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A disordered linker in the Polycomb protein Polyhomeotic tunes phase separation and oligomerization

Molecular Cell 2025年第11期85卷 2128-2146.e15页

作者： Gemeinhardt, Tim M. Regy, Roshan M. phan, Tien M. Pal, Nanu Sharma, Jyoti Senkovich, Olga Mendiola, Andrea J. Ledterman, Heather J. Henrickson, Amy Lopes, daniel Kapoor, Utkarsh Bihani, Ashish Sihou, djamouna Kim, Young C. Jeruzalmi, david demeler, Borries Kim, Chongwoo A. Mittal, Jeetain Francis, Nicole J. Montreal Clinical Research Institute (IRCM) Montreal QC Canada Division of Experimental Medicine McGill University Montreal QC Canada Artie McFerrin Department of Chemical Engineering Texas A&M University College Station TX United States Department of Biochemistry and Molecular Medicine University of Montreal Montreal QC Canada Department of Biochemistry and Molecular Genetics Midwestern University Glendale AZ United States Department of Chemistry and Biochemistry The University of Lethbridge Lethbridge AB Canada Department of Chemistry and Biochemistry City College of New York New York NY United States Department of Chemical and Biomedical Engineering University of Wyoming Laramie WY United States Center for Materials Physics and Technology Naval Research Laboratory Washington DC United States Ph.D. Program in Biochemistry The Graduate Center of the City University of New York New York NY United States Ph.D. Program in Biology The Graduate Center of the City University of New York New York NY United States Ph.D. Program in Chemistry The Graduate Center of the City University of New York New York NY United States Department of Chemistry and Biochemistry University of Montana Missoula MT United States Department of Chemistry Texas A&M University College Station TX United States Interdisciplinary Graduate Program in Genetics and Genomics Texas A&M University College Station TX United States

Biomolecular condensates are increasingly recognized as key regulators of chromatin organization, yet how their formation and properties arise from protein sequences remains incompletely understood. Cross-species comparisons can reveal both conserved functions and significant evolutionary differences. Here, we integrate in vitro reconstitution, molecular dynamics simulations, and cell-based assays to examine how drosophila and human variants of Polyhomeotic (ph)—a subunit of the PRC1 chromatin regulatory complex—drive condensate formation through their sterile alpha motif (SAM) oligomerization domains. We identify divergent interactions between SAM and the disordered linker connecting it to the rest of ph. These interactions enhance oligomerization and modulate both the formation and properties of reconstituted condensates. Oligomerization influences condensate dynamics but minimally impacts condensate formation. Linker-SAM interactions also affect condensate formation in drosophila and human cells and growth in drosophila imaginal discs. Our findings show how evolutionary changes in disordered linkers can fine-tune condensate properties, providing insights into sequence-function relationships. © 2025 The Author(s)

关键词： analytical ultracentrifugation biochemistry biomolecular condensates CRISPR drosophila gene regulation intrinsically disordered regions molecular dynamics simulations oligomerization phase separation Polycomb sterile alpha motif

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Boosting piezoelectric catalytic ammonia synthesis: A synergistic approach with sulfur vacancy engineered CdS pyramid-surface nanospheres

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Nano Energy 2025年 142卷

作者： Fang-Rong Hsu Yu-Ching Chen Cheng-Hsi Yeh Hsun-Yen Lin Hsin-Yi Tiffany Chen Jyh Ming Wu Department of Materials Science and Engineering National Tsing Hua University 101 Section 2 Kuang Fu Road Hsinchu 300 Taiwan Ph.D. Program in Prospective Functional Materials Industry National Tsing Hua University No. 101 Section 2 Kuang Fu Road Hsinchu 300 Taiwan Department of Engineering and System Science National Tsing Hua University No. 101 Section 2 Kuang-Fu Road Hsinchu 300 Taiwan College of Semiconductor Research National Tsing Hua University No. 101 Section 2 Kuang Fu Road Hsinchu 300 Taiwan

The nitrogen reduction reaction (NRR) is essential for sustainable ammonia synthesis but suffers from low selectivity and sluggish kinetics due to hydrogen evolution. Piezocatalysis offers a promising alternative by leveraging strain-induced polarization to enhance reaction specificity and efficiency. We develop a sulfur vacancy-engineered cadmium sulfide (CdS) piezoelectric catalytic system to optimize nitrogen activation. Sulfur vacancies improve nitrogen adsorption, enhance charge separation, and lower the hydrogenation energy barrier, overcoming limitations of traditional electrocatalysts. Through a systematic investigation of charge separation mechanisms, combining theoretical calculations and experimental validation, we demonstrate the crucial role of sulfur vacancies and surface morphology in optimizing catalytic performance. Finite element method (FEM) simulations reveal that the pyramid-like CdS surface generates a strong piezopotential under mechanical stress, enhancing charge transfer and redox reactions. density functional theory (dFT) calculations show sulfur vacancies increase electron availability near the Fermi level, facilitating dinitrogen activation and stabilizing intermediates. Therefore, the optimized CdS catalyst achieves an ammonia production rate of 1702 µg g −1 h −1 —four times higher than pristine CdS—demonstrating the effectiveness of defect engineering in piezoelectric catalysis. This study highlights the synergy between piezoelectric activation and defect engineering, offering insights into charge separation and advancing piezoelectric catalysis for sustainable ammonia synthesis.

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TRPM1 promotes tumor progression in acral melanoma by activating the Ca 2+ /CaMKIIδ/AKT pathway

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Journal of Advanced Research 2023年 43卷 45-57页

作者： Chi-Che Hsieh Yue-Chiu Su Kuan-Ying Jiang Takamichi Ito Ting-Wei Li Yumiko Kaku-Ito Shih-Tsung Cheng Li-Tzong Chen daw-Yang Hwang Che-Hung Shen National Institute of Cancer Research National Health Research Institutes Tainan 704 Taiwan Department of Pathology Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung 807 Taiwan Department of Dermatology Graduate School of Medical Sciences Kyushu University Fukuoka 812-8582 Japan Department of Life Sciences National Cheng Kung University Tainan 704 Taiwan Department of Dermatology Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung 807 Taiwan Department of Dermatology College of Medicine Kaohsiung Medical University Kaohsiung 807 Taiwan Department of Internal Medicine Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung 807 Taiwan Center for Cancer Research Kaohsiung Medical University Kaohsiung 807 Taiwan Ph.D. Program in Tissue Engineering and Regenerative Medicine Biotechnology Center National Chung Hsing University Taichung 402 Taiwan

Introduction Acral melanoma is a predominant and aggressive subtype of melanoma in non-Caucasian populations. There is a lack of genotype-driven therapies for over 50% of patients. TRPM1 (transient receptor potential melastatin 1), a nonspecific cation channel, is mainly expressed in retinal bipolar neurons and skin. Nonetheless, the function of TRPM1 in melanoma progression is poorly understood. Objectives We investigated the association between TRPM1 and acral melanoma progression and revealed the molecular mechanisms by which TRPM1 promotes tumor progression and malignancy. Methods TRPM1 expression and CaMKII phosphorylation in tumor specimens were tested by immunohistochemistry analysis and scored by two independent investigators. The functions of TRPM1 and CaMKII were assessed using loss-of-function and gain-of-function approaches and examined by western blotting, colony formation, cell migration and invasion, and xenograft tumor growth assays. The effects of a CaMKII inhibitor, KN93, were evaluated using both in vitro cell and in vivo xenograft mouse models. Results We revealed that TRPM1 protein expression was positively associated with tumor progression and shorter survival in patients with acral melanoma. TRPM1 promoted AKT activation and the colony formation, cell mobility, and xenograft tumor growth of melanoma cells. TRPM1 elevated cytosolic Ca 2+ levels and activated CaMKIIδ (Ca 2+ /calmodulin-dependent protein kinase IIδ) to promote the CaMKIIδ/AKT interaction and AKT activation. The functions of TRPM1 in melanoma cells were suppressed by a CaMKII inhibitor, KN93. Significant upregulation of phospho-CaMKII levels in acral melanomas was related to increased expression of TRPM1. An acral melanoma cell line with high expression of TRPM1, CA11, was isolated from a patient to show the anti-tumor activity of KN93 in vitro and in vivo . Conclusions TRPM1 promotes tumor progression and malignancy in acral melanoma by activating the Ca 2+/ CaMKIIδ/AKT pathway.

关键词： Acral melanoma TRPM1 CaMKII Ca 2+ channel

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Targeting the Neuropilin-1 receptor with Ovatodiolide and progress in using periodontal ligament organoids for COVId-19 research and therapy

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Life sciences 2024年 351卷 122764页

作者： Hsieh, Ming-Shou Chen, Ming-Yao Chang, Yu-Sheng Huang, Chin-Sheng Hsu, Tung-Nien Huang, Mao-Suan Yeh, Chi-Tai Tzeng, Yew-Min Department of Otolaryngology School of Medicine College of Medicine Taipei Medical University Taipei City 11031 Taiwan Department of Otolaryngology-Head and Neck Surgery Shuang Ho Hospital Taipei Medical University New Taipei City 23561 Taiwan Division of Gastroenterology and Hepatology Department of Internal Medicine School of Medicine College of Medicine Taipei Medical University Taipei City 110 Taiwan Division of Gastroenterology and Hepatology Department of Internal Medicine Taipei Medical University-Shuang Ho Hospital New Taipei City 235 Taiwan Division of Allergy Immunology and Rheumatology Department of Internal Medicine Shuang Ho Hospital Taipei Medical University New Taipei City 23561 Taiwan Division of Allergy Immunology and Rheumatology Department of Internal Medicine School of Medicine College of Medicine Taipei Medical University Taipei 11031 Taiwan Department of Medical Research & Education Taipei Medical University-Shuang Ho Hospital New Taipei City 23561 Taiwan International Ph.D. Program in Medicine College of Medicine Taipei Medical University Taipei City 11031 Taiwan Continuing Education Program of Food Biotechnology Applications College of Science and Engineering National Taitung University Taitung 95092 Taiwan Department of Applied Science National Taitung University Taitung 95092 Taiwan TMU Research Center for Digestive Medicine Taipei Medical University Taipei 110 Taiwan

The discovery of SARS-CoV-2 RNA in the periodontal tissues of patients who tested positive for COVId-19, 24 days post the initial symptom onset, indicates the oral cavity could serve as a viral reservoir. This research aims to investigate the antiviral capabilities of Ovatodiolide, introducing a novel periodontal ligament organoid model for the study of SARS-CoV-2. We have successfully established a reliable and expandable organoid culture from the human periodontal ligament, showcasing characteristics typical of epithelial stem cells. This organoid model enables us to delve into the lesser-known aspects of dental epithelial stem cell biology and their interactions with viruses and oral tissues. We conducted a series of in vitro and ex vivo studies to examine the inhibitory impacts of Ova on SARS-CoV-2. Our findings indicate that Ovatodiolide molecules can bind effectively to the NRP1 active domain. Our study identifies potential interaction sites for Ovatodiolide (OVA) within the b1 domain of the NRP1 receptor. We generated point mutations at this site, resulting in three variants: Y25A, T44A, and a double mutation Y25A/T44A. While these mutations did not alter the binding activity of the spike protein, they did impact the concentration of OVA required for inhibition. The inhibitory concentrations for these variants are 15 μM for Y25A, 15.2 μM for T44A, and 25 μM for the double mutant Y25A/T44A. In addition, in vitro inhibition experiments demonstrate that the EC50 of Ova against the main protease (Mpro) of the SARS-CoV-2 virus is 7.316 μM. Our in vitro studies and the use of the periodontal ligament organoid model highlight Ovatodiolide's potential as a small molecule therapeutic agent that impedes the virus's ability to bind to the Neuropilin-1 receptor on host cells. The research uncovers various pathways and biochemical strategies through which Ovatodiolide may function as an effective antiviral small molecule drug. © 2024 Elsevier Inc.

关键词： Human Neuropilin-1 Main protease Ovatodiolide Periodontal ligament organoids SARS-CoV-2

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Electronic structures of NANOMET-based nanocrystalline soft magnetic Alloys: Magnetic properties

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physica B: Condensed Matter 2025年 714卷

作者： Jihye Park Minyeong Choi Hyunkyung Lee Haein Choi-Yim Yang-Ki Hong Seong-Gon Kim C. Heath Turner Department of Applied Physics Sookmyung Women's University Seoul 04310 South Korea Hyundai Motor Company 150 HyundaiYeonguso-ro Namyang-eup Hwaseong-si Gyeonggi-do 18280 South Korea Department of Electrical and Computer Engineering and Materials Science Ph.D. Program The University of Alabama Tuscaloosa AL 35487 USA Department of Physics and Astronomy Mississippi State University Mississippi State MS 39762 USA Department of Chemical and Biological Engineering The University of Alabama Tuscaloosa AL 35487 USA

We developed new nanocrystalline Fe-Co-B-P-Cu soft magnetic alloys and studied their magnetic properties by calculating electronic structures using first-principles calculations based on density functional theory within the local spin density approximation and the Brillouin function. The supercell Fe-B-P-Cu was equilibrated at 3000 K for 12 ps using ab initio molecular dynamics (AIMd). Consequently, Fe, B, P, and Cu atoms are distributed randomly in an amorphous matrix formed by cooling it to 0 K. The ferromagnetic bcc α -(Fe 50 Co 50 ) crystallites were formed in the amorphous matrix by annealing the mixture at 300 K and cooling to 0 K. This resulted in the formation of nanocrystalline (Fe, Co)-B-P-Cu soft magnetic alloys. The ferromagnetic bcc α -Fe(Co) crystallites, embedded in an amorphous matrix, were confirmed experimentally for the first time. The experiment involved quickly cooling and heating a melted mixture of Fe, Co, B, Fe 3 P, and Cu to create both amorphous ribbons and crystallites. The Fe-Co-B-P-Cu alloy designed for the experiment has a saturation magnetization ( μ 0 M S ) of over 1.9 T (T) at 0 K and ranging from 1.87 to 1.92 T at 300 K. The magnetocrystalline anisotropy constant (K) decreased significantly to 142 J/m 3 from 5.2 × 104 J/m 3 with an increase in the number of embedded crystallites from one to five, indicating that the alloy became magnetically soft. At 300 K, the experimental μ 0 M S ranged from 1.79 to 1.89 T. Additionally, as the concentration of Co increased, the Curie temperature (T C ) also increased and reached about 800 °C at 3.5 at.%. The study revealed that the average grain size of the synthesized Fe-Co-B-P-Cu alloys was 29 nm. The experimental μ 0 M S was slightly lower than the calculated value for all designed Fe-Co-B-P-Cu alloys, indicating that the recrystallization process was not entirely controlled. The experimental results confirmed that the designed alloy system has achieved the target saturation magnetization of o

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Coronary heart diseases prediction based on cardiology clinical features 5

Coronary heart diseases prediction based on cardiology clini...

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5th IEEE International Conference on Big data Intelligence and Computing, dataCom 2019

作者： Yang, Cheng-Hong Chuang, Li-Yeh Chang, Po-Yin National Kaohsiung University of Science and Technology Ph. D. Program in Biomedical Engineering Kaohsiung Medical University Dept. of Electronic Engineering Kaohsiung Taiwan I-Shou University Dept. of Chemical Engineering Institute of Biotechnology and Chemical Engineering Kaohsiung Taiwan National Kaohsiung University of Science and Technology Dept. of Electronic Engineering Kaohsiung Taiwan

ISBN: (纸本)9781728141176

The development of modern health systems has generated a large amount of medical data. Recent research has shown that data mining technology can discover potential patterns from a vast array of medical data, providing insight into disease and predicting disease. Coronary heart disease (CHd) is one of the most important research topics in the health field. In recent years, research on CHd has been extensively studied;however, the accuracy of CHd prediction needs to be improved. Here, a hybrid prediction method BOSVM combining Bayesian optimization (BO) and support vector machine (SVM) is proposed to predict the CHd. In BOSVM, BO aims to adjust of SVM parameters for enhancing the accuracy of CHd prediction. BOSVM compares performance of CHd prediction with five forecasting algorithms, including classification and regression tree, logistic regression, k-nearest neighbors, AdaBoost, and SVM. The experimental results show that the BOSVM has superior prediction accuracy than other algorithms in CHd prediction, indicating BOSVM can effectively predict CHd. © 2019 IEEE.

关键词： Support vector regression

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Rapid optimal work extraction from a quantum-dot information engine

arXiv

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arXiv 2024年

作者： Aggarwal, Kushagra Rolandi, Alberto Yang, Yikai Hickie, Joseph Jirovec, daniel Ballabio, Andrea Chrastina, daniel Isella, Giovanni Mitchison, Mark T. Perarnau-Llobet, Martí Ares, Natalia Department of Engineering Science University of Oxford Parks Road OxfordOX1 3PJ United Kingdom Département de Physique Appliquée Université de Genève Genève1211 Switzerland Atominstitut TU Wien Vienna1020 Austria Department of Materials University of Oxford Parks Road OxfordOX1 3PH United Kingdom Institute of Science and Technology Austria Am Campus 1 Klosterneuburg3400 Austria L-NESS Physics Department Politecnico di Milano via Anzani 42 Como22100 Italy School of Physics Trinity College Dublin College Green Dublin 2 D02 K8N4 Ireland Trinity Quantum Alliance Unit 16 Trinity Technology and Enterprise Centre Pearse Street Dublin 2 D02 YN67 Ireland Física Teòrica Informació i Fenòmens Quàntics Department de Física Universitat Autònoma de Barcelona Bellaterra Barcelona08193 Spain

The conversion of thermal energy into work is usually more efficient in the slow-driving regime, where the power output is vanishingly small. Efficient work extraction for fast driving protocols remains an outstanding challenge at the nanoscale, where fluctuations play a significant role. In this Letter, we use a quantum-dot Szilard engine to extract work from thermal fluctuations with maximum efficiency over two decades of driving speed. We design and implement a family of optimised protocols ranging from the slow- to the fast-driving regime, and measure the engine’s efficiency as well as the mean and variance of its power output in each case. These optimised protocols exhibit significant improvements in power and efficiency compared to the naive approach. Our results also show that, when optimising for efficiency, boosting the power output of a Szilard engine inevitably comes at the cost of increased power fluctuations. © 2024, CC BY.

关键词： Semiconductor quantum dots

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Improving the Concentration of Students With Attention deficit Hyperactivity disorder and Autism Spectrum disorder: Electroencephalographic Analysis on the Effect of Learning Activity Interventions

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International Journal of Intelligent Technologies & Applied Statistics 2020年第1期13卷 49-63页

作者： Ming-Hseuh Tsai Sy-Ruen Huang Shao-Chin Chang Yu-Ling Lo Yun-Chieh Lu Research Center for Education Systems and Policy National Academy f or Educational Research New Taipei City Taiwan Chung Chou University of Science and Technology Changhua County Taiwan Ph.D. Program of Electrical and Communications Engineering Feng-Chia University Taichung City Taiwan Department of Early Childhood Education Asia University Taichung City Taiwan

This study examined whether the learning concentration of students with attention deficit hyperactivity disorder (AdHd) or autism spectrum disorder (ASd) can be improved through participation in one-on-one learning activities. A total of 13 students with AdHd or ASd were recruited to participate in various weekly one-on-one learning activities, in an effort to improve the concentration of students with special needs. Brainwave data were collected through electroencephalography and analyzed to explore students' concentration performance in different learning activities. To achieve the objective of this study, a multi-baseline design (ABAB), a type of single-subject design method, was employed. The experiment spanned 21 weeks, covering a fall and a spring semester: the first three weeks were defined as the 1st baseline phase, the 4th to 10th weeks as the 1st experimental phase, the 11th to 13th weeks as the 2nd baseline phase, and the 14th to 21th weeks as the 2nd experimental phase. The learning activities took place in the morning self-study period once a week, and the experiment was only suspended during two of the weeks because of school events. The purpose of the two baseline phases was to collect students' brainwave data. Students' brainwaves were measured for two minutes under two scenarios; first, while they were relaxed with eyes looking straight ahead; second, they were reading a passage. The purpose of the two experimental phases was to gradually enhance students' concentration by training them to perceive their own emotions through brainwave lamps. Initial results yielded different brainwave data for students with different types of disorders. After participating in the training on learning concentration, some students demonstrated improved concentration; however, after the 2nd experimental phase, students' concentration declined. The reason was that the activities in both experimental phases were identical, and thus, they no longer provoked students' inte

关键词： Attention def icit hyperactivity disorder (AdHd) Autism spectrum disorder (ASd) Brainwave test Concentration

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Transdermal nanolipoplex simultaneously inhibits subcutaneous melanoma growth and suppresses systemically metastatic melanoma by activating host immunity

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Nanomedicine: Nanotechnology, Biology, and Medicine 2023年 47卷 102628-102628页

作者： Chen, Chia-Hung Weng, Tzu-Han Chuang, Cheng-Hsun Huang, Kai-Yao Huang, Sih-Cheng Chen, Pin-Rong Huang, Hsiao-Hsuan Huang, Ling-Ya Shen, Pei-Chun Chuang, Po-Ya Huang, Hsiao-Yen Wu, Yi-Syuan Chang, Hao-Chiun Weng, Shun-Long Liao, Kuang-Wen Department of Medical Research Hsinchu MacKay Memorial Hospital Hsinchu City30071 Taiwan Dependent of Medical Education MacKay Memorial Hospital Taipei10449 Taiwan Institute of Molecular Medicine and Bioengineering National Yang Ming Chiao Tung University Hsinchu City30068 Taiwan Department of Biological Science and Technology National Yang Ming Chiao Tung University Hsinchu City30068 Taiwan Industrial Development Graduate Program of College of Biological Science and Technology National Yang Ming Chiao Tung University Hsinchu City30068 Taiwan Institute of Bioinformatics and Systems Biology National Yang Ming Chiao Tung University Hsinchu City30068 Taiwan Department of Medicine MacKay Medical College New Taipei City25245 Taiwan Department of Obstetrics and Gynecology Hsinchu MacKay Memorial Hospital Hsinchu City30071 Taiwan MacKay Junior College of Medicine Nursing and Management Taipei City11260 Taiwan Drug Development and Value Creation Research Center College of Dental Medicine Kaohsiung Medical University School of Dentistry Graduate Institute of Medicine College of Medicine Center for Cancer Research Kaohsiung Medical University Kaohsiung City80708 Taiwan Center for Intelligent Drug Systems and Smart Bio-devices National Yang Ming Chiao Tung University Hsinchu City30068 Taiwan Department of Biotechnology and Bioindustry Sciences National Cheng Kung University Tainan City70101 Taiwan Ph.D. Degree Program of Biomedical Science and Engineering National Yang Ming Chiao Tung University Hsinchu City30068 Taiwan

Benefit for clinical melanoma treatments, the transdermal neoadjuvant therapy could reduce surgery region and increase immunotherapy efficacy. Using lipoplex (Lipo-PEG-PEI-complex, LPPC) encapsulated doxorubicin (dOX) and carrying CpG oligodeoxynucleotide;the transdermally administered nano-liposomal drug complex (LPPC-dOX-CpG) would have high cytotoxicity and immunostimulatory activity to suppress systemic metastasis of melanoma. LPPC-dOX-CpG dramatically suppressed subcutaneous melanoma growth by inducing tumor cell apoptosis and recruiting immune cells into the tumor area. Animal studies further showed that the colonization and growth of spontaneously metastatic melanoma cells in the liver and lung were suppressed by transdermal LPPC-dOX-CpG. Furthermore, NGS analysis revealed IFN-γ and NF-κB pathways were triggered to recruit and activate the antigen-presenting-cells and effecter cells, which could activate the anti-tumor responses as the major mechanism responsible for the therapeutic effect of LPPC-dOX-CpG. Finally, we have successfully proved transdermal LPPC-dOX-CpG as a promising penetrative carrier to activate systemic anti-tumor immunity against subcutaneous and metastatic tumor. © 2022

关键词： Tumors

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HER2 amplification in colorectal cancer with brain metastasis: A propensity score matching study

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European journal of cancer (Oxford, England : 1990) 2023年 181卷 62-69页

作者： Po-Chuan Chen Yu-Min Yeh Chun-Ting Chu Pei-Fang Su Pin-Hsuan Chiu Bo-Wen Lin Shang-Hung Chen Peng-Chan Lin Chung-Ta Lee Helen H W Chen Chien-Chin Chen Division of Colorectal Surgery Department of Surgery National Cheng Kung University Hospital College of Medicine National Cheng Kung University Tainan 704 Taiwan. Department of Oncology National Cheng Kung University Hospital College of Medicine National Cheng Kung University Tainan 704 Taiwan. Division of Colorectal Surgery Department of Surgery Ditmanson Medical Foundation Chia-Yi Christian Hospital Chiayi 600 Taiwan. Department of Statistics National Cheng Kung University Tainan 701 Taiwan. The Center of Quantitative Sciences Clinical Medicine Research Center National Cheng Kung University Hospital Tainan 704 Taiwan. Department of Oncology National Cheng Kung University Hospital College of Medicine National Cheng Kung University Tainan 704 Taiwan National Institute of Cancer Research National Health Research Institute Tainan 704 Taiwan. Department of Genomic Medicine National Cheng Kung University Hospital College of Medicine National Cheng Kung University Tainan 704 Taiwan Department of Computer Science and Information Engineering College of Electrical Engineering and Computer Science National Cheng Kung University Tainan 704 Taiwan. Department of Pathology National Cheng Kung University Hospital College of Medicine National Cheng Kung University Tainan 704 Taiwan. Department of Oncology National Cheng Kung University Hospital College of Medicine National Cheng Kung University Tainan 704 Taiwan. Electronic address: helen@mail.ncku.edu.tw. Department of Pathology Ditmanson Medical Foundation Chia-Yi Christian Hospital Chiayi 600 Taiwan Department of Cosmetic Science Chia Nan University of Pharmacy and Science Tainan 717 Taiwan Department of Biotechnology and Bioindustry Sciences College of Bioscience and Biotechnology National Cheng Kung University Tainan 701 Taiwan Ph.D. Program in Translational Medicine Rong Hsing Research Center for Translational Medicine National Chung Hsing University Taichung 40227 Taiwan. Electronic address: hlmarkc@gmail.c

BACKGROUNd:The association between human epidermal growth factor receptor-2 (HER2) amplification and brain metastasis (BM) in patients having colorectal cancer (CRC) has been suggested but not yet established. This study investigated the expression patterns of HER2, its association with BM, and its prognostic value in patients having CRC. METHOdS:We retrospectively identified 99 patients having metastatic CRC (mCRC) and BM (the BM cohort) and compared them with a cohort of 249 patients having mCRC and without BM (the stage IV cohort) by propensity score matching. Immunohistochemical studies of HER2 on all available paraffin-embedded tumour samples, either from the primary tumour, the metastasis (brain and/or extracranial sites) or both, were performed and analysed. HER2 fluorescent in situ hybridisation was applied when necessary. The expression of HER2 was compared and correlated with survival. RESULTS:HER2 amplifications were detected in 16 (18.4%) of 87 and 9 (3.6%) of 249 patients who had specimens available in the BM and stage IV cohorts, respectively (P < .001). After propensity score matching, HER2 amplification was significantly associated with BM (odds ratio: 5.38, P = .003). HER2 heterogeneity was frequently observed not only at the single tumour level but also in paired tumour samples. A marginally significant longer survival since BM was found in patients having HER2-amplified mCRC than in those without (P = .07). CONCLUSIONS:HER2 amplification was significantly associated with BM in patients having mCRC and might have prognostic value for survival since BM. Given the heterogeneity of HER2 expression, the testing of HER2 status on available tissues from both primary and metastatic tumours should be encouraged.

关键词： Brain metastasis Colorectal cancer HER2 amplification Heterogeneity Propensity score matching

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