Biology subjects

Lim, J. S.

Publications and source records attributed to Lim, J. S..

7 recordsLinked to original sources

bioRxiv2026

Graft-Induced Reprogramming Under Arterial Hemodynamic Stress is Associated with a Shared Proteomic Phenotype in Arterial and Venous Conduits Following Coronary Artery Bypass Grafting

BackgroundAutologous venous conduits remain the mainstay of coronary artery bypass grafting (CABG); however, their long-term patency is limited by adverse vascular remodeling. While arterial and venous grafts undergo structural and molecular adaptation to arterial hemodynamics, the mechanisms underlying successful adaptation remain poorly characterized owing to the scarcity of functioning human graft tissues. MethodsWe analyzed bypass grafts explanted en bloc during orthotopic heart transplantation, comprising patent vein grafts (VGP, n=19), occluded vein grafts (VGO, n=9), and patent arterial grafts (AGP, n=13), alongside freshly harvested controls (vein, n=23; artery, n=11). Quantitative histomorphometry, label-free LC-MS/MS proteomics, pathway analysis, and immunohistochemistry were performed. ResultsWhile patent arterial and venous grafts exhibited medial elastin reinforcement, adventitial neovascularization, and organized intimal remodeling, occluded vein grafts demonstrated elastic layer disruption, medial degeneration, and collagen-dense fibrosis. Proteomic analysis revealed a convergent adaptive signature in patent grafts enriched for RNA metabolism, protein synthesis, cytoskeletal dynamics, and extracellular matrix organization, with shared activation of NR4A3, STAT1, and EGFR signaling. Vein-specific adaptation involved SRC-PTGES activation with concomitant STAT3 suppression, whereas arterial grafts engaged IGF1-RUNX2-associated proliferative programs. Failed venous grafts exhibited angiotensin-driven fibroinflammatory remodeling. Endothelial nitric oxide synthase expression was markedly upregulated in the luminal endothelium and adventitial neovessels of patent grafts. ConclusionsDespite distinct vascular origins, arterial and venous grafts converged toward a shared adaptive phenotype characterized by structural maturation and vasoprotective signaling. Targeting common adaptive pathways--including NR4A3, STAT1, EGFR, and adventitial eNOS--may offer therapeutic strategies to enhance long-term graft durability. WHAT ARE THE CLINICAL IMPLICATIONS?This study provides human tissue-based evidence that patent coronary bypass grafts share a common adaptive remodeling program, irrespective of whether the conduit is arterial or venous. Rather than simple venous "arterialization," successful grafts converged on a phenotype characterized by coordinated biosynthetic activity, structural maturation, and vasoprotective signaling, whereas occluded vein grafts exhibited a distinct angiotensin-driven fibroinflammatory remodeling program. Importantly, patent grafts demonstrated conserved upregulation of NR4A3, STAT1, EGFR, and endothelial nitric oxide synthase (eNOS) in both luminal and adventitial endothelial compartments, identifying molecular features that distinguish adaptive from maladaptive remodeling in humans. These findings are clinically relevant because they highlight shared, potentially targetable pathways that may support graft durability across conduit types and provide mechanistic support for surgical strategies that preserve perivascular adipose tissue during vein harvesting. Moreover, the association of graft failure with angiotensin-centered extracellular matrix remodeling suggests a modifiable biological axis that warrants further investigation. Together, this work establishes a human molecular framework for graft adaptation that may inform future biomarker development, therapeutic targeting, and precision strategies aimed at improving outcomes after coronary artery bypass grafting.

pathology↗

bioRxiv2024

Unraveling the Complexity of Abdominal Aortic Aneurysm: Multiplexed Imaging Insights into C-Reactive Protein-Related Variations

BackgroundAbdominal aortic aneurysm (AAA) is a potentially lethal condition that often remains asymptomatic until it ruptures. Recent research suggests that immune-inflammatory processes are associated with AAA development, yet the exact mechanisms remain unclear. Serum C-reactive protein (CRP) serves as a prognostic marker for AAA and various cardiovascular diseases. When CRP accumulates in damaged tissues, it transforms into a monomeric form, exacerbating tissue damage. Our previous study confirmed the presence of CRP deposition in eroded AAA and atherosclerosis regions, accompanied by an increased infiltration of inflammatory cells. However, a comprehensive understanding of the specific changes in the inflammatory cellular landscape attributable to CRP deposition is lacking. Here, we aimed to explore cellular-level alterations in AAAs associated with varying CRP levels. MethodsWe categorized AAA patients into High-CRP ([≥]0.1 mg/dL, and [≥]3+ CRP IHC score, n=6) and Low-CRP ([≤]0.1 mg/dL, and [≤]1+ CRP IHC score, n=3), and used normal aorta specimens as a baseline control. The cellular landscape of immune and stromal components was characterized using Co-Detection by Indexing (CODEX) tissue imaging with 31 DNA-barcoded antibodies, followed by single-cell-based analysis and GPU-accelerated unsupervised clustering. ResultsWe identified 51 distinct immune and stromal cell types in the cohort and revealed significant differences in protein expression patterns among the groups. In AAA, stromal cells decreased significantly, while immune cell proportions sharply increased. Lag3+ T cell regulators decreased, leading to an increase in CD3+ T cells. The composition of immune cells within atherosclerotic plaques was associated with the degree of CRP deposition in AAA. The High-CRP group showed increased M1 and Ki67+ proliferating macrophages, while the Low-CRP group exhibited intensified fibrosis with M2 macrophages. ConclusionsOur study found significant variations in immune cell distribution within AAA walls based on CRP levels. These findings suggest a potential link between CRP-related immune changes and AAA progression. HIGHLIGHTSO_LIBy performing CODEX (co-detection by indexing) multiplexed imaging on paraffin-embedded, formalin-fixed archived abdominal aortic aneurysm (AAA) tissue samples with varying CRP levels, we segmented 415,365 cells into 51 distinct clusters. C_LIO_LIIn AAA, the presence of CRP deposition led to variations in the spatial relationships, distances, and enrichment patterns among immune and stromal cells.. C_LIO_LIIn AAA-High CRP, there was an intensified infiltration of M1 macrophages and various immune cells observed in the atherosclerotic plaque. C_LIO_LIIn AAA-Low CRP, severe stromal fibrosis was associated with M2 macrophages. C_LIO_LIOur results suggest that the deposition of CRP into the atherosclerotic plaque alters the immune-stromal landscape in AAA. C_LI

pathology↗

bioRxiv2021

Mutual Regulation between PFKP and VEGF Promotes Glioblastoma Tumor Growth

Glioblastoma (GBM) is highly vascular malignant brain tumor that overexpresses vascular endothelial growth factor (VEGF) and phosphofructokinase 1 platelet isoform (PFKP), which catalyzes a rate-limiting reaction in glycolysis. However, it remains unknown whether PFKP and VEGF are reciprocally regulated during GBM tumor growth. Here, we show that PFKP promotes EGFR activation-induced VEGF expression in HIF-1-dependent and -independent manners in GBM cells. Importantly, we demonstrate that EGFR-phosphorylated PFKP Y64 has critical roles in the AKT/SP1-mediated transcriptional expression of HIF-1 and in the AKT-mediated {beta}-catenin S552 phosphorylation, to fully enhance VEGF transcription and subsequent blood vessel formation and brain tumor growth. The levels of PFKP Y64 phosphorylation in human GBM specimens positively correlate with HIF-1 expression, {beta}-catenin S552 phosphorylation, and VEGF expression. Conversely, VEGF upregulates PFKP expression in a PFKP S386 phosphorylation-dependent manner, leading to increased PFK enzyme activity, aerobic glycolysis, and proliferation in GBM cells. These findings highlight a novel mechanism underlying the mutual regulation that occurs between PFKP and VEGF for promoting GBM tumor growth and provide the therapeutic potential of targeting the PFKP/VEGF regulatory loop for GBM patients.

cancer biology↗

bioRxiv2020

CRP immunodeposition and proteomic analysis in abdominal aortic aneurysm

ObjectiveThe molecular mechanisms of the degeneration of the aortic wall in abdominal aortic aneurysm (AAA) are poorly understood. The monomeric form of C-reactive protein (mCRP) is deposited in damaged cardiovascular organs and aggravates the prognosis; however, it is unknown whether mCRP is deposited in the degenerated aorta of abdominal aortic aneurysm (AAA). We investigated whether mCRP is deposited in AAA and examined the associated pathogenic signaling pathways. MethodsTwenty-four cases of AAA were analyzed and their histological features were compared according to the level of serum CRP and the degree of mCRP deposition. Proteomic analysis was performed in AAA cases with strong and diffuse CRP immunopositivity (n=7) and those with weak, focal, and junctional CRP immunopositivity (n=3). ResultsmCRP was deposited in the aortic specimens of AAA in a characteristic pattern that coincided with the lesion of the diminished elastic layer of the aortic wall. High serum CRP level was associated with stronger mCRP immunopositivity and a larger maximal diameter of aortic aneurysm. Proteomic analysis in AAA showed that multiple proteins were differentially expressed according to mCRP immunopositivity. Also, ingenuity pathway analysis showed that pathways associated with atherosclerosis, acute phase response, complement system, immune system, and coagulation were enriched in AAA cases with high mCRP immunopositivity. ConclusionsAAA showed a characteristic deposition of mCRP, and multiple potentially pathologic signaling pathways were upregulated in AAA cases with strong CRP immunopositivity. mCRP and the aforementioned pathological pathways may serve as targets for managing the progression of AAA.

pathology↗

bioRxiv2019

Axon-like protrusions promote small cell lung cancer migration and metastasis

Metastasis is the main cause of death in cancer patients but remains a poorly understood process. Small cell lung cancer (SCLC) is one of the most lethal and most metastatic types of human cancer. SCLC cells normally express neuroendocrine and neuronal gene programs but accumulating evidence indicates that these cancer cells become relatively more neuronal and less neuroendocrine as they gain the ability to metastasize. Here we show that mouse and human SCLC cells in culture and in vivo can grow cellular protrusions that resemble axons. The formation of these protrusions is controlled by multiple neuronal factors implicated in axonogenesis, axon guidance, and neuroblast migration. Disruption of these axon-like protrusions impairs cell migration in culture and inhibits metastatic ability in vivo. The co-option of developmental neuronal programs is a novel molecular and cellular mechanism that contributes to the high metastatic ability of SCLC.

cancer biology↗

bioRxiv2018

Small Cell Lung Cancer subtypes identified by systems-level modeling of transcription factor networks

Adopting a systems approach, we devise a general workflow to define actionable subtypes in human cancers. Applied to small cell lung cancer (SCLC), the workflow identifies four subtypes based on global gene expression patterns and ontologies. Three correspond to known subtypes, while the fourth is a previously undescribed neuroendocrine variant (NEv2). Tumor deconvolution with subtype gene signatures shows that all of the subtypes are detectable in varying proportions in human and mouse tumors. To understand how multiple stable subtypes can arise within a tumor, we infer a network of transcription factors and develop BooleaBayes, a minimally-constrained Boolean rule-fitting approach. In silico perturbations of the network identify master regulators and destabilizers of its attractors. Specific to NEv2, BooleaBayes predicts ELF3 and NR0B1 as master regulators of the subtype, and TCF3 as a master destabilizer. Since the four subtypes exhibit differential drug sensitivity, with NEv2 consistently least sensitive, these findings may lead to actionable therapeutic strategies that consider SCLC intratumoral heterogeneity. Our systems-level approach should generalize to other cancer types.

systems biology↗

bioRxiv2017

Accurate detection of low-level somatic mutations with technical replication for next-generation sequencing

Accurate genome-wide detection of somatic mutations with low variant allele frequency (VAF, <1%) has proven difficult, for which generalized, scalable methods are lacking. Herein, we describe a new computational method, called RePlow that we developed to detect low-VAF somatic mutations based on simple, library-level replicates for next-generation sequencing on any platform. Through joint analysis of replicates, RePlow is able to remove prevailing background errors in next-generation sequencing analysis, facilitating remarkable improvement in the detection accuracy for low-VAF somatic mutations (up to [~]99% reduction in false positives). The method was validated in independent cancer panel and brain tissue sequencing data. Our study suggests a new paradigm with which to exploit an overwhelming abundance of sequencing data for accurate variant detection.

genomics↗