Biology subjects

Park, H. G.

Publications and source records attributed to Park, H. G..

11 recordsLinked to original sources

bioRxiv2026

Proteomic Profiling Identifies CLDN3 as a Tumor-Selective Therapeutic Target in Small Cell Lung Cancer

Small cell lung cancer (SCLC) remains a highly lethal disease with limited targetable surface antigens beyond delta-like ligand 3 (DLL3). We sought to systematically identify and validate tumor-selective cell-surface targets in relapsed SCLC. To this end, we developed an integrated proteogenomic pipeline combining single-cell RNA sequencing, combinatorial optimization, mass spectrometry-based proteomics, and immunohistochemistry to systematically map the SCLC surfaceome of 49 tumors across 25 patients with relapsed SCLC. Using this approach we found claudin-3 (CLDN3) to be a consistently expressed and tumor-selective antigen, with broader coverage than DLL3, which is the current clinical benchmark. CLDN3 was highly expressed across various treatment states, while maintaining low expression in most nonmalignant tissues. Functional validation using a novel CLDN3-specific monoclonal antibody (ABN501) demonstrated NK cell-mediated cytotoxicity in vitro and tumor regression in vivo, as well as a favorable safety profile. These findings support clinical development of CLDN3-directed therapies and demonstrate the utility of integrated proteogenomic approaches for antigen discovery in solid tumors.

cancer biology↗

bioRxiv2026

Cortical eigenmode coordinates provide compact subject-level signatures across structural MRI, resting-state fMRI, and EEG

A practical barrier in multimodal neuroimaging is that structural MRI, fMRI, and EEG are often analyzed in modality-specific spaces or reduced to atlas- and sensor-based summaries, limiting the construction of common, interpretable subject-level brain signatures. We evaluate cortical Laplace-Beltrami eigenmode coordinates as a shared geometry-aligned language for structural MRI (sMRI), resting-state fMRI (rs-fMRI), and EEG. In this framework, sMRI morphometric fields are represented by cortical eigenmode coefficients, rs-fMRI by covariance among eigenmode time-series coefficients, and EEG by mode-frequency-condition summaries. Using the Max Planck Institute Leipzig Mind-Brain-Body dataset (MPI-LEMON), we compared unimodal eigenmode-coordinate summaries, multimodal cortical eigenmode-coordinate PCA, conventional atlas/sensor-based PCA and ridge representations, and geometric eigenmode multiview factorization (GEMF). GEMF is a structured decomposition that preserves the modality-native organization of the data objects while separating shared from modality-specific variation. Eigenmode-coordinate representations yielded compact subject-level signatures with strong external validity for chronological age and a secondary cognitive outcome. Multimodal eigenmode-coordinate PCA was among the strongest-performing approaches, reached high age-prediction performance at moderate dimension, and consistently outperformed conventional low-dimensional PCA. GEMF selected an even lower-dimensional shared representation and remained competitive with the benefit of providing interpretable shared and modality-specific factors. These findings support cortical eigenmode coordinates as a practical foundation for compact, interpretable, and multimodally aligned subject-level brain signatures.

neuroscience↗

bioRxiv2026

Bandwidth-aware fusion of resting-state EEG-fMRI connectivity in cortical eigenmode space

We introduce a geometry-informed, bandwidth-aware model for fusing resting-state EEG and fMRI connectivity by treating each modality as a masked, physics-limited observation of a shared latent cortical connectivity structure. Both modalities are represented in a shared cortical Laplace-Beltrami (LB) eigenmode basis that provides an anatomically grounded ordering of spatial scales. In this coordinate system, fMRI constrains connectivity across a broad range of spatial scales but only at slow timescales, whereas EEG provides frequency-resolved information primarily for coarse spatial modes. We formalize this complementarity through a latent spatio-spectral connectivity object and estimate it using a low-rank factorization with shared eigenmode-network factors and subject- and frequency-specific nonnegative strengths. Estimation is driven by the regions supported by each modality (EEG: coarse spatial modes across broad frequencies; fMRI: broad spatial modes at low frequencies), while unobserved bands are inferred through shared low-rank structure and spectral smoothness regularization. In the MPI-LEMON cohort, the fused representation yields compact, interpretable subject features (fMRI network strengths and EEG oscillatory summaries) that support out-of-sample age prediction under nested cross-validation, and coherent multi-view interpretation through cortical maps, spectral profiles, and atlas-referenced system composition summaries. These results demonstrate that explicitly modeling modality-specific bandwidth gaps enables principled EEG-fMRI connectivity fusion and provides a practical route to multimodal network biomarkers for individual-differences research.

neuroscience↗

bioRxiv2026

Age-dependent spatial transfer of cortical harmonics to scalp EEG in infancy

Infancy is a period of rapid change in cortical geometry and head volume conduction, raising a central question for developmental neuroimaging: how should spatial brain coordinates be defined so that they remain interpretable across age? In scalp electrophysiology, this question has two coupled aspects. First, age-dependent forward propagation through the head determines which cortical spatial patterns are expressed at the scalp. Second, cortical Laplace-Beltrami (LB) eigenmodes computed independently on age-specific templates need not remain directly comparable by mode index, even when they represent related low-dimensional structure. Using age-specific infant anatomical templates distributed through MNE-Python, we computed age-specific cortical LB eigenmodes, age-specific EEG forward models, and the corresponding forward-projected cortical harmonic dictionaries. We then quantified (i) age-dependent forward transfer to the scalp, (ii) cross-age mismatch in cortical basis, coefficient, and sensor spaces, and (iii) the improvement obtained from a simple local tracking procedure. Forward-projected scalp gain was consistently concentrated in lower cortical harmonic orders across infancy, with a broadly stable coarse-to-fine profile across age, although the absolute gain varies over age. In cortical mode space, independently computed neighboring-age cortical LB bases were only locally comparable by nominal mode index, exhibiting local reordering, mode-index drift, and coefficient leakage into nearby modes. This non-equivalence had practical consequences: neighboring-age infant dictionaries were not fully interchangeable across age in low-dimensional sensor space, and a fixed adult-derived basis was systematically suboptimal for recovering infant same-index harmonic coordinates, with the largest penalties in early-to mid-infancy. Sequential Procrustes tracking substantially improved same-index neighboring-age consistency. Together, these results motivate age-parameterized or explicitly tracked cortical harmonic coordinates for longitudinal developmental EEG and, more broadly, for lifespan analyses that seek geometrically meaningful spatial coordinates across changing brains.

neuroscience↗

bioRxiv2026

Cortex-anchored sensor-space harmonics for event-related EEG

Scalp event-related potentials (ERPs) measured with electroencephalography (EEG) are temporally precise but spatially bandwidth-limited: skull and scalp blur cortical activity, and event-related EEG is still usually represented in electrode coordinates or dataset-specific data-driven components rather than in a sensor-space coordinate system linked to cortical anatomy. Here we introduce a cortex-anchored sensor-space basis obtained by forward-projecting cortical Laplace-Beltrami (LB) eigenmodes through a realistic EEG head model, yielding a multiscale dictionary whose ordering follows cortical spatial frequency. Using ERP-CORE (7 paradigms, 39 participants), we benchmarked the forward-projected LB basis against (i) spherical harmonics defined on the same montage and (ii) group PCA/ICA bases learned from trial-averaged time-frequency (TF) maps. Across canonical components (N170, N2pc, N400, P3b, LRP, ERN), we quantified reconstruction efficiency (R2 as a function of the number of modes), concentration of evoked TF energy across modes, split-half reliability of mode scores (ICC), and low-dimensional reconstruction of group-level ERP contrast topographies. LB closely matched spherical harmonics in R2, but concentrated evoked TF energy more strongly in low-order modes: for N170, N400, P3b, and ERN, the first 10 LB modes captured about 70% of normalized TF energy, whereas spherical harmonics typically required 15-18 modes. Low-to-mid LB mode scores showed moderate-to-excellent reliability, often comparable to or slightly exceeding spherical harmonics. In addition, 10- 15 LB modes reconstructed canonical ERP contrast maps with high correlations while preserving expected sensor-space organization (posterior N170, centro-parietal N400/P3, fronto-central ERN). These results show that forward-mapped LB eigenmodes provide a compact, anatomy-linked sensor representation for event-related EEG that complements spherical and data-adaptive bases and offers a reusable feature space for geometryinformed neural signal analysis.

neuroscience↗

bioRxiv2025

Forward-projected cortical eigenmodes provide an efficient sensor-space representation of resting-state EEG

Sensor-space EEG analyses typically rely on electrode layouts or data-driven components and rarely encode cortical geometry, making scalp patterns difficult to link to anatomy and to compare across participants. We introduce a sensor-space basis dictionary that explicitly integrates cortical geometry. Laplace-Beltrami (LB) eigenmodes are computed on a standard cortical template (fsaverage) and mapped by the lead-field matrix of a three-layer boundary-element (BEM) head model to yield cortex-anchored sensor-space harmonics. The leadfield-mapped LB dictionary spans scalp topographies, while pre-serving a meaningful spatial-frequency ordering inherited from the cortical manifold. We assess representational efficiency using ordinary least squares (OLS) projections of resting EEG (eyes-closed/open) across 59-, 32-, and 19-channel montages, and compare against spherical harmonics (SPH), principal components (PCA), and independent components (ICA). Efficiency is quantified by the variance explained R2(K) (by leading K modes) and the efficiency indices K70 and K90 (fewest modes reaching R2 [≥] 0.70 and 0.90) and reliability by ICC(3,1) of eyes-open/closed coefficients. The cortex-anchored basis shows higher early-K R2 than SPH and PCA (e.g., 59-channel eyes-closed at K=4: LB R2 {approx} 0.56 [95% CI: 0.54, 0.59] vs. SPH {approx} 0.44 [0.42, 0.46], PCA {approx} 0.08 [0.07, 0.09]) and reaches 70% and 90% variance with fewer modes (LB K70 {approx} 8.6; SPH {approx} 12.3; PCA {approx} 19.3; ICA {approx} 22.8; LB K90 {approx} 22.6; SPH {approx} 25.3; PCA {approx} 23.2; ICA {approx} 30.2). Mode-wise coefficient reliability (eyes-open vs. eyes-closed) is comparable between LB and SPH. By combining cortical eigenmodes with a forward head model, this approach yields a geometry-aligned, interpretable representation of sensor-space EEG that offers superior fidelity-complexity trade-offs at small K and a principled scaffold for low-dimensional EEG sensor space analysis.

neuroscience↗

bioRxiv2025

CRISPR-Induced NUT Suppression Promotes Differentiation and Enhances Trop2-Targeted Immunocytokine Response in NUT Carcinoma

NUT carcinoma (NC) is an aggressive malignancy driven by NUTM1 gene rearrangements with limited therapeutic options. Here, we show that direct suppression of NUTM1 using CRISPR/Cas9 induces squamous-like differentiation and upregulates TROP2 expression in NC cells. Building on this finding, we developed a TROP2-interferon beta (IFN-{beta}) mutein immunocytokine that selectively targets TROP2-expressing tumors. Combined NUTM1 suppression and TROP2-targeted immunotherapy synergistically enhanced cytotoxic and immune-mediated responses in vitro. Transcriptomic and spatial analyses of NC patient tumors revealed that differentiation status correlates with TROP2 expression, upregulated immune pathways, and favorable clinical outcomes. Our results suggest that overcoming differentiation blockade not only alters tumor phenotype but also creates a more immune-permissive microenvironment. These findings highlight the therapeutic potential of sequential tumor reprogramming followed by targeted immunotherapy in treating NC and propose a broader strategy for overcoming differentiation blockade in fusion-driven cancers.

cancer biology↗

bioRxiv2024

High dose ω3 eicosapentaenoic acid and docosahexaenoic acid block, whereas ω6 arachidonic acid accelerates, MYCN-driven tumorigenesis in vivo

Background/ObjectivesNeuroblastoma is a genetically diverse, highly metastatic pediatric cancer accounting for 15% of childhood cancer deaths despite only having ~8% of childhood cancer incidence. The current standard of care for high-risk disease is highly genotoxic. This, combined with less than 50% survival in high-risk disease and an abysmal 5% survival in relapsed cases, makes discovering novel, effective, and less toxic treatments essential. MethodsA prophylactic syngeneic mouse model was used to test high-dose lipid-mediator highly unsaturated fatty acids on tumorigenesis. Wild-type mice were gavaged with 12.3-14.6 g/d (adult human equivalent) omega-3 EPA, DHA, or oxidation-resistant bis allylic deuterated DHA (D-DHA) and 4.6-6.0 g/d arachidonic acid (ARA). At seven days, MYCN-expressing murine neuro-2a cells syngeneic to the gavaged mice were injected subcutaneously. Oral gavage continued for 10-20 d post-injection when tumors and tissues were harvested. ResultsFifty percent of control (not gavaged) animals form tumors (4/8) at about 10 d. High-dose DHA, D-DHA, and EPA block tumor formation completely in n=8 or 10 animals. In contrast, {omega}6 arachidonic acid (4.6-6.0 g/d) enhances tumor formation (6/10 tumors) and reduces latency (5.5 to 10 days)compared to control. Co-delivery of ARA and EPA results in a reduced tumor burden analogous to the control group, suggesting that EPA directly opposes the mechanism of ARA-mediated tumor formation. DHA acts through a non-oxidative mechanism. ConclusionsSustained high dose {omega}3 (weeks/months) is safe and well tolerated in humans. These results suggest that {omega}3 DHA and EPA delivery at ultra-high doses may represent a viable low-toxicity therapy for neuroblastoma. Simple SummaryPediatric Neuroblastoma has an overall mortality rate above 50%, and the current standard of care consists of highly genotoxic compounds. The biological actions of omega-6 ({omega}6) and omega-3 ({omega}3) highly unsaturated fatty acids (HUFA) generally oppose one another with the {omega}6 HUFA signaling for inflammation and angiogenesis (new blood vessel formation). Prolonged use of ultrahigh dose (15-20 g/d) {omega}3 HUFA has shown efficacy in catastrophic human traumatic brain injury and is well tolerated. Tumors form in about 50% of mice in our pediatric neuro-blastoma model. We show that 12-14 g/d adult human equivalent doses of {omega}3 EPA or DHA, as well as an oxidation-resistant form of DHA (D-DHA), completely block tumor formation, whereas a dose of about 5 g/d of {omega}6 ARA enhances tumorigenesis. Our data suggest that ultra-high dose {omega}3 therapy should be carefully investigated as a low-toxicity approach to neuroblastoma intervention.

cancer biology↗

bioRxiv2023

Unsaturated fatty acid synthesis is associated with poor prognosis in pediatric neuroblastoma and is differentially regulated by MYCN and tumor suppressor microRNAs.

MYCN amplification and disruption of tumor suppressor microRNA (TSmiR) function are central drivers of poor outcomes in neuroblastoma (NB). MYC, MYCN, and TSmiRs regulate glucose metabolism; however, their role in unsaturated fatty acid synthesis (UFAS) remains poorly understood. Here we show that de novo and UFAS pathway genes FASN, ELOVL6, SCD, FADS2, and FADS1 are upregulated in high-risk NB and are associated with poor prognosis. RNA-Seq analysis of eight human NB cell lines revealed parallel UFAS gene expression patterns. Consistent with this, we found that NB-related TSmiRs were predicted to extensively target these genes. In addition, we observed that both MYC and MYCN upregulated UFAS pathway genes while suppressing TSmiR host gene expression, thereby creating a possible UFAS regulatory network between MYCN and TSmiRs in NB. Furthermore, NB cells are high in omega 9 ({omega}9) unsaturated fatty acids that can be synthesized de novo and low in both {omega}6 and {omega}3, providing a plausible means for NB to limit cell-autonomous immune stimulation and reactive oxygen species (ROS)-driven apoptosis from {omega}6 and {omega}3 unsaturated fatty acid derivatives, respectively. We propose a model in which the UFAS pathway, through novel regulation by MYCN and TSmiRs, plays a key role in neuroblastoma pathology with implications for other MYC-driven cancers.

cancer biology↗

bioRxiv2022

Remodeling of gene regulatory networks underlying thermogenic stimuli-induced adipose beiging

Beige adipocytes are induced by cold temperatures or {beta}3-adrenergic receptor (Adrb3) agonists. They create heat through glucose and fatty acid (FA) oxidation, conferring metabolic benefits. The distinct and shared mechanisms by which these treatments induce beiging are unknown. Here, we performed single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq) on adipose tissue from mice exposed to cold or an Adrb3 agonist to identify cellular and chromatin accessibility dynamics during beiging. Both stimuli induce chromatin remodeling that influence vascularization and inflammation in adipose. Beige adipocytes from cold-exposed mice have increased accessibility at genes regulating glycolytic processes, whereas Adrb3 activation increases cAMP responses. While both thermogenic stimuli increase accessibility at genes regulating thermogenesis, lipogenesis, and beige adipocyte development, the kinetics and magnitudes of the changes are distinct for the two stimuli. Accessibility changes at lipogenic genes are linked to functional changes in lipid composition of adipose. Both stimuli tend to decrease the proportion of palmitic acids, a saturated FA in adipose. However, Adrb3 activation increases the proportion of monounsaturated FAs, whereas cold increases the proportion of polyunsaturated FAs. These findings reveal common and distinct mechanisms of cold and Adrb3 induced beige adipocyte biogenesis, and identify the unique functional consequences of manipulating these pathways in vivo.

genomics↗

bioRxiv2021

Single-cell Chromatin Accessibility and Lipid Profiling Reveals a Metabolic Shift in Adipocytes Induced by Bariatric Surgery

Obesity promotes type 2 diabetes and cardiometabolic pathologies. Vertical sleeve gastrectomy (VSG) is used to treat obesity resulting in long-term weight loss and health improvements that precede weight loss; however, the mechanisms underlying the immediate benefits remain incompletely understood. Because adipose plays a crucial role in energy homeostasis and utilization, we hypothesized that VSG exerts its influences, in part, by modulating adipose functional states. We applied single-cell ATAC sequencing and lipid profiling to inguinal and epididymal adipose depots from mice that received sham surgery or VSG. We observed depot-specific cellular composition and chromatin accessibility patterns that were altered by VSG. Specifically, accessibility at Scd1, a fatty acid desaturase, was substantially reduced after VSG in mature adipocytes of inguinal but not epididymal depots. This was accompanied by reduced accumulation of SCD1-produced unsaturated fatty acids. Given these findings and reports that reductions in Scd1 attenuate obesity and insulin resistance and that unsaturated fatty acids stimulate glucose uptake, storage, and oxidation, our results suggest VSG exerts its beneficial effects through modifications of fatty acid profiles mediated by Scd1.

genomics↗