Biology subjects

Kwon, H. J.

Publications and source records attributed to Kwon, H. J..

8 recordsLinked to original sources

bioRxiv2025

Unraveling Tyrosine-Kinase Inhibitor Resistance in NSCLC Cells via Same-cell Measurement of RNA, Protein, and Morphological Responses

Non-small cell lung cancer (NSCLC) frequently develops resistance to tyrosine kinase inhibitors (TKIs), limiting the long-term success of targeted therapies. A deeper understanding of resistance mechanisms at the molecular and cellular levels may enable the development of more effective treatment strategies. Here, we applied the Teton detection assay on the AVITI24 platform to measure concurrently RNA, protein, and cellular morphology in NSCLC cell lines treated with the TKIs gefitinib and osimertinib. This single-cell, multiomic analysis revealed distinct expression and morphological profiles between drug-sensitive and resistant cells, including differences in MAPK-related pathway activity. Stratifying responses at the single-cell level uncovered subtle responses not detectable in bulk measurements. We identified CDK4/6 activity as a route of cell survival under TKI treatment and demonstrated that co-treatment with the CDK4/6 inhibitor palbociclib enhanced TKI efficacy. The ability to measure multiomics and cellular morphology in the same cells opens new avenues for future studies aimed at improving personalized treatment strategies in NSCLC and overcoming the obstacles posed by drug resistance.

genomics↗

bioRxiv2024

A novel monomeric amyloid β-activated signaling pathway regulates brain development via inhibition of microglia

Amyloid {beta} (A{beta}) forms aggregates in the Alzheimers disease brain and is well known for its pathological roles. Recent studies show that it also regulates neuronal physiology in the healthy brain. Whether A{beta} also regulates glial physiology in the normal brain, however, has remained unclear. In this article, we describe the discovery of a novel signaling pathway activated by the monomeric form of A{beta} in vitro that plays essential roles in the regulation of microglial activity and the assembly of neocortex during development in vivo. We find that activation of this pathway depends on the function of amyloid precursor (APP) and the heterotrimeric G protein regulator Ric8a in microglia and inhibits microglial immune activation at transcriptional and post-transcriptional levels. Genetic disruption of this pathway during neocortical development results in microglial dysregulation and excessive matrix proteinase activation, leading to basement membrane degradation, neuronal ectopia, and laminar disruption. These results uncover a previously unknown function of A{beta} as a negative regulator of brain microglia and substantially elucidate the underlying molecular mechanisms. Considering the prominence of A{beta} and neuroinflammation in the pathology of Alzheimers disease, they also highlight a potentially overlooked role of A{beta} monomer depletion in the development of the disease.

neuroscience↗

bioRxiv2024

Identifying Ferroptosis Inducers, HDAC, and RTK Inhibitor Sensitivity in Melanoma Subtypes through Unbiased Drug Target Prediction

The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem. Here we mine large scale MM proteogenomic data integrating it with MM cell line dependency screen, and drug sensitivity data to identify druggable targets and forecast treatment efficacy and resistance. Leveraging protein profiles from established MM subtypes and molecular structures of 82 cancer treatment drugs, we identified nine candidate hub proteins, mTOR, FYN, PIK3CB, EGFR, MAPK3, MAP4K1, MAP2K1, SRC and AKT1, across five distinct MM subtypes. These proteins serve as potential drug targets applicable to one or multiple MM subtypes. By analyzing transcriptomic data from 48 publicly accessible melanoma cell lines sourced from Achilles and CRISPR dependency screens, we forecasted 162 potentially targetable genes. We also identified genetic resistance in 260 genes across at least one melanoma subtype. In addition, we employed publicly available compound sensitivity data (Cancer Therapeutics Response Portal, CTRPv2) on the cell lines to assess the correlation of compound effectiveness within each subtype. We have identified 20 compounds exhibiting potential drug impact in at least one melanoma subtype. Remarkably, employing this unbiased approach, we have uncovered compounds targeting ferroptosis, that demonstrate a striking 30x fold difference in sensitivity among different subtypes. This implies that the proteogenomic classification of melanoma has the potential to predict sensitivity to ferroptosis compounds. Our results suggest innovative and novel therapeutic strategies by stratifying melanoma samples through proteomic profiling, offering a spectrum of novel therapeutic interventions and prospects for combination therapy. Highlights(1) Proteogenomic subtype classification can define the landscape of genetic dependencies in melanoma (2) Nine proteins from molecular subtypes were identified as potential drug targets for specified MM patients (3) 20 compounds identified that show potential effectiveness in at least one melanoma subtype (4) Proteogenomics can predict specific ferroptosis inducers, HDAC, and RTK Inhibitor sensitivity in melanoma subtypes O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/579424v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@73dd77org.highwire.dtl.DTLVardef@d0cb8eorg.highwire.dtl.DTLVardef@1e4117forg.highwire.dtl.DTLVardef@38b727_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

cancer biology↗

bioRxiv2022

Structural and functional characteristics of SARS-CoV-2 Omicron subvariant BA.2 spike

The Omicron subvariant BA.2 has become the dominant circulating strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in many countries. We have characterized structural, functional and antigenic properties of the full-length BA.2 spike (S) protein and compared replication of the authentic virus in cell culture and animal model with previously prevalent variants. BA.2 S can fuse membranes more efficiently than Omicron BA.1, mainly due to lack of a BA.1-specific mutation that may retard the receptor engagement, but still less efficiently than other variants. Both BA.1 and BA.2 viruses replicated substantially faster in animal lungs than the early G614 (B.1) strain in the absence of pre-existing immunity, possibly explaining the increased transmissibility despite their functionally compromised spikes. As in BA.1, mutations in the BA.2 S remodel its antigenic surfaces leading to strong resistance to neutralizing antibodies. These results suggest that both immune evasion and replicative advantage may contribute to the heightened transmissibility for the Omicron subvariants.

microbiology↗

bioRxiv2021

Camel nanobodies broadly neutralize SARS-CoV-2 variants

With the emergence of SARS-CoV-2 variants, there is urgent need to develop broadly neutralizing antibodies. Here, we isolate two VHH nanobodies (7A3 and 8A2) from dromedary camels by phage display, which have high affinity for the receptor-binding domain (RBD) and broad neutralization activities against SARS-CoV-2 and its emerging variants. Cryo-EM complex structures reveal that 8A2 binds the RBD in its up mode and 7A3 inhibits receptor binding by uniquely targeting a highly conserved and deeply buried site in the spike regardless of the RBD conformational state. 7A3 at a dose of [≥]5 mg/kg efficiently protects K18-hACE2 transgenic mice from the lethal challenge of B.1.351 or B.1.617.2, suggesting that the nanobody has promising therapeutic potentials to curb the COVID-19 surge with emerging SARS-CoV-2 variants. One-Sentence SummaryDromedary camel (Camelus dromedarius) VHH phage libraries were built for isolation of the nanobodies that broadly neutralize SARS-CoV-2 variants.

immunology↗

bioRxiv2021

B.1.1.7 and B.1.351 variants are highly virulent in K18-ACE2 transgenic mice and show different pathogenic patterns from early SARS-CoV-2 strains

SARS-CoV-2 continues to circulate globally resulting in emergence of several variants of concern (VOC), including B.1.1.7 and B.1.351 that show increased transmissibility and enhanced resistance to antibody neutralization. In a K18-hACE2 transgenic mouse model, we demonstrate that Both B.1.1.7 and B.1.351 are 100 times more lethal than the original SARS-CoV-2 bearing 614D. Mice infected with B.1.1.7 and B.1.351 exhibited more severe lesions in internal organs than those infected with early SARS-CoV-2 strains bearing 614D or 614G. Infection of B.1.1.7 and B.1.351 also results in distinct tissue-specific cytokine signatures, significant D-dimer depositions in vital organs and less pulmonary hypoxia signaling before death as compared to the mice infected with early SARS-CoV-2 strains. However, K18-hACE2 mice with the pre-existing immunity from prior infection or immunization were resistant to the lethal reinfection of B.1.1.7 or B.1.351, despite having reduced neutralization titers against these VOC. Our study reveals distinguishing pathogenic patterns of B.1.1.7 and B.1.351 variants from those early SARS-CoV-2 strains in K18-hACE2 mice, which will help to inform potential medical interventions for combatting COVID-19.

immunology↗

bioRxiv2020

Mapping the Antibody Repertoires in Ferrets with Repeated Influenza A/H3 Infections: Is Original Antigenic Sin Really "Sinful"?

The influenza-specific antibody repertoire is continuously reshaped by infection and vaccination. The host immune response to contemporary viruses can be redirected to preferentially boost antibodies specific for viruses encountered early in life, a phenomenon called original antigenic sin (OAS) that is suggested to be responsible for diminished vaccine effectiveness after repeated vaccination. In this study, we used a new computational tool called Neutralization Map to determine the hemagglutination inhibition profiles of individual antibodies within ferret antisera elicited by repeated influenza A/H3 infections. Our results suggest that repeated infections continuously reshape the ferret antibody repertoire, but that a broadly neutralizing antibody signature can nevertheless be induced irrespective of OAS. Overall, our study offers a new way to visualize how immune history shapes individual antibodies within a repertoire, which may help inform future vaccine design.

immunology↗

bioRxiv2019

Inhibitory effects of β-caryophyllene on Helicobacter pylori infection in vitro and in vivo

The human specific bacterial pathogen Helicobacter pylori (H. pylori) is a Gram-negative microaerophilic bacterium and associated with severe gastric diseases such as peptic ulceration and gastric cancer. Recently, the increasing resistance and the emergence of adverse effects make the usage of antibiotics less effectively. Therefore, development of new antimicrobial agent is required to control H. pylori infection. In the current study, it has been demonstrated the inhibitory effect of {beta}-caryophyllene on H. pylori growth and the protective effect against H. pylori infection as well as antibacterial therapeutic effect. {beta}-caryophyllene inhibited H. pylori growth via down-regulation of dnaE, dnaN, holB and gyrA and also down-regulated virulence factors such as CagA, VacA and SecA proteins. {beta}-caryophyllene inhibited expression of several type IV secretion system (T4SS) components including virB2, virB4 and virB8, so that CagA translocation into H. pylori-infected AGS cells was decreased by {beta}-caryophyllene treatment. {beta}-caryophyllene also inhibited VacA toxin entry through down-regulation of type IV secretion system (T5SS). In vivo experiments using Mongolian gerbils demonstrated antibacterial therapeutic effects of {beta}-caryophyllene. After {beta}-caryophyllene administration, immunohistochemistry (IHC) stain using anti-H. pylori antibody showed the antibacterial effect and H&E stain showed the therapeutic effect in treated groups. Hematological data which conformed with histological data support the therapeutic effect of {beta}-caryophyllene administration. Such a positive effect of {beta}-caryophyllene on H. pylori infection potently substantiate that this natural compound could be used as a new antimicrobial agent or functional health food to help the patients whom suffering from gastroduodenal diseases due to H. pylori infection. Author summaryThe inhibitory effect on {beta}-caryophyllene on H. pylori growth and the protective effect against H. pylori infection as well as antibacterial therapeutic effect have been elucidated in this study. {beta}-caryophyllene inhibited H. pylori growth via downregulation of replication machinery of H. pylori. {beta}-caryophyllene also downregulated virulence factors such as CagA, VacA and SecA proteins which are necessary for successful colonization and pathogenesis of H. pylori. Besides, {beta}-caryophyllene significantly reduced H. pylori-induced actin-cytoskeletal rearrangement, vacuolation and apoptosis in AGS cells. In in vivo infection model, {beta}-caryophyllene showed splendid therapeutic effect against H. pylori infection. In particular, this is the first report that evaluates the toxicological effects of {beta}-caryophyllene administration on Mongolian gerbils. Such a positive effect of {beta}-caryophyllene on H. pylori infection potently substantiate that this natural compound could be used as a new antimicrobial agent or functional health food to help the patients whom suffering from gastroduodenal diseases due to H. pylori infection.

microbiology↗