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Biology subjects

Kim, B. J.

Publications and source records attributed to Kim, B. J..

11 recordsLinked to original sources

Cross-cancer knowledge transfer for lymph node metastasis prediction: Applicability of an axillary lymph node-based deep learning model

Evaluation of lymph node (LN) metastasis is critical for cancer staging and treatment planning. Since radiologic hallmarks of metastatic LNs are shared across primary cancers, a computed tomography (CT)-based deep learning (DL) classifier developed from one anatomy may transfer to others. This study built a DenseNet-121 ensemble model using clinical-implication-applied preprocessing and evaluated its cross-anatomical generalizability to LNs from diverse primary cancers. A DenseNet-121 ensemble model combining fixed-size cropping (FSC) and adjustable square cropping (ASC) was trained from ImageNet initialization on an axillary lymph node (ALN) dataset (n = 1,128 from 523 breast cancer patients). The model utilized clinical-implication-applied perinodal cropping with bicubic filtering and standardized resizing. To test cross-anatomical generalizability, an external dataset of 256 CT images across four anatomical regions was evaluated: cervical, mediastinal, upper-abdominal, and lower-abdominal LNs. Perinodal free margins were systematically varied from 10% to 40% to optimize the balance between context preservation and surround interference. Bicubic filtering and standardized resizing yielded the highest internal performance on the original ALN dataset (FSC-ASC ensemble area under the receiver operating characteristic curve [AUROC] 0.958, 95% confidence interval [CI] 0.920-0.987 at 40% margin). The model demonstrated site-dependent, above-chance generalizability across all external regions. Cervical LNs achieved the highest performance at a 40% margin (AUROC 0.939, 95% CI 0.875-0.989). Mediastinal LNs peaked at a 10% margin (AUROC 0.796, 95% CI 0.672-0.903), with wider margins degrading performance due to adjacent structural interference. Upper-abdominal and lower-abdominal LNs reached optimal performance at a 30% margin (AUROC 0.814 for upper; AUROC 0.917 for lower). A single ALN-trained DL model can accurately predict LN metastasis across cervical, mediastinal, and abdominal stations through site-specific perinodal margin tuning. These findings support the feasibility of cross-cancer knowledge transfer and the clinical utility of generalizable backbones for pan-cancer nodal assessment.

bioinformatics↗

A pectin-based formulation protects milk fat globule membranes in stored human milk

During household storage, expressed human milk can develop odor and flavor changes that trigger infant refusal and lead caregivers to discard their saved milk supply. We show that typical refrigeration and freezing conditions disrupt the milk fat globule membrane (MFGM), exposing milk lipids to lipases that catalyze hydrolysis and oxidation. A pectin-based formulation (PBF) maintains MFGM integrity during storage and following lipase challenge, suppressing production of glycerol, free fatty acid, and oxylipin byproducts without broadly affecting milk macronutrients, the proteome, and culturable microbial burden. Across an independent cohort of lactating individuals, lipase activity varied but tracked with maternal milk lipase gene expression, implicating endogenous lipolysis in stored-milk deterioration. In a blinded olfactory panel, PBF-treated, lipase-challenged milk smelled more like fresh milk than untreated controls. Together, these findings show that stabilizing the MFGM can protect stored human milk from lipase-driven deterioration, preserve sensory quality, and support use for infant feeding.

biochemistry↗

AI-powered Deep Visual Proteomics reveals critical molecular transitions in pancreatic cancer precursors

Pancreatic ductal adenocarcinoma (PDAC) evolves through non-invasive precursor lesions, yet its earliest molecular events remain unclear. We established the first spatially resolved proteomic atlas of these lesions using Deep Visual Proteomics (DVP). AI-driven computational pathology classified normal ducts, acinar-ductal metaplasia (ADM), and pancreatic intraepithelial neoplasia (PanIN) from cancer-free organ donors (incidental, "iPanINs") and PDAC patients (cancer-associated, "cPanINs"). Laser microdissection of 96 discrete regions containing as few as 100 phenotypically matched cells and ultrasensitive mass spectrometry quantified a total of 8,512 proteins from formalin-fixed tissues. Distinct molecular signatures stratifying cPanINs from iPanINs, and remarkably, many cancer-associated proteins already marked histologically normal epithelium. Four core programs - stress adaptation, immune engagement, metabolic reprogramming, mitochondrial dysfunction - emerged early and intensified during progression. By integrating DVP with AI-guided tissue annotation, we demonstrate that molecular reprogramming precedes histological transformation, creating opportunities for earlier detection and interception of a near-uniformly lethal cancer. SignificanceOur spatially-resolved proteomics atlas uncovers distinct molecular signatures in pancreatic cancer adjacent precursor lesions, clearly diverging from those in incidental, cancer-free pancreatic lesions. Our deep proteomics dataset offers a valuable resource for identifying novel biomarkers and therapeutic targets, informed by the earliest cancer-associated molecular events in archival pancreatic tissues.

cancer biology↗

Targeted suppression of type 1 interferon signaling during RNA delivery enhances vaccine-elicited immunity

RNA vaccines have emerged as a breakthrough technology, and one promising modality employs alphavirus-derived self-replicating RNA (repRNA) to express vaccine antigens. However, both the lipid nanoparticles (LNP) commonly used to deliver RNA and virus-like amplification of repRNAs trigger innate immune recognition, especially via type I interferon (IFN) signaling. To modulate IFN responses during vaccination, we formulated LNPs co-delivering antigen-encoding RNA together with siRNA targeting the interferon-/{beta} receptor-1 (IFNAR1). siRNA-mediated repression of IFNAR1 increased antigen expression from repRNAs by >10-fold, increased immune cell infiltration, and increased antigen presenting cell activation in the injection site and draining lymph nodes. Compared to repRNA alone, siRNA/repRNA co-delivery increased serum antibody titers >10-fold, dramatically augmented antigen-specific germinal center (GC) B cell responses, and primed 4.4-fold more antigen-specific T cells. Ifnar1 silencing by siRNA co-delivery similarly enhanced mRNA vaccines. Thus, siRNA co-delivery is a readily translatable approach to substantially enhance the immunogenicity of RNA vaccines.

bioengineering↗

Visualizing lipid nanoparticle trafficking for mRNA vaccine delivery in non-human primates

mRNA delivered using lipid nanoparticles (LNPs) has become an important subunit vaccine modality, but mechanisms of action for mRNA vaccines remain incompletely understood. Here, we synthesized a metal chelator-lipid conjugate enabling positron emission tomography (PET) tracer labeling of LNP/mRNA vaccines for quantitative visualization of vaccine trafficking in live non-human primates (NHPs). Following i.m. injection, we observed LNPs distributing through injected muscle tissue, simultaneous with rapid trafficking to draining lymph nodes (dLNs). Deltoid injection of LNPs mimicking human vaccine administration led to stochastic LNP delivery to 3 different sets of dLNs. LNP uptake in dLNs was confirmed by histology, and cellular analysis of tissues via flow cytometry identified antigen-presenting cells as the primary cell type responsible for early LNP uptake and mRNA translation. These results provide insights into the biodistribution of mRNA vaccines administered at clinically relevant doses, injection volumes, and injection sites in an important large animal model for vaccine development.

bioengineering↗

A primary culture method for the easy, efficient and effective acquisition of oligodendrocyte lineage cells

Oligodendrocytes (OL) are myelin forming glial cells in the central nervous system. In vitro primary OL culture models provide the benefit of a more readily controlled environment facilitating the evaluation of diverse OL stages and convoluted dynamics. Conventional methods of primary OL culture do exist, but their performance in terms of efficiency and simplicity has room for improvement. We present a novel method of primary OL culture, namely the E3 (Easy, efficient, and effective) method, which greatly improves cell yield and reduces time required to oligodendrocyte progenitor cell (OPC) acquisition and maturation into OLs. We also provide optimal media compositions for augmentation of OPC proliferation and a more robust maturation into myelin forming OLs. In vitro characteristics of the OL lineage discovered during the development of the E3 method present implications for further research on OL physiology and pathophysiology.

neuroscience↗

Modeling, dissecting, and subtyping of E-Cadherin inactivation-associated diffuse-type gastric adenocarcinoma

This study investigates diffuse-type gastric adenocarcinoma (DGAC), a deadly and treatment-resistant cancer. It reveals that CDH1 inactivation occurs in a subset of DGAC patient tumors, leading to the identification of two distinct DGAC subtypes. The findings emphasize the importance of understanding DGACs molecular diversity for personalized medicine in patients with CDH1 inactivation.

cancer biology↗

Strategic infarct locations for post-stroke depressive symptoms: a lesion- and disconnection-symptom mapping study

BackgroundDepression is the most common neuropsychiatric complication after stroke. Infarct location is associated with post-stroke depressive symptoms (PSDS), but it remains debated which brain structures are critically involved. We performed a large-scale lesion-symptom mapping study to identify infarct locations, and white matter disconnections, associated with PSDS. MethodsWe included 553 patients (age 69{+/-}11 years, 42% female) with acute ischemic stroke. PSDS were measured using the 30-item Geriatric Depression Scale (GDS-30). Multivariable support vector regression (SVR)-based analyses were performed both at the level of individual voxels (SVR-VLSM) and predefined regions of interest (SVR-ROI) to relate infarct location to PSDS. We externally validated our findings in an independent stroke cohort (N=459). Finally, disconnectome-based analyses were performed using SVR-VLSM, in which white matter fibers disconnected by the infarct were analyzed instead of the infarct itself. Results: Infarcts in the right amygdala, right hippocampus and right pallidum were consistently associated with PSDS (permutation-based p<0.05) in SVR-VLSM and SVR-ROI. External validation (N=459) confirmed the association between infarcts in the right amygdala and pallidum, but not the right hippocampus, and PSDS. Disconnectome-based analyses revealed that disconnections in the right parahippocampal white matter, right thalamus and pallidum, and right anterior thalamic radiation were significantly associated (permutation-based p<0.05) with PSDS. ConclusionsInfarcts in the right amygdala and pallidum, and disconnections of right limbic and frontal cortico-basal ganglia-thalamic circuits, are associated with PSDS. Our findings provide a comprehensive and integrative picture of strategic infarct locations for PSDS, and shed new light on pathophysiological mechanisms of depression after stroke.

neuroscience↗

SOX7 deficiency causes ventricular sepal defects through its effects on endocardial-to-mesenchymal transition and the expression of Wnt4 and Bmp2

SOX7 is located in a region on chromosome 8p23.1 that is recurrently deleted in individuals with septal defects. Sox7-/- embryos die of heart failure around E11.5 due to defects in vascular remodeling. These embryos have hypocellular endocardial cushions with severely reduced numbers of mesenchymal cells. We also observed a ventricular septal defect in a rare Sox7flox/-;Tie2-Cre embryo that escaped early lethality. This led us to hypothesize that SOX7 plays a critical developmental role in the endocardium of the atrioventricular (AV) canal. We subsequently used AV explant studies to show that SOX7 deficiency leads to a severe reduction in endocardial-to-mesenchymal transition (EndMT). Since SOX7 is a transcription factor, we hypothesized that it functions in the endocardium by regulating the expression of EndMT-related genes. To identify these genes in an unbiased manner, we performed RNA-seq on pooled E9.5 hearts tubes harvested from Sox7-/- embryos and their wild-type littermates. We found that Wnt4 transcript levels were severely reduced, which we confirmed by RNA in situ hybridization. Previous studies have shown that WNT4 is expressed in the endocardium and promotes EndMT by acting in a paracrine manner to increase the expression of BMP2 in the myocardium. Consistent with these findings, we found that Bmp2 transcript levels were diminished in Sox7-/- embryonic hearts. We conclude that SOX7 promotes EndMT in the developing AV canal by modulating the expression of Wnt4 and Bmp2. These data also provide additional evidence that haploinsufficiency of SOX7 contributes to the congenital heart defects seen in individuals with recurrent 8p23.1 microdeletions. SUMMARY STATEMENTIn the developing atrioventricular canal, SOX7 promotes endocardial-to-mesenchymal transition (EndMT) by positively regulating Wnt4 and Bmp2 expression. SOX7 deficiency leads to the development of hypocellular endothelial cushions and ventricular septal defects.

developmental biology↗

Regeneration of a Full-Thickness Defect in Rotator Cuff Tendon with Umbilical Cord-Derived Mesenchymal Stem Cells in a Rat Model

Although rotator cuff disease is a common cause of shoulder pain, there is still no treatment method that could halt or reveres its development and progression. The purpose of this study was to investigate the efficacy of umbilical cord-derived mesenchymal stem cells (UC MSCs) on the regeneration of a full-thickness rotator cuff defect (FTD) in a rat model. We injected either UC MSCs or saline to the FTD and investigated macroscopic, histological and biomechanical results and cell trafficking. Treatment with UC MSCs improved macroscopic appearance in terms of tendon thickness at two weeks, and inflammation, defect size, swelling/redness and connection surrounding tissue and slidability at four weeks compared to the saline group. Histologically, UC MSCs induced the tendon matrix formation recovering collagen organization, nuclear aspect ratio and orientation angle of fibroblast as well as suppressing cartilage-related glycosaminoglycan compared to saline group at four weeks. The UC MSCs group also improved ultimate failure load by 25.0% and 19.0% and ultimate stress by 27.3% and 26.8% at two and four weeks compared to saline group. UC MSCs labeled with PKH26 exhibited 5.3% survival at four weeks compared to three hours after injection. This study demonstrated that UC MSCs regenerated the FTD with tendon tissue similar properties to the normal tendon in terms of macroscopic, histological and biomechanical characteristics in a rat model.View Full Text

pathology↗

Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression

The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers. We previously screened genes upregulated in human hepatocellular carcinomas for their metastatic function in a mouse model of pancreatic neuroendocrine tumor (PNET) and identified that human RHAMMB promoted liver metastasis. It was unknown whether RHAMMB is upregulated in pancreatic cancer or contributes to its progression. In this study, we found that RHAMM protein was frequently upregulated in human PNETs. We investigated alternative splicing isoforms, RHAMMA and RHAMMB, by RNA-Seq analysis of primary PNETs and liver metastases. RHAMMB, but not RHAMMA, was significantly upregulated in liver metastases. RHAMMB was crucial for in vivo metastatic capacity of mouse and human PNETs. RHAMMA, carrying an extra 15-amino acid-stretch, did not promote metastasis in spontaneous and experimental metastasis mouse models. Moreover, RHAMMB was substantially higher than RHAMMA in pancreatic ductal adenocarcinoma (PDAC). RHAMMB, but not RHAMMA, correlated with both higher EGFR expression and poorer survival of PDAC patients. Knockdown of EGFR abolished RHAMMB-driven PNET metastasis. Altogether, our findings suggest a clinically relevant function of RHAMMB, but not RHAMMA, in promoting PNET metastasis in part through EGFR signaling. RHAMMB can thus serve as a prognostic factor for pancreatic cancer.

cancer biology↗