolipoprotein(a) [apo(a)], Lp(a) exhibits unique atherogenic, thrombogenic, and inflammatory properties, largely due to its role as a carrier of oxidized phospholipids (OxPL). Plasma Lp(a) concentrations are predominantly determined by the number of kringle IV type 2 (KIV-2) repeats in the LPA gene, with minimal influence from lifestyle or environmental factors. Despite substantial evidence linking elevated Lp(a) to cardiovascular risk, clinical testing remains underutilized, especially in East Asian countries. In Taiwan, although population-level Lp(a) concentrations are comparatively low, a significant subset exceeds risk thresholds, with local studies confirming its prognostic value in coronary artery disease and ischemic stroke. Barriers, including limited physician awareness, implementation barriers, and therapeutic nihilism, contribute to its under-recognition. This review highlights the molecular features of Lp(a), its pathogenesis of cardiovascular disorders, epidemiology, and current barriers and future advances in diagnostic testing, with a particular focus on implications for cardiovascular risk management in Taiwan. Show less

This study aimed to identify different symptom profiles of complicated grief/bereavement-related posttraumatic stress disorder (PTSD) and examine the associations with social life factors, posttraumatic growth, and quality of life in a sample of parents whose children died in Sewol ferry accident. A total of 272 bereaved parents affected by the Sewol ferry accident participated and completed self-report scales about traumatic loss-related symptoms. The latent profile analysis (LPA) of complicated grief and posttraumatic symptoms was classified. To examine the predictors (interpersonal stress/familial conflict/social support) and outcomes (posttraumatic growth/quality of life) of the traumatic loss symptom profiles, an automatic three-step approach was chosen. The LPA identified three symptom profiles of complicated grief and posttraumatic stress: low symptomatology group (30.4%), moderate symptomatology group (49.6%), and high symptomatology group (20.0%). Higher perceived interpersonal stress significantly increased the odds of moderate and high symptomatology, while higher family stress was a significant predictor for high symptomatology compared to both low and moderate symptomatology groups. In addition, higher perceived social support significantly decreased the odds of being in both moderate and high symptomatology groups compared to the low group. The low symptomatology group showed the highest quality of life, followed by the moderate and high groups. Posttraumatic growth was also significantly different between the classes, with the moderate symptomatology group reporting higher growth than the low symptomatology group. Our findings suggest that managing the mental health of people who have experienced a traumatic loss will be a critical component of their quality of life in the future. In addition, interventions to help reduce family conflict and interpersonal stress may be necessary to reduce difficulties associated with psychopathology. Show less

Current treatments for idiopathic pulmonary fibrosis (IPF) slow but do not stop/reverse disease progression. The lysophosphatidic acid (LPA) axis is identified as a therapeutic target for IPF. This study aims to assess BI 1819479, an LPA pathway inhibitor, in patients with IPF (ClinicalTrials.gov Identifier: NCT06335303). In this placebo-controlled, phase II trial, patients will be randomised (2:1:1:1) to receive one of three oral doses of BI 1819479 or placebo, stratified by nintedanib/pirfenidone use. Patients aged ≥40 years with IPF, forced vital capacity (FVC) ≥45% of predicted normal and haemoglobin-corrected diffusing capacity for carbon monoxide ≥25% of predicted normal at screening will be included. Patients with relevant airway obstruction (pre-bronchodilator forced expiratory volume in 1 s/FVC <0.7), acute IPF exacerbation ≤12 weeks prior to screening, treatment with immunosuppressive medications (other than oral corticosteroids) or prednisone >15 mg·day This trial evaluates the efficacy, safety and dose range of BI 1819479 in patients with IPF, offering a potential additional treatment option, and will establish appropriate dosing for phase III trials. Show less

Resilience is a critical indicator of the personal recovery process for people with serious mental illness (SMI). However, little is known about resilience subtypes among this population. Grounded in Kumpfer's resilience model (KRM), the study aims to identify latent types of resilience among people with SMI using latent profile analysis (LPA). A cross-sectional survey design was used. A total of 297 individuals with self-reported SMI completed an online survey, including demographic variables and measures that resemble core components of the KRM. The LPA identified three resilience profiles: Maladaptive, Homeostatic and Resilient. One-way analyses of variance (ANOVA) revealed distinct patterns of the three resilience profiles on all factors in the KRM and the outcome variable-adaptation to psychiatric disability. ANOVA and Chi-square tests indicated several demographic variables predict profile membership, including age, marital status, highest educational attainment, employment status, average weekly work hours and primary SMI diagnosis. However, sex, race-ethnicity, annual income and years since SMI diagnosis do not predict profile membership. The study contributes to the understanding of resilience subtypes and associated protective and risk factors for resilience among people with SMI, suggesting early, tailored strength-based interventions to promote resilience and personal recovery. Show less

Autotaxin (ATX), the enzyme responsible for generating lysophosphatidic acid (LPA), is a validated target for fibrosis and cancer immunotherapy. Current ATX inhibitors face challenges related to insufficient efficacy or safety concerns, reflecting trade-offs between zinc engagement and selectivity. Here, we report a rigid triazolyl-azabicyclo[3.1.0]hexanyl-oxadiazolyl-pyrimidine scaffold developed through structure-based design, designed to potentially enhance ATX selectivity by promoting defined binding geometry. Systematic studies identified 14e as the most potent inhibitor (IC Show less

Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS), with plasma levels largely unaffected by lifestyle modification or conventional lipid-lowering therapy. Although international guidelines increasingly recognize Lp(a) as a risk-enhancing factor, in many Asian populations thresholds for high Lp(a) and treatment strategies remain undefined. This Korean position paper, developed by the Lp(a) Task Force of the Korean Society of Lipid and Atherosclerosis, presents an evidence-based summary of the pathophysiology, clinical relevance, and therapeutic landscape surrounding Lp(a), with a focus on Korean-specific data. It reviews the genetic architecture of Lp(a), ethnic variability in concentrations, and its mechanistic roles in inflammation, thrombosis, and calcification. Based on large Korean cohorts, a 3-tiered classification is proposed of normal (<30 mg/dL), borderline high (30-49 mg/dL), and high (≥50 mg/dL), harmonizing global thresholds with local data. The document also highlights the limitations of current Lp(a) assays in Korea, and calls for standardized, isoform-insensitive testing. Novel therapeutics, including antisense oligonucleotides, small interfering RNAs, and small molecular inhibitors, have shown promising Lp(a)-lowering effects, with multiple phase 3 trials currently ongoing, or in planning. Given the unmet clinical need, the paper recommends incorporating Lp(a) into cardiovascular risk assessment, and calls for Korean-specific longitudinal studies, national screening strategies, and participation in clinical trials. These efforts will help clarify Lp(a)-associated risk in Korean patients and guide the adoption of future targeted therapies. Show less

Current evidence is unclear due to methodological limitations. We bridge critical knowledge gaps by quantifying the longitudinal changes in movement behaviours and their correlates from early childhood through adolescence. Longitudinal observational cohort study. General healthy child and adolescent sample in Singapore. Growing Up in Singapore Towards healthy Outcomes study participants. We used wrist-worn accelerometry and proxy-reported data to examine movement behaviours (sleep, inactivity, light physical activity (PA; LPA) and moderate-to-vigorous PA (MVPA) and screen-viewing) at ages 5.5, 8, 10 and 12 years and the sociodemographic and maternal lifestyle-related correlates using linear regression models with generalised estimating equations. Among 837 children, sleep, LPA and MVPA declined by 3% (from 9.1 to 8.8 hours/day), 24% (from 5.8 to 4.4 hours/day) and 44% (from 71.3 to 40.1 min/day), respectively, while inactivity and screen viewing increased by 26% (from 8.0 to 10.1 hours/day) and 155% (from 1.8 to 4.6 hours/day), respectively, from ages 5.5 to 12 years. The greatest annual increase in inactivity (0.6 hour/annum) and screen-viewing (0.8 hour/annum) and decrease in LPA (0.3 hour/annum) and MVPA (10.4 min/annum) occurred from ages 8 to 10 years. Girls of Malay ethnicity and lower socioeconomic status, and whose mothers had less favourable movement behaviours, had significantly less sleep, higher inactivity and screen-viewing and/or lower PA. Maternal PA levels and/or sitting time were associated with children's sleep, inactivity and MVPA up to age 8 years, while maternal sitting and screen-viewing behaviours were associated with children's screen-viewing at all ages. Using contemporaneous datasets relevant to the present day, we confirmed that children become less physically active and have longer screen-viewing as they transition into adolescence and highlighted characteristics to be prioritised in future interventions. Show less

Mothers of children with developmental disabilities (DD) experience chronic and cumulative stress, yet many also report positive psychological changes such as post-traumatic growth (PTG). Few studies have examined how depression and PTG co-occur as distinct mental-health patterns or how psychosocial resources influence these profiles. This study identified latent profiles of depression and PTG among Korean mothers of children with DD and examined whether social support and religious participation predicted profile membership. A total of 488 mothers of children with DD participated in a survey conducted in Seoul and surrounding areas (2017-2018). Measures included the Post-Traumatic Growth Inventory, PHQ-9 depression scale, perceived informal support, formal service use, and religious participation. Latent profile analysis (LPA) was used to identify distinct psychological profiles, followed by multinomial logistic regression to examine predictors of class membership. A three-class solution best represented the data: (1) Low PTG/High Depression (13.4 %), (2) Moderate PTG/Moderate Depression (47.9 %), and (3) High PTG/Low Depression (38.6 %). Higher levels of family support, formal support services for caregivers, and active religious participation significantly increased the likelihood of belonging to the High PTG/Low Depression class. Self-rated health also differentiated class membership. Mothers of children with DD demonstrate heterogeneous combinations of distress and growth, supporting a dual-axis understanding of mental health. Social support-especially family support-and active religious participation emerged as key correlates of more adaptive profiles. Findings highlight the importance of culturally embedded support systems and tailored interventions that address both distress reduction and growth promotion. Show less

Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS), with plasma levels largely unaffected by lifestyle modification or conventional lipid-lowering therapy. Although international guidelines increasingly recognize Lp(a) as a risk-enhancing factor, in many Asian populations thresholds for high Lp(a) and treatment strategies remain undefined. This Korean position paper, developed by the Lp(a) Task Force of the Korean Society of Lipid and Atherosclerosis, presents an evidence-based summary of the pathophysiology, clinical relevance, and therapeutic landscape surrounding Lp(a), with a focus on Korean-specific data. It reviews the genetic architecture of Lp(a), ethnic variability in concentrations, and its mechanistic roles in inflammation, thrombosis, and calcification. Based on large Korean cohorts, a 3-tiered classification is proposed of normal (<30 mg/dL), borderline high (30-49 mg/dL), and high (≥50 mg/dL), harmonizing global thresholds with local data. The document also highlights the limitations of current Lp(a) assays in Korea, and calls for standardized, isoform-insensitive testing. Novel therapeutics, including antisense oligonucleotides, small interfering RNAs, and small molecular inhibitors, have shown promising Lp(a)-lowering effects, with multiple phase 3 trials currently ongoing, or in planning. Given the unmet clinical need, the paper recommends incorporating Lp(a) into cardiovascular risk assessment, and calls for Korean-specific longitudinal studies, national screening strategies, and participation in clinical trials. These efforts will help clarify Lp(a)-associated risk in Korean patients and guide the adoption of future targeted therapies. Show less

Dysregulated blood lipids are a major predictor of cardiovascular events. A recent genome-wide association study (GWAS) with five clinically relevant lipid traits in 1.65 million individuals implicated over 770 genomic regions in regulating blood lipid metabolism. To translate these associations into clinical applications, a functional understanding of their roles in lipoprotein metabolism, transport and remodeling (LPmtr) is required. Here, we report the deep molecular fine-mapping of 554 of these lipid risk loci using 168 lipoprotein-related traits and all possible ratios between them in over 273,000 participants of the UK Biobank. We identified new ratio-based markers of pathways shared by multiple LPmtr genes, such as the linoleic acid fraction of the polyunsaturated fatty acid pool to reveal potential causal genes at poorly characterized lipid risk loci, the percentage of esterified cholesterol moieties in LDL particles as a proxy for soluble LDL receptor levels, and the HDL fraction of total lipoprotein particle number as a predictor of incident myocardial infarction. We demonstrate how lipoprotein fine-mapping can generate new hypotheses for drug target development while uncovering new mechanisms relevant to hyperlipidemia. Ratio-driven clustering further implicated miR-148 in TG secretion, linking ER-stress responses at postprandial state to VLDL metabolism via mTORC1, shown through series of integrated cellular assays and mouse studies. Moreover, consistent with its regulatory influence on lipid flux we identify miR-148a a previously unrecognized determinat of Show less

Elevated lipoprotein(a) predicts high risk of cardiovascular disease among a modest proportion of healthy individuals, an issue that complicates screening guidelines. To examine spline models, clinical thresholds, and percentiles of baseline lipoprotein(a) levels as 30-year determinants of cardiovascular risk. This cohort study was conducted among female health professionals participating in the Women's Health Study, who were followed up prospectively from 1993 to 2023. Women without cardiovascular disease, cancer, and other major chronic illnesses had blood samples taken at baseline. All individuals with lipoprotein(a) measurements and/or of European ancestry with genotype information for the LPA rs3798220 variation were included. Data analyses were performed from January through April 2025. Continuously valued baseline lipoprotein(a), lipoprotein(a) clinical thresholds and percentiles, and LPA rs3798220 genotypes known to predict lipoprotein(a) levels among individuals of European ancestry. The primary outcomes were incident major cardiovascular events, coronary heart disease, ischemic stroke, and cardiovascular death. Age- and multivariable-adjusted cause-specific Cox models were used to calculated hazard ratios for the cardiovascular outcomes. The hypothesis was formulated after collection of the data. A total of 27 748 women with baseline lipoprotein(a) measurements and 23 279 women of European ancestry with rs3798220 genotype information were included (median [IQR] age, 53 [49-60] years), among whom 3707 and 3165 major cardiovascular events, respectively, accrued during a median (IQR) follow-up period of 27.8 (22.8-29.4) years. Among women with lipoprotein(a) measurements, lipoprotein(a) levels above 30 mg/dL or the 75th percentile (31 mg/dL) were associated with increased 30-year risk of major cardiovascular events and coronary heart disease. Levels above 120 mg/dL or the 99th percentile (131 mg/dL) were associated with increased risk of ischemic stroke and cardiovascular death. Multivariable adjusted hazard ratios for levels above 120 mg/dL vs below 10 mg/dL or above the 99th percentile vs below the 50th percentile (11 mg/dL) were 1.54 (95% CI, 1.24-1.92) and 1.74 (95% CI, 1.35-2.25) for major cardiovascular events, 1.80 (95% CI, 1.36-2.37) and 2.06 (95% CI, 1.49-2.84) for coronary heart disease, 1.41 (95% CI, 0.93-2.15) and 1.85 (95% CI, 1.17-2.93) for ischemic stroke, and 1.63 (95% CI, 1.16-2.28) and 1.86 (95% CI, 1.26-2.72) for cardiovascular death, respectively. Among women with genotype information, rs3798220 minor allele carriers had a higher risk of major cardiovascular events. Per the results of this cohort study, very high lipoprotein(a) levels correlated with increased 30-year risk of cardiovascular disease among healthy women. Screening for elevated lipoprotein(a) in the general population may be warranted. Show less

Movement behaviours, including moderate-to-vigorous-intensity physical activity (MVPA), light-intensity physical activity (LPA), sedentary behaviour (SB), and sleep, influence childhood adiposity. However, their collective impact on adiposity from a sex-specific perspective remains underexplored. Our research examined the sex-specific longitudinal associations of 24-h movement behaviours with body mass index (BMI) and abdominal adiposity among children. In the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort study, we repeatedly measured 24-h movement behaviours using wrist-worn accelerometers (ActiGraph GT3x) and assessed adiposity (BMI, abdominal circumference, and MRI-based abdominal fat volumes) at three time points (ages 5.5-6, 7.5-8, and 10-10.5 years) within the same children in a longitudinal design. Compositional multivariable linear mixed-effect modelling and isotemporal substitution were used to estimate the associations. 531 children (49.5% girls) were included in the analysis. Significant interactions between movement behaviours and sex were observed across all outcomes. In girls, higher MVPA relative to other behaviours was linked to lower BMI [-0.8 (-1.5, -0.1) kg/m²] and total abdominal adiposity [-225.5 (-451.6, -2.5) mL], while in boys, longer sleep duration was associated with lower BMI [-1.6 (-3.2, -0.1) kg/m²] and total abdominal adiposity [-624.2 (-1225.6, -31.3) mL]. The isotemporal substitution model showed that replacing 30 min of LPA/SB with MVPA reduced BMI and abdominal circumference by 1-2% and MRI-measured abdominal adiposity by 6-9% in both sexes. However, replacing LPA/SB with sleep reduced BMI and abdominal circumference by 1% and MRI-measured adiposity by 3-6% only in boys, with no changes in girls. These associations were pronounced on visceral adiposity. This study highlights sex-specific associations of movement behaviours with adiposity in school-aged children, with stronger associations observed in MRI-derived measures compared to conventional adiposity indices. Replacing LPA/SB with MVPA reduced BMI and abdominal adiposity in both sexes, with particularly pronounced effects on visceral adiposity. However, sleep replacement benefits were observed only in boys, suggesting the need for gender-sensitive approaches in lifestyle interventions. Show less

G-protein-coupled receptors (GPCRs) are high-value therapeutic targets, yet antibody discovery remains limited by difficulties in preparing antigens that preserve native conformations. Here, we engineered a native-like, full-length human LPA2 antigen by combining N-terminal P9* fused with amphipathic poly-γ-glutamate (APG) stabilization, affording an antigen suitable for the selection of antibodies with therapeutic efficacy. By screening a large synthetic human scFv library, we isolated an antagonistic antibody against LPA2 that bound LPA2 selectively over LPA1 (EC Show less

Based on epidemiological and genetic studies in recent decades, lipoprotein(a) (Lp(a)) has been accepted as a causal risk factor for atherosclerotic cardiovascular disease and aortic stenosis. Although inter-ethnic differences exist, Lp(a) level ≥50 mg/dL is commonly reported to indicate elevated cardiovascular risk. Blood Lp(a) levels are largely determined based on genetic background, and the kringle IV type 2 repeat variant is a major factor. Lp(a) is structurally similar to low-density lipoprotein (LDL) but also contains apolipoprotein(a) (apo(a)), which includes kringle domains associated with diverse effects depending on particles and individuals. The LDL-like property of Lp(a) and effect of apo(a) on vascular cells can promote atherosclerosis. Apo(a) competes with plasminogen and can inhibit the role of plasmin during fibrinolysis. Furthermore, oxidized phospholipids on apo(a) may induce oxidative stress to enhance atherosclerosis and can affect valve calcification. Trials on new therapeutics targeting Lp(a) RNA, including antisense oligonucleotide (e.g., pelacarsen), siRNAs (e.g., olpasiran, lepodisiran, and zerlasiran), and small molecules (e.g., muvalaplin), are under way. Depending on the study or dose, these agents lowered Lp(a) levels by 80-100% compared with the control; however, results of clinical outcomes have yet to be reported. Show less

Diabetes affects over half a billion people worldwide, with cardiovascular disease being its leading cause of death, either occurring secondary to atherosclerosis or due to an intrinsic defect in heart muscle (diabetic cardiomyopathy, DbCM). One instigator for DbCM is impaired cardiac metabolism characterized by excessive fatty acid (FA) delivery and utilization by the heart, causing oxidative stress and toxic lipid accumulation. Inhibition of vascular endothelial growth factor B (VEGFB) has been shown to counter these factors associated with abnormal cardiac metabolism by inducing metabolic flexibility and preventing cardiac lipid accumulation in Type 2 diabetes. However, its impact on lipoprotein lipase (LPL) and the sources of FA for cardiac use in Type 1 diabetes is unknown. Global Show less