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Overcoming the Blood-Brain Tumor Barrier with Docetaxel-Loaded Mesoporous Silica Nanoparticles for Treatment of Temozolomide-Resistant Glioblastoma

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ACS Applied Materials and Interfaces 2024年第17期16卷 21722-21735页

作者： Hsu, Tsung-I Chen, Yi-Ping Zhang, Rong-Lin Chen, Zih-An Wu, Cheng-Hsun Chang, Wen-Chang Mou, Chung-Yuan Chan, Hardy Wai-Hong Wu, Si-Han Ph.D. Program in Medical Neuroscience College of Medical Science and Technology Taipei Medical University and National Health Research Institutes Taipei110 Taiwan International Master Program in Medical Neuroscience College of Medical Science and Technology Taipei Medical University Taipei110 Taiwan Graduate Institute of Nanomedicine and Medical Engineering Taipei Medical University Taipei110 Taiwan International Ph.D. Program in Biomedical Engineering College of Biomedical Engineering Taipei Medical University Taipei110 Taiwan Nano Targeting & Therapy Biopharma Inc. Taipei110 Taiwan Graduate Institute of Medical Sciences College of Medicine Taipei Medical University Taipei110 Taiwan Department of Chemistry National Taiwan University Taipei106 Taiwan

While temozolomide (TMZ) has been a cornerstone in the treatment of newly diagnosed glioblastoma (GBM), a significant challenge has been the emergence of resistance to TMZ, which compromises its clinical benefits. Additionally, the nonspecificity of TMZ can lead to detrimental side effects. Although TMZ is capable of penetrating the blood-brain barrier (BBB), our research addresses the need for targeted therapy to circumvent resistance mechanisms and reduce off-target effects. This study introduces the use of PEGylated mesoporous silica nanoparticles (MSN) with octyl group modifications (C8-MSN) as a nanocarrier system for the delivery of docetaxel (DTX), providing a novel approach for treating TMZ-resistant GBM. Our findings reveal that C8-MSN is biocompatible in vitro, and DTX@C8-MSN shows no hemolytic activity at therapeutic concentrations, maintaining efficacy against GBM cells. Crucially, in vivo imaging demonstrates preferential accumulation of C8-MSN within the tumor region, suggesting enhanced permeability across the blood-brain tumor barrier (BBTB). When administered to orthotopic glioma mouse models, DTX@C8-MSN notably prolongs survival by over 50%, significantly reduces tumor volume, and decreases side effects compared to free DTX, indicating a targeted and effective approach to treatment. The apoptotic pathways activated by DTX@C8-MSN, evidenced by the increased levels of cleaved caspase-3 and PARP, point to a potent therapeutic mechanism. Collectively, the results advocate DTX@C8-MSN as a promising candidate for targeted therapy in TMZ-resistant GBM, optimizing drug delivery and bioavailability to overcome current therapeutic limitations. © 2024 The Authors. Published by American Chemical Society.

关键词： Tumors

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Environmental genotoxicity assessment of nanoparticles using human airway epithelial model

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Emerging Contaminants 2024年第4期10卷 308-316页

作者： Sirirak Hemmaphan Kotchapawn Somprasong Narisa K.Bordeerat Graduate Program in Biomedical Sciences Faculty of Allied Health SciencesThammasat UniversityPathum ThaniThailand Department of Medical Technology Faculty of Allied Health SciencesThammasat UniversityPathum ThaniThailand

Because of the growing use of nanoparticles(NPs)in manufacturing consumer goods,it is essential to identify new in vitro approaches to assess their toxicity and improve risk *** are exposed to NPs from contaminated aerosol via multiple routes,such as inhalation,ingestion,and dermal *** airway epithelial cells are a promising tool for assessing the genotoxicity of NPs in *** study aims to evaluate the genotoxic effects of titanium dioxide(TiO_(2)),zinc oxide(ZnO),and silver oxide(AgO)NPs on human bronchial/tracheal epithelial cells(HBTECs)using the comet *** exposure duration was set to 24 h,and two-(2D)and three-dimensional(3D)spheroid models were *** genotoxicity of TiO_(2)NPs in 2D and 3D HBTEC cells was not statistically significant based on the concentration points examined in *** NPs at concentrations ranging from 10 to 50 mg/mL,when exposed to 2D HBTEC cultures for 24 h,did not show any genotoxic ***,genotoxicity was observed at higher *** contrast,treatment of 2D HBTEC cultures with AgO NPs increased the percentage of tail DNA damage from 50 to 100 mg/mL in a concentration-dependent *** a controlled laboratory environment,ZnO and AgO NPs exhibited a reduction in the length of the tail in 3D spheroid *** evaluating genotoxicity,spheroids(3D)represent in vivo-like cell behavior more accurately than monolayer cultures(2D).Collectively,our findings illustrate the harmful effects of NPs on genetic material and emphasize the significance of employing cell culture models to evaluate the risk of toxicity.

关键词： Genotoxicity Nanoparticles Human bronchial/tracheal epithelial cell 3D spheroid

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Unitig-centered pan-genome machine learning approach for predicting antibiotic resistance and discovering novel resistance genes in bacterial strains

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Computational and Structural Biotechnology Journal 2024年 23卷 1864-1876页

作者： Do, Duyen Thi Yang, Ming-Ren Vo, Tran Nam Son Le, Nguyen Quoc Khanh Wu, Yu-Wei Graduate Institute of Biomedical Informatics College of Medical Science and Technology Taipei Medical University Taipei Taiwan Department of Electrical Engineering National Taiwan University of Science and Technology Taipei Taiwan Department of Business Administration College of Management Lunghwa University of Science and Technology Taoyuan City Taiwan Professional Master Program in Artificial Intelligence in Medicine College of Medicine Taipei Medical University Taipei Taiwan Clinical Big Data Research Center Taipei Medical University Hospital Taipei Taiwan TMU Research Center for Digestive Medicine Taipei Medical University Taipei Taiwan

In current genomic research, the widely used methods for predicting antimicrobial resistance (AMR) often rely on prior knowledge of known AMR genes or reference genomes. However, these methods have limitations, potentially resulting in imprecise predictions owing to incomplete coverage of AMR mechanisms and genetic variations. To overcome these limitations, we propose a pan-genome-based machine learning approach to advance our understanding of AMR gene repertoires and uncover possible feature sets for precise AMR classification. By building compacted de Brujin graphs (cDBGs) from thousands of genomes and collecting the presence/absence patterns of unique sequences (unitigs) for Pseudomonas aeruginosa, we determined that using machine learning models on unitig-centered pan-genomes showed significant promise for accurately predicting the antibiotic resistance or susceptibility of microbial strains. Applying a feature-selection-based machine learning algorithm led to satisfactory predictive performance for the training dataset (with an area under the receiver operating characteristic curve (AUC) of > 0.929) and an independent validation dataset (AUC, approximately 0.77). Furthermore, the selected unitigs revealed previously unidentified resistance genes, allowing for the expansion of the resistance gene repertoire to those that have not previously been described in the literature on antibiotic resistance. These results demonstrate that our proposed unitig-based pan-genome feature set was effective in constructing machine learning predictors that could accurately identify AMR pathogens. Gene sets extracted using this approach may offer valuable insights into expanding known AMR genes and forming new hypotheses to uncover the underlying mechanisms of bacterial AMR. © 2024 The Authors

关键词： Genes

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Exploring the mechanistic role of epidermal growth factor receptor activation in non-cancer kidney disease

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BIOCELL 2025年第1期49卷 79-92页

作者： JU-YEON LEE DAEUN MOON JINU KIM Medical Course College of MedicineCatholic Kwandong UniversityGangneung25601Republic of Kore Department of Anatomy College of MedicineJeju National UniversityJeju63243Republic of Korea Interdisciplinary Graduate Program in Advanced Convergence Technology&Science Jeju National UniversityJeju63243Republic of Korea

The epidermal growth factor receptor(EGFR)is a transmembrane glycoprotein that plays a crucial role in signal transduction and cellular *** review explores the function of EGFR in kidney physiology and its implications for various kidney *** signaling is essential for kidney function and repair mechanisms,and its dysregulation significantly impacts both acute and chronic kidney *** review discusses the normal distribution of EGFR in kidney tubular segments,the mechanism of its activation and inhibition,and the therapeutic potential of EGFR-targeting antagonists and ***,it explores the pathophysiological characteristics observed in rodent models of kidney diseases through pharmacological and genetic inhibition of EGFR,highlighting therapeutic challenges and limitations such as species differences,variability in disease models,and potential adverse ***,the findings underscore the multifaceted role of EGFR in kidney diseases,influencing inflammation,fibrosis,and tissue *** complex involvement suggests that targeting EGFR may be a beneficial therapeutic strategy for managing these conditions,potentially mitigating inflammation and fibrosis while promoting tissue repair.

关键词： Epidermal growth factor receptor Chronic kidney disease Acute kidney injury Tubulointerstitial fibrosis

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Preclinical Assessment of Enhanced Chemodynamic Therapy by an FeMnOx-Based Nanocarrier: Tumor-Microenvironment-Mediated Fenton Reaction and ROS-Induced Chemotherapeutic for Boosted Antitumor Activity

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ACS Applied Materials and Interfaces 2023年第48期15卷 55258-55275页

作者： Dirersa, Worku Batu Kan, Tzu-Chun Getachew, Girum Wibrianto, Aswandi Ochirbat, Sonjid Rasal, Akash Chang, Jungshan Chang, Jia-Yaw Department of Chemical Engineering National Taiwan University of Science and Technology Taiwan Taipei106335 Taiwan Graduate Institute of Medical Sciences College of Medicine Taipei Medical University Taipei11031 Taiwan International Master/Ph.D. Program in Medicine College of Medicine Taipei Medical University Taipei11031 Taiwan International Ph.D. Program for Cell Therapy and Regeneration Medicine College of Medicine Taipei Medical University Taipei11031 Taiwan

In recent studies, iron-containing Fenton nanocatalysts have demonstrated significant promise for clinical use due to their effective antitumor activity and low cytotoxicity. A new approach was reported in this work utilizing cation exchange synthesis to fabricate FeMnOx nanoparticles (NPs) that boost Fenton reactions and responses to the tumor microenvironment (TME) for chemodynamic therapy (CDT) and chemotherapy (CT). Within the TME, the redox metal pair of Fe2+/Mn2+ helps break down endogenous hydrogen peroxide (H2O2) into very harmful hydroxyl radicals (•OH) while simultaneously deactivating glutathione (GSH) to boost CDT performance. To further enhance the therapeutic potential, FeMnOx NPs were encapsulated with thioketal-linked camptothecin (CPT-TK-COOH), a reactive oxygen species (ROS)-responsive prodrug, achieving a high CPT-loading capacity of up to 51.1%. Upon ROS generation through the Fenton reaction, the prodrug TK linkage was disrupted, releasing 80% of the CPT payload within 48 h. Notably, FeMnOx@CPT exhibited excellent dual-modal imaging capabilities, enabling magnetic resonance and fluorescence imaging for image-guided therapy. In vitro studies showed the cytocompatibility of FeMnOx NPs using MDA-Mb-231 and 4T1 cells, but in the presence of H2O2, they induced significant cytotoxicity, resulting in 80% cell death through CDT and CT effects. Upon intravenous administration, FeMnOx@CPT displayed remarkable tumor accumulation, which enhanced tumor suppression in xenografts through improved CDT and CT effects. Moreover, no significant adverse effects were observed in the FeMnOx NP-treated animals. In the current study, the FeMnOx@CPT anticancer platform, with its boosted •OH-producing capability and ROS-cleavable drug release, has been validated utilizing in vitro and animal studies, suggesting its capacity as a viable strategy for clinical trials. © 2023 American Chemical Society.

关键词： Chemotherapy

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Watermelons Talk: Predicting Ripeness through Tapping

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IEEE Internet of Things Magazine 2024年第4期7卷 154-161页

作者： Lin, Yun-Wei Lin, Yi-Bing Chen, Wen-Liang Chang, Chia-Hui Li, Han-Kuan College of Artificial Intelligence Yang Ming Chiao Tung University (NYCU) NYCU China Medical University Miin Wu School of Computing National Cheng Kung University Research Center for Information Technology Innovation Academia Sinica College of Biological Science and Technology NYCU Industrial Development Graduate Program of College of Biological Science and Technology

During the commercial production of watermelons, farmers must swiftly assess fruit ripeness post-harvest to minimize losses through sorting based on edibility time. This process enhances marketability and productivity but is often very tedious in traditional approaches. This article delves into the multifaceted realm of Internet of Things (IoT) based real-time watermelon ripeness evaluation. Watermelons, subject to diverse degrees of ripeness, significantly impact the fruit's taste and texture. Notably, watermelons cease to mature after detachment from the vine, underscoring the importance of selecting the ripest specimens at purchase. Prompt post-harvest fruit ripeness assessment is pivotal to mitigate losses, ensuring accurate sorting based on edibility timeline. Consequently, diligent watermelon ripeness assessment by farmers gains importance for enhanced marketability and productivity. While manual techniques like tapping, color examination, and day counting serve practical purposes, their accuracy relies on subjective judgment. Currently, the prevailing method for assessing watermelon ripeness is the sound test. This tapping technique surprisingly rests on logical grounds, as the resulting sounds offer an adequate ripeness indicator. However, personal interpretations of these sounds are influenced by subjective experiences and traditional wisdom. This article investigates non-destructive methodologies for evaluating watermelon ripeness. Then we propose WatermelonTalk, an IoT based real-time deep learning platform designed for acoustic watermelon testing. We also introduce the concept of the 'tapping ensemble,' not previously found in the literature, which significantly enhances prediction accuracy. The article's contributions encompass the most comprehensive categorization of watermelons in the literature, specifically categorizing 1698 watermelons across 343 varieties by ripeness. Previous studies have considered either the 2-level test (unripe and ripe) or th

关键词： Productivity Deep learning Accuracy Real-time systems Acoustics Crops Farming Agricultural products Commercialization Color Testing

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Effects of Exercise Training on Immune-Related Genes and Pathways in the Cortex of Animal Models of Alzheimer’s Disease: A Systematic Review

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Journal of Alzheimer's Disease 2024年第4期98卷 1219-1234页

作者： Widjaya, Michael Anekson Lee, Shin-Da Cheng, Wei-Chung Wu, Bor-Tsang Graduate Institute of Biomedical Sciences College of Medicine China Medical University Taichung Taiwan Department of Physical Therapy PhD program in Healthcare Science China Medical University Taichung Taiwan Cancer Biology and Precision Therapeutics Center China Medical University Taichung Taiwan Program for Cancer Biology and Drug Discovery China Medical University Academia Sinica Taichung Taiwan Department of Senior Citizen Service Management National Taichung University of Science and Technology Taichung Taiwan

Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disease that affects the immune system due to the accumulation of amyloid-b (Ab) and tau associated molecular pathology and other pathogenic processes. To address AD pathogenesis, various approaches had been conducted from drug development to lifestyle modification to reduce the prevalence of AD. Exercise is considered a prominent lifestyle modification to combat AD. Objective: This observation prompted us to review the literature on exercise related to immune genes in the cortex of animal models of AD. We focused on animal model studies due to their prevalence in this domain. Methods: The systematic review was conducted according to PRISMA standards using Web of Science (WoS) and PubMed databases. Any kind of genes, proteins, and molecular molecules were included in this systematic review. The list of these immune-related molecules was analyzed in the STRING database for functional enrichment analysis. Results: We found that 17 research studies discussed immune-related molecules and 30 immune proteins. These studies showed that exercise had the ability to ameliorate dysfunction in AD-related pathways, which led to decreasing the expression of microglia-related pathways and Th17-related immune pathways. As a result of decreasing the expression of immune-related pathways, the expression of apoptosis-related pathways was also decreasing, and neuronal survival was increased by exercise activity. Conclusions: Based on functional enrichment analysis, exercise not only could reduce apoptotic factors and immune components but also could increase cell survival and Ab clearance in cortex samples. PROSPERO ID: CRD42022326093. © 2024 – IOS Press. All rights reserved.

关键词： Alzheimer’s disease apoptosis-related pathway brain microglia-related pathway physical activity Th17-related pathway

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Single-cell transcriptomics uncovers EGFR signaling-mediated gastric progenitor cell differentiation in stomach homeostasis (vol 14, 3750, 2023)

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NATURE COMMUNICATIONS 2023年第1期14卷 1-16页

作者： Takada, Hitomi Sasagawa, Yohei Yoshimura, Mika Tanaka, Kaori Iwayama, Yoshimi Hayashi, Tetsutaro Isomura-Matoba, Ayako Nikaido, Itoshi Kurisaki, Akira Laboratory of Stem Cell Technologies Graduate School of Science and Technology Nara Institute of Science and Technology Takayama-cho Ikoma Nara Japan Laboratory for Bioinformatics Research RIKEN Center for Biosystems Dynamics Research Wako Saitama Japan Department of Functional Genome Informatics Biological Data Science Medical Research Institute Tokyo Medical and Dental University Bunkyo Tokyo Japan Master’s/Doctoral Program in Life Science Innovation (Bioinformatics) Degree Programs in Systems and Information Engineering Graduate School of Science and Technology University of Tsukuba Tsukuba Ibaraki Japan

Defects in gastric progenitor cell differentiation are associated with various gastric disorders, including atrophic gastritis, intestinal metaplasia, and gastric cancer. However, the mechanisms underlying the multilineage differentiation of gastric progenitor cells during healthy homeostasis remain poorly understood. Here, using a single-cell RNA sequencing method, Quartz-Seq2, we analyzed the gene expression dynamics of progenitor cell differentiation toward pit cell, neck cell, and parietal cell lineages in healthy adult mouse corpus tissues. Enrichment analysis of pseudotime-dependent genes and a gastric organoid assay revealed that EGFR-ERK signaling promotes pit cell differentiation, whereas NF-κB signaling maintains gastric progenitor cells in an undifferentiated state. In addition, pharmacological inhibition of EGFR in vivo resulted in a decreased number of pit cells. Although activation of EGFR signaling in gastric progenitor cells has been suggested as one of the major inducers of gastric cancers, our findings unexpectedly identified that EGFR signaling exerts a differentiation-promoting function, not a mitogenic function, in normal gastric homeostasis.

关键词： Adult stem cells Stem-cell differentiation Stem-cell niche

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The largest genome-wide association study for breast cancer in Taiwanese Han population

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Breast Cancer Research and Treatment 2024年第2期203卷 291-306页

作者： Hsu, Yu-Ching Chen, Hung-Lin Cheng, Chi-Fung Chattopadhyay, Amrita Chen, Pei-Shan Lin, Che-Chen Chiang, Hsiu-Yin Liu, Ting-Yuan Huang, Chi-Hao Kuo, Chin-Chi Chuang, Eric Y. Lu, Tzu-Pin Tsai, Fuu-Jen Bioinformatics Program Taiwan International Graduate Program National Taiwan University Taipei Taiwan Bioinformatics Program Institute of Statistical Science Taiwan International Graduate Program Academia Sinica Taipei Taiwan Institute of Health Data Analytics and Statistics Department of Public Health College of Public Health National Taiwan University Taipei Taiwan Big Data Center China Medical University Hospital Taichung Taiwan Center for Translational Genomic Research Department of Medical Research China Medical University Hospital Taichung Taiwan Million-Person Precision Medicine Initiative Department of Medical Research China Medical University Hospital Taichung Taiwan Division of Breast Surgery Department of Surgery China Medical University Hospital Taichung Taiwan Division of Nephrology Department of Internal Medicine China Medical University Hospital Taichung Taiwan Department of Medical Research China Medical University Hospital Taichung Taiwan Bioinformatics and Biostatistics Core Center of Genomic and Precision Medicine National Taiwan University Taipei Taiwan Graduate Institute of Biomedical Electronics and Bioinformatics National Taiwan University Taipei Taiwan Biomedical Technology and Device Research Laboratories Industrial Technology Research Institute Hsinchu Taiwan Genetic Center Department of Medical Research China Medical University Hospital Taichung Taiwan

Purpose: Breast cancer is a molecularly heterogeneous disease, and multiple genetic variants contribute to its development and prognosis. Most of previous genome-wide association studies (GWASs) and polygenic risk scores (PRSs) analyses focused on studying breast cancers of Caucasian populations, which may not be applicable to other population. Therefore, we conducted the largest breast cancer cohort of Taiwanese population to fill in the knowledge gap. Methods: A total of 152,534 Participants recruited by China medical University Hospital between 2003 and 2019 were filtered by several patient selection criteria and GWAS quality control steps, resulting in the inclusion of 2496 cases and 9984 controls for this study. We then conducted GWAS for all breast cancers and PRS analyses for all breast cancers and the four breast cancer subtypes, including luminal A, luminal B, basal-like, and HER2-enriched. Results: The GWAS analyses identified 113 SNPs, 50 of which were novel. The PRS models for all breast cancers and the luminal A subtype showed positively correlated trends between the PRS and the risk of developing breast cancer. The odds ratios (95% confidence intervals) for the groups with the highest PRS in all breast cancers and the luminal A subtype were 5.33 (3.79–7.66) and 3.55 (2.13–6.14), respectively. Conclusion: In summary, we explored the association of genetic variants with breast cancer in the largest Taiwanese cohort and developed two PRS models that can predict the risk of developing any breast cancer and the luminal A subtype in Taiwanese women. © 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

关键词： Breast cancer Genome-wide association study Polygenic risk score Taiwanese population

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Development of a Thin-Film pH Sensor for Quantitative Detection of MicroRNAs

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IEEJ Transactions on Sensors and Micromachines 2024年第7期144卷 185-186页

作者： Suzuki, Kazuya Tabata, Miyuki Miyahara, Yuji Arakawa, Takahiro Sustainable Engineering Program Graduate School of Engineering Tokyo University of Technology 1404-1 Katakura-cho Hachioji Tokyo192-0982 Japan Graduate School of Bio-applications and Systems Engineering Tokyo University of Agriculture and Technology 2-24-16 Naka-cho Tokyo Koganei184-8588 Japan Institute of Biomaterials and Bioengineering Tokyo Medical and Dental University 2-3-10 Kanda-surugadai Chiyoda-ku Tokyo101-0062 Japan

Quantification methods for microRNAs (miRNAs) are attracting attention, because miRNAs provide a potential biomarker in liquid biopsy. In this research, we developed an electrical monitoring device of nucleic acid amplification that is simpler than the conventional PCR method, combining an isothermal amplification method and a thin-film Iridium/Iridium oxide (Ir/IrOx) electrode. The fabricated Ir/IrOx electrode showed ideal Nernstian response under the various pH buffer solutions. Moreover, we successfully real-time monitored three-way junction primer generation-rolling circle amplification (3WJ-PGRCA) at the 0.01, 0.1 pM, Negative Control of target miRNA based on fluorescence detection. The fabricated Ir/IrOx electrode would be a promising liquid biopsy platform by detecting released proton during amplification reaction at the constant reaction temperature. © 2024 The Institute of Electrical Engineers of Japan.

关键词： pH sensors

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