Biology subjects

Ozawa, H.

Publications and source records attributed to Ozawa, H..

5 recordsLinked to original sources

bioRxiv2025

M1C is a druggable target for NSCLC KRAS G12C mutant tumors resistant to KRAS inhibitors

Treatment of NSCLC KRAS G12C mutant tumors with the allele-selective sotorasib inhibitor is invariably associated with acquired resistance. The MUC1-encoded oncogenic M1C protein is necessary for self-renewal of NSCLC KRAS mutant cells. We report that treatment of NSCLC KRAS G12C cells with sotorasib induces M1C expression by a STAT1-dependent pathway. In turn, M1C drives sotorasib resistance by NF-{kappa}B-mediated induction of the epithelial-mesenchymal transition (EMT). Targeting M1C(R)NF-{kappa}B signaling (i) suppresses EMT, and (ii) reverses sotorasib resistance. Of translational relevance, treatment with a M1C antibody-drug conjugate (ADC) is effective against sotorasib-resistant NSCLC KRAS G12C cell line and patient-derived tumor xenografts. Clinically, targeted treatment of patients with NSCLC KRAS G12C tumors overexpressing MUC1 associates with decreases in overall survival. These findings identify M1C as a key effector of sotorasib resistance and as a target for treatment of patients with refractory NSCLC KRAS G12C mutant tumors.

cancer biology↗

bioRxiv2025

Integrative taxonomic revision of turtle barnacle genus Platylepas (Cirripedia: Coronuloidea): an ancient host-range expansion to sea snakes and sirenians

The barnacle genus Platylepas contains obligate epibionts of marine vertebrates, but the taxonomic status and evolutionary history of the sea-snake specialist, P. ophiophila, have remained unclear. Here, we reassess species boundaries and host associations in Platylepas using shell-morphological comparisons and sequence data from mitochondrial COI and nuclear H3 genes from specimens collected from sea turtles, sea snakes, and a dugong. Our results show that P. ophiophila is a valid species, phylogenetically and morphologically distinct from the widespread turtle barnacles P. decorata and P. hexastylos. Furthermore, we report the first record of P. ophiophila from a sirenian host (Dugong dugon), a discovery that necessitates the re-examination of historical records of barnacles on sirenians worldwide. Our phylogeny places P. decorata, a turtle epibiont, as the earliest diverging lineage within the genus. This is consistent with the hypothesis that the ancestor of Platylepas was associated with sea turtles, a conclusion supported by the ichnofossil record. The subsequent divergence of the P. ophiophila clade may represent an important host-use transition: an ancient host shift from sea turtles to the taxonomically disparate but ecologically linked inhabitants--sea snakes and sirenians--of seagrass ecosystems. This study clarifies species limits within Platylepas and provides a framework for discussing host associations and potential host shifts in light of existing molecular and fossil evidence.

zoology↗

bioRxiv2020

Behavioural cue reactivity to alcohol and non-alcohol-related stimuli among individuals with severe alcohol use disorder: an fMRI study with a visual task

Patients with alcohol use disorder (AUD) have difficulties controlling alcohol cravings and thus exhibit increased use and earlier relapse. Although patients tend to respond more strongly to alcohol-related images compared with non-alcohol-related images, few researchers examined the factors that modulate cravings. Here, we examined whole-brain blood oxygen level-dependent (BOLD) responses to behavioural cues in individuals with AUD and healthy controls (HCs). The participants included 24 patients with severe AUD and 15 HCs. We presented four beverage images (juice, drinking juice, sake, and drinking sake) and compared participant BOLD responses between the two groups. Multiple comparisons revealed that the AUD group had lower BOLD responses compared with the HC group to images of drinking juice in the left precuneus (p = 0.036) and the left posterior cingulate cortex (PCC) (p = 0.044) and higher BOLD responses to images of drinking sake in the left PCC (p = 0.044). Furthermore, compared to the HCs, the AUD patients had decreased BOLD responses associated with cue reactivity to drinking juice in the left precuneus during the period from 15 to 18 s (p = 0.004, df = 37) and 18 to 21 s (p = 0.002, df = 37). Using the Spearman correlation, we found a significant negative correlation between BOLD responses in the left PCC of the AUD patients and Mini-Mental State Examination (MMSE) scores (r = -0.619, p = 0.001). Our findings suggest that HCs and severe AUD patients differ in their responses not to images of alcoholic beverages but those related to alcohol drinking behavior. Thus, these patients appear to have different patterns of brain activity. This information may aid clinicians in developing treatments for patients with AUD.

neuroscience↗

bioRxiv2020

Phase transition of prion protein initiates proteinase K resistant amyloid formation

Prion diseases are characterized by accumulation of amyloid fibrils. The causative agent is an infectious amyloid that is comprised solely of misfolded prion protein (PrPSc). Prions can convert PrPC to proteinase-resistant PrP (PrP-res) in vitro; however, the intermediate steps involved in the spontaneous conversion remain unknown. We investigated whether recombinant prion protein (rPrP) can directly convert into PrP-res via liquid-liquid phase separation in the absence of PrPSc. We found that rPrP underwent liquid-liquid phase separation at the interface of the aqueous two-phase system (ATPS) of polyethylene glycol (PEG) and dextran, whereas single-phase conditions were not inducible. Fluorescence recovery assay after photobleaching revealed that the liquid-solid phase transition occurred within a short time. The aged rPrP-gel acquired proteinase-resistant amyloid accompanied by {beta}-sheet conversion, as confirmed by western blotting, Fourier transform infrared spectroscopy, and Congo red staining. The reactions required both the N-terminal region of rPrP (amino acids 23-89) and kosmotropic salts, suggesting that the kosmotropic anions may interact with the N-terminal region of rPrP to promote liquid-liquid phase separation. Thus, structural conversion via liquid-liquid phase separation and liquid-solid phase transition are intermediate steps in the conversion of prions.

biochemistry↗

bioRxiv2017

Untangling The Gene-Epigenome Networks: Timing Of Epigenetic Regulation Of Gene Expression In Acquired Cetuximab Resistance

BACKGROUNDTargeted therapies specifically act by blocking the activity of proteins that are encoded by genes critical for tumorigenesis. However, most cancers acquire resistance and long-term disease remission is rarely observed. Understanding the time course of molecular changes responsible for the development of acquired resistance could enable optimization of patients treatment options. Clinically, acquired therapeutic resistance can only be studied at a single time point in resistant tumors. To determine the dynamics of these molecular changes, we obtained high throughput omics data weekly during the development of cetuximab resistance in a head and neck cancer in vitro model.\n\nRESULTSAn unsupervised algorithm, CoGAPS, was used to quantify the evolving transcriptional and epigenetic changes. Applying a PatternMarker statistic to the results from CoGAPS enabled novel heatmap-based visualization of the dynamics in these time course omics data. We demonstrate that transcriptional changes result from immediate therapeutic response or resistance, whereas epigenetic alterations only occur with resistance. Integrated analysis demonstrates delayed onset of changes in DNA methylation relative to transcription, suggesting that resistance is stabilized epigenetically.\n\nCONCLUSIONSGenes with epigenetic alterations associated with resistance that have concordant expression changes are hypothesized to stabilize resistance. These genes include FGFR1, which was associated with EGFR inhibitor resistance previously. Thus, integrated omics analysis distinguishes the timing of molecular drivers of resistance. Our findings provide a relevant towards better understanding of the time course progression of changes resulting in acquired resistance to targeted therapies. This is an important contribution to the development of alternative treatment strategies that would introduce new drugs before the resistant phenotype develops.

cancer biology↗