Biology subjects

Kim, I.-H.

Publications and source records attributed to Kim, I.-H..

4 recordsLinked to original sources

bioRxiv2024

Deep Gaussian Process with Uncertainty Estimation for Microsatellite Instability and Immunotherapy Response Prediction Based on Histology

Determining tumor microsatellite status has significant clinical value because tumors that are microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) respond well to immune check-point inhibitors (ICIs) and oftentimes not to chemotherapeutics. We propose MSI-SEER, a deep Gaussian process-based Bayesian model that analyzes H&E whole-slide images in weakly-supervised-learning to predict microsatellite status in gastric and colorectal cancers. We performed extensive validation using multiple large datasets comprised of patients from diverse racial backgrounds. MSI-SEER achieved state-of-the-art performance with MSI prediction, which was by integrating uncertainty prediction. We achieved high accuracy for predicting ICI responsiveness by combining tumor MSI status with stroma-to-tumor ratio. Finally, MSI-SEERs tile-level predictions revealed novel insights into the role of spatial distribution of MSI-H regions in the tumor microenvironment and ICI response.

bioinformatics↗

bioRxiv2023

Habitat use of loggerhead (Caretta caretta) and green (Chelonia mydas) turtles in the Northwest Pacific Ocean, the northern limit of their distribution range

Verifying habitats, including the foraging and nesting areas for sea turtles, enables an understanding of their spatial ecology and successful planning of their conservation and management strategies. Recently, the observation frequency and bycatch of loggerhead (Caretta caretta) and green (Chelonia mydas) turtles have increased in the northern limit of their distribution range, in the northern part of the East China Sea and East Sea (Sea of Japan). We conducted satellite tracking to investigate the habitat use of seven loggerhead and eight green turtles from June 2016 to August 2022 in this area, where little is known about their spatial ecology. We applied a 50 percent volume contour method to determine their main foraging areas and analyzed 6 environmental variables to characterize their habitats. Loggerhead turtles mainly stayed in and used the East China Sea as a foraging area during the tracking period, while two individuals among them also used the East Sea as a seasonal foraging area. Most green turtles also used the East China Sea as a foraging area, near South Korea and Japan, with one individual among them using the southern part of the East Sea as a seasonal foraging area. Notably, one green turtle traveled to Hainan Island in the South China Sea, a historical nesting area. Our results showed that the two sea turtle species included the East Sea as a seasonal foraging area, possibly owing to the abundance of food sources available, despite its relatively lower sea temperature. Considering that loggerhead and green sea turtles were observed using the northern part of the East China Sea and East Sea more frequently than previously known and that the sea temperature gradually increases due to climate change, conservation and management activities are required for sea turtles in these areas.

zoology↗

bioRxiv2019

Discovery of a small molecule having both potent anti-fibrotic and anti-inflammatory capabilities

AbstractsIdiopathy pulmonary fibrosis (IPF) is an intractable and fatal human disorder. Our previous study showed that eupatilin exerted a potent anti-fibrotic effect on both in vitro fibrogenesis and bleomycin-induced lung fibrosis model (BLM). Subsequently, an analog called ONG41008 had been identified as a more potent anti-fibrotic than eupatilin and also showed a potent anti-inflammatory capability. Orally administered ONG41008 significantly improved onset of BLM in both prophylactic and therapeutic model and its therapeutic efficacy was similarly compared to or better than pirfenidone by measuring production of collagen and hydroxyproline. Staining collagen or SMA corroborated these results. As in vitro fibrogenesis models, DHLF (Diseased Human Lung Fibroblasts from IPF patients) and HSC (hepatic stellate cells) were used for direct effects of ONG41008 on pivotal cellular and molecular functions associated with pathogenic myofibroblasts; ONG41008 dismantled latent TGFb complex (LTC), generating inactive forms of TGF{beta}, likely limiting TGF{beta} to TGF{beta} receptor via depolymerization of F-actin and this blunted SMAD2/SMAD3 phosphorylation, thereby reprogramming EMT. A set of cell imaging studies and transcriptomic analysis were conducted to explore how ONG41008 elicited both anti-fibrotic and anti-inflammatory capabilities. Elastin (ELN) seemed to be a pioneering pharmacodynamic marker. It was also found that NOX4 played an important role in anti- fibrosis because it was functionally connected to major central nod proteins such as lysyl- oxidase (LOX) and numerous collagen family members in an ONG41008-specific fibrogenic interactome. Human NOX4 was significantly induced by TGF{beta} and completely knocked down by ONG41008. It has been shown that production of reactive oxygen species (ROS) led to activation of inflammasome. ONG41008 may be likely related to anti-inflammation, leading to a key protective effect on fibrogenesis. Concomitant with downregulation of NOX4, expression of macrophages homing chemokines, CCL2 and CCL7 were significantly attenuated by ONG41008. In vitro anti-inflammatory activities of ONG41008 were investigated in RAW264.7 cells, a mouse monocytic cell line stimulated with LPS. ONG41008 substantially attenuated TNF, CXCL10, CCL2 and CCL7, which are proinflammatory cytokine and important chemokines influencing T cells or macrophages. TNF was situated at the central nod in LPS-treated macrophages via an ONG41008-specific interactome analysis. Taken together, ONG41008 is a TGF{beta} biogenesis inhibitor, being a potent drug for a broad range of fibrotic diseases and could antagonize inflammatory diseases as well.

pharmacology and toxicology↗

bioRxiv2017

Small molecule-mediated reprogramming of epithelial-mesenchymal transition thereby blocking fibrosis

Fibrotic diseases are major causes of morbidity and mortality, and the epithelial-mesenchymal transition (EMT) plays a central role in the development of tissue/organ fibrosis. We discovered that eupatilin, a member of the chromone scaffold (CS)-containing compounds found ubiquitously in the plant kingdom, completely reversed fibrogenesis in vitro and substantially ameliorated bleomycin-induced lung fibrosis (BILF). Furthermore, eupatilin-induced growth arrest and morphological changes in primary fibroblasts derived from a patient with idiopathic pulmonary fibrosis (IPF). To better understand fibrosis, we established a mouse hepatic stellate cell (HSC) line that was robustly differentiated into myofibroblasts upon treatment with TGF{beta}. HSC-derived fibrogenesis was completely blocked by eupatilin, which caused dramatic morphological changes while inhibiting expression of EMT-related genes. The chemical groups linked to the 2nd carbon (C2), C3, C6, and C7 on the CS of eupatilin were essential for its anti-fibrogenic effects. Unlike eupatilin, pirfenidone failed to block HSC fibrogenesis and did not affect the morphology of HSCs or lung fibroblasts. Although pirfenidone affected local production of TGF{beta}, as reflected by a reduction in the TGF{beta} level in lung lysates of BILF model mice, eupatilin is likely to act via a different therapeutic mechanism. In particular, eupatilin had greater anti-fibrotic capacity and EMT-inhibitory activity and significantly attenuated the phosphorylation of Erk by TGF{beta}. Based on the interactome, Integrin{beta}3 seems to be a major player in integration of TGF{beta} signaling into the eupatilin-mediated anti-fibrosis. Our findings suggest that combinatorial use of eupatilin and pirfenidone may augment the therapeutic efficacy of IPF treatment.

cell biology↗