Biology subjects

Hwang, C.

Publications and source records attributed to Hwang, C..

6 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↗

bioRxiv2025

Decoding pathogen ecological memory from chemical-stress phenotypes

Can standardized chemical stress reveal a reproducible, taxonomy-agnostic stress-response fingerprint that is predictive of sample-source labels (crop-of-isolation) in fungal isolates? Six coffee{square}associated Colletotrichum isolates were profiled using four phenolic{square}branched compounds and compared them with a previously characterized cacao panel. Quantitative morphology, hyperspectral imaging (HSI), and supervised machine learning (ML) yielded panel-specific fingerprints under uniform, isotropic in vitro conditions. Circularity, a measure of edge symmetry, was the most informative morphological feature, and ML classified the crop-of-isolation label (coffee vs cacao, in this panel) with 86.7% accuracy in within-panel cross-validation. HSI detected dose-dependent spectral shifts in a targeted subset of isolates and compounds, including changes near 1930 nm in the short-wave infrared, a moisture-sensitive region that warrants robustness checks (e.g., band masking or preprocessing sensitivity) prior to biochemical attribution. Multi{square}locus phylogeny showed the coffee isolates are polyphyletic, so the predictive signal should be interpreted conservatively as a taxonomy-agnostic phenotype fingerprint associated with crop background in this mixed-lineage panel, acknowledging that crop labels are partially confounded with phylogenetic structure. We propose a "chemical priors" framework as a working hypothesis, in which long-term environmental exposure may imprint stress-response pathways that become legible under simple, standardized probes. This integrative workflow supports scalable screening of eco-friendly antifungals and sensor-driven decision support for high-throughput phenotype-based screening workflows. HighlightsO_LITaxonomy-agnostic workflow integrates hyperspectral imaging and morphology. C_LIO_LIMachine learning predicts crop-source labels with 86.7% accuracy in mixed lineages. C_LIO_LISystem exhibits robustness, maintaining >86% accuracy even after feature ablation. C_LIO_LINon-linear ML captures structure missed by linear stats (1.7% variance). C_LIO_LIEnables rapid, sensor-driven antifungal screening without prior DNA sequencing. C_LI

microbiology↗

bioRxiv2025

Multiblock Integration and Modeling of Localized Microbiome, Metabolome, and Clinical Metadata to Identify Biomarkers Predictive of Outcome in Veterans with Non-Healing Wounds

The chronic wound microenvironment consists of a complex milieu of host cells, microbial species, and metabolites. While much is known about wound microbiomes, our knowledge of metabolic landscapes influencing wound healing is limited. Furthermore, integrating complex datasets into predictive models of wound healing is almost non-existent. Microbial rRNA and total metabolites were extracted from 45 diabetic foot ulcers (DFU) debridement samples from 13 patients, with 25 from non-healing wounds and 20 from healing wounds that remained closed for over 30 days. 16S rRNA sequencing and global metabolomics were performed and clinical metadata collected. Healing outcome was modeled as a function of three blocks of features (N = 21 clinical, 634 microbiome, and 865 metabolome) using DIABLO (Data Integration Analysis for Biomarker Discovery using Latent Components). The final model selected 176 features (N = 15 clinical, 8 microbiome, and 153 metabolome) and the correct clinical outcome was predicted with an accuracy of nearly 94%. These results indicate that integrating multi-omics data with clinical metadata can predict clinical wound healing with low error rates. Furthermore, the biomarkers selected within the model offer novel insights into wound microenvironment composition which may reveal innovative therapeutic approaches and improve treatment efficacy in difficult-to-heal wounds.

systems biology↗

bioRxiv2019

Regulation of heterotopic ossification through local inflammatory monocytes in a mouse model of aberrant wound healing

Heterotopic ossification (HO) is an aberrant regenerative process with ectopic bone induction in response to musculoskeletal trauma, in which mesenchymal stem cells (MSC) differentiate into osteochondrogenic cells instead of myocytes or tenocytes. Despite frequent cases of hospitalized musculoskeletal trauma, the inflammatory responses and cell population dynamics that regulate subsequent wound healing and tissue regeneration are still unclear. Here we examine, using a mouse model of trauma-induced HO, the local microenvironment of the initial post-injury inflammatory response. Single cell transcriptome analyses identify distinct monocyte/macrophage populations at the injury site, with their dynamic changes over time elucidated using trajectory analyses. Mechanistically, transforming growth factor beta-1 (TGF{beta}1)-producing monocytes/macrophages are associated with HO and aberrant chondrogenic progenitor cell differentiation, while CD47-activating peptides that reduce systemic TGF{beta} levels help ameliorate HO. Our data thus implicate CD47 activation as a novel therapeutic approach for modulating monocyte/macrophage phenotypes, MSC differentiation and HO formation during wound healing.

immunology↗

bioRxiv2019

Pseudogene associated recurrent gene fusion in prostate cancer

Analysis of next generation transcriptome sequencing data of prostate cancer identified a novel gene fusion formed by the fusion of a protein coding gene (KLK4) with a non-coding pseudogene (KLKP1) and expression of its cognate protein. Screening of 659 prostate cancer TMA showed about 32% of positive cases predominantly expressed in higher Gleason grade tumors. Concomitant expression with ERG but not with SPINK1 and other ETS fusion positive tumors. Fusion gene expression potentially regulated by AR and ERG. Antibody specific to the KLK4-KLKP1 fusion protein was validated by immunohistochemistry and western blot methods. Oncogenic properties were validated by in vitro and in vivo functional studies. Clinical data analysis shows significant association with prostate cancer in young men and overall survival analysis indicate favorable prognosis. Non-invasive detection in urine samples has been confirmed. Taken together, we present a novel biomarker for routine screening of high Gleason grade prostate cancer at diagnosis.\n\nSIGNIFICANCEWe discovered and validated a novel prostate cancer (PCa) specific fusion gene involving a protein coding (KLK4) and a pseudogene (KLKP1) and its cognate protein. The unique feature of this fusion gene is the conversion of the noncoding pseudogene into a protein coding gene and its unique expression only in about 30% of high Gleason grade PCa. Expression of this gene is found to be concomitant in ERG fusion positive prostate cancer but mutually exclusive with SPINK1, ETV1, ETV4 and ETV5 positive tumors. Like other ETS family gene fusions, KLK4-KLKP1 can be detected in the urine samples of patients with prostate cancer enabling non-invasive detection of high Gleason grade prostate cancer. Given the unique feature of this fusion oncogenic potential, high Gleason grade specific expression and noninvasive detection, this novel gene fusion has a potential to be used as a biomarker for early detection of high-grade prostate cancer and a therapeutic target.

cancer biology↗

bioRxiv2019

Castration-resistant prostate cancer: Androgen receptor inactivation induces telomere DNA damage, and damage response inhibition leads to cell death

Telomere stability is important for cell viability, as cells with telomere DNA damage that is not repaired do not survive. We reported previously that androgen receptor (AR) antagonist induces telomere DNA damage in androgen-sensitive LNCaP prostate cancer cells; this triggers a DNA damage response (DDR) at telomeres that includes activation of ATM, and blocking ATM activation prevents telomere DNA repair and leads to cell death. Remarkably, AR antagonist induces telomere DNA damage and triggers ATM activation at telomeres also in 22Rv1 castration-resistant prostate cancer (CRPC) cells that are not growth inhibited by AR antagonist. Treatment with AR antagonist enzalutamide (ENZ) or ATM inhibitor (ATMi) by itself had no effect on growth in vitro or in vivo, but combined treatment with ENZ plus ATMi significantly inhibited cell survival in vitro and tumor growth in vivo. By inducing telomere DNA damage and activating a telomere DDR, an opportunity to inhibit DNA repair and promote cell death was created, even in CRPC cells. 22Rv1 cells express both full-length AR and AR splice variant AR-V7, but full-length AR was found to be the predominant form of AR associated with telomeres and required for telomere stability. Although 22Rv1 growth of untreated 22Rv1 cells appears to be driven by AR-V7, it is, ironically, expression of full-length AR that makes them sensitive to growth inhibition by combined treatment with ENZ plus ATMi. Notably, this combined treatment approach to induce telomere DNA damage and inhibit the DDR was effective in inducing cell death also in other CRPC cell lines (LNCaP/AR and C4-2B). Thus, the use of ENZ in combination with a DDR inhibitor, such as ATMi, may be effective in prolonging disease-free survival of patients with AR-positive metastatic CRPC, even those that co-express AR splice variant.

cancer biology↗