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Liu, Yen-Lin, Yin-Ju Chen, Shu-Huey Chen, Yu-Mei Liao, Wu Shih-Pei, Yi-Hsuan Chen, Wan-Ling Ho et al. "Abstract 6723: Application of in vitro drug screening of circulating tumor cells in pediatric glioma therapy". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 6723. http://dx.doi.org/10.1158/1538-7445.am2023-6723.
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Abstract Twenty-one gliomas in patients aged 0-21 years were evaluated for drug sensitivity by ex vivo expanded circulating tumor cells (CTC). The results were correlated with clinical outcomes. Venous blood samples were obtained prior to drug treatment. Peripheral blood mononuclear cells were processed in a 3D cell culture system (EVA Select™, Cancer Free Biotech Ltd., Taipei, Taiwan) and cultured for 3 weeks. Expanded CTCs were successfully cultured into organoids from 18 out of 21 patients and were analyzed for ATP abundance. Staining with CD45, a marker for blood cells, and pancytokeratin, a marker for keratinocytes, was performed on the cultured cells. Staining of GFAP, a marker of glioma cells, was performed in a subset of samples. These cells were then tested in cytotoxicity assays in triplicate with a panel of chemotherapeutic and targeted agents at clinically relevant concentrations. The surviving fraction was normalized to a buffer-only control. Based on the percentage of cell viability, the agent was chosen for clinical treatment. Comparing the results among low-grade glioma (LGG; n = 6), diffuse midline glioma (DMG; n = 4), and high-grade glioma (HGG, n = 8; including glioblastoma multiforme [GBM; n = 5]), the mean surviving fraction to temozolomide was similarly high across the three tumor types (LGG vs. DMG vs. HGG = 57.5% vs. 50.6% vs. 49.5%, respectively). 6 of 6 patients in the LGG group showed CTC sensitivity to at least one chemotherapeutic agent tested. The clinical response of patients treated with selected agents was evaluated with the RANO criteria at 6 months after initiation of treatment. Among the 24 agents tested with clinical correlation, the CTC surviving fraction after exposure to the agent was significantly higher in patients who had progressive disease within 6 months (n = 11; 68%) vs. in patients with no progression at 6 months (n = 13; 39%; P = 0.039). Treating CTCs with histone deacetylase inhibitors in vitro resulted in a consistently lower surviving fraction (15.1% ± 12.0%) for DMG and HGG/GBM; however, clinical correlation was not available. The 1 patient with clinical correlation with HGG had a 34.9% surviving fraction to a Tyrosine kinase inhibitor (TKI) in vitro and showed a 42.9% shrinkage at 6 months after treatment with the TKI. The expansion of CTCs in patients with relapsed/refractory pediatric gliomas provides the ability to test drug sensitivity of patient-derived organoids. Our data suggest a correlation between the ex vivo drug sensitivity of CTCs and clinical response. Citation Format: Yen-Lin Liu, Yin-Ju Chen, Shu-Huey Chen, Yu-Mei Liao, Wu Shih-Pei, Yi-Hsuan Chen, Wan-Ling Ho, Liang-Yi Juo, Chia-Yau Chang, Jinn-Li Wang, Min-Yu Su, Pei-Chin Lin, Shih-Chung Wang, James S. Miser, Tai-Tong Wong, Yuan-Hung Wu, Peng Yuan Wang, Thierry Burnouf, Jeng-Fong Chiou, Long-Sheng Lu. Application of in vitro drug screening of circulating tumor cells in pediatric glioma therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6723.
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Chien, Po-Chen, Rong-Hsuan Wang, Pin-Ru Chen, Yue-Ting Chen, Yi-Chang Chen, Yu-Hsin Chu, Chia-Chen Chien et al. "Abstract 437: Hydrogen sulfide switches the glucose metabolism through sulfhydration on pyruvate kinase M2". Cancer Research 84, n.º 6_Supplement (22 de março de 2024): 437. http://dx.doi.org/10.1158/1538-7445.am2024-437.
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Abstract Cancer cells reprogram their glucose metabolism from oxidative phosphorylation to aerobic glycolysis. This metabolic transformation is partly based on the activity alterations of a rate limiting enzyme known as the pyruvate kinase M2 (PKM2), which is responsible for the conversion of phosphoenolpyruvate (PEP) into pyruvate. Attributed to its critical regulatory role. PKM2 is recognized as the pivotal enzyme in cancer glucose metabolism By reducing the enzyme activity of PKM2, cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Hydrogen sulfide (H2S), an endogenously produced gasotransmitter that acts as a critical mediator in multiple physiological processes, modifies proteins mainly through the persulfide (-SSH) bond formation, which is called sulfhydration. Our preliminary study demonstrates that H2S stimulates PKM2 sulfhydration at multiple cysteine residues, including cysteine 326, leading to the destabilization of active tetrameric PKM2 form into dimers or monomers. The PKM2 dimer/monomer further translocates into the nucleus to simulate the activation of glycolytic related genes. Blocking PKM2 sulfhydration at cysteine 326 through amino acid mutation stabilizes PKM2 tetramer and crystal structure further indicates that the tetramer organization of PKM2C326S is different from the currently known T or R states, revealing PKM2C326S as a newly identified intermediate form. Blocking PKM2 sulfhydration at cysteine 326 inhibited cell proliferation and tumor growth in xenograft mouse model. In summary, our current study illustrates that H2S-mediated sulfhydration induces the dissociation of the PKM2 tetramer, resulting in the reduced PKM2 activity and subsequently inhibits breast cancer cell proliferation and tumor growth. Targeting the sulfhydration site of PKM2 emerges as a promising therapeutic target specific for cancer metabolism. Citation Format: Po-Chen Chien, Rong-Hsuan Wang, Pin-Ru Chen, Yue-Ting Chen, Yi-Chang Chen, Yu-Hsin Chu, Chia-Chen Chien, Shao-Yun Lo, Zhong-Liang Wang, Min-Chen Tsou, Ssu-Yu Chen, Guang-Shen Chiu, Wen-Ling Chen, Yi-Hsuan Wu, Hui-Ching Wang, Shu-Yi Lin, Wen-Ching Wang, Hsing-Jien Kung, Lu-Hai Wang, Hui-Chun Cheng, Kai-Ti Lin. Hydrogen sulfide switches the glucose metabolism through sulfhydration on pyruvate kinase M2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 437.
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Cheng, Kai-Lin, Chih-I. Chen, Shu-Han Yu, Huai-Wen Liang, Yi-Wei Tsai, Chen-Ting Hung, Yu-Shan Lin et al. "Abstract 285: Targeting TXNDC5 in stromal fibroblasts resolves desmoplasia and resistance to immune checkpoint blockade in mesenchymal-type colorectal cancer". Cancer Research 84, n.º 6_Supplement (22 de março de 2024): 285. http://dx.doi.org/10.1158/1538-7445.am2024-285.
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Abstract Objectives: Mesenchymal-type colorectal cancer (CRC), characterized by strong stromal infiltration and immune tolerance, resists immune checkpoint blockade and has poor outcomes. Cancer-associated fibroblasts (CAFs), abundant in tumor stroma, actively remodel the extracellular matrix (ECM), modulate immune evasion, and drive tumor progression. We have recently identified thioredoxin domain-containing protein 5 (TXNDC5), a protein disulfide isomerase (PDI), as a critical mediator of fibroblast activation and ECM remodeling in organ fibrosis. We hypothesized that TXNDC5 could contribute to fibroblast activation, stroma formation and disease progression in cancer, especially in the stroma-enriched fibrogenic mesenchymal-type CRC. Methods: Transcriptome databases of CRC were re-analyzed to determine the clinical relevance of TXNDC5. Experimentally, CRC was induced in mouse lines by azoxymethane (AOM) and dextran sulfate sodium (DSS) stimuli, a model sharing multiple characteristics with human mesenchymal-type CRC. Human colonic fibroblast line CCD-18co was used to investigate the molecular mechanisms by which TXNDC5 regulates colonic fibroblast activities. Fibroblast-specific TXNDC5 knockout (Col1a2-Cre/ERT2*TXNDC5fl/fl) mice were generated, combining with single-cell RNA sequencing analyses on AOM/DSS-induced CRC tumors in these animals, to clarify how fibroblast TXNDC5 impact tumor microenvironment, CRC progression and response to immune checkpoint blockade. Findings: TXNDC5 was predominantly expressed in stromal fibroblasts of human and mouse CRC. Fibroblast-specific deletion of Txndc5 lessened CAF activation, attenuated tumor fibrosis and reduced tumor burden in AOM/DSS-induced CRC. Mechanistically, increased TXNDC5 levels augments TGFβ signaling in CAF by post-translational stabilization of TGFBR1 through its PDI activity. In addition, deletion of Txndc5 in CAFs led to less tumor desmoplasia, decompressed tumor vessels and attenuated intra-tumoral hypoxia, thereby easing immune tolerance and increasing cytotoxic T cell infiltration in CRC. Single-cell transcriptome analysis revealed a marked change of intra-tumoral immune cell populations upon fibroblast-specific deletion of TXNDC5, shifting from myeloid-derived suppressive cells to cytotoxic tumor-infiltrating lymphocytes. Importantly, depletion of TXNDC5 in CAFs potentiated the anti-tumor effects of immune checkpoint blockade with anti-PD1 therapy in CRC. Conclusions: Our data suggest an important yet previously unrecognized role of fibroblast TXNDC5 in CRC progression, through enhancing CAF activation, stroma formation and immune escape. Combining immune checkpoint blockade with TXNDC5 deletion synergistically improved anti-tumor effects in CRC. Targeting TXNDC5, therefore, can be a novel therapeutic approach for CRC patients. Citation Format: Kai-Lin Cheng, Chih-I Chen, Shu-Han Yu, Huai-Wen Liang, Yi-Wei Tsai, Chen-Ting Hung, Yu-Shan Lin, Yi-Shiuan Tzeng, Sung-Jan Lin, Yueh-Feng Wu, Jen-Kuang Lee, Chia-Hui Yu, Shuei-Liong Lin, Shih-Yu Chen, Tzu-Tang Wei, Yun-Ju Huang, Ruey-Hwa Chen, Ching-Chow Chen, Kai-Chien Yang. Targeting TXNDC5 in stromal fibroblasts resolves desmoplasia and resistance to immune checkpoint blockade in mesenchymal-type colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 285.
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Yao, Yanbo. "Collaborative translation as an instrument for creating Uncle Tom’s Cabin in the early twentieth century’s China". International Journal of Arts and Humanities 4, n.º 1 (11 de maio de 2023): 147–56. http://dx.doi.org/10.25082/ijah.2023.01.003.
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The reception of translations of foreign literary works can vary depending on a variety of historical, social and cultural factors. The paper endeavors to examine how the collaborative translation between an interpreter and a writer can effectively address those interrelated factors that constrain the reception of the translation of foreign literary works with a case study of Wei Yi and Lin Shu’ translation of Harriet Beacher Stowe’s Uncle Tom’s Cabin in China in the early 20th century. When translating the novel, Wei Yi and Lin Shu Wei Yi and Lin Shu combined their strengths as an interpreter and a writer. They manipulated the original themes of slavery and religious belief to express their patriotic ideals and raise awareness of the national crisis, while also arousing their readers’ national spirit. Besides, they employed different translation strategies: additions to supplement the traditional Chinese literal styles and bridge the cultural gap between English and Chinese; deletions to overcome cultural vacuum and handle religious materials; abridgement to remove what they thought was trivial messages, and adaptation to rewrite the cultural knowledge. The paper contends that Wei Yi and Lin Shu’s collaboration as an interpreter and a writer contributed the more appropriate contextualization and reception of the Chinese translation of Uncle Tom’s Cabin to the target readership in the Chinese context in the early 20th century. This study of collaborative translation between an interpreter and a writer is expected to shed some light on literary translation across different countries.
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Lung, Rachel. "The Oral Translator’s “Visibility”: The Chinese Translation of David Copperfield by Lin Shu and Wei Yi". TTR : traduction, terminologie, rédaction 17, n.º 2 (20 de julho de 2006): 161–84. http://dx.doi.org/10.7202/013277ar.
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Abstract An important feature in the translation history of China in the early 20th century was the collaboration between a Chinese monolingual and a Chinese bilingual in a large-scale translation of Western fiction. Such a collaboration pattern lasted for almost two decades before more Chinese bilinguals were trained in the 1920s. The partnership of Lin Shu (1852-1924) (a prominent written translator) and Wei Yi (1880-1933) (one of Lin Shu’s oral translators) lasted for 10 years, during which they translated over 40 English novels into Chinese. Through textual analyses of their co-translation of Charles Dickens’s David Copperfield in 1908, this article unravels the long-neglected contribution of Wei Yi in the work, and points to the importance of “orality” in their translation process in shaping Lin Shu’s translations. The article is structured into two parts: first, the background of Lin Shu and Wei Yi, and their collaboration; second, evidence of Wei Yi’s visibility in the translation in terms of textual changes from indirect speech to direct speech, the use of annotations, and the characteristics of the translation.
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LIN, JIAN-ZHEN, e ZHI-QIANG ZHANG. "Bdelloidea of China: a review of progress on systematics and biology, with a checklist of species". Zoosymposia 4, n.º 1 (30 de junho de 2010): 42–50. http://dx.doi.org/10.11646/zoosymposia.4.1.3.
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This paper reviews the research on the systematics and biology of the superfamily Bdelloidea in China, with an updated checklist of 48 species belonging to 16 genera in the family Cunaxidae and 26 species belonging to nine genera in the family Bdellidae. Important contributions to the Chinese fauna of the Bdellidae were made by Tseng Yi-Hsiung (Taiwan), Hong Mei (former with Fudan University in Shanghai) and Lin Jian-Zhen (and colleagues in Fujian Academy of Agricultural Sciences, Fuzhou), and those to the Cunaxidae by Tseng Yi-Hsiung, Li Long-Shu (and colleagues in Southwest University, Chongqing) and Lin Jian-Zhen (and colleagues). There have been relatively few studies on the biology and use in biological control of the Bdelloidea in China, and these are briefly reviewed.
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Gao, Yue, Chun-Jie Liu, Hua-Yi Li, Xiao-Ming Xiong, Sjors G. j. g. In ‘t Veld, Gui-Ling Li, Jia-Hao Liu et al. "Abstract LB168: Platelet RNA signature enables early and accurate detection of ovarian cancer: An intercontinental, biomarker identification study". Cancer Research 82, n.º 12_Supplement (15 de junho de 2022): LB168. http://dx.doi.org/10.1158/1538-7445.am2022-lb168.
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Abstract Background: Morpho-physiological alternations of platelets provided a rationale to harness RNA sequencing of tumor-educated platelets (TEPs) for preoperative diagnosis of cancer. Timely, accurate, and non-invasive detection of ovarian cancer in women with adnexal masses presents a significant clinical challenge. Patients and Methods: This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n=3; Netherlands, n=5; Poland, n=1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. Results: The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. Analysis of public datasets suggested that TEPs had potential to detect multiple malignancies (Table 1). Conclusions: TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, early-stage ovarian cancer as well as other malignancies. However, these observations warrant prospective validations in a larger population before clinical utilities. Table 1. Performance for TEPs in public pan-cancer datasets. Disease n Healthy Control AUC, area under the curve (95% CI) Women NSCLC (non-small-cell lung cancer) 126 77 0.758 (0.691-0.825) Breast cancer 38 77 0.817 (0.726-0.909) Colorectal cancer 18 77 0.973 (0.945-1.000) Pancreatic cancer 16 77 0.993 (0.981-1.000) Glioblastoma 10 77 0.923 (0.831-1.000) Men NSCLC 119 82 0.746 (0.677-0.815) Colorectal cancer 25 82 0.933 (0.884-0.982) Pancreatic cancer 22 82 0.993 (0.984-1.000) Glioblastoma 19 82 0.981 (0.959-1.000) All NSCLC 245 159 0.774 (0.728-0.820) Colorectal cancer 40 159 0.978 (0.961-0.996) Breast cancer 38 159 0.821 (0.736-0.906) Pancreatic cancer 35 159 0.987 (0.974-0.999) Glioblastoma 35 159 0.931 (0.890-0.972) Hepatobiliary carcinomas 14 159 0.991 (0.978-1.000) Citation Format: Yue Gao, Chun-Jie Liu, Hua-Yi Li, Xiao-Ming Xiong, Sjors G.j.g. In ‘t Veld, Gui-Ling Li, Jia-Hao Liu, Guang-Yao Cai, Gui-Yan Xie, Shao-Qing Zeng, Yuan Wu, Jian-Hua Chi, Qiong Zhang, Xiao-Fei Jiao, Lin-Li Shi, Wan-Rong Lu, Wei-Guo Lv, Xing-Sheng Yang, Jurgen M.j. Piek, Cornelis D de Kroon, C.a.r. Lok, Anna Supernat, Sylwia Łapińska-Szumczyk, Anna Łojkowska, Anna J. Żaczek, Jacek Jassem, Bakhos A. Tannous, Nik Sol, Edward Post, Myron G. Best, Bei-Hua Kong, Xing Xie, Ding Ma, Thomas Wurdinger, An-Yuan Guo, Qing-Lei Gao. Platelet RNA signature enables early and accurate detection of ovarian cancer: An intercontinental, biomarker identification study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB168.
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Chao, Xue-lin, Shu-zhen Jiang, Jian-wen Xiong, Jin-qiong Zhan, Bo Wei, Chun-nuan Chen e Yuan-jian Yang. "Erratum to: Changes of Serum Insulin-like Growth Factor-2 Response to Negative Symptom Improvements in Schizophrenia Patients Treated with Atypical Antipsychotics". Current Medical Science 40, n.º 5 (outubro de 2020): 997. http://dx.doi.org/10.1007/s11596-020-2256-3.
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The article “Changes of Serum Insulin-like Growth Factor-2 Response to Negative Symptom Improvements in Schizophrenia Patients Treated with Atypical Antipsychotics”, written by Xue-lin CHAO, Shu-zhen JIANG, Jian-wen XIONG, Jin-qiong ZHAN, Bo WEI, Chun-nuan CHEN, Yuan-jian YANG was originally published electronically on the publisher’s internet portal on June 2020 without open access. With the author(s)’ decision to opt for Open Choice, the copyright of the article is changed to © The Author(s) 2020 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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Du, Xue, e Lingsheng Shi. "Trees with given maximum degree minimizing the spectral radius". Electronic Journal of Linear Algebra 31 (5 de fevereiro de 2016): 335–61. http://dx.doi.org/10.13001/1081-3810.3323.
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The spectral radius of a graph is the largest eigenvalue of the adjacency matrix of the graph. Let $T^*(n,\Delta ,l)$ be the tree which minimizes the spectral radius of all trees of order $n$ with exactly $l$ vertices of maximum degree $\Delta $. In this paper, $T^*(n,\Delta ,l)$ is determined for $\Delta =3$, and for $l\le 3$ and $n$ large enough. It is proven that for sufficiently large $n$, $T^*(n,3,l)$ is a caterpillar with (almost) uniformly distributed legs, $T^*(n,\Delta ,2)$ is a dumbbell, and $T^*(n,\Delta ,3)$ is a tree consisting of three distinct stars of order $\Delta $ connected by three disjoint paths of (almost) equal length from their centers to a common vertex. The unique tree with the largest spectral radius among all such trees is also determined. These extend earlier results of Lov\' asz and Pelik\'an, Simi\' c and To\u si\' c, Wu, Yuan and Xiao, and Xu, Lin and Shu.
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Lee, Soon-ok. "A Study on Aesthetics of Confucian & Taoistic Calligraphic Theory in East Han". Korean Society of Calligraphy 43 (28 de setembro de 2023): 77–98. http://dx.doi.org/10.19077/tsoc.2023.43.4.
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An overview of the history of Chinese calligraphy shows that many people in Tang Dynasty such as Zang Huaiguan(張懷瓘), Yu Shinan(虞世南), expressed very precise and philosophical views on calligraphy. Yet, there have already been discussions related to calligraphy in thr Eastern Han Dynasty before such in-depth views of calligraphy in Tang Dynasty. Yang Xiong(揚雄) has already clarified the espression of the mind of calligraphy by saying that 'Shu(書)〔originally a book, but later understood as a calligraphy〕is picture of the mind, which is composed of characters written with a brush. however, people that understood and practically applied it to calligraphy are the Cui Yuan(崔瑗) and Cai Yong(蔡邕) in the Eastern Han Dynasty.
In「Caushushi(草書勢)」, Cui Yuan gave calligraphy an independent aesthetic value that deviated from practical functionality. Moreover, it contains content that shows the aftistry of the individual's self-awarenss. In order words, it describes the artistic characteristics of the cursive script through the origin of calligraphy, the occurrence of the cursive script and the feeling of the shape and its force of the cursive script.
Cai Yong wrote「Bilun(筆論)」, and it says what kind of mindset and brushstroke is used in calligraphy creation to make calligraphy creation with true beauty possible. It is the so-called ‘calligraphy is an art that works on creation by relaxing the tension of the mind 〔書者, 散也〕’ In other words, it revealed for the first time what kind of mind could be conveyed through what kind of creative attitude and what kind of movement of the brush could be used to write truly beautiful writing. It shows that the recognized calligraphy in Taoist aesthetic thought.
Cui Yuan and Cai Yong not only mentioned calligraphy techniques and the method of wielding brush related to actual calligraphy creation but also clarified what conditions must be met for calligraphy to become a magnificent art. Such remarks by Cui Yuan and Cai Yong contain. the contents of understanding calligraphy through the taoist philosophy, on their views. Thus, from the perspective of calligraphy aesthetics, various andswers to the question 'what kind of art is calligraphy can be obtained through the views and perceptions of calligraphy by Cui Yuan, Zhao Yi and Cai Yong in the Eastern Han Dynasty.
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Chen, Pie-Che, Guan-Ling Lin, Hon-Yi Lin, Wan-Hong Huang, Yu-Ming Chuang, Ru-Inn Lin, Shu-Fen Wu, Cheng-Huang Shen e Michael W. Y. Chan. "Abstract 2243: Cyproheptadine exhibits anti-tumor activity by reversing the epigenetic silencing of IRF6 in urothelial carcinoma". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 2243. http://dx.doi.org/10.1158/1538-7445.am2023-2243.
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Abstract Urothelial carcinoma (UC) is the second most common malignancy of the urinary system with high rate of recurrence, UC patients therefore needed to be treated with surgery followed by chemotherapy. Development of novel therapeutics with minimal side-effect is an urgent issue. Our previous study showed that cyproheptadine (CPH), an anti-histamine, exhibited antitumor activity in UC in vitro and in an xenograft model. In this study, we performed RNA-Seq to examine genes that are differentially expressed after treatment with CPH in UC cells. Our result showed that several genes, including IRF6, were upregulated after treatment with CPH in BFTC905 UC cells. Further experiments found that treatment of CPH could restore the expression of IRF6 in several other UC cell lines, which is due to promoter hypomethylation and enrichment of H3K27 acetylation, as well as H3K4 mono-methylation. Importantly, treatment of CPH can inhibit tumor growth in a syngeneic mouse tumor model. The tumor growth can be further inhibited by combination treatment of CPH and immune checkpoint blockade. Flow cytometric analysis of the tumor found that NK cells are significantly enriched in the CPH treatment group, as compared to DMSO control. Co-culture experiments confirmed that UC cells pretreated with CPH showed an increased NK-92-mediated cytotoxicity. In conclusion, these results suggested that treatment of CPH can inhibit tumor growth, by epigenetic priming of IRF6 in UC. The role of CPH in eliciting anti-tumor innate immune response deserves further investigation. Citation Format: Pie-Che Chen, Guan-Ling Lin, Hon-Yi Lin, Wan-Hong Huang, Yu-Ming Chuang, Ru-Inn Lin, Shu-Fen Wu, Cheng-Huang Shen, Michael W.Y. Chan. Cyproheptadine exhibits anti-tumor activity by reversing the epigenetic silencing of IRF6 in urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2243.
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Liu, Chun-Yu, Chi-Cheng Huang, Yi-Fang Tsai, Ta-Chung Chao, Yen-Shu Lin, Chin-Jung Feng, Jiun-I. Lai et al. "Abstract P6-01-45: Correlation of an immune-related 8-gene panel with the efficacy of neoadjuvant chemotherapy for breast cancer". Cancer Research 83, n.º 5_Supplement (1 de março de 2023): P6–01–45—P6–01–45. http://dx.doi.org/10.1158/1538-7445.sabcs22-p6-01-45.
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Abstract Introduction: Neoadjuvant chemotherapy, one of systemic treatment of breast cancer, is employed for downstaging of inoperable tumor. Pathological complete response (pCR) after neoadjuvant chemotherapy is associated with good prognosis for breast cancer. The critical role of anti-tumor immune responses in conventional chemotherapy and targeted therapy has been reported. However, the pCR-associated immune genes are still ambiguous. Materials and Methods: Thirty-seven primary breast cancer patients receiving neoadjuvant chemotherapy as the first-line treatment for breast cancer were recruited in this VGH-TAYLOR study (NCT04626440). Total RNA of fresh tumor tissues was isolated and then reverse transcribed into cDNA. The Oncomine Immune Response Research Assay was employed for examination of immune-related gene expressions. In silico analyses were performed using the public databases, including Gene Expression Omnibus, Kaplan-Meier plotter, ROC Plotter, Cancer Therapeutics Response Portal, and The Cancer Genome Atlas. Results: Patients achieved a pCR were associated with lower tumor stage and HER2 expression. The next-generation sequencing-based analysis showed that the expression of eight genes were higher in tissues of patients with pCR than non-pCR, including KLRK1, IGJ, CD69, CD40LG, MS4A1, CD1C, KLRB1, and CA4. The 8-gene score was associated with better recurrence-free survival in patients receiving chemotherapy. Data from an ROC Plotter database showed that higher expressions of IGJ, CD69, and MS4A1 in patients respond to neoadjuvant chemotherapy compared to non-responders. In silico analysis revealed that the negative correlation between pCR-associated gene expressions and IC50 values suggesting the gene high expression was sensitive to the drugs. Moreover, the levels of pCR-associated gene were downregulated in breast tumor tissues and positively correlated with immune cell infiltrations. Conclusion: We identified eight immune genes which were associated with better prognosis and drug responses. The 8-gene score may serve as a prognostic marker for breast cancer patients who receiving neoadjuvant chemotherapy. Citation Format: Chun-Yu Liu, Chi-Cheng Huang, Yi-Fang Tsai, Ta-Chung Chao, Yen-Shu Lin, Chin-Jung Feng, Jiun-I Lai, Ji-Lin Chen, Yen-Jen Chen, Jen-Hwey Chiu, Chih-Yi Hsu, Ling-Ming Tseng. Correlation of an immune-related 8-gene panel with the efficacy of neoadjuvant chemotherapy for breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-45.
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Jin, Yong-zhen. "On the Influence of Tao Yuan-ming on the Poetry Creation of Joseon Scholar of the 16th Century－Take Lin Yi-ling for Example－". Journal of Chinese Studies 90 (30 de novembro de 2019): 173–90. http://dx.doi.org/10.36493/jcs.90.6.
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Guimin, Wang. "6. A Tentative Description of the Civilization of the Middle Period of Late Shang". Early China 9, S1 (1986): 11–14. http://dx.doi.org/10.1017/s0362502800002935.
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ABSTRACTThe late Shang represents a peak in bronze culture, and was the culmination of a long period of development. The words of the Duke of Zhou in the “Wu yi” chapter of the Shang shu that “The kings who arose after [Zu Jia], during their (whole) life enjoyed ease …. After this there were none who had any chance of reaching a high age…” is not sufficient to be relied upon. Nor is it appropriate to evaluate the entirety of Late Shang history solely on the basis of the large number of oracle bones from the reign of Wu Ding. The primary purpose of this paper is to demonstrate, through an analysis of the contents of oracle-bone inscriptions from the Middle Late Shang, i.e., from Lin Xin to Wen Wu Ding, that there was continued progress in the fields of society, economy, and culture and in the political and military affairs of the ruling house.Agriculture under the direct control of the Shang ruling house, including all sorts of agricultural activities, continued as before, and in some cases advanced beyond that of the previous age. In the area of handicrafts, metal casting, the “hundred craftsmen,” organizations of craftsmen and the official position of Director of Craftsmen all appear in the oracle bones. In terms of archaeology, the number, shape, manufacture, decoration, and inscriptions of bronze vessels reached a new plateau. The palace architecture and the geographical extent of residences at Yinxu were greatly expanded.
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Liu, Chun-Yu, Chi-Cheng Huang, Ji-Lin Chen, Yi-Fang Tsai, Ta-Chung Chao, Pei-Ju Lien, Yen-Shu Lin et al. "Abstract 2271: Characteristics of peripheral blood T cell receptor repertoire and correlation with response to chemotherapy in patients with breast cancer". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 2271. http://dx.doi.org/10.1158/1538-7445.am2023-2271.
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Abstract Purpose: The success of immune checkpoint inhibitors therapy in triple negative breast cancer highlights the potential immunogenic characteristics of breast cancer. Increasing evidence have suggested that conventional chemotherapy can exert anti-cancer activity through various immune-based mechanisms. T cell receptor (TCR) diversity is crucial for immune responses and TCR repertoire has been reported acting as predictive and prognostic markers for cancer outcome. Here, we reported the TCR repertoire profiling in breast cancer and its association with chemotherapy and treatment response in breast cancer patients. Experimental design: This study is part of VGH-TAYLOR study, a comprehensive precision medicine study protocol on the heterogeneity of Taiwanese breast cancer patients (NCT04626440). A total of 856 female patients with luminal A, luminal B1, luminal B2, HER2-enriched, or triple-negative breast cancers were recruited. The enrolled subjects contains patients who receive surgery as the first-line treatment followed by adjuvant therapy and who receive neoadjuvant therapy as the first-line treatment followed by surgery. The blood samples from patients during chemotherapy were collected for TCR sequencing. The Oncomine TCR Beta-LR Assay was applied to determine the dynamic change in TCR repertoire. We examined TCR repertoire in terms of clonality, TCR richness/evenness and convergence. Results: Higher TCR clonality in breast cancer patients was associated with lower clonal richness. TCR clonality was positively correlated with age and stage but not tumor size. Patients with recurrence had higher TCR clonality and lower Shannon diversity. Patients with luminal B2 breast cancer showed lower TCR diversity compared to luminal A and triple-negative breast cancer. However, there were no significant differences in CDR3 length and the usage of variable and joining genes among breast cancer subtypes. Notably, both of adjuvant and neoadjuvant chemotherapies increased convergence and clonality while decreased Shannon diversity of TCR. In neoadjuvant settings, lower post-treatment blood TCR richness was associated with complete pathologic response. Conclusion: These data suggested that TCR repertoire is associated with clinicopathological characteristics including stage and recurrence. TCR clonal richness might provide prognostic value for patients receiving neoadjuvant chemotherapy. Citation Format: Chun-Yu Liu, Chi-Cheng Huang, Ji-Lin Chen, Yi-Fang Tsai, Ta-Chung Chao, Pei-Ju Lien, Yen-Shu Lin, Chin-Jung Feng, Yen-Jen Chen, Jiun-I Lai, Jen-Hwey Chiu, Chih-Yi Hsu, Ling-Ming Tseng. Characteristics of peripheral blood T cell receptor repertoire and correlation with response to chemotherapy in patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2271.
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Wang, Nan, Zhuonan Wang e Hongyu Zheng. "Round Heaven and Square Earth, the Unity of the Pagoda and Statues—A Study on the Geometric Proportions of the Architectural Space, Statues, and Murals in Ying Xian Fogong Si Shijia Ta 應縣佛宮寺釋迦塔 (Sakyamuni Pagoda of Fogong Temple in Ying County)". Religions 15, n.º 7 (30 de junho de 2024): 802. http://dx.doi.org/10.3390/rel15070802.
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In Ying Xian Fogong Si Shijia Ta 應縣佛宮寺釋迦塔 (Sakyamuni Pagoda of Fogong Temple in Ying County), Shanxi, there are statues set on each floor, and 26 exist in total, with six murals painted on the first floor. The pagoda was designed as a vertically rising Buddhist temple, and the interior space of each floor was customized for the statues. Based on previous research and through surveying and mapping of the architecture and statuary (including the murals on the first floor) combined with geometric design analysis, this paper proposes the following: First, there exists a clear geometric proportion among the interior space and statues on each floor of the pagoda. Second, clear proportional relationships also exist among the statues on each floor, and each of the 26 statues has ‘classical’ proportion rules. Third, the height of the giant Buddha statue on the first floor is the module for not only the height of the statues on each floor but also the construction of the whole pagoda such that the height of the statue on the first floor is 1/6 of the total height of the pagoda (excluding the base). And the ratio of the pagoda’s total height to the first floor’s diameter, the ratio of the total height to the top-story height under the column capital, and all the other geometric proportions are closely related to the architectural modeling. And finally, in the construction of the pagoda, statues, and murals, the scale is deduced to be 1 chi 尺 (Chinese foot) = 29.5 cm. These values give clear scale logics not only to the construction but also to the details of the statues. Accordingly, the most frequently used proportions in the architectural space, statues, and murals of the Pagoda of Fogong Temple are 2, 3:2, 5:3 (or 8:5), and 9:5, which are imbued with cultural messages, like Zhou Bi Suan Jing 周髀算經 (The Mathematical classic of the Zhou shadow-gauging instrument), Ying Zao Fa Shi 營造法式 (Treatise on Architectural Methods or State Building Standards), the ancient Chinese world view—tian yuan di fang 天圜地方 (the dome-shaped heaven and the flat, square earth) reflected from “ yuan fang tu 圓方圖 (rounded-square map)” and “fang yuan tu 方圓圖 (squared-circle map)”, ancient Chinese ideas that ”san tian liang di er yi shu 參天兩地而倚數 (‘three’ is the number of the heaven and ‘two’ is the number of the earth, and all numbers are based on them)” and “jiu wu zhi zun 九五之尊 (nine and five are the numbers of the honorable central position)”, and most probably related to the “mandala” of Esoteric Buddhism and to the Western “Golden Ratio”, which all need further research in depth.
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Chen, I.-Chun, Ching-Hung Lin, Dwan-Ying Chang, Tom Wei-Wu Chen, Ming-Yang Wang, Wei-Li Ma, Yi-Ting Lin, Shu-Min Huang e Yen-Shen Lu. "Abstract CT141: Combination of hormone therapy, GnRH agonist, and immunotherapy enhance immune activation in premenopausal ER+/HER2- metastatic breast cancer patients: Results of biomarker analysis from a pilot phase II study". Cancer Research 83, n.º 8_Supplement (14 de abril de 2023): CT141. http://dx.doi.org/10.1158/1538-7445.am2023-ct141.
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Abstract Introduction: Immunotherapy has not been proved to be efficacious in ER+/HER2- metastatic breast cancer. Our team has reported an effective combination of exemestane, gonadotropin releasing hormone agonist, and pembrolizumab in premenopausal ER+/HER2- MBC. Here we report the updates of the final results and biomarker associates of the study. Methods: Premenopausal ER+/HER2- MBC patients who failed no more than 2 lines of hormone therapy without chemotherapy for MBC were enrolled in a tertiary medical center in Taiwan (NCT02990845). The primary endpoint was progression-free survival (PFS) rate at 8 months. The secondary endpoints included overall response rate, overall survival (OS), progression-free survival (PFS), and other biomarkers. Pre-treatment (N=12) and post-treatment (N=5) tumor tissue were collected for biomarker analysis, including tumor-infiltrating lymphocyte(TIL), PD-L1 expression by immunohistochemical staining, tumor mutational burden, RNAseq, and IO360 analysis. Results: A total of 15 patients were enrolled in the study with 14 evaluable patients. The progression-free survival rate at 8 months was 64.3%. The median PFS and OS were 10.34 months and 39.56 months respectively. The overall response was 35.7%. TIL, tumor mutational burden, or PD-L1 expression were not associated with the response to the treatment. In the NanoString IO-360 analysis, increased expression of genes in the immune related signature was noted in the post-treatment samples as compared to the pre-treatment samples. The expression levels of MHC class II and T cell-related genes were upregulated in the post-treatment samples. Most of the immune cell populations are increased after pembrolizumab/exemestane/leuprolide treatment. CD56 dim NK cells, Th1 cells, and NK cells are the top 3 populations that are increased after treatment. Using CIBERSORT algorithms to analyze RNAseq data from pretreatment samples, dendritic cells (p=0.039) and NK cells (p=0.082) were associated with the responders versus non-responders in the study. Conclusion: In this final analysis, pembrolizumab, exemestane, and leuprolide remain an effective treatment for premenopausal ER+/HER2- MBC. Pembrolizumab, exemestane, and leuprolide treatment is associated with immune system activation, turning the tumor microenvironment from cold to hot in luminal disease. Citation Format: I-Chun Chen, Ching-Hung Lin, Dwan-Ying Chang, Tom Wei-Wu Chen, Ming-Yang Wang, Wei-Li Ma, Yi-Ting Lin, Shu-Min Huang, Yen-Shen Lu. Combination of hormone therapy, GnRH agonist, and immunotherapy enhance immune activation in premenopausal ER+/HER2- metastatic breast cancer patients: Results of biomarker analysis from a pilot phase II study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT141.
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Chang, Li-Hsin, Hao-Han Chang, Xin-Yi Lin, Shu-Chi Wang, Chih-Pin Chuu, Deng-Neng Chen, Shu-Pin Huang e Chia-Yang Li. "Abstract 5651: Personalized transcriptomic profiling for advanced prostate cancer: Guiding second-generation hormonal drug selection". Cancer Research 84, n.º 6_Supplement (22 de março de 2024): 5651. http://dx.doi.org/10.1158/1538-7445.am2024-5651.
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Abstract Introduction: Second-generation hormonal drugs have demonstrated significant efficacy in extending the survival of patients with advanced prostate cancer. These drugs operate through two distinct molecular mechanisms: inhibition of androgen biosynthesis and blockade of the androgen receptor. However, due to concerns of side effects, concurrent usage of multiple drugs is not recommended. A notable challenge is the eventual development of drug resistance, rendering all second-generation hormonal therapies ineffective. Currently, there is a lack of guidelines for helping patients choose the most suitable drug. In the context of pharmacogenomics, genetic differences can influence drug susceptibility and efficacy, with variations in genomic sequences and regulatory mechanisms impacting drug response at the transcriptional and translational levels. Considered the rapid processing capabilities of Affymetrix transcriptomic microarrays, we hypothesized that distinct gene signatures in patients who respond well or poorly to second-generation hormonal drugs could be identified and could act as a companion diagnostic tool. Methods: We enrolled 180 advanced prostate cancer patients, who fulfilled Taiwan national health insurance criteria of using second-generation hormonal drugs, from seven medical centers or regional hospitals in Taiwan at 3 time points: prior to drug administration, 3 months after treatment started and drug resistance developed. The RNA expression data and clinical parameters were analyzed, and classification models were built using IPA and R. Good or poor responders were defined by 3-month prostate-specific antigen (PSA) lowered by 90 percent. Results:: Differential expression and enrichment analyses post-treatment highlighted the activation of NF-kappa B signaling and various immune cell pathways. Notably, pathways related to primary immunodeficiency and IL-17 became prominent following the development of drug resistance. At the initial stages, distinct alterations in cell cycle pathways, particularly G1/S and G2/M, were observed between good and poor responders. This was elucidated through principal component analysis and subsequent dbscan clustering. To further distinguish between these responder groups, we utilized an integrative approach for feature selection, combining support vector machine, random forest classifier, and lasso regression. Despite the innovative approach, the model's error rate stood at approximately 15%, attributed mainly to the limited number of cases. Conclusion: Our study highlights the potential of using transcriptomic analysis to predict responses to second-generation hormonal drugs in advanced prostate cancer, paving the way for personalized treatment strategies. However, the need for larger cohort studies is evident to refine these predictive models and enhance their accuracy. Citation Format: Li-Hsin Chang, Hao-Han Chang, Xin-Yi Lin, Shu-Chi Wang, Chih-Pin Chuu, Deng-Neng Chen, Shu-Pin Huang, Chia-Yang Li. Personalized transcriptomic profiling for advanced prostate cancer: Guiding second-generation hormonal drug selection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5651.
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Chen, MeiKuang, Yuan Gao, Weiya Xia, Yu-Han Wang, Jennifer K. Litton, Yu-Yi Chu, Funda Meric-Bernstam et al. "Abstract 1792: FGFR3 mediated PARP1 tyrosine 158 phosphorylation promotes PARP inhibitor resistance". Cancer Research 82, n.º 12_Supplement (15 de junho de 2022): 1792. http://dx.doi.org/10.1158/1538-7445.am2022-1792.
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Abstract Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), which induce DNA damage by inhibiting PARP1 enzymatic activity and trapping PARP on the damaged DNA, are used to eliminate BRCA1/2-mutated (BRCAm) cancer. However, clinical observations suggest that BRCAm tumors develop PARPi resistance. Current strategies to overcome PARPi resistance include impeding multiple DNA repair pathways to induce excessive DNA damage. Here, we propose a novel strategy targeting oncogenic receptor tyrosine kinases to enhance PARP trapping. By developing triple-negative breast cancer (TNBC) cells with acquired talazoparib resistance, we observed a high prevalence of activated fibroblast growth factor receptor 3 (FGFR3) kinase in these cells through kinase antibody array analysis. Mass spectrometry analysis and in vitro kinase assay suggested that FGFR3 phosphorylated PARP1 at tyrosine residues 158 and 176. Biochemistry studies suggested that only PARP1 tyrosine 158 phosphorylation contributes to PARPi resistance in the cells we developed. We then developed a monoclonal antibody against tyrosine 158 phosphorylated PARP1, and found that high-level PARP1 tyrosine 158 phosphorylation positively correlated with PARPi resistance in breast cancer patient-derived xenograft models. We further demonstrated that the combination of FGFR inhibitor and PARPi delayed DNA repair with prolonged PARP trapping. Moreover, synergy between PARPi and FGFR inhibition was observed in multiple TNBC cell lines with PARPi resistance in vitro. The combination of PARPi and FGFR inhibitor also showed synergism in vivo, and treatment with the combination of PARPi and FGFR inhibitor was tolerated in mouse models. These findings reveal that PARP1 tyrosine 158 phosphorylation facilitates resolving of the PARPi-induced PARP-trapping, and that the tyrosine 158 phosphorylated PARP1 may be an effective biomarker to indicate FGFR3 mediated PARPi resistance. Citation Format: MeiKuang Chen, Yuan Gao, Weiya Xia, Yu-Han Wang, Jennifer K. Litton, Yu-Yi Chu, Funda Meric-Bernstam, Helen Piwnica-Worms, Banu Arun, Jordi Rodon Ahnert, Yongkun Wei, Wei-Chao Chang, Hung-Ling Wang, Coya Tapia, Constance T. Albarracin, Shao-Chun Wang, Ying-Nai Wang, Gabriel N. Hortobagyi, Chunru Lin, Liuqing Yang, Dihua Yu, Mien-Chie Hung. FGFR3 mediated PARP1 tyrosine 158 phosphorylation promotes PARP inhibitor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1792.
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Lin, Yuan, Theresa A. Ramelot, Simge Senyuz, Attila Gursoy, Hyunbum Jang, Ruth Nussinov, Ozlem Keskin e Yi Zheng. "Abstract 4388: Tumor-associated RhoA mutants interact with effectors in both GDP- and GTP-bound states". Cancer Research 84, n.º 6_Supplement (22 de março de 2024): 4388. http://dx.doi.org/10.1158/1538-7445.am2024-4388.
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Abstract RhoA is the founding member of the Ras-homology (Rho) small GTPase family and is a master regulator for multiple cell functions. Recurrent RhoA mutations have been identified in several human cancers, particularly in leukemia/lymphoma and gastric cancer. Intriguingly, both gain-of-function and loss-of-function mutations of RhoA are present, suggesting that RhoA GTPase may have a more sophisticated role in cancer and requires more rigorous investigations. Here, we have focused on two of the gain-of-function RhoA mutations identified in Adult T cell Leukemia/lymphoma (ATLL) at residue A161 (A161P and A161V) and aim to reveal the underlying mechanistic basis for their function by biochemical and structural analyses. We found that in contrast to conventional gain-of-function RhoA mutants such as RhoAG14V and RhoAQ63L which affect the GTP-hydrolysis activity, RhoAA161P and RhoAA161Vare both fast-cycling with drastically increased nucleotide dissociation and association rates, but only slightly reduced GTP-hydrolysis activity. We solved the crystal structures of GDP-bound RhoAA161P and RhoAA161V and saw that while RhoAA161P displays impaired solvent-mediated interactions to the bound nucleotide, RhoAA161V has a more exposed nucleotide binding pocket compared to RhoAWT and RhoAA161P. Interestingly, RhoAA161P and RhoAA161Vcan interact with effector targets in the GDP-bound states. Further 1H-15N HSQC NMR study provides evidence of the active population in GDP-bound RhoAA161V. Molecule dynamics (MD) simulations show that the dynamic properties of RhoA switch regions are affected differently by the two mutations. Thus, RhoAA161V and RhoAA161P are fast-cycling mutants with distinct mechanisms, and both likely endow their GDP-bound state towards an active conformation. These findings provide a better understanding of the oncogenic role of RhoA mutations in cancer and shine light on how changes in RhoA protein dynamic properties caused by mutations may affect its function. Citation Format: Yuan Lin, Theresa A. Ramelot, Simge Senyuz, Attila Gursoy, Hyunbum Jang, Ruth Nussinov, Ozlem Keskin, Yi Zheng. Tumor-associated RhoA mutants interact with effectors in both GDP- and GTP-bound states [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4388.
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Chen, Shu-Mei, Hsieng-Yun Huang, Chien-Kai Wang, Yi-Yuan Yang, Sy-Jye Leu e Ying-Ying Li. "Abstract 152: Exploring the impact of heat shock protein 90 on the antitumor efficacy and stemness in medulloblastoma cells". Cancer Research 84, n.º 6_Supplement (22 de março de 2024): 152. http://dx.doi.org/10.1158/1538-7445.am2024-152.
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Abstract Background: Medulloblastoma (MB) is the most common children’s malignant brain tumor. Although MB can be treated with conventional chemotherapies, chemoresistance has been frequently developed and thereby hampers their therapeutic effectiveness. The preliminary reports of our research showed that some heat shock proteins have higher levels in MB cells. Among these heat shock proteins, HSP70 and HSP90 expressions are particularly high in MB CD133+ cancer stem cells (CSCs), which arouses our attention and interest. Numerous studies demonstrated that heat shock proteins are prominent in some chemotherapy-resistant cancer cells and CSCs. As known HSP90 and its client proteins are required for the maintenance of self-renewal/stemness and regulation of cell cycle, synergistic killing of cancer cells by simultaneous inhibition of HSP90 expression and activity may be a considerable good therapeutic strategy for treating MB. The purpose of this study is to verify the regulatory function of HSP90 in chemoresistance and stemness of MB. Materials and Methods: The levels of HSP90, its client proteins (P13K/pAKT, Erk, NFκB, and c-Myc), and stemness makers were detected using immunoblotting and immunoprecipitation after the treatment of HSP90 inhibitor (17-AAG) or knockdown of HSP90 by siRNA in MB and MB CSCs. The antitumor effects of HSPs inhibitors or knockdown of HSPs on these cells were evaluated by MTT assay, Annexin V/PI analysis and cell cycle analysis. Results: Our findings revealed elevated expression of HSP90 and its target client proteins in MB cells compared to normal astrocytes. Silencing or inhibiting HSP90 expression induced cell cycle arrest in MB cells. Notably, CD133+ MB CSCs exhibited higher HSP90 levels than parental MB cells. Inhibition of HSP90 led to reduced sphere formation and expression of stemness markers in CD133+ MB CSCs. Treatment with 17-AAG demonstrated antitumor activity in CD133+ MB CSCs, and a synergistic effect was observed when combining conventional chemotherapeutic agents with 17-AAG in MB cells Conclusion: These results illustrated that inhibition of HSP90 could eliminate CSCs, and thereby overcome resistance to chemotherapeutic agents in MB. Chemotherapies in combination with HSP90 blockade may be an emerging MB therapy in the future. Citation Format: Shu-Mei Chen, Hsieng-Yun Huang, Chien-Kai Wang, Yi-Yuan Yang, Sy-Jye Leu, Ying-Ying Li. Exploring the impact of heat shock protein 90 on the antitumor efficacy and stemness in medulloblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 152.
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Bamdad, Cynthia Carol, Joanne E. Mortimer, Yuan Yuan, Jennifer M. Specht, Andrew K. Stewart, Benoit J. Smagghe, Stephen C. Lin et al. "Abstract CT096: Phase I first-in-human MUC1* targeted autologous CAR T cells for the treatment of metastatic breast cancers". Cancer Research 84, n.º 7_Supplement (5 de abril de 2024): CT096. http://dx.doi.org/10.1158/1538-7445.am2024-ct096.
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Abstract Purpose: First-in-human Phase I study for advanced MUC1* positive breast cancer with autologous T cells engineered to express either a chimeric antigen receptor, huMNC2-CAR44 or huMNC2-CAR22, which specifically bind to a cleaved form of MUC1 (MUC1*); evaluate the safety and preliminary anti-tumor activity. Methods: MUC1* (muk 1 star) is the growth factor receptor form of MUC1, created by cleavage and release of the N-terminal portion of MUC1. The targeting antibody, huMNC2, only recognizes the conformational epitope created when MUC1 is cleaved by specific tumor-associated enzymes that are correlated with poor prognosis. huMNC2 does not bind to full-length MUC1, which is expressed on all normal epithelial cells. huMNC2-scFv was incorporated into huMNC2-CAR44, comprising a CD8 hinge and transmembrane region, 4-1BB costimulatory domain and wild-type CD3z. huMNC2-scFv was also incorporated into huMNC2-CAR22 wherein the hinge, transmembrane and co-stimulatory portions were derived from CD28 and CD3z bears the 1XX mutations to increase in vivo persistence. Inclusion criteria require that the patient’s tumor is at least 30% MUC1* positive and that patient has progressed through 2 or 3 prior therapies, while in the metastatic setting. Patients receive standard Cy/Flu lymphodepletion approximately 3-days before CAR T treatment, administered at 1 of 4 dose levels ranging from 3.3X10^5 up to 1.0X10^7 CAR+ T cells. Results: To date, 8 patients have been treated with huMNC2-CAR44. No patients experienced neuro toxicities. No off-target toxicities were observed. 3 patients experienced CRS Grade 1-3. In 6 of the 8 patients, side effects were non-existent or minimal. However, one patient experienced a Grade 5 SAE that was deemed to be possibly related to the treatment. Best responses include Partial Responses and Stable Disease at a low CAR-T dose. Greatest efficacy was observed for patients whose biopsy showed H Scores >120. Patients are currently being enrolled for treatment with huMNC2-CAR22, where the 1XX mutations are expected to increase in vivo persistence, durability of response and reduced incidence of CRS. Conclusions: These data support a conclusion that the MUC1* antibody, huMNC2, is safe and could have high therapeutic value as a CAR T treatment for solid tumors with moderate to high antigen density. As the huMNC2-CAR22 (1XX) trial proceeds, we will assess if patient responses mirror our animal results that show that the 1XX mutations confer increased persistence, reduced exhaustion and the ability to kill tumors with low antigen density. Citation Format: Cynthia Carol Bamdad, Joanne E. Mortimer, Yuan Yuan, Jennifer M. Specht, Andrew K. Stewart, Benoit J. Smagghe, Stephen C. Lin, Mark G. Carter, Tim W. Synold, Mark D. Fleming, Stanley R. Hamilton, Vishwas Parekh, Danica M. Walkley, Qing Liu-Michael, Kevin R. Yi, Jac-Leen S. Nash, Michael J. Nash, Stephen J. Forman. Phase I first-in-human MUC1* targeted autologous CAR T cells for the treatment of metastatic breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT096.
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Shu, Yongqian, Yueyin Pan, Ping Lu, Yi Jiang, Jingdong Zhang, Xiaohong Wu, Yuanhu Yao et al. "Abstract CT076: Randomized, global, phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-306): China subgroup analysis". Cancer Research 83, n.º 8_Supplement (14 de abril de 2023): CT076. http://dx.doi.org/10.1158/1538-7445.am2023-ct076.
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Abstract Background: Tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, + chemotherapy (chemo) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) vs placebo + chemo, with a manageable safety profile, as a first line (1L) treatment for patients (pts) with advanced or metastatic esophageal squamous cell carcinoma (ESCC) at interim analysis of the phase 3 RATIONALE-306 study. We report data from the China subgroup analysis. Methods: In this randomized, double-blind, global study, adults with unresectable locally advanced or metastatic ESCC, with no prior systemic treatment for advanced disease were enrolled regardless of programmed death-ligand 1 (PD-L1) expression status. Pts were randomized (1:1); stratified by region, prior definitive therapy, and investigator-chosen chemo (platinum + fluoropyrimidine or platinum + paclitaxel). Pts received tislelizumab (T) 200 mg intravenously + chemo (C) (Arm T+C) or placebo (P) + chemo (Arm P+C) once every three weeks; treatment continued until disease progression by investigator per RECIST v1.1, intolerable toxicity, or withdrawal. The primary endpoint was OS in the intent-to-treat (ITT) population. Secondary endpoints included investigator-assessed progression-free survival (PFS) per RECIST v1.1, objective response rate (ORR), and duration of response (DoR), in addition to safety. Results: Of 649 pts in the overall population, 370 (57.0%) were enrolled from China. At data cutoff (Feb 28, 2022), the median study follow-up in the China subgroup (ITT population) was 15.8 months (mo) in Arm T+C (n=182) and 10.6 mo in Arm P+C (n=188). Longer OS (median OS 16.6 mo vs 11.2 mo; unstratified hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.54, 0.89) and PFS (median PFS 8.3 mo vs 5.6 mo; unstratified HR 0.58, 95% CI 0.45, 0.75) indicate survival benefit in Arm T+C vs P+C, respectively. Arm T+C had higher response rates and more durable responses than Arm P+C; ORR was 64.8% vs 44.1% (odds ratio 2.33 [95% CI 1.53, 3.55]) respectively, and median DoR was 7.4 mo (95% CI 5.6, 9.5) vs 5.7 mo (95% CI 4.3, 7.5), respectively. Similar proportions of pts in Arm T+C vs P+C had ≥1 treatment-related adverse event (TRAE; 98.8% vs 98.9%) and ≥grade 3 TRAEs (72.9% vs 73.4%). Serious TRAEs occurred in 27.6% vs 21.2% of pts in Arm T+C vs P+C, and TRAEs leading to death occurred in 2.9% vs 1.6% of pts, respectively. Treatment-emergent adverse events leading to discontinuation occurred in 28.2% vs 17.4%, in Arm T+C vs P+C. Conclusions: In the China subgroup, 1L tislelizumab + chemo demonstrated clinically meaningful improvement in OS, PFS, ORR, and DoR vs placebo + chemo in pts with advanced or metastatic ESCC, with a manageable safety profile, consistent with published results in the overall population. Acknowledgments: This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Emma Ashman, BSc, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd. Citation Format: Yongqian Shu, Yueyin Pan, Ping Lu, Yi Jiang, Jingdong Zhang, Xiaohong Wu, Yuanhu Yao, Lin Shen, Yi Ba, Zhiyong He, Yuxian Bai, Jianhua Chen, Guohua Yu, Yanyan Peng, Hongqian Wu, Lei Wang, Liyun Li, Jianming Xu. Randomized, global, phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-306): China subgroup analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT076.
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Aberin, Marvin A., Yu-Ling (Pony) Lee, Xin-Guo Hsu, Chen-Yang Shen, Yao-Ming Chang, Kun-Yuan Lin, Chandan Guha e Shu-Ping Wang. "Abstract 3646: New functional role of tamoxifen in breast cancer immunomodulation: role of RACK7 in activation of type I interferon signaling and CEACAM1/TIM-3-dependent immunosuppression". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 3646. http://dx.doi.org/10.1158/1538-7445.am2023-3646.
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Abstract Despite advancements of immunotherapy against various cancers, breast cancer still retains poor response to immune checkpoint blockade (ICB) therapy. Therefore, the identification of promising target or new strategy to enhance ICB therapy in breast cancer is crucial. Here, we uncover that the DNA-damaging potential of tamoxifen (TAM) can shape the unfavorable but ready-to-fire tumor immune microenvironment in breast cancer. We discover that a long-term TAM administration unexpectedly induces JAK/STAT signaling and Type I interferon (IFN)-stimulated gene expression to promote T-cell infiltration. Furthermore, TAM also induces the expression of CEACAM1, which acts as an alternative T-cell inhibitory ligand via binding to TIM-3, a “checkpoint” receptor expressed on CD4+ and CD8+ T cells. The chromatin ‘‘reader’’ RACK7/ZMYND8, which functions as a transcriptional repressor of IFN-stimulated gene (ISG) and a critical factor in DNA repair, is found to be downregulated upon tamoxifen exposure and involved in the tamoxifen-mediated cellular modulation. We demonstrate that TAM in conjunction with RACK7-knockdown (KD) triggers robust upregulation of ISGs and CEACAM1 in both estrogen receptor-positive (ER+) and triple negative breast cancer (TNBC) cells. This immunomodulatory effect lead by loss of RACK7 is specific to TAM treatment, and is not observed when combined with other endocrine therapeutics. TAM combined with RACK7-KD promotes mitochondrial DNA damage, which leads to accumulation of cytosolic DNA and subsequent activation of the cGAS/STING pathway. The murine breast orthotopic models with TS/A, EO771 and 4T1 cells further demonstrate that TAM-mediated immunomodulatory in conjunction with RACK7-KD evokes cytokine/chemokine secretion and further induces T-cell infiltration into tumor microenvironment. However, the tumor killing effect is limited due to promotion of T-cell exhaustion from CEACAM1-TIM-3 interaction between tumor and T cells. Thus, our study indicates that targeting CEACAM1-TIM-3 interaction is crucial for TAM-mediated tumor immune response. This brings promising therapeutic approach with TAM by combining RACK7-KD with blockage to CEACAM1-TIM-3 interaction in breast cancer. The resistance of tamoxifen treatment may be overcome, and RACK7 may serve as both a therapeutic target and a biomarker to enable ICB therapy. Citation Format: Marvin A. Aberin, Yu-Ling (Pony) Lee, Xin-Guo Hsu, Chen-Yang Shen, Yao-Ming Chang, Kun-Yuan Lin, Chandan Guha, Shu-Ping Wang. New functional role of tamoxifen in breast cancer immunomodulation: role of RACK7 in activation of type I interferon signaling and CEACAM1/TIM-3-dependent immunosuppression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3646.
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Lee, Pony Yu-Ling, Marvin A. Aberin, Chien-Chang Shen, Kun-Yuan Lin, Chao Di Chang, Chih-Chieh Yang, Shan-Yun Cheng, Ya Wen Hung, Xin-Guo Hsu e Shu-Ping Wang. "Abstract 5953: Reshaping the tumor microenvironment: new application of tamoxifen in triple negative breast cancer immunomodulation". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 5953. http://dx.doi.org/10.1158/1538-7445.am2023-5953.
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Abstract Tamoxifen is a widely known estrogen receptor (ER) modulator which has been employed in adjuvant treatment of ER+ breast cancer for over 30 years. Interestingly, clinical observations reveal that tamoxifen is capable of inducing regression of some tumors lacking ER expression whereas tamoxifen is also capable of increasing host resistance against cancer in an ER-independent mechanism. These findings suggest the immunomodulatory effects of tamoxifen may be ER-independent, but little is known about the underlying mechanism and the potential clinical implication. Recently, we identified a novel mechanism by which tamoxifen exerts its DNA-damaging potential by re-shaping the unfavorable tumor microenvironment in breast cancer. A long-term tamoxifen administration induces downregulation of the chromatin ‘‘reader’’ RACK7/ZMYND8, which acts as a suppressor of interferon-stimulated genes (ISGs, including cytokines and chemokines) and CEACAM1 in both ER+ and triple negative breast cancer (TNBC) cells. To investigate the immunomodulatory effects of tamoxifen in conjunction with RACK7-knockdown, the orthotopic murine TNBC 4T1 model was employed to investigate tamoxifen-mediated cellular modulation in TNBC. The control and RACK7-knockdown 4T1 cells are orthotopically implanted into the mammary fat pad of female BALB/c mice. Peripheral cytokines/chemokines and high-content biomarker studies (multiplex immunoassays, flow cytometry, and single-cell RNA sequencing) are deployed to obtain insights into the mechanistic rationale behind the immunomodulatory effects of tamoxifen and/or RACK7-knockdown. The tamoxifen-mediated cellular modulation evokes cytokine/chemokine secretion and further induces T-cell infiltration into tumor area. However, tumor reduction was limited due to extensive T-cell exhaustion from interaction of CEACAM1 and TIM-3, a “checkpoint” receptor expressed in CD4+ and CD8+ T cells. The expression patterns of CEACAM1 and PD-L1 in 4T1 tumor cells and that of TIM-3 and PD-1 in CD4+ and CD8+ T-cells correlate with intra-tumor infiltration of T-cells and tumor cell growth. Therefore, targeting the interaction between CEACAM1 and TIM-3 to overcome T-cell exhaustion is crucial for the new therapeutic role of tamoxifen treatment in TNBC breast cancer in conjugation with RACK7-knockdown. Altogether, our findings provide direct evidence to support a new therapeutic opportunity by targeting CEACAM1-TIM-3 interaction in the tamoxifen-mediated tumor immune microenvironment for improving immune checkpoint blockade therapy in breast cancer. Citation Format: Pony Yu-Ling Lee, Marvin A. Aberin, Chien-Chang Shen, Kun-Yuan Lin, Chao Di Chang, Chih-Chieh Yang, Shan-Yun Cheng, Ya Wen Hung, Xin-Guo Hsu, Shu-Ping Wang. Reshaping the tumor microenvironment: new application of tamoxifen in triple negative breast cancer immunomodulation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5953.
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Lee, Chuan-Chun, Wan-Rong Wu, Yi-Chun Shen, Feng-Chi Chung, Yuan-Liang Wang, You-Zhe Lin, Chih-Hao Lu et al. "Abstract 2690: The role of PCNA tyrosine phosphorylation in evading innate immune surveillance". Cancer Research 84, n.º 6_Supplement (22 de março de 2024): 2690. http://dx.doi.org/10.1158/1538-7445.am2024-2690.
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Abstract Cancer cells are continually exposed to intrinsic and extrinsic proliferative stresses that can send the genome stability awry. The aberrant DNA metabolism, evolving through deregulated replicative growth in cancer cells, is increasingly recognized as a major mechanism bridging the crosstalk between the immune microenvironment and tumor tissue, thereby either promoting or suppressing tumor progression. However, the triggering and regulation of these mechanisms remain largely unknown. Proliferating cell nuclear antigen (PCNA) and its homologs are the evolutionarily conserved central components of the DNA replication machinery. In eukaryotic cells, PCNA forms homotrimeric rings encircling the DNA double helix to coordinate the complex processes of DNA replication and damage repair, directed at least in part by differential post-translational modifications of the PCNA protein. In cancer cells, growth signal-stimulated phosphorylation at tyrosine 211 of PCNA (pY211-PCNA) is known to play an important function for active proliferation. Here, we demonstrate that inhibition of pY211 disrupts the processivity of replication forks. This disruption triggers single-stranded DNA (ssDNA) production catalyzed by the MRE11 nuclease, activating the cGAS-STING axis to launch an anti-tumor immune response by natural killer (NK) cells. We further show that the pY211 regulates site-specific post-translational modifications of MRE11, and loss of pY211 promotes the endonuclease mode of MRE11. This causes ssDNA generation in the cytosol, subsequently inducing type I interferon-activated cytotoxicity by NK cells and fostering an anti-tumor immunity that abrogates distant metastasis. Mechanistically, the pY211 determines the recruitment of the writer or eraser of the modification on MRE11, thus tuning the nucleolytic modes of MRE11 and, consequently, ssDNA generation. Therapeutic measures promoting MRE11-dependent ssDNA enhance the response of triple-negative breast cancer to cytotoxic killing mediated by endogenous or allogenic NK cells in mice. In breast cancer patients, the level of cytosolic ssDNA is inversely correlated with the expression of the eraser and pY211-PCNA, which is associated with poor overall survival in cancer patients. Our studies shed new light on the shaping of the tumor immune microenvironment and demonstrate the potential to develop therapeutic approaches that proactively leverage genomic instability and immune activation to target malignant tumors. Citation Format: Chuan-Chun Lee, Wan-Rong Wu, Yi-Chun Shen, Feng-Chi Chung, Yuan-Liang Wang, You-Zhe Lin, Chih-Hao Lu, Wei-Chung Cheng, Han Chang, Liang-Chih Liu, Ji-An Liang, Chang- Fang Chiu, Mien-Chie Hung, Shao-Chun Wang. The role of PCNA tyrosine phosphorylation in evading innate immune surveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2690.
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Yin, Xin, Rie Kishida, Sarah Krull Abe, Md Rashedul Islam, Md Shafiur Rahman, Eiko Saito, Qing Lan et al. "Abstract 4200: Association between reproductive factors with lung cancer incidence and mortality: A pooled analysis of over 308,000 females in the Asia Cohort Consortium". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 4200. http://dx.doi.org/10.1158/1538-7445.am2023-4200.
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Abstract Background: Previous studies have investigated the association between reproductive factors and lung cancer risk; however, findings have been inconsistent. This study aims to assess the association between reproductive factors with lung cancer incidence and mortality among Asian women. Methods: A total of 308,949 female participants with a mean age of 55.13 from 11 prospective cohorts and four Asian countries (Japan, Korea, China, and Singapore) in the Asia Cohort Consortium (ACC) were included. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CIs). Results: A total of 3,119 primary lung cancer cases and 2,247 lung cancer deaths were identified with a mean follow-up of 16.4 years. Parous women had a lower risk of lung cancer incidence and mortality as compared with nulliparous women, with HRs of 0.82 (95% CI = 0.70 - 0.96) and 0.78 (95% CI = 0.65 - 0.94). Corresponding HRs were lowest among women with 1-2 children, with HRs of 0.78 (95% CI = 0.66 - 0.93) and 0.72 (95% CI = 0.59 - 0.87) for lung cancer incidence and mortality. The protective association of parity and lung cancer incidence was greater among ever-smokers (HR=0.66, 95% CI = 0.49 - 0.87) than in never-smokers (HR=0.90, 95% CI = 0.74 - 1.09) (P-interaction = 0.029). Compared with age at first delivery ≤20 years, older age at first delivery (≥26 years) was associated with a lower risk of lung cancer incidence and mortality. Compared with age at menopause <45 years, older age at menopause (≥55 years) was associated with a decreased risk of lung cancer mortality (HR=0.75, 95% CI = 0.58 - 0.96). Women who ever used hormone replacements had a higher likelihood of developing non-small cell lung cancer (HR = 1.30, 95% CI = 1.01 - 1.67), compared to those who never used hormone replacements. Conclusions: Distinct from Western women, Asian parous women, especially those who have 1-2 children had a lower risk of lung cancer incidence and mortality compared with nulliparous women. Future studies are needed to assess the underlying mechanisms, the relationships within these female reproductive factors, and the potential changes in smoking habits over time. Citation Format: Xin Yin, Rie Kishida, Sarah Krull Abe, Md. Rashedul Islam, Md. Shafiur Rahman, Eiko Saito, Qing Lan, Batel Bletcher, Melissa Merritt, Ji-Yeob Choi, Aesun Shin, Ryoko Katagiri, Xiao-Ou Shu, Norie Sawada, Akiko Tamakoshi, Woon-Puay Koh, Ichiro Tsuji, Chisato Nagata, Sue K. Park, Sun-Seog Kweon, Yu-Tang Gao, Shoichiro Tsugane, Takashi Kimura, Jian-Min Yuan, Yukai Lu, Seiki Kanemura, Yumi Sugawara, Keiko Wada, Min-Ho Shin, Habibul Ahsan, Paolo Boffetta, Kee Seng Chia, Keitaro Matsuo, You-Lin Qiao, Nathaniel Rothman, Wei Zheng, Manami Inoue, Daehee Kang, Wei Jie Seow. Association between reproductive factors with lung cancer incidence and mortality: A pooled analysis of over 308,000 females in the Asia Cohort Consortium. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4200.
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Lee, Pony Yu-Ling, Kun-Yuan Lin, Chao-Di Chang, Shan-Yun Cheng, Ya-Wen Hung, Chih-Chieh Yang, Yu-Hsien Chang et al. "Abstract 1449: Targeting squalene epoxidase for breast cancer brain metastasis: The evaluation of a new therapeutic target for brain extravasation and colonization using animal models". Cancer Research 84, n.º 6_Supplement (22 de março de 2024): 1449. http://dx.doi.org/10.1158/1538-7445.am2024-1449.
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Abstract Breast cancer brain metastasis is one of the most common forms of breast cancer metastasis and a major cause of morbidity and mortality. Patients who develop brain metastases tend to be associated with progressive neurologic deficits and short overall survival, which represents an unmet medical need. Extensive research has been conducted to elucidate the mechanism of cancer metastasis with limited information gained as to how cancer cells extravasate and colonize to the brain. Recently, we identified a novel mechanism by which squalene epoxidase (SQLE), the second rate-limiting enzyme in cholesterol biosynthesis, plays a critical role in the process of breast cancer metastasis to the brain. Thus, toward a better understanding of the underlying molecular mechanisms and applications of molecular target(s) for brain metastasis therapy, murine models were employed for investigation of brain extravasation and colonization with intracardiac or direct intracranial injections of GFP/FLuc-labeled human MDA-MB-231 metastatic breast carcinoma cells. The MDA-MB-231 cells were found to metastasize to the brain and other organs following intracardiac implantation into nude mice and were further isolated from each tissue. Interestingly, the isolated brain-metastasized tumor cells (MDA-MB-231-BrM) exhibited a significant upregulation of SQLE expression when compared with those that metastasized to other distal sites. The essential role of SQLE in the specific steps of the breast cancer-to-brain metastatic process was evaluated by ex vivo immunofluorescence analysis and immunohistochemistry staining of brain slices from the study subjects. Our data demonstrate that high SQLE expression is essential for MDA-MB-231-BrM to extravasate into the parenchyma, as well as the formation of micro- and macro-metastases in the brain. Interestingly, we found that blood vessel co-option and the surrounding neuronal cells play key roles in supporting MDA-MB-231-BrM to develop brain macro-metastases. In vitro blood-brain barrier (BBB) models further demonstrated the critical role of SQLE in promoting tumor cell invasion and penetration through the BBB. To verify SQLE as an oncogenic factor that can be selected as a potential therapeutic target in suppressing breast cancer brain metastasis, we evaluated the inhibitory effects of terbinafine (a SQLE inhibitor) in both the MDA-MB-231-BrM orthotopic and intracardiac mouse models. Pharmacologic inhibition of SQLE by terbinafine suppressed MDA-MB-231-BrM tumor growth at the mammary fat pad and distal metastases to the brain, suggesting that targeting SQLE represents a therapeutic opportunity for breast cancer brain metastasis. Citation Format: Pony Yu-Ling Lee, Kun-Yuan Lin, Chao-Di Chang, Shan-Yun Cheng, Ya-Wen Hung, Chih-Chieh Yang, Yu-Hsien Chang, Chien-Chang Shen, Jia-Yun Yeh, Yung-Lung Yu, Shu-Ping Wang. Targeting squalene epoxidase for breast cancer brain metastasis: The evaluation of a new therapeutic target for brain extravasation and colonization using animal models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1449.
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Bamdad, Cynthia, Joanne Mortimer, Yuan Yuan, Jennifer M. Specht, Benoit Smagghe, Stephen Chi-Min Lin, Andrew Stewart et al. "Abstract PO5-19-03: 1st-in-human CAR T targets MUC1 transmembrane cleavage product". Cancer Research 84, n.º 9_Supplement (2 de maio de 2024): PO5–19–03—PO5–19–03. http://dx.doi.org/10.1158/1538-7445.sabcs23-po5-19-03.
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Abstract Background: huMNC2-CAR44 and huMNC2-CAR22 are autologous CAR T cell therapies under study in an ongoing 1st-in-human trial for metastatic breast cancers (NCT04020575), being performed at City of Hope. Both CARs are targeted to the tumor by an antibody, huMNC2, that recognizes a cryptic binding site on MUC1*, which is the transmembrane cleavage product of MUC1. The antibody binds to an epitope that is only unmasked when MUC1 is cleaved to MUC1* by enzymes in the tumor microenvironment. huMNC2 strongly reacts with over 90% of breast cancers. No therapeutic that targets MUC1* had ever been tested in humans before this trial. We note that neither 5E5 nor antibodies that bind to a MUC1 “heterodimer” recognize MUC1*. Eight patients have already been treated with huMNC2-CAR44. The next 8 patients will be treated with huMNC2-CAR22 to enable comparison and inform decision as to which CAR to bring forward for completion of Phase 1 and entry into Phase 2. huMNC2-CAR22 differs from huMNC2-CAR44 in that it is resistant to exhaustion. CAR22 achieves greater in vivo persistence due to Sadelain’s “1XX” mutations of Tyr to Phe in 2 of the 3 ITAMs, which prevent Tyr phosphorylation and signaling, leaving signaling through ITAM 1 alone. Trial Design: Dose escalation or de-escalation is tested in cohorts of 3 patients each using standard “3+3” dose-finding, with the starting dose of 3.3x105 CAR+ T cells/kg up to a maximum of 1.0x107 CAR+ T cells/kg. Patients receive cyclophosphamide (300 mg/m2/day) and fludarabine (30 mg/m2/day) for 3 days prior to CAR T cell infusion. Safety will be evaluated by CTCAE version 5.0 and Lee criteria. Anti-tumor activity will be assessed by imaging studies completed between 1 and 3 months after huMNC2-CAR T cell infusion for determination of response by RECIST 1.1 or by FDG PET modified PERCIST for patients with predominant bone disease. Inclusion Criteria: Patients with confirmed diagnosis of breast cancer, with documented ER, PR, and HER2 status per ASCO/CAP guidelines. Patients with MUC1* expression of at least 30% by IHC. Patients must have received standard metastatic systemic therapy per NCCN guidelines which are known to confer benefit. No maximum on number of prior treatments. Patients must have received at least 2 or 3 prior lines of chemotherapy in the metastatic setting. Exclusion Criteria: Patients requiring >15 mg of prednisone per day or immunosuppressives; patients with major organ dysfunction; Serum creatinine > 2 mg/dL; Bilirubin ≥ 1.5 mg/dL; AST/ALT ≥ 2.5 x upper limit normal; 3x upper limit for patients with known liver metastasis; significant pulmonary dysfunction; significant cardiovascular abnormalities; ANC < 1000/mm3. Primary Objectives: To determine the safety and maximally tolerated cell dose (MTD) and recommended phase 2 cell dose (RP2D) of ex vivo expanded autologous huMNC2-CAR T cells for patients with advanced MUC1* positive breast cancer using CTCAE version 5.0 and Lee criteria. Secondary: Determine duration of in vivo persistence and phenotype of adoptively transferred huMNC2-CAR T cells. Determine antitumor activity by RECIST 1.1. Determine MTD/RP2D. Contact: City of Hope Comprehensive Cancer Center Joanne Mortimer, MD 1-800-826-4673 Minerva18625@coh.org Citation Format: Cynthia Bamdad, Joanne Mortimer, Yuan Yuan, Jennifer M. Specht, Benoit Smagghe, Stephen Chi-Min Lin, Andrew Stewart, Danica Walkley, Mark Carter, Timothy Synold, Vishwas Parekh, Kevin Yi, Jac-Leen Nash, Michael Nash, Qing Liu-Michael, Stanley Hamilton, Stephen Forman. 1st-in-human CAR T targets MUC1 transmembrane cleavage product [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-03.
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Wang, Hsin-Yi, Chao-Chi Ho, Yen-Ting Lin, Wei-Yu Liao, Chung-Yu Chen, Jin-Yuan Shih e Chong-Jen Yu. "Abstract 6702: The clinical characteristics and outcomes of NSCLC patients with genomic alterations detected by blood-based NGS ctDNA assay". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 6702. http://dx.doi.org/10.1158/1538-7445.am2023-6702.
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Abstract Background: The Blood First Assay Screening Trial (BFAST) (NCT03178552) is a prospective study screening for actionable genetic alterations using NGS of ctDNA among patients with treatment-naive advanced or metastatic NSCLC. We aimed to perform a more systematic investigation of genomic alterations in Asia/Taiwan NSCLC patients through the BFAST database at NTUH. Materials and Methods: There was a total of 269 patients enrolled and receiving FoundationOne Liquid Companion Diagnostic (F1LCDx) assay at cancer diagnosis between Feb, 2019 and Mar, 2022 in NTUH. The concordance of tissue-based genetic testing in the real-life clinical setting and the blood-based NGS testing in the clinical trial were analyzed. The co-occurrence of genomic alterations detected with blood-based NGS ctDNA assay were also interpreted. Results: A total of 206 patients (76.5%) detected driver mutations. Tissue-based genetic testing in the real-life clinical setting missed driver mutations in 67 (24.9%) patients with a sensitivity of 67.32%. Liquid NGS detected 38 (14%) patients with RET, KRAS, Met or ErbB2 mutations which were beyond the scope of current genetic testing in the clinical settings. Also, the F1LCDx assay detected more uncommon EGFR mutations than the Roche Cobas EGFR Mutation Test V2 (P < 0.0001). Thirty-four (12.6%) patients had non-detected results in the F1LCDx assay which produced a sensitivity of 83.41%. By multivariate analysis, the predictors associated with discordant blood-based NGS ctDNA results were T stage (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.15-0.79, p = 0.012) and M stage (OR 0.21, 95% CI 0.09-0.49, p < 0.0001). The most common co-occurring mutations in the blood-based NGS ctDNA assay were TP53, DNMT3A, TET2, PIK3CA and CTNNB1. Among the EGFR mutant population, first-generation compared to third-generation TKI use (hazard ratio [HR] = 0.43, 95% CI 0.22-0.85, P=0.02) and co-occurring genomic alterations in TET2 (HR = 2.35, 95% CI 1.15-3.48, P=0.02) were associated with shorter progression free survival of EGFR TKIs treatment in multivariate analysis. Disease stage was the only factor associated with overall survival in the EGFR mutant population. Conclusion: NGS ctDNA analysis provided a more comprehensive genetic testing than conventional single gene testing kits. The lower stage which could imply lower or lack of ctDNA shedding into the blood was associated with a discordant result of the blood-based NGS ctDNA assay. Co-occurring mutations might have an impact on the treatment duration of EGFR-TKI. Citation Format: Hsin-Yi Wang, Chao-Chi Ho, Yen-Ting Lin, Wei-Yu Liao, Chung-Yu Chen, Jin-Yuan Shih, Chong-Jen Yu. The clinical characteristics and outcomes of NSCLC patients with genomic alterations detected by blood-based NGS ctDNA assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6702.
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Wang, Shu-Ping, Jia-Yun Yeh, Yu-Ling (Pony) Lee, Kun-Yuan Lin, Chao-Di Chang, Chih-Chieh Yang, Shan-Yun Cheng et al. "Abstract 1550: Identification of a novel squalene epoxidase function in breast cancer brain metastasis". Cancer Research 84, n.º 6_Supplement (22 de março de 2024): 1550. http://dx.doi.org/10.1158/1538-7445.am2024-1550.
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Abstract Brain metastases are serious complications of breast cancer, especially in triple-negative breast cancer (TNBC) patients. There is currently no effective treatment due to the unique brain microenvironment and limitation for drugs to cross the blood-brain barrier (BBB). BBB limits access of nutrients from the circulation and thereby makes the brain hypoxic and depleted of metabolites, growth factors and proteins. However, it remains poorly understood how breast cancer cells manipulate for adaption and colonization in the brain. To probe the molecular mechanism of breast cancer brain metastasis (BCBM), we compared gene signatures in primary breast tumors and BCBM tumors, and identified that SQLE (encodes squalene epoxidase, the second rate-limiting enzyme in the cholesterol biosynthesis) could be a leading-edge gene in breast cancer brain metastasis. To explore the role of SQLE in BCBM, we established the brain metastatic TNBC MDA-MB-231 (MDA231-BrM) cell line from brain metastatic subpopulation that originated from its parental MDA-MB-231 (MDA231) cell line. We found that SQLE expression was greatly upregulated in MDA231-BrM cells compared with the parental MDA231 cells. Using MDA231-BrM and MDA231 cell lines expressing SQLE shRNAs, we evaluated the effects of SQLE loss on cancer cell migration, invasion, and stemness by wound-healing, transwell invasion/migration, and tumorsphere formation assays. While loss of SQLE greatly attenuated cell invasiveness and stemness in both MDA231 and MDA231-BrM cells, loss of SQLE could only affect the cell migration activity on MDA231 cells but not MDA231-BrM cells. Our RNA-seq data further identified a subset of SQLE-affected genes that is uniquely enriched in MDA231-BrM cells and favors brain extravasation and colonization. To explore the potential function of SQLE in brain extravasation and colonization, we established in vitro BBB models and ex vivo mouse brain slice organotypic cultures. We showed that loss of SQLE inhibited the ability of MDA231-BrM cells to across the BBB-mimic astrocyte-endothelial structures as well as impaired the co-option with blood capillaries in the mouse brain slices. Although SQLE-deficient MDA231-BrM cells could still spread on the surface of the blood vessels, they seemed to undergo apoptosis. Since the ability to invade, migrate, and penetrate is critical for invasion of cancer cells, our results strongly imply the novel function of SQLE in breast cancer cell invasion, penetration, and even colonization in the brain through blood vessel co-option. In summary, our data reveal a novel role for SQLE in two critical requisites for breast-to-brain extravasation and colonization - the ability to penetrate through BBB and to co-opt brain vessels for metastatic expansion. Our findings indicate that targeting SQLE may represent a therapeutic opportunity for breast cancer brain metastases. Citation Format: Shu-Ping Wang, Jia-Yun Yeh, Yu-Ling (Pony) Lee, Kun-Yuan Lin, Chao-Di Chang, Chih-Chieh Yang, Shan-Yun Cheng, Ya-Wen Hung, Yu-Hsien Chang, Yao-Feng Li, Yung-Lung Yu. Identification of a novel squalene epoxidase function in breast cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1550.
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Hsu, B. C., H. H. Chen, C. H. Lin, Y. M. Chen, K. L. Lai, D. Y. Chen, W. N. Huang e Y. H. Chen. "OP0069 FACTORS ASSOCIATED WITH THE RISK OF SEPSIS IN PATIENTS WITH IMMUNE-MEDIATED INFLAMMATORY DISEASES TREATED WITH ANTI-TUMOR NECROSIS FACTOR-ALPHA: A NATIONWIDE, POPULATION-BASED COHORT STUDY". Annals of the Rheumatic Diseases 79, Suppl 1 (junho de 2020): 46.1–47. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1601.
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Background:Anti-TNF-α agents have been proven to be effective for patients with immune-medicated inflammatory diseases (IMIDs) including rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriasis (PsO), psoriatic arthritis (PsA), Crohn’s disease (CD) and ulcerative colitis (UC). Prior studies have shown an increased risk of infection in IMID patients treated with anti-TNF-α but limited studies investigated factors associated with the development of sepsis in patients with IMIDs.Objectives:To investigate factors associated with the development of sepsis in patients with IMIDs using the Taiwanese National Health Insurance Research Database (NHIRD).Methods:We identified all biologic-naïve patients with RA, AS, PsO, PsA, or CD/UC from the claim data via the NHIRD who started their first anti-TNF-α agent (etanercept (ETN), adalimumab (ADA) or golimumab (GOL)) between 2003 and 2017 as study subjects. The index date was the first date of anti-TNF-α prescription. Sepsis was defined based on the sepsis-3 definition. We identified sepsis patients using a validated ICD-9-CM coding system proposed by Angus et al, in which a diagnosis of bacterial/fungal infection with one or more acute organ dysfunction is required to define an episode of sepsis. All study subjects were followed up till the date of first hospitalization due to sepsis, 90 days after the last date of anti-TNF-α prescription, withdrawal from NHIRD or death, whichever came first. We used a Cox regression analysis to assess the associations of covariates with the risk of sepsis shown as hazard ratios (HRs) with 95% confidence interval (CIs). Covariates included anti-TNF-α agent, IMID, age, sex, insured amount, level of urbanization, disease duration, Charlson comorbidity index (CCI), a history of prior hospitalization due to sepsis within 3 months before the index date and medication use within 12 months before the index date and during the follow-up period.Results:We identified 18105 biologic-naïve patients with IMIDs, including 8123 ETN users, 7623 ADA users and 2359 GOL users. The incidence rates (IRs) of sepsis in patients treated with ETN, ADA and GOL were 1080, 1181, and 617 per 105years respectively. Multivariable regression analyses showed that factors associated with an increased risk of sepsis were use of ADA (ETN as reference: HR, 1.21; 95% CI, 1.02–1.42), male (HR, 1.24; 95% CI, 1.04–1.48), age (HR, 1.06; 95% CI, 1.05–1.07), CD/UC (HR, 2.35; 95% CI, 1.57–3.53), CCI (HR, 1.30; 95% CI, 1.23–1.38), prior sepsis (HR, 2.42; 95% CI, 1.78–3.29), prior use of sulfasalazine (HR, 1.25, 95% CI, 1.00-1.55), lower levels of urbanization (level III: HR, 1.37; 95% CI, 1.06–1.77; level IV: HR, 1.68, 95% CI, 1.35–2.10). Factors associated with a decreased risk of sepsis were use of GOL (ETN as reference: HR, 0.59; 95% CI, 0.39–0.84), use of methotrexate (HR, 0.78; 95% CI, 0.65–1.00), and higher insured amount (reference: ≤ 15480 NTD; 15480–28800 NTD: HR, 0.83; 95% CI, 0.68–0.99; 28800–45800 NTD: HR, 0.58; 95% CI, 0.45–0.74; >45800 NTD: HR, 0.33; 95% CI, 0.21–0.54).Conclusion:Our study revealed that among biologic-naïve IMID patients initiating anti-TNF-α treatment, use of ADA, age, sex, CD/UC, CCI, prior sepsis, prior use of sulfasalazine and lower levels of urbanization were associated with an increased risk of sepsis, while use of GOL, use of methotrexate, and higher insured amount were associated with a decreased risk of sepsis.Disclosure of Interests:BO-CHUEN HSU: None declared, Hsin-Hua Chen: None declared, Ching-Heng Lin: None declared, Yi-Ming Chen: None declared, Kuo-Lung Lai: None declared, Der-Yuan Chen: None declared, Wen-Nan Huang: None declared, Yi-Hsing Chen Grant/research support from: Taiwan Ministry of Science and Technology, Taiwan Department of Health, Taichung Veterans General Hospital, National Yang-Ming University, GSK, Pfizer, BMS., Consultant of: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, GSK, Astra& Zeneca, Sanofi, MSD, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Gilead., Paid instructor for: Pfizer, Novartis, Johnson & Johnson, Roche, Lilly, Astra& Zeneca, Sanofi, Astellas, Agnitio Science Technology, United Biopharma., Speakers bureau: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, GSK, Astra& Zeneca, Sanofi, MSD, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Gilead.
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Chen, Tom Wei-Wu, Wen Hsiao, Ming-Shen Dai, Ching-Hung Lin, Dwang-Ying Chang, I.-Chun Chen, Ming-Yang Wang et al. "Abstract P2-01-09: Clinical impact of ESR1 mutation ctDNA on survival outcome is dependent on PI3KCA/TP53 ctDNA mutation status". Cancer Research 82, n.º 4_Supplement (15 de fevereiro de 2022): P2–01–09—P2–01–09. http://dx.doi.org/10.1158/1538-7445.sabcs21-p2-01-09.
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Abstract Background: With more endocrine therapies- (ET) based treatment (tx) available, genomic markers that could assist in the prediction of tx outcome is critical. The role of ctDNA mutations in ER+/HER2- metastatic breast cancer (MBC) after prior ET is based on retrospective study results. Methods: ER+/HER2- MBC patients (pts) starting ET-based salvage tx were eligible (NCT04212702). Cell-free DNA (cfDNA) was extracted from plasma before tx, and prepared for next-generation sequencing (NGS) analysis. The targeted NGS for ctDNA included regions of the ESR1 ligand-binding domain, PIK3CA hotspot mutations, and TP53 DNA-bonding domain mutations. 96% of the samples were sequenced at an average depths >10000x using the Ion Torrent platform. Progression-free survival (PFS) was defined from the start of the salvage tx to the date of progression. Results: From 2015/08 to 2020/05, a total of 163 pts treated with ET-based tx were prospectively enrolled. The median age was 60 (32-92). 13%, 15%, 48%, and 17% of pts received ET only, ET + CDK4/6 inhibitor, ET + everolimus, and ET + metronomic chemotherapy, respectively. Only 14 patients received fulvestrant as ET. The median level of recovered cfDNA was 38.5 ng (range 4.4-1935) and the level of cfDNA was significantly and inversely correlated with PFS (p = 0.0032). With mutation ctDNA ≥ 0.5% as a threshold for positive calling, 100 (61.3%), 41 (25.1%), and 25 (15.3) pts have at least one ESR1, PIK3CA, and TP53 mutation, respectively and 61 (37.4%) pts had >1 ESR1 mutation genotypes. The median PFS of the cohort (n=163) was 8.3 mos (95% CI 5.7 – 11.1 mos). PIK3CA mutation (MT) in ctDNA was associated with a worse outcome in all patients (HR 1.91, 95% CI 1.20 to 3.04, p = 0.0064) and the subgroups of ET + everolimus (HR 2.20, 95% CI 1.10 – 4.39, p = 0.025) and ET + metronomic chemotherapy (HR 5.34, 95% CI 1.63- 17.54, p = 0.006). The presence of TP53 MT ctDNA was also associated with worse PFS (HR 1.81, p = 0.043, n = 163) but also exerted a poor prognostic impact in pts with wild type (WT) PIK3CA (HR 3.28, 95% CI 1.44 – 7.48, p = 0.0048). However, the variant allelic frequency (VAF) of PIK3CA MT (p = 0.0421), but not TP53 MT (p = 0.7723), had a inverse linear correlation with PFS. Surprisingly, pts with ESR1 MT had a better PFS as compared to ESR1 WT pts (HR 0.68 95% CI 0.46 – 0.99, p = 0.049). However, if the threshold for. variant calling was raised to 2%, then ESR1 MT (n= 52, 31.9%) vs WT pts had similar PFS (median PFS 8.6 vs 7.8 mos, HR 0.92, 95% CI 0.62-1.37, p = 0.69), suggesting that defining different VAF threshold of MT ESR1 may have divergent PFS impact. How ERS1 MT ctDNA affected PFS was dependent on PIK3CA/TP53 status. When either PIK3CA or TP53 MT ctDNA was present, the ESR1 MT ctDNA did not have any impact on PFS, regardless of VAF. In pts with WT PIK3CA/TP53, pts with ESR1 MT ctDNA VAF 0.5 – 2.0% had a significant better PFS as compared with triple WT pts (HR 1.9, p = 0.0035). Conclusion: Using a 3-gene panel for ctDNA testing with MT ctDNA ≥ 0.5% as a threshold for positive calling in ER+/HER2- MBC pts treated with ET-based tx, the presence of PIK3CA and TP53 mut in ctDNA conferred a worse prognosis. The positive prognostic impact of ESR1 was only noticeable in pts with PIK3CA and TP53 WT ctDNA, and the presence of a low VAF ESR1 MT ctDNA, which may suggest an ER denpendency, was significantly correlated with a better outcome. Table 1.Median PFS of pts with and without PIK3CA, TP53 and ESR in ctDNAPopulation (n)Genotype(s)Median PFS (mos)Hazard Ratiop-valueAll (163)PIK3CA MT (41) vs. WT (122)(VAF ≥ 0.5%)5.4 vs. 10.31.910.0064TP53 MT (25) vs. WT (143)(VAF ≥ 0.5%)4.1 vs. 8.91.810.0439ESR1 MT vs. WT(VAF ≥ 0.5%)9.8 vs. 5.80.680.0493ET + everolimus (82)PIK3CA MT vs. WT(VAF ≥ 0.5%)2.8 vs. 5.92.200.0254PIK3CA and TP53 WT (106)WT vs ESR1 MT (VAF ≥ 0.5% - < 2%)6 vs 15.61.910.0035WT vs ESR1 MT (VAF ≥ 2%)6 vs 121.360.355 Citation Format: Tom Wei-Wu Chen, Wen Hsiao, Ming-Shen Dai, Ching-Hung Lin, Dwang-Ying Chang, I-Chun Chen, Ming-Yang Wang, Ling-Yi Huang, Shu-Han Chang, Shu-Min Huang, Ann-Lii Cheng, Kien Thiam Tan, Yen-Shen Lu. Clinical impact of ESR1 mutation ctDNA on survival outcome is dependent on PI3KCA/TP53 ctDNA mutation status [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-01-09.
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Blechter, Batel, Chao Agnes Hsiung, Keitaro Matsuo, Kouya Shiraishi, Kevin Wang, Haoyu Zhang, Wei Jie Seow et al. "Abstract 6149: Polygenic risk score and lung adenocarcinoma risk among never-smokers by EGFR mutation status". Cancer Research 84, n.º 6_Supplement (22 de março de 2024): 6149. http://dx.doi.org/10.1158/1538-7445.am2024-6149.
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Abstract Background: Lung cancer is the leading cause of cancer mortality worldwide, and incidence rates for the disease in never-smokers is among the highest in East Asian (EAS) women. Epidermal growth factor receptor (EGFR) is a transmembrane protein that regulates cellular proliferation and apoptosis, and mutations in the EGFR gene have been found to be a defining hallmark of lung adenocarcinoma (LUAD). We investigated if overall genetic susceptibility to LUAD, defined as a polygenic risk score (PRS), is differentially associated with LUAD by EGFR mutation status. Methods: The study consists of 998 female never-smoking histologically confirmed LUAD cases with data on EGFR mutation status and 4,544 female never-smoking controls from the Female Lung Cancer Consortium in Asia. Germline DNA samples were genotyped using the 370K, 610Q, or 660W microarrays. Genomic DNA extracted from fresh, frozen or formalin-fixed paraffin-embedded tumor tissue samples of LUAD cases were genotyped for EGFR mutations on exons 19 and 21. We defined cases with EGFR mutation on either exon as EGFR+ (n=518) and cases without such EGFR mutation as EGFR- (n=480). Weights from 942,592 single nucleotide variants derived from a previously conducted genome-wide association study were used in a Bayesian-based approach, LDpred2, to derive a PRS for all participants. We estimated the odds ratios (OR) and 95% confidence intervals (CI) for the association between continuous PRS, PRS quartiles and tumor EGFR mutation status using logistic regression models in a case-case analysis, as well as using a multinomial logistic regression treating controls as the reference. All models were adjusted for age, study and the top 10 principal components. Results: In case-case comparisons, compared to EGFR- LUAD, we found a positive association between continuous PRS and risk of EGFR+ LUAD (OR=1.17, 95% CI: 1.02, 1.34), as well as a dose-response relationship between quartiles of the PRS and EGFR+ LUAD (p-trend=0.003). We further found that the association between the fourth quartile of the PRS with EGFR+ LUAD (OR=8.63, 95% CI: 5.67, 13.14) was significantly higher than the association between the fourth quartile of the PRS with EGFR- LUAD (OR=3.50, 95% CI: 2.44, 5.00) compared to controls (p-heterogeneity=0.004). Conclusions: We found that the PRS developed for LUAD in EAS individuals was more strongly associated with EGFR+ LUAD compared to EGFR- LUAD, suggesting that germline genetic susceptibility may be differentially associated with LUAD in never-smoking female EAS patients depending on the cancer’s mutation status. Given that patients with LUAD respond differently to treatments that are used as targeted therapy depending on their EGFR mutation status, our findings may have important public health and clinical implications, which may guide risk stratification, screening, and treatment. Citation Format: Batel Blechter, Chao Agnes Hsiung, Keitaro Matsuo, Kouya Shiraishi, Kevin Wang, Haoyu Zhang, Wei Jie Seow, Jianxin Shi, Nilanjan Chatterjee, Jason Y.Y. Wong, Juncheng Dai, H. Dean Hosgood, I-Shou Chang, Jiyeon Choi, Wei Hu, Wei Zheng, Young Tae Kim, Xiao-Ou Shu, Qiuyin Cai, Pan-Chyr Yang, Dongxin Lin, Kexin Chen, Yi-Long Wu, Hongbin Shen, Takashi Kohno, Stephen J. Chanock, Nathaniel Rothman, Qing Lan. Polygenic risk score and lung adenocarcinoma risk among never-smokers by EGFR mutation status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6149.
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Benn, P. "Re: Non-invasive prenatal testing for trisomies 21, 18 and 13: clinical experience from 146 958 pregnancies. H. Zhang, Y. Gao, F. Jiang, M. Fu, Y. Yuan, Y. Guo, Z. Zhu, M. Lin, Q. Liu, Z. Tian, H. Zhang, F. Chen, T. K. Lau, L. Zhao, X. Yi, Y. Yin and W. W". Ultrasound in Obstetrics & Gynecology 45, n.º 5 (24 de abril de 2015): 512–13. http://dx.doi.org/10.1002/uog.14846.
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Chen, H. H., W. C. Chao, Y. H. Chen, D. Y. Chen e C. H. Lin. "FRI0531 AIR POLLUTANTS AND DEVELOPMENT OF INTERSTITIAL LUNG DISEASE IN PATIENTS WITH AUTOIMMUNE DISEASES". Annals of the Rheumatic Diseases 79, Suppl 1 (junho de 2020): 865.1–865. http://dx.doi.org/10.1136/annrheumdis-2020-eular.204.
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Background:Interstitial lung disease (ILD) is characterized by progressive inflammation and fibrosis, and accumulating evidence have shown that exposure to air pollutants was associated with the development of ILD. Autoimmune diseases are highly correlated with ILD, including connective tissue disease-associated ILD (CTD-ILD) as well as interstitial pneumonia with autoimmune features (IPAF), and the development of ILD is a crucial cause of morbidity and mortality in patients with autoimmune diseases. One recent Taiwanese study reported that exposure to air pollutants was associated with incident systemic lupus erythematosus (SLE). However, the impact of air pollutants on the development of ILD among patients with autoimmune diseases remains unknown.Objectives:The study aimed to address the impact of accumulating exposure to air pollutant above moderate level, defined by Air Quality Index (AQI) value higher than 50, on the development of ILD in patients with autoimmune diseases including SLE, rheumatoid arthritis (RA) and primary Sjögren’s syndrome (SS).Methods:We used a National Health Insurance Research Database in Taiwan to enroll patients with SLE (International Classification of Diseases (ICD)-9 code 710.0, n=13,211), RA (ICD-9 code 714.0 and 714.30–714.33, n=32,373), and primary SS (ICD-9 code, 710.0, n=15,246) between 2001 and 2013. We identified newly diagnosed ILD cases (ICD-code 515) between 2012 and 2013 and selected age, sex, disease duration and index-year matched (1:4) patients as non-ILD controls. The hourly levels of air pollutants one year prior to the index-date were obtained from 60 air quality monitoring stations across Taiwan, and the air pollutants in the present study consisted of particulate matter <2.5 μm in size (PM2.5), particulate matter <10 μm in size (PM10), nitrogen dioxide (NO2), carbon monoxide (CO), sulfur dioxide (SO2) and ozone (O3). We used a spatio-temporal model built by a deep-learning mechanism to estimate levels of air pollutants at 374 residential locations based on data of 3 air quality monitoring stations near the location (8). Notably, we used cumulative exposed hours to air pollutants higher than modest level, defined by AQI criteria, given that daily mean level of air pollutants might possibly underestimate the triggered inflammatory effect by a temporary exposure of high-level air pollutant. A conditional logistic regression was used to determine the association between exposure to air pollutant and the development of ILD, adjusting age, gender, Charlson Comorbidity Index (CCI), urbanization, family income, and medications for autoimmune diseases.Results:A total of 272 patients with newly diagnosed ILD were identified among patients with autoimmune diseases, including 39 with SLE, 135 with RA, and 98 with primary SS. We found that the duration of exposure to PM 2.5 higher than modest level was associated with the risk of ILD development in patients with SS (adjOR 1.07, 95% CI 1.01–1.13), and similar trends were also found in patients with SLE (adjOR 1.03, 95% CI 0.95–1.12) and RA (adjOR 1.03, 95% CI 0.99–1.07). Intriguingly, we observed an inverse correlation between the duration of exposure to O3 and the development of ILD in patients with SS (adjOR 0.83, 95% CI 0.70–0.99); however, the finding was not found in patients with SLE (adjOR 1.13, 95% CI 0.92–1.37) and RA (adjOR 0.98, 95% CI 0.87–1.11).Conclusion:In conclusion, we identified that longer exposure to PM2.5 higher than modest level tended to be associated with the development of ILD in patients with autoimmune diseases, mainly SS.References:[1] Araki T, Putman RK, Hatabu H, Gao W, Dupuis J, Latourelle JC, et al. Development and Progression of Interstitial Lung Abnormalities in the Framingham Heart Study. Am J Respir Crit Care Med 2016;194:1514-1522.[2] Tang KT, Tsuang BJ, Ku KC, Chen YH, Lin CH, Chen DY. Relationship between exposure to air pollutants and development of systemic autoimmune rheumatic diseases: a nationwide population-based case-control study. Ann Rheum Dis 2019;78:1288-1291.Disclosure of Interests:Hsin-Hua Chen: None declared, Wen-Cheng Chao: None declared, Yi-Hsing Chen Grant/research support from: Taiwan Ministry of Science and Technology, Taiwan Department of Health, Taichung Veterans General Hospital, National Yang-Ming University, GSK, Pfizer, BMS., Consultant of: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, GSK, Astra& Zeneca, Sanofi, MSD, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Gilead., Paid instructor for: Pfizer, Novartis, Johnson & Johnson, Roche, Lilly, Astra& Zeneca, Sanofi, Astellas, Agnitio Science Technology, United Biopharma., Speakers bureau: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, GSK, Astra& Zeneca, Sanofi, MSD, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Gilead., Der-Yuan Chen: None declared, Ching-Heng Lin: None declared
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Deng, Yilun, Harshita Gupta, Myrna Garcia, Aravind Kancharla, Ryan Reyes, Alvaro Padron e Tyler Curiel. "234 Distinct efficacy and immunological responses to αPD-1, αPD-L1 and αPD-L2 immunotherapy in aged versus young hosts". Journal for ImmunoTherapy of Cancer 9, Suppl 2 (novembro de 2021): A249—A250. http://dx.doi.org/10.1136/jitc-2021-sitc2021.234.
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BackgroundAging is the biggest risk factor for cancer, yet there are limited pre-clinical/clinical data regarding aging effects on immune checkpoint (IC) inhibition (ICI) outcomes. αPD-1 can potentially block PD-L1 and PD-L2 while αPD-L1 can block PD-1 and CD80. Melanoma response to αPD-1/αPD-L1 correlates with CD8+TCF-1+ T cell stem cell (TCSC) generation.1 Lack of host IL-17 can lead to increased IFN-γ production.2 3MethodsWe tested αPD-1 (200 μg/mouse), αPD-L1 (100 μg/mouse) or αPD-L2 (200 μg/mouse) in aged (18–33 months) and young (3–8 months) mice challenged orthotopically with B16 (WT or PD-L1ko) or TPN61R melanoma (NRAS mutation melanoma model)4 (αPD-L2 only) (SQ). Tumors were analyzed by flow. We tested αPD-L2 (20 μg/ml) effects by co-culturing young or aged T cells ± young or aged myeloid cells.ResultsWe reported that αPD-1 treats young and aged with B16 whereas αPD-L1 treats young not aged.5 αPD-L2 treated B16 and TPN61R melanoma in aged but, remarkably, not young, the first single agent anti-cancer immunotherapy exhibiting this property (figure 1). B16 tumors from aged had differential IC content (PD-1, PD-L1, CD80, PD-L2) versus tumors from young (e.g., more PD-L2+ tumor and stroma cells in aged mice; figure 2). Efficacy in young (αPD-1, αPD-L1) and aged (αPD-L2) correlated with increased tumor TCSC content (figure 3). αPD-L2 efficacy against B16 in aged mice required host IFN-γ and IL-17 (figure 4). αPD-1 efficacy against B16 in aged appeared to be host and tumor PD-L1 independent (figure 5). PD-L1KO B16 response to αPD-1 in aged also correlated with increased tumor TCSC content. Myeloid cell PD-L2 signaling inhibited aged but not young CD8+ T cell IL-2 production in vitro (figure 6).Abstract 234 Figure 1Abstract 234 Figure 2Abstract 234 Figure 3Abstract 234 Figure 4Abstract 234 Figure 5Abstract 234 Figure 6ConclusionsTreatment differences in aged versus young could depend on IC, TCSC and/or host cytokine differences (IL-17/IFN-γ). αPD-1 efficacy in aged PD-L1KO mice challenged with PD-L1KO B16 suggests that PD-L2 block is sufficient for αPD-1 efficacy in aged. PD-L2 expression differences in the tumor microenvironment could also contribute to treatment efficacy differences. PD-L2 inhibitory signaling on aged but not young CD8+ T cells is a likely mechanism for αPD-L2 efficacy in aged but not young. We are now testing the role of IL-17 in αPD-L2 efficacy as it could be upstream of IFN-γ effects, and TCSC effects in aged versus young. Our work can improve cancer immunotherapy in aged hosts and provides insights into treatment failure, including in young hosts.AcknowledgementsSouth Texas MSTP training grant (NIH T32GM113896), TL1TR002647, NIH T32AI138944, R01 CA231325, Waxman Grant, UL1 TR001120ReferencesMiller BC, Sen DR, Al Abosy R, Bi K, Virkud YV, LaFleur MW, Yates KB, Lako A, Felt K, Naik GS, et al. Subsets of exhausted CD8(+) T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol 2019;20(3):326–336.Moroda M, Takamoto M, Iwakura Y, Nakayama J, Aosai F. Interleukin-17A-deficient mice are highly susceptible to toxoplasma gondii infection due to excessively induced T. gondii HSP70 and interferon gamma production. Infection and immunity 2017;85(12):e00399–00317.Yi T, Zhao D, Lin C-L, Zhang C, Chen Y, Todorov I, LeBon T, Kandeel F, Forman S, Zeng D. Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease. Blood, The Journal of the American Society of Hematology 2008;112(5):2101–2110.Burd CE, Liu W, Huynh MV, Waqas MA, Gillahan JE, Clark KS, Fu K, Martin BL, Jeck WR, Souroullas GP. Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma. Cancer discovery 2014;4(12):1418–1429.Padron A, Hurez V, Gupta HB, Clark CA, Pandeswara SL, Yuan B, Svatek RS, Turk MJ, Drerup JM, Li R, et al. Age effects of distinct immune checkpoint blockade treatments in a mouse melanoma model. Exp Gerontol 2018;105:146–154.Ethics ApprovalAll animal studies are approved by UTHSA IACUC.
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Nataliia, Sun. "The genesis of Taiwanese piano art: historical and cultural context". Problems of Interaction Between Arts, Pedagogy and the Theory and Practice of Education 63, n.º 63 (23 de janeiro de 2023): 52–74. http://dx.doi.org/10.34064/khnum1-63.03.
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Introduction. The article examines the origins of Taiwanese piano art, its evolution, the influence of national and numerous non-national musical traditions. Until today, no special study devoted to the general panorama of these important processes has been created. The general picture of the formation and development of Taiwanese musical culture in the context of the political, economic and social situation is considered. The purpose of the article is to highlight the origins of Taiwanese piano art, which influenced its evolution, the process of introducing national and numerous non-national elements at the main stages of its formation and development. With the help of analytical, historical, comparative, interdisciplinary methods of research, a number of tasks are solved: the role of Western Christian missionaries in the development of musical education and piano art on the island is determined, the reasons why the Western classical music was accepted by the local society, the questions about the founders of the system of Western of classical music education, the programs and forms of learning in the first music schools in Taiwan, the names of the first Taiwanese composers-pianists are clarified; а periodization of the development of piano art in Taiwan is proposed. Results. The most important historical stages of the formation and development of Taiwanese piano art can be considered: – the period of its creation from the end of the 16th century to 1894; – the period of Japanese colonial rule from 1895 to 1945; – the period of development of national self-awareness, 1946–1986; – the period of reunification with mainland China from 1987. The proposed periodization makes it possible to reveal the entire historical and cultural context of the existence of piano art in Taiwan, to project its genetic settings for further stages of its development. Its basis was national folklore, but since the middle of the 16th century, the island was visited by Spanish, Portuguese, Dutch and Canadian colonists, and the first contacts of Western music with the indigenous population of Taiwan were made thanks to the activities of Western missionaries and were subordinated mainly to religious purposes. The stage of Japanese colonial rule was important for the development of piano art on the island. Due to the influence of Japan, Taiwanese musicians had further opportunities to join the system of Western classical music education, as the Japanese government was helping Taiwanese youth to obtain it. After 1920, Western classical music becomes popular in Taiwan; the formation of composer creativity in the field of piano music also takes place – the activities of such Taiwanese composers and pianists as Chiang Wen-Yeh, Chen Sizhi, Kuo Chih-Yuan, Kao Tzu-Mei and others. In the years 1946–1986, we observe the further development of performing and teaching activities at the island, a bright burst of creativity by such composers as Chang-Hui Hsu, Hsiao Tyzen, Shui-Long Ma and others. After 1987, active musical contacts between China and Taiwan contribute to the further progress of the island’s piano art. The piano works of Taiwanese composers Shih-Hui Chen, Fan-Ling Su, Chien-Yu Huang and others are widely popularized. In recent decades, the performing activities of Taiwanese pianists, represented in the international space by the names of Chien-Yu Huang, Yi Chih Lu, Chiu Tze Lin and many others, have become very active. Today, the piano art of Taiwan is the most important part of not only Chinese, but also world music culture. Conclusions. The study of the origins of the piano art of Taiwan, the periods of its development, ways of refracting different musical traditions will help to understand both the historical-theoretical and aesthetic-pedagogical and artistic significance of this phenomenon in musical art. The most important events in the social and cultural life of Taiwan, since the end of the 16th century, indirectly affected the development of national piano art, which underwent qualitative changes connected with the emergence of new musical forms and means of expression, the methods of using the national and Western compositional techniques. The prospect of further study of the topic consists in a more detailed study of the modern stage of developing piano art in Taiwan and clarifying the influence of its extensive genetic roots on the compositional and performing creativity of representatives of Taiwanese musical culture.
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"MSOM Society Student Paper Competition: Abstracts of 2023 Winners". Manufacturing & Service Operations Management 26, n.º 3 (maio de 2024): 1184–87. http://dx.doi.org/10.1287/msom.2024.studentabs.v26.n3.
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The journal is pleased to publish the abstracts of the six finalists of the 2023 Manufacturing and Service Operations Management Society’s student paper competition. The 2023 prize committee was chaired by Ersin Korpeoglu (UCL), Simone Marinesi (Wharton), and Nur Sunar (UNC). The judges were Adam Elmachtoub, Adem Orsdemir, Agni Orfanoudaki, Alper Nakkas, Amrita Kundu, Antoine Desir, Antoine Feylessoufi, Anton Ovchinnikov, Anyan Qi, Arian Aflaki, Arzum Akkas, Ashish Kabra, Auyon Siddiq, Bilal Gokpinar, Bin Hu, Bob Batt, Bora Keskin, Brent Moritz, Can Zhang, Chloe Glaeser, Cuihong Li, Daniel Freund, Daniel Lin, David Drake, Divya Singhvi, Dongyuan Zhan, Ekaterina Astashkina, Elena Belavina, Elodie Adida, Emre Nadar, Enis Kayis, Fabian Sting, Fanyin Zheng, Fei Gao, Florin Ciocan, Francisco Castro, George Chen, Georgina Hall, Gloria Urrea, Gonzalo Romero, Guihua Wang, Guoming Lai, Heikki Peura, Hessam Bavafa, Hummy Song, Huseyin Gurkan, Ioannis Stamatopoulos, Iris Wang, Jiankun Sun, Jiayi Joey Yu, Jing Wu, Joel Wooten, John Silberholz, Jonas Oddur Jonasson, Jonathan Helm, Jose Guajardo, Junyu Cao, Kaitlin Daniels, Karen Zheng, Ken Moon, Kostas Bimpikis, Lennart Baardman, Lesley Meng, Lina Song, Luyi Yang, Mazhar Arikan, Mehmet Ayvaci, Meng Li, Mengzhenyu Zhang, Miao Bai, Michael Freeman, Mika Sumida, Ming Hu, Morvarid Rahmani, Mostafa Rezaei, Mumin Kurtulus, Nan Yang, Nazli Sonmez, Negin Golrezaei, Nektarios Oraiopoulos, Nikhil Garg, Nikos Trichakis, Nil Karacaoglu, Olga Perdikaki, Onesun Steve Yoo, Ovunc Yilmaz, Ozan Candogan, Panos Markou, Pengyi Shi, Philipp Cornelius, Qiuping Yu, Renyu Zhang, Robert Bray, Ruth Beer, Ruxian Wang, Saed Alizamir, Safak Yucel, Sanjith Gopalakrishnan, Santiago Gallino, Sarah Yini Gao, Scott Rodilitz, Sebastien Martin, Seyed Emadi, Sheng Liu, Shouqiang Wang, Siddharth Singh, Sidika Candogan, Sina Khorasani, So Yeon Chun, Somya Singhvi, Soo-Haeng Cho, Sriram Dasu, Stefanus Jasin, Stephen Leider, Suresh Muthulingam, Sytske Wijnsma, Taghi Khaniyev, Tian Chan, Tim Kraft, Tom Tan, Tugce Martagan, Vasiliki Kostamj, Velibor Misic, Vishal Agrawal, Xiaojia Guo, Xiaoshuai Fan, Xiaoyang Long, Yannis Bellos, Yao Cui, Yehua Wei, Yiangos Papanastasiou, Yi-Chun Chen, Yinghao Zhang, Ying-Ju Chen, Yinghao Zhang, Yuan-Mao Kao, Yuexing Li, Zhaohui (Zoey) Jiang, Zhaowei She, and Zumbul Atan.
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Thanh Huyen, Le, Dao Sy Duc, Nguyen Xuan Hoan, Nguyen Huu Tho e Nguyen Xuan Viet. "Synthesis of Fe3O4-Reduced Graphene Oxide Modified Tissue-Paper and Application in the Treatment of Methylene Blue". VNU Journal of Science: Natural Sciences and Technology 35, n.º 3 (20 de setembro de 2019). http://dx.doi.org/10.25073/2588-1140/vnunst.4883.
Texto completo da fonteResumo:
Graphene-based composites have received a great deal of attention in recent year because the presence of graphene can enhance the conductivity, strength of bulk materials and help create composites with superior qualities. Moreover, the incorporation of metal oxide nanoparticles such as Fe3O4 can improve the catalytic efficiency of composite material. In this work, we have synthesized a composite material with the combination of reduced graphene oxide (rGO), and Fe3O4 modified tissue-paper (mGO-PP) via a simple hydrothermal method, which improved the removal efficiency of the of methylene blue (MB) in water. MB blue is used as the model of contaminant to evaluate the catalytic efficiency of synthesized material by using a Fenton-like reaction. The obtained materials were characterized by SEM, XRD. The removal of materials with methylene blue is investigated by UV-VIS spectroscopy, and the result shows that mGO-PP composite is the potential composite for the color removed which has the removal efficiency reaching 65% in acetate buffer pH = 3 with the optimal time is 7 h.
Keywords
Graphene-based composite, methylene blue, Fenton-like reaction.
References
[1] Ma Joshi, Rue Bansal, Reng Purwar, Colour removal from textile effluents, Indian Journal of Fibre & Textile Research, 29 (2004) 239-259 http://nopr.niscair.res.in/handle/123456789/24631.[2] Kannan Nagar, Sundaram Mariappan, Kinetics and mechanism of removal of methylene blue by adsorption on various carbons-a comparative study, Dyes and pigments, 51 (2001) 25-40 https://doi.org/10.1016/S0143-7208(01)00056-0.[3] K Rastogi, J. N Sahu, B. C Meikap, M. N Biswas, Removal of methylene blue from wastewater using fly ash as an adsorbent by hydrocyclone, Journal of hazardous materials, 158 (2008) 531-540.https://doi.org/10.1016/j.jhazmat.2008.01. 105.[4] Qin Qingdong, Ma Jun, Liu Ke, Adsorption of anionic dyes on ammonium-functionalized MCM-41, Journal of Hazardous Materials, 162 (2009) 133-139 https://doi.org/10.1016/j.jhazmat. 2008.05.016.[5] Mui Muruganandham, Rps Suri, Sh Jafari, Mao Sillanpää, Lee Gang-Juan, Jaj Wu, Muo Swaminathan, Recent developments in homogeneous advanced oxidation processes for water and wastewater treatment, International Journal of Photoenergy, 2014 (2014). http://dx. doi.org/10.1155/2014/821674.[6] Herney Ramirez, Vicente Miguel , Madeira Luis Heterogeneous photo-Fenton oxidation with pillared clay-based catalysts for wastewater treatment: a review, Applied Catalysis B: Environmental, 98 (2010) 10-26 https://doi.org/ 10.1016/j.apcatb.2010.05.004.[7] Guo Rong, Jiao Tifeng, Li Ruifei, Chen Yan, Guo Wanchun, Zhang Lexin, Zhou Jingxin, Zhang Qingrui, Peng Qiuming, Sandwiched Fe3O4/carboxylate graphene oxide nanostructures constructed by layer-by-layer assembly for highly efficient and magnetically recyclable dye removal, ACS Sustainable Chemistry & Engineering, 6 (2017) 1279-1288 https://doi.org/10.1021/acssuschemeng.7b03635.[8] Sun Chao, Yang Sheng-Tao, Gao Zhenjie, Yang Shengnan, Yilihamu Ailimire, Ma Qiang, Zhao Ru-Song, Xue Fumin, Fe3O4/TiO2/reduced graphene oxide composites as highly efficient Fenton-like catalyst for the decoloration of methylene blue, Materials Chemistry and Physics, 223 (2019) 751-757 https://doi.org/ 10.1016/j.matchemphys.2018.11.056.[9] Guo Hui, Ma Xinfeng, Wang Chubei, Zhou Jianwei, Huang Jianxin, Wang Zijin, Sulfhydryl-Functionalized Reduced Graphene Oxide and Adsorption of Methylene Blue, Environmental Engineering Science, 36 (2019) 81-89 https://doi. org/10.1089/ees.2018.0157.[10] Zhao Lianqin, Yang Sheng-Tao, Feng Shicheng, Ma Qiang, Peng Xiaoling, Wu Deyi, Preparation and application of carboxylated graphene oxide sponge in dye removal, International journal of environmental research and public health, 14 (2017) 1301 https://doi.org/10.3390/ijerph14111301.[11] Yu Dandan, Wang Hua, Yang Jie, Niu Zhiqiang, Lu Huiting, Yang Yun, Cheng Liwei, Guo Lin, Dye wastewater cleanup by graphene composite paper for tailorable supercapacitors, ACS applied materials & interfaces, 9 (2017) 21298-21306 https://doi.org/10.1021/acsami.7b05318.[12] Wang Hou, Yuan Xingzhong, Wu Yan, Huang Huajun, Peng Xin, Zeng Guangming, Zhong Hua, Liang Jie, Ren MiaoMiao, Graphene-based materials: fabrication, characterization and application for the decontamination of wastewater and wastegas and hydrogen storage/generation, Advances in Colloid and Interface Science, 195 (2013) 19-40 https://doi. org/10.1016/j.cis.2013.03.009.[13] Marcano Daniela C, Kosynkin Dmitry V, Berlin Jacob M, Sinitskii Alexander, Sun Zhengzong, Slesarev Alexander, Alemany Lawrence B, Lu Wei, Tour James M, Improved synthesis of graphene oxide, ACS nano, 4 (2010) 4806-4814 https://doi.org/10.1021/nn1006368.[14] Zhang Jiali, Yang Haijun, Shen Guangxia, Cheng Ping, Zhang Jingyan, Guo Shouwu, Reduction of graphene oxide via L-ascorbic acid, Chemical Communications, 46 (2010) 1112-1114 http://doi. org/10.1039/B917705A [15] Gong Ming, Zhou Wu, Tsai Mon-Che, Zhou Jigang, Guan Mingyun, Lin Meng-Chang, Zhang Bo, Hu Yongfeng, Wang Di-Yan, Yang Jiang, Nanoscale nickel oxide/nickel heterostructures for active hydrogen evolution electrocatalysis, Nature communications, 5 (2014) 4695 https:// doi.org/10.1038/ncomms5695.[16] Wu Zhong-Shuai, Yang Shubin, Sun Yi, Parvez Khaled, Feng Xinliang, Müllen Klaus, 3D nitrogen-doped graphene aerogel-supported Fe3O4 nanoparticles as efficient electrocatalysts for the oxygen reduction reaction, Journal of the American Chemical Society, 134 (2012) 9082-9085 https://doi.org/10.1021/ja3030565.[17] Nguyen Son Truong, Nguyen Hoa Tien, Rinaldi Ali, Nguyen Nam Van, Fan Zeng, Duong Hai Minh, Morphology control and thermal stability of binderless-graphene aerogels from graphite for energy storage applications, Colloids and Surfaces A: Physicochemical and Engineering Aspects, 414 (2012) 352-358 https://doi.org/ 10.1016/j.colsurfa.2012.08.048.[18] Deng Yang, Englehardt James D, Treatment of landfill leachate by the Fenton process, Water research, 40 (2006) 3683-3694 https://doi.org/ 10.1016/j.watres.2006.08.009.
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魏, 艷. "晚清時期偵探小説的翻譯". 人文中國學報, 1 de setembro de 2014, 421–49. http://dx.doi.org/10.24112/sinohumanitas.202171.
Texto completo da fonteResumo:
LANGUAGE NOTE | Document text in Chinese; abstract also in English.
本文通過分析三位譯者林紓、周桂笙以及周作人的譯作，以案例研究的方式對晚清時期偵探小説的翻譯作出探討。分析的譯作包括魏易、林紓譯的《歇洛克奇案開場》、周桂笙譯的《毒蛇圈》以及周作人譯的《玉蟲緣》。晚清時期的翻譯，無論是林紓和周作人所追求的古文的意境，還是周桂笙、吳趼人等採取的章回小説評點本的形式，都與中國傳統舊小説有著千絲萬縷的關係。同時，由於晚清時期面臨著列强侵略、國力衰退、新舊思想對立，偵探小説在時人當中的理解也體現出了這些時代精神，與原本西方偵探小説中强調的科學性和趣味性有一定區别，例如林紓翻譯的福爾摩斯故事特别認同罪犯的復仇主張，周作人則通過《玉蟲緣》的翻譯聯想到獲取財富手段要正當，周桂笙在《毒蛇圈》翻譯中宣揚的父慈子孝的主題等。
This paper discussed the translation of late Qing detective fiction through three case studies: A Study in Scarlet translated by Wei Yi and Lin Shu; In the Serpents’ Coils translated by Zhou Guisheng and “the Gold Bug” translated by Zhou Zuoren. Both Lin Shu and Zhou Zuoren’s translations aimed to be fit into the style and aesthetics of guwen, a traditional prose style of used in ancient Chinese texts, while Zhou Guisheng was interested in translating the Western detective story in the format of traditional Chinese novels. Meanwhile, the particular political and social reform context of the late Qing period also influenced the contemporary readers in their understanding of Western detective fiction. In Lin Shu’s translation, he was sympathized with the criminal and his enduring yet vindictive spirit rather than the detective Holmes and his scientific attitude. Zhou Zuoren encouraged his readers to gain their wealth in justified ways and Zhou Guisheng stressed the filial theme in his translation.
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陳, 雄根. "從《廣雅疏證》看王念孫的聲義相通説". 人文中國學報, 1 de agosto de 2005, 345–96. http://dx.doi.org/10.24112/sinohumanitas.112440.
Texto completo da fonteResumo:
LANGUAGE NOTE | Document text in Chinese; abstract also in English. 王念孫《廣雅疏證•序》云：“訓話之旨，本於聲音。”書中每以聲義相通來疏解古義。近世學者，對王氏所言“某與某通”的語言成分、聲音關係，以及王氏聲義相通説，論之未深。本文就全書聲義相通的文例進行分析，闡釋其中所用術語，指出聲義相通的字，除通假字外，尚包括同源字和異體字。其次，本文考察不同術語所言相通字例，均屬音同或音近，並列表作出統計。第三是尋找王氏論定通用字的依據。最後對王氏聲義相通説的得失，作出評價，以補前人研究的不足。 In his introduction to Kuang-ya Shu-cheng, Wang Nien-sun notes that "the essence of meaning is lodged in the sound". In interpreting ancient meaning, Kuang-ya Shu-cheng usually takes different phonetics that convey the same meaning as interchangeable. In recent studies, not much has been written on the linguistic components and the tonal relations concerning Wang's interchangeable theory, and there still awaits an in-depth analysis of his theory of the interdependence of sound and meaning. This paper provides a throughout analysis of examples concerning the interdependence of sound and meaning in Kuang-ya Shu-cheng. This paper (1) explains the special terms used in the work, showing that characters of different sound but conveying the same meaning include not only loan characters (t'ung-chia tzu 通假字) but also cognate words (t'ung-yuan tzu 同源字) and variants (yi-t'i tzu 異體字). (2) provides statistical tables in support of the point that examples of interchangeable characters mentioned by various special terms are in fact homophones or near homophones. (3) examines the rationale behind Wang's discussion of loan characters. (4) evaluates Wang's theory of the interdependence of sound and meaning, so as to serve as a supplement to existing research.
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Huu Tho, Nguyen, Trang Thanh Tu, Trac Minh Nhan, Pham Hong Cam e Pham Thi Thi. "The Geometries and Stabilities of Neutral and Anionic Vanadium Doped Germanium Clusters VGen0/-( n = 9 - 13): Density Functional Theory Investigations". VNU Journal of Science: Natural Sciences and Technology 35, n.º 1 (26 de março de 2019). http://dx.doi.org/10.25073/2588-1140/vnunst.4827.
Texto completo da fonteResumo:
The geometries, stabilities of VGen0/- (n = 9 - 13) clusters were systematically studied by the density functional theory (DFT) using the BP86 functional and LANL2DZ basis set. Several possible multiplicities of each cluster were tested to determine the most stable structure among the isomers. The average binding energy per atom, fragmentation energy, second order energy difference and HOMO-LUMO gaps were evaluated. The results indicated that the neutral and anionic clusters possess higher stability when n = 10 and 12. The vertical detachment energy (VDE) and adiabatic detachment energy (ADE) were also calculated for anionic cluster to investigate their stabilities. Among neutral clusters, VGe10 had both the highest vertical ionization potential (VIP) and chemical hardness.
Keywords
BP86/LANL2DZ, binding energy, VGen0/- clusters, structure of clusters
References
[1] Shunping Shi, Yiliang Liu, Chuanyu Zhang, Banglin Deng, Gang Jiang (2015). A Computational Investigation of Aluminum-doped Germanium Clusters by Density Functional Theory Study. Computational and Theoretical Chemistry, 1054, pp. 8-15[2] Wen-Jie Zhao, Yuan-Xu Wang (2009). Geometries, stabilities, and Magnetic Properties of MnGen (n = 2 – 16) Clusters: Density-functional Theory Investigations. Journal of Molecular Structure: THEOCHEM, 901 (1–3), pp. 18-23.[3] Shi Shun-Ping, Liu Yi-Liang, Deng Bang-Lin, Zhang Chuan-Yu, and Jiang Gang (2016). Density Functional Theory Study of The Geometrical and Electronic Structures of (n = 1 - 9) clusters. World Scientific Publishing Company, 30, pp. 1750022-1750039.[4] J.Stato, H.Kobayashi, K. Ikarashi, N.Saito, H.Nishiyama, and Y. Inoue (2004). Photocatalitic Activity for Water Decomposition of RuO2-Dispersed Zn2GeO4 with d10 Configuration. The Journal of Physical Chemistry B, 108 (14), pp. 4369-4375.[5] Daoxin Dai, Molly Piels, and John E. Bowers (2014). Monolithic Germanium/Silicon Photodetectors With Decoupled Structures: Resonant APDs and UTC Photodiodes. IEEE Journal of Selected Topics in Quantum Electronics, 20 (6), pp. 3802214-3802227.[6] Chia-Yun Chou, Gyeong S. Hwang (2014). On The Origin of The Significant Difference in Lithiation Behavior Between Silicon and Germanium. Journal of Power Sources, 263, pp. 252-258.[7] Siwen Zhang, Bosi Yin, Yang Jiao, Yang Liu, Xu Zhang, Fengyu Qu, Ahmad Umar, Xiang Wu (2014). Ultra-long Germanium Oxide Nanowires: Structures and Optical Properties. Journal of Alloys and Compounds, 606, pp. 149-153.[8] T. Herrmannsdörfer, V. Heera, O. Ignatchik, M. Uhlarz, A. Mücklich, M. Posselt, H. Reuther, B. Schmidt, K.-H. Heinig, W. Skorupa, M. Voelskow, C. Wündisch, R. Skrotzki, M. Helm, and J. Wosnitza (2009).Superconducting State in a Gallium-Doped Germanium Layer at Low Temperatures. Physical Review Letters, 102, pp. 217003-217006.[9] Vijay Kumar, and Yoshiyuki Kawazoe (2002). Metal-Encapsulated Caged Clusters of Germanium with Large Gaps and Different Growth Behavior than Silicon. Physical Review Letters, 88, pp. 235504-235507.[10] Xiao-Jiao Deng, Xiang-Yu Kong, Hong-Guang Xu, Xi-Ling Xu, Gang Feng, and Wei-Jun Zheng (2015). Photoelectron Spectroscopy and Density Functional Calculations of VGen- (n = 3 − 12) Clusters. The Journal of Physical Chemistry C, 119 (20), pp. 11048-11055.[11] John P. Perdew, Kieron Burke, and Matthias Ernzerhof (1996).Generalized Gradient Approximation Made Simple. Physical Review Letters, 77, pp. 3865-3868.[12] Chaouki Siouani, Sofiane Mahtout, Sofiane Safer, and Franck Rabilloud (2017).Structure, Stability and Electronic and Magnetic Properties of VGen (n = 1 - 19) Clusters. The Journal of Physical Chemistry A, 121 (18), pp. 3540-3554.[13] Jin Wang, and Ju-Guang Han (2006).A Theoretical Study on Growth Patterns of Ni-Doped Germanium Clusters.The Journal of Physical Chemistry B, 110 (15), pp. 7820-7827.[14] Debashis Bandyopadhyay and Prasenjit Sen (2010). Density Functional Investigation of Structure and Stability of Gen and GenNi (n = 1 − 20) Clusters: Validity of the Electron Counting Rule. The Journal of Physical Chemistry A, 114 (4), pp. 1835-1842[15] Soumaia Djaadi, Kamal Eddine Aiadi, and Sofiane Mahtout (2018). Frist Principles Study of Structural, electronic and magnetic properties of (n = 1 - 17) clusters. Journal of Semiconductors, 39 (4), pp. 42001-420013.[16] İskender Muz,Mustafa Kurban,Kazım Şanlıc (2018). Analysis of the Geometrical Properties and Electronic Structure of Arsenide Doped Boron Cluster: Ab-initio approach. Inorganica Chimica Acta, 474, pp. 66-72.[17] Axel D. Becke (1988). Density-functional exchange - energy approximation with correct asymptotic behavior.Physical Review A, 38, pp. 3098-3100.[18] Willard R. Wadt, P. Jeffrey Hay (1985). Ab initio effective core potentials for molecular calculations.Potentials for main group elements Na to Bi.The Journal of Chemical Physics, 82 (1), pp. 284-298.[19] Willard R. Wadt, P. Jeffrey Hay (1985). Ab initio effective core potentials for molecular calculations.Potentials for K to Au including the outermost core orbitals.The Journal of Chemical Physics, 82 (1), pp. 299-310.[20] Willard R. Wadt, P. Jeffrey Hay (1985). Ab initio effective core potentials for molecular calculations. Potentials for the transition metal atoms Sc to Hg. The Journal of Chemical Physics, 82 (1), pp. 270-283.[21] Gabriele Manca, Samia Kahla, Jean-Yves Saillard, Rémi Marchal, Jean-François Halet (2017). Small Ligated Organometallic Pdn Clusters (n = 4 - 12): A DFT Investigation. Journal of Cluster Science, 28 (2), pp. 853-868.[22] Tran Dieu Hang, Huynh Minh Hung, Lam Ngoc Thiem. Hue M. T. Nguyen (2015). Electronic structure and thermochemical properties of neutral and anionic rhodium clusters Rhn, n = 2 – 13. Evolution of structures and stabilities of binary clusters RhmM (M = Fe, Co, Ni; m = 1 – 6). Computational and Theoretical Chemistry, 1068, pp. 30–41.[23] Michael J. Frisch, et al. (2010). Gaussian 09, Revision C.01.Gaussian, Inc., Wallingford CT.
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"Withdrawn paper: “Yi-Jan Lin, Lin Hao, Yuan-Chung Lin, Chung-Wen Kuo, Pin-Rong Chen, Tzi-Yi Wu, I-Wen Sun, A Comparative Study of Ionic Conductivity, Translational Diffusion, Molecular Motion, and Physicochemical Properties in Lithium Bis(trifluoromethanesulfonyl)imide-Doped 1-Methyl-3-pentyl- and 1,2-Dimethyl-3-pentyl-substituted Imidazolium-Based Ionic Liquids” (Int. J. Electrochem. Sci., 8 (2013) 8097 - 8114 )”". International Journal of Electrochemical Science 10, n.º 6 (junho de 2015): 5210. http://dx.doi.org/10.1016/s1452-3981(23)06698-1.
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馮, 志弘. "《東京夢華録》是否“著其盛，正著其所以衰”———兼論宋人的“華胥之夢”". 人文中國學報, 1 de dezembro de 2016, 93–125. http://dx.doi.org/10.24112/sinohumanitas.232109.
Texto completo da fonteResumo:
LANGUAGE NOTE | Document text in Chinese; abstract also in English.
考察北宋以迄宋南渡時期著述，可以發現宋人筆下“華胥”一詞的涵義，很多時候都不是指向《列子》所載黄帝“夢遊華胥”的本義，而是指現實世界中最愜意的生活方式。晏殊、蘇軾、吕陶、王庭珪、趙鼎，更直接以“華胥”比喻城市繁華、歌舞昇平。這是孟元老以“華胥”比喻東京繁華的主要背景。
《東京夢華録》四次寫到“奢侈”、“侈奢”、“侈縱”、“侈靡”，都没有明顯批判意味。相反，書中序文强調“侈奢則長人精神”———運用“貶詞正用”的方式，藉此指出“奢侈”的觀念和生活方式，是東京繁華的重要體現。
比較《東京夢華録》、《都城紀勝》、《夢粱録》、《武林舊事》對於妓女、惡少年、游民等的描寫，可以發現孟元老對此等人物並無批評，其餘三部著作卻多作貶抑。
雖然從“解讀史”的角度而論，《東京夢華録》足以引起諷喻的聯想；但考察文本的内證和相關外證，這種理解並不符合書中的主導觀念，也和孟元老對東京繁華的認知有所矛盾。
This article indicates:
1. By investigating works from the Northern Song to the southern migration of the Song Dynasty, meaning of “Huaxu” depicted by Song people mostly not referring to the original essence of “Dream of Huaxu” of Huangdi which recorded in Liezi. On the other hand, it indicated most satisfactory living style within the secular world. Yan Shu, Su Shi, Lu Tao, Wang Ting-gui and Zhao Ding even directly used “Huaxu” as a metaphor for peace and prosperity of city; which was also the major context for Meng Yuan-lao to use “Huaxu” as a metaphor for prosperity of Dongjing (Kaifeng).
2. Dongjing Menghua Lu used the vocabulary “extravagance” for four times without an apparent critical attitude. Conversely, its preface “manipulated the derogatory terms for complimentary use” to emphasize idea of “extravagance strengthen people’s spirit”; which indicated “extravagant” value and living style was an important manifestation of Dongjing’s prosperity.
3. By comparing depictions towards prostitutes, evil youngsters and loafers from Dongjing Menghua Lu, Du Cheng Ji Sheng (Documenting Capital’s Glories), Meng Liang Lu (Dream of Grain) and Wu lin jiu shi (Old stories of Lin’an), Meng Yuan-lao was revealed not criticizing against these characters in Dongjing Menghua Lu, but the other three works derogated these people obviously.
4. Analyzing from perspective of interpretative History, Dongjing Menghua Lu may capable for intriguing association of irony; nonetheless, internal textual evidences as well as relevant external evidences had proven such interpretation did not comply with the main concept of the book, and even contrasted to the comprehension of Dongjing’s prosperity from Meng Yuan-lao.