Articoli di riviste sul tema "Wu xing(zhong yi)"

ABSTRACT(N.B. A version of this paper has now been published in Kaogu 1983.6:537-41.)Fu Hao (or Fu Zi ) appears in the oracle-bone inscriptions from Anyang. The name is often seen in Period I inscriptions (from the time of Wu Ding) and occasionally in Period IV inscriptions (from the time of Wu Yi and Wen Ding). The two are separated by four kings (Zu Geng, Zu Jia, Lin Xin, and Kang Ding), perhaps by as much as one hundred years. Does the Fu Hao in both periods refer to the same person? How can we explain this phenomenon?In the oracle-bone records of people and their activities there are cases where one figure is active in different periods. These names are often also place names, and these figures possess a populace and products. These names are probably what is termed “Clan-Territory titles” (a term found in the Gu shi kao, as quoted in the “Zheng yi” commentary to the Zuo zhuan). Based on their clan name they served hereditarily as officials. These clan names occur in historical literature, as in “In the past, our former kings were for generations Lords of Millet (Hou Ji ), serving under the Yü and Xia “(Guo yü “Zhou Yü” ); or “The Zhong and Li clans generation after generation ordered heaven and earth, … the Sima clan for generation after generation was in charge of the history of Zhou” (Shi ji, “Taishigong zixu” ).

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.

First, regarding the study of “Zhong Yi Zhi Yan”(忠义直言) there are 14 articles on the grammar, 6 on versions, 2 on vocabulary, and 1 on education. It can be observed that currently, there is the most research on the grammar of “Zhong Yi Zhi Yan”, while research on vocabulary and education is still relatively insufficient. Second, before the discovery of “Zhong Yi Zhi Yan”, there was very little colloquial Chinese language data from the early Ming Dynasty. Therefore, the discovery of “Zhong Yi Zhi Yan” addresses the issue of insufficient linguistic materials in the diachronic study of Chinese grammar and vocabulary. Third, the written title “Zhong Yi Zhi Yan SHANG, ZHONG XIA”(忠义直言上中下) in “Zhong Yi Zhi Yan” was added by later generations during restoration. Fourth, according to the judgment of Wu Yong(吴庸), the author of “Zhong Yi Zhi Yan”，the composition time of this book can be estimated to be between 1370 and 1410. Fifth, the appearance of Classical Chinese grammar and vocabulary in “Zhong Yi Zhi Yan” is due to the residue from the process of translating from literary Chinese to spoken language. Sixth, “Zhong Yi Zhi Yan” is the closest to the spoken Mandarin of that time, serving as a unique educational material with functions in both Chinese language education and humanities education during the Goryeo and Joseon periods.

Abstract Killer lymphocyte-mediated tumor cell killing is a vital and final step of anti-tumor protective immunity. Killer cells, including cytotoxic CD8 T cells and Natural Killer (NK) cells, deliver granzymes (Gzm) into target cells, which normally activates noninflammatory cell death, but becomes inflammatory when target cells express the gasdermin (GSDM) proteins responsible for pyroptosis. GzmA and GzmB cleave and activate GSDMB and GSDME, respectively. However, the role of GSDMB in anti-tumor immunity is unclear - GSDMB pore formation is controversial and GSDMB expression has been linked to both anti- and pro-tumor functions. Here we found that GSDMB splicing variants are functionally distinct. Cleaved N-terminal (NT) fragments of isoforms 3 and 4 caused pyroptosis, but isoforms 1, 2 and 5, which deleted or modified exon 6, did not. Structural analysis based on AlphaFold predictions and the cryoEM structures of GSDMA3 and GSDMD showed that pore formation required the formation of a functional stabilizing belt structural element near the C-terminus of the cleaved N-terminal fragment, which was disrupted in the non-cytotoxic alternatively spliced isoforms. NK attack of GSDMB3-expressing cells caused pyroptosis, but GSDMB4 cells died mostly by apoptosis, and GSDMB1/2 cells died only by apoptosis. GSDMB4 partially resisted NK cell-triggered cleavage, suggesting that only GSDMB3 is fully functional. GSDMB1-3 were the most abundant isoforms in tested cells and were similarly induced by IFNγ and a chemotherapy drug methotrexate. Expression of cytotoxic GSDMB3/4, but not GSDMB1/2, was associated with better outcome in bladder and cervical cancer, suggesting GSDMB-mediated pyroptosis was protective in those tumors. Our study uncovers a novel role of alternative splicing in modulating caner-associated pyroptosis, and suggests that tumors may manipulate GSDMB splicing to avoid pyroptosis. Thus, modulating GSDMB splicing to increase cytotoxic GSDMB variants but suppress non-cytotoxic GSDMB isoforms could improve anti-tumor immunity and have therapeutic utility. Citation Format: Qing Kong, Shiyu Xia, Xingxin Pan, Kaixiong Ye, Zhouyihan Li, Haoyan Li, Nidhi Sahni, S. Stephen Yi, Xing Liu, Hao Wu, Judy Lieberman, Zhibin Zhang. Alternative splicing of GSDMB modulates killer lymphocyte-triggered pyroptosis [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 6145.

The article is devoted to the study of the Song of the Great Dao of the Spiritualized Source (Ling yuan da dao ge). This is a work on Daoist “inner alchemy”, which describes the process of transforming the spirit and the breath in poetic form. The author of Ling yuan da dao ge was the Daoist nun and poetess Cao Wen-yi (1039–1115). Cao Wen-yi is the only woman-philosopher who wrote a commentary on the Dao De jing, which has survived to this day in the Daoist Canon (Dao zang). Her talents were highly appreciated by Emperor Huizong, who granted her the title “Excellent in Literary Talent” (Wen-yi zhen-ren). The goal of the study is to highlight the most important ideological and theoretical components of the Song of the Great Dao of the Spiritualized Source. As a result of the study, the cultural and historical environment of this work was reconstructed, its earlier list written in prose was identified, the dating of the full version of Ling yuan da dao ge was clarified, and its content features were revealed. The main task of the Song of the Great Dao of the Spiritualized Source is to explain the principle of simultaneous improvement of inner nature and vitality (xing ming shuang xiu). This principle became the main vector of development of Daoist psychophysiological methods, starting from the Song era. Improving the inner nature, according to Cao Wen-yi, is achieved by detaching the heart from feelings and desires. This state is called “no heart” (wu xin) and is the “true heart of the Dao”. Improving vitality is achieved through breathing exercises, which should be based on the principles of suchness (zi ran) and non-action (wu wei).

ABSTRACTThis paper assembles three oracle-bone inscriptions divined at the same time from the Wu Yi-Wen Ding period. Two are identical, being a paired divination inquiring into whether the event ri yue you shi was or was not auspicious. The third asks whether, in light of this ri yue you shi, it would be auspicious to sacrifice to Shang Jia.Since 1925, when Wang Xiang , first proposed th at the character yue should be read as xi, his position has been accepted by Liu Chaoyang De Xiaoqian , Chen Mengijia , Zhang Peiyü , Xu Zhentao , the Zhongguo Tianwenxue jianshi bianxiezu , and the Zhongguo Tianwenxueshi zhengli yenjiu xiaozu Yue was first interpreted as yue in 1933 by Shang Chengzuo . Those subscribing to this reading include Dong Zuobin , Chen Zungui , Yü Xingwu Liu Chaoyang, Chen Mengiia, Joseph Needham, Zhao Quemin and Chen Banghuai .Among these scholars Liu Chaoyang holds that “there is no distinction between xi and yue,” while Chen Mengjia believes that the phrase “ri yue you shi” can also be read “ri xi you shi,” hence they accept both interpretations.

The military art of Ancient China, which was developed on the basis of the military-theoretical heritage of Sun Tzu, Wu Tzu, contains many examples of achieving victory in war through military cunning, improving tactical techniques of armed struggle, as well as information and psychological impact on the enemy’s troops and population. The era of the Three Kingdoms in the history of China occupies a relatively short period of time – 220–280 A.D., however, the qualitative characteristics of the military aspect deserve special attention. The mili-tary leadership abilities of Cao Cao, Zhuge Liang, Sima Yi and other commanders clearly demonstrate the pro-gress in the development of strategy and tactics, military engineering construction of the Celestial Empire. Along with land forces, consisting of infantry and cavalry, there is a river flotilla, capable of solving problems of a strategic nature. The confrontation of the three kingdoms is reflected in the historical chronicles of Chen Shou, the epic of Luo Guan-zhong, numerous studies by Chinese and foreign experts. Sun Tzu’s recommen-dations and instructions were applied in the United States to wage psychological warfare against Russia.

“Traditional Chinese Medicine” (TCM; Zhong Yi) is a concept that keeps evolving with the change of times and clinical practice. From the aspect of the category of modern science, there were not appropriate boundaries set for the literature, history and philosophy in the realm of Chinese traditional academics. Thanks to the eastward spread of Western culture and science, the category of disciplines in modern times then came into being. In order to be listed in the system of modern disciplines, traditional disciplines have always been trying to redefine themselves, and “TCM,” of course, is involved. Considering the fact that “TCM” is now an academic discipline in the field of medicine, here we reviewed not only the transition of the concept of “TCM” from a primitive and then a hierarchical medical term to a relatively full-fledged one that is, to some extent, opposite to the concept of Western Medicine or modern medicine, from a narrow medical term that is peculiar to Han Medicine to a broad one that pertains to Han Medicine along with ethnic traditional medicines in China, but also the transition of the development from merely highlighting TCM and then equally emphasizing TCM together with modern medicine to comprehensively converging TCM, modern medicine and Integrative Medicine, which contributes to the evolution from the dominance of TCM, the coexistence of TCM and modern medicine, the confluence of TCM and modern medicine, and finally to the integration of TCM and modern medicine. In addition, we introduced pioneering medical concepts, epistemology and methodology such as Chinese Traditional Medicine (CTM; Da Zhong Yi), Trichotomy (San Fen Fa), Five Key Elements (Wu Yao Su) and Three-dimensional Integration (San Rong He), proposed the potential future direction of medicine, stressed the importance of taking the essence and discarding the dregs in TCM, and appreciated those who are able to perceive similarities in differences. We looked forward to reconstructing the system of TCM by the integration of the part that is unconsciously ahead of modern medicine and that has already reached consensus with modern medicine from all the traditional medicines in China, which would promise a brand new system of medicine harmoniously integrating traditional medicine and modern medicine.

Abstract Microsatellite instability (MSI) is an important genomic biomarker for cancer diagnosis and treatment. For some cancers with high-degree of heterogeneity, e.g. endometrial cancer, the existing approaches always fail to identify the micro-satellite instability on one or multiple sub-clones, which would deprive the chance for patients to benefit from treatments. However, it is a computational challenge to estimate the sub-clonal MSI because multiple sub-clones may share the genomic status. Herein, in this paper, we propose an accurate and efficient algorithm, named scMSI, to estimate the sub-clonal microsatellite status. scMSI adopts an alternating iterative model to de-convolute the length distribution, which is a mixture of sub-clones. During the deconvolution, an optimized division of each sub-clone is achieved by a heuristic algorithm, which is bounded to the clonal proportions best consistent with the known clonal structure. To evaluate the performance, we conducted a series of experiments on simulation datasets. The results supported that scMSI solved the detection problem of MSI on sub-clones. It outperforms the existing approaches on multiple metrics. In addition, we collected a cohort of 16 endometrial cancer patients, who have positive responses on the treatment but with negative MSI status. We sequenced these patients. scMSI reported MSI on sub-clones according the sequencing data, which are further validated by the conclusions on immunohistochemistry. Thus, scMSI could provide a powerful tool for MSI analysis. Citation Format: Yuqian Liu, Yan Chen, Huanwen Wu, Xuanping Zhang, Xin Lai, Xin Yi, Zhiyong Liang, Jiayin Wang. scMSI: Accurately detect the sub-clonal micro-satellite instability by an integrative Bayesian model. [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 4283.

BackgroundColorectal cancer is a heterogeneous disease with complicated genetic alterations. Right colon and left colon have different features while right colon cancer displays an even worse prognosis. The randomized phase III FOxTROT trial demonstrated better downstaging effect with neoadjuvant plus adjuvant chemotherapy compared with adjuvant chemotherapy alone (P=0.04).1 Moreover, 2-year relapse rate was improved with neoadjuvant therapy, though the difference was not statistically significant. The NICHE study of neoadjuvant immunotherapy (maximum 6 weeks) showed that the pathological response was observed in 20/20 mismatch repair-deficient (dMMR) resectable colon cancers, with 19 major pathological responses and 12 pathological complete responses (pCRs).2 Recently, KEYNOTE-177 study showed improved progression-free survival with PD-1 inhibitor over chemotherapy (16.5 months vs. 8.2 months) in untreated microsatellite instability-high (MSI-H)/dMMR colon cancer patients, including 68% of right colon cancers.3 In addition, camrelizumab (PD-1 inhibitor) plus apatinib (vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor) demonstrated favorable antitumor effects and a manageable safety profile in advanced hepatocellular carcinoma and gastric cancer.4 5 This phase II trial aims to explore whether the combination of camrelizumab, apatinib and chemotherapy (mFOLFOX6) could significantly improve the pathological regression rate in locally advanced right colon cancer so as to bring considerable survival benefit for patients.MethodsEligible patients are aged 18–75 years, with locally advanced (T4 or T3 with extramural depth ≥5 mm, N0-2, M0, AJCC 8th) adenocarcinoma of right colon (including ileocecal area, ascending colon, and transverse colon to splenic flexion), and without prior systemic chemotherapy or immunotherapy. All patients will receive 5 cycles of camrelizumab (200 mg once every 2 weeks) plus mFOLFOX6 and 2 months of apatinib (250 mg orally once a day), followed by surgery and 7 cycles of adjuvant camrelizumab plus mFOLFOX6. The primary endpoint is the proportion of patients with tumor regression grade (TRG) 2–4 according to the Dworak criteria (TRG2: dominantly fibrotic changes with few tumor cells or groups; TRG3: very few tumor cells in fibrotic tissue; TRG4: no tumor cells). Secondary endpoints include downstaging rate, pCR rate, R0 resection rate, 2-year disease-free survival rate, 2-year event-free survival, overall survival, quality of life, and safety.ResultsTo date, three of planned 64 patients have been enrolled. Two patients have completed surgery. According to Dworak criteria, TRG ranked 4 (pathologic complete response) for the first patient and 3 (very few tumor cells in fibrotic tissue) for the second patient. No severe adverse events have been observed for all patients.Trial RegistrationThis trial has been registered at ClinicalTrials.gov (NCT04625803).ReferencesG. Foxtrot Collaborative. Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: the pilot phase of a randomised controlled trial. Lancet Oncol 13(11) (2012):1152–60.Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, Lopez-Yurda M, Grootscholten C, Beets GL, Snaebjornsson P, Maas M, Mertz M, Veninga V, Bounova G, Broeks A, Beets-Tan RG, de Wijkerslooth TR, van Lent AU, Marsman HA, Nuijten E, Kok NF, Kuiper M, Verbeek WH, Kok M, Van Leerdam ME, Schumacher TN, Voest EE, Haanen JB. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 26(4) (2020):566–576.André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz Jr LA. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 383(23) (2020):2207–2218.Xu J, Shen J, Gu S, Zhang Y, Wu L, Wu J, Shao G, Zhang Y, Xu L, Yin T, Liu J, Ren Z, Xiong J, Mao X, Zhang L, Yang J, Li L, Chen X, Wang Z, Gu K, Chen X, Pan Z, Ma K, Zhou X, Yu Z, Li E, Yin G, Zhang X, Wang S, Wang Q. Camrelizumab in combination with apatinib in patients with advanced hepatocellular carcinoma (RESCUE): a nonrandomized, open-label, phase II trial. Clin Cancer Res 27(4) (2021):1003–1011.Xu J, Shen J, Gu S, Zhang Y, Wu L, Wu J, Shao G, Zhang Y, Xu L, Yin T, Liu J, Ren Z, Xiong J, Mao X, Zhang L, Yang J, Li L, Chen X, Wang Z, Gu K, Chen X, Pan Z, Ma K, Zhou X, Yu Z, Li E, Yin G, Zhang X, Wang S, Wang Q, Xu J, Zhang Y, Jia R, Yue C, Chang L, Liu R, Zhang G, Zhao C, Zhang Y, Chen C, Wang Y, Yi X, Hu Z, Zou J, Wang Q. Camrelizumab in combination with apatinib in patients with advanced hepatocellular carcinoma (RESCUE): a nonrandomized, open-label, phase II trial anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: an open-label, dose escalation and expansion study. Clin Cancer Res 27(4) (2021):1003–1011.Ethics ApprovalStudy protocol was approved by the Clinical Research Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University (2020–119)ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Abstract Up to 80% of breast cancer (BCa) expresses estrogen receptor-α (ER). Over 60% ER+ BCa metastasizes to the bone and are challenging to treat. This study investigates what drives bone metastasis by focusing on a key tumor suppressor neurofibromin (NF1), a GTPase-activating protein that represses RAS signaling. Earlier, we reported that NF1 acts as a transcriptional corepressor for ER in BCa. Our group established that combination fulvestrant (selective ER degrader) and binimetinib (MEK-inhibitor) induces tumor regression in NF1lowER+ models. This combination is now in clinical trial, NCT05554354 (NCI ComboMATCH). Numerous studies indicate that the NF1 loss may impact bone health by altering the equilibrium between bone formation and resorption. Since, bone is the primary site of metastasis in 50-70% of ER+ BCa, understanding the role of NF1 loss in bone metastases becomes imperative. An osteolytic vicious cycle may drive bone metastasis, where cancer cells in the bone stimulate the bone-destructing osteoclasts (OC); leading to subsequent bone deterioration, which in turn, releases growth factors to further promote tumor growth. OCs and many cells in the bone are ER+. We thus hypothesize that deregulated RAS and ER signaling by NF1 loss can drive ER+ bone metastasis by promoting an osteolytic vicious cycle. To assess the clinical impact of NF1 loss on bone metastasis, we analyzed metastatic BCa patient data from cBioPortal and the MSK-EMC cohort. To define how NF1 loss affect bone metastasis, NF1 knockout (KO) ER+ BCa cells were tested in vitro and in vivo for bone tropism, growth in bone and effect on the vicious cycle. Analyses of clinical data suggest that NF1 copy number (CN) loss in ER+ tumors associates with accelerated metastasis to the bone. Additionally, NF1 CN loss and mutations are more prevalent in bone metastasis BCa patients. Lower levels of NF1 mRNA are correlated with shorter duration of bone metastasis-free survival.Our preclinical studies further supported the driver role of NF1 in bone metastasis. NF1KO ER+ BCa cells migrate more efficiently toward the bone in vitro compared to their NF1+ counterparts. When injected into the mammary fat pads of mice, NF1KO cells more frequently metastasized to the bone compared to NF1+ cells. When NF1KO cells were delivered to the mouse femur by intra-iliac injection, they grew more efficiently and induced more bone degradation. This is consistent with our in vitro results, which show that NF1KO ER+ BCa cells can more efficiently promote OC formation from progenitor cells. For this experiment, Mass-spectrometry based unbiased profiling of the conditioned medium showed that osteolytic factors, such as ICAM1 and OSTF1, were enriched in the NF1KO medium. Hence, we conclude that the loss of NF1 deregulates RAS and ER, leading to increased osteolytic factors, that drive bone metastasis. Co-targeting RAS and ER can be a potential treatment for NF1 loss-induced bone metastasis in ER+ BCa. Citation Format: Zifan Zhao, Ze-Yi Zheng, Jonathan Lei, Matthew J. Baik, Yi-Hsuan Wu, Junkai Wang, Igor Bado, Meenakshi Anurag, Bing Zhang, Xiang Zhang, Eric Chang. NF1 loss promotes bone metastasis in estrogen receptor positive breast cancer [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 LB213.

The article is devoted to the analysis of the influence of the ancient Chinese philosophy of Taiji on artistic creativity and the development of the internal evolution of artistic culture. Taoist philosophy of nature and Confucian ethics synthesized the philosophical core of the traditional Chinese worldview with its emphasis on the simplicity and naturalness of the world order, and formed the fundamental principles of Taiji. Fundamental to Taiji, the concept of Yin and Yang emphasizes the dual nature of the existence of movement and variability as a balance of opposing forces of development. The Taiji philosophy of dialectical development is supplemented by the idea of ​​the genesis of renewal energy - Qi. The main research method is the method of revitalizing traditional systems on a new intellectual basis. The method of diachronic analysis of the social situation that influenced the development of Chinese neorealism in art was used. As a result of the study, the functional significance of the influence of the principles and philosophical ideas of taiji on the evolution of neorealism is described. Using the example of the work of Chinese neorealist artists Xin Dongwan and Zheng Yi, the authors come to the conclusion that there are three driving factors of artistic motivation for creativity: internal, external and subjective. The basic principles of Taiji philosophy and ethics, such as: the naturalness of change without the use of force (Wu Wei), change as the only constant in the existence of the world and its stability, gentleness - help develop the creative power of renewal. The idea is shown that in the ancient Chinese philosophical heritage, Confucianism and Taoism became two full-fledged directions, functionally complementing each other in explaining differences in cultural, political, philosophical and social environments.

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.

Abstract Background: Anti-HER2 targeted therapy has achieved a series of breakthroughs. However, the current treatment strategy regarding HER2-positive breast cancer remains indiscriminate and lacks specificity, which limits the further improvement of overall treatment response and may lead to overtreatment and extra cost for some patients. Our study aims to reveal the molecular heterogeneity of HER2-positive breast cancer to guide a more precise treatment. Patients and methods: We selected HER2-positive breast cancer patients treated at Fudan University Shanghai Cancer Center between 2013 and 2014 and conducted genomic, transcriptomic, proteomic and metabolomic profiling. We then applied a non-negative matrix factorization algorithm on transcriptomic data to obtain an unsupervised classification. And we further studied the correlation between subtypes and corresponding treatment strategies in multiple cohorts of adjuvant and neoadjuvant therapy. For clinical accessibility, we developed convolutional neural network models through deep learning algorithm based on digital pathology to identify different subtypes. Additionally, we explored novel treatment strategies using the patient-derived organoids (PDOs) models. Results: We established a novel multiomics cohort of 180 HER2- breast cancer patients and classified them into four clinically significant molecular subtypes: (1) A classical HER2-enriched (HER2-CLA, N=51) subtype characterized by strong ERBB2 signaling and remarkable sensitivity to anti-HER2-targeted therapy (pathologic complete response with dual-targeted therapy: 93%). (2) an immunomodulatory (HER2-IM, N=36) subtype characterized by an immune-activated microenvironment and excellent prognosis with current treatment (no relapse in 97% of patients with a median follow-up of 86 months). Tumors of this subtype were therefore candidates for de-escalatory treatment. (3) A luminal-like (HER2-LUM, N=55) subtype distinguished by activated estrogen receptor signaling and (4) a basal/mesenchymal-like (HER2-BM, N=38) subtype enriched in activated receptor tyrosine kinase pathways. HER2-LUM and HER2- BM showed limited benefit from anti-HER2 therapy, and thus, add-on therapies might be needed. The overall area under the curve (AUC) of the convolutional neural network model based on digital pathology for identifying different subtypes is 0.77. In the exploration of novel treatment strategies, we found in the PDO model that the HER2-LUM subtype is more sensitive to a treatment regimen combining standard (chemotherapy and targeted therapy) with subsequent endocrine therapy and CDK4/6 inhibitors compared to other subtypes. Additionally, the HER2-BM subtype demonstrated greater sensitivity to treatment with a combination of EGFR inhibitors, PDGFR inhibitors or VEGFR inhibitors. Conclusion: We uncovered a high degree of molecular heterogeneity in HER2-positive breast cancer and illustrated its impact on treatment response. More precise treatment can be given according to the characteristics of different subtypes, which may achieve good efficacy and simultaneously reduce overtreatment and extra cost. The comprehensive profiling of HER2-positive breast cancers could also serve as an important resource for further exploration. Key Words: HER2-positive breast cancer cohort; molecular classification; targeted therapy; precision treatment; de-escalatory treatment. Citation Format: Yu-Wei Li, Ding Ma, Xiang-Rong Wu, Lei-Jie Dai, Shen Zhao, Yu-Zheng Xu, Xi Jin, Xiao Yi, Ying Wang, Cai-Jin Lin, Yi-Fan Zhou, Tong Fu, Wen-Tao Yang, Ming Li, Hong Lv, Yi-Zhou Jiang, Zhi-Ming Shao. Multiomics profiling and molecular classification refine precision treatment strategies for HER2-positive breast cancer [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 PS09-09.

Abstract HER2+ BC is an aggressive subtype with increased metastatic tropism towards brain. Small molecule anti-HER TKIs are still a key treatment choice in this setting owing to their competency to cross the blood brain barrier. Despite the efficacy, resistance to HER2-targeted agents often arises either due to compensatory signaling from other HER receptors or due to dysregulation in the downstream signaling pathway. We have previously shown that the mechanism of resistance to each TKI differs based on its HER receptor specificity profile. Here, we sought to evaluate the aggressiveness and metastatic ability of our HER2+ cell models with acquired resistance to different clinically relevant anti-HER TKIs. Dual GFP-Luc tagged HER2+ BT474 naïve parental cells and their acquired lapatinib (LapR), neratinib (NeraR), and tucatinib (TucaR) resistant (Res) derivatives harboring acquired HER2 L755S, HER2 L755S and a pathogenic PIK3CA mutation, or EGFR amplification, respectively were used. We have previously shown that while the LapR and NeraR cells are cross-Res to Tuca, the LapR and TucaR cells remain sensitive to Nera. Changes in cell growth and migration were evaluated by methylene blue or Incucyte wound healing assays, respectively. The metastatic phenotype of parental and the acquired Res models was assessed by intracardiac injection in NSG mice and metastasis was monitored by bioluminescence imaging. Metastatic lesions from different organs/sites were harvested to establish GFP-positive in vitro cell cultures. Our recent data showed that the LapR, NeraR, and TucaR derivatives are significantly more migratory compared to naïve parental cells suggesting their enhanced metastatic potential. Indeed, our in vivo studies revealed that all the Res derivatives and parental cells were highly metastatic to the brain, proving the well-established notion that HER2+ BC cells are brain tropic. Further, the involvement of ovary, lung, and liver, among others, were observed as additional common metastatic sites. We have now successfully established in vitro cultures of harvested metastatic lesions from different sites for each cell model. Growth assays using the cells established from LapR ovary metastatic lesions (LapR/OvMet) revealed that they are indeed Res to Lap, while importantly, consistent with the drug sensitivity profile of the original LapR 2D cells, the LapR/OvMet line was highly sensitive to Nera but cross-Res to Tuca. Additional studies to investigate the organ-specific metastatic tropism of each acquired resistant model are currently ongoing. Molecular and functional characterization of our established metastatic cultures will guide future in vivo studies, including testing the efficacy of new targeted treatment regimens to treat organ-specific metastasis, and expanding such studies to additional relevant cell and patient-derived xenograft/organoid models. Citation Format: Fu-Tien Liao, Lanfang Qin, Martin J. Shea, Igor Bado, Yi-Hsuan Wu, Ling Wu, Yang Gao, Sarmistha Nanda, Tia Gordon, Chia Chia Liu, Xiang H.-F. Zhang, C. Kent Osborne, Mothaffar F. Rimawi, Jamunarani Veeraraghavan, Rachel Schiff. Metastatic models of resistance to next generation tyrosine kinase inhibitors (TKIs) in HER2-positive breast cancer (BC) [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 386.

Abstract Background: In the global, phase 3 KEYNOTE-042 study, pembrolizumab (pembro) significantly prolonged OS vs chemotherapy (chemo) in patients (pts) with previously untreated advanced/metastatic NSCLC with PD-L1 TPS ≥1% without EGFR/ALK alterations. Among pts enrolled in China, pembro prolonged OS (HR; 95% CI) vs chemo in pts with PD-L1 TPS ≥50% (0.63; 0.43-0.94), TPS ≥20% (0.66; 0.47-0.92), and TPS ≥1% (0.67; 0.50-0.89). We present efficacy and safety outcomes with an additional 14 calendar mo of follow-up in Chinese pts in KEYNOTE-042. Methods: Pts enrolled in China in the KEYNOTE-042 global (NCT02220894) and China extension (NCT03850444) studies were randomized 1:1 to pembro 200 mg Q3W for ≤35 cycles or carboplatin+paclitaxel or pemetrexed with optional pemetrexed maintenance (nonsquamous only). Primary endpoints were OS in pts with PD-L1 TPS ≥50%, ≥20%, and ≥1%. Eligible pts who completed 35 cycles of pembro could receive a second course of pembro. No alpha was allocated to the China extension analysis. Results: 262 pts with PD-L1 TPS ≥1% were randomized in China to pembro (n = 128) or chemo (n = 134). Median time from randomization to data cutoff (Apr 28, 2021) was 47.2 (range, 39.8-56.1) mo. Pembro prolonged OS (HR, 95% CI) vs chemo in pts with PD-L1 TPS ≥50% (0.66, 0.45-0.95), ≥20% (0.68, 0.49-0.93), and ≥1% (0.67, 0.51-0.89; Table). 19.5% and 68.8% of pts in the pembro and chemo groups experienced treatment-related grade 3-5 AEs. Among 22 pts who completed 35 cycles of pembro, ORR was 81.8% (95% CI, 59.7%-94.8%); estimated OS rate 4 y after randomization was 69.1%. At data cutoff, 79 pts in each group had begun subsequent therapy; 4 pts began a second course of pembro. Conclusion: Similar to the global KEYNOTE-042 study, first-line pembro continues to prolong OS and provide durable response in pts in China with advanced/metastatic PD-L1-positive NSCLC without EGFR/ALK alterations after nearly 4 y of follow-up. Pembro monotherapy remains a standard of care in these pts. Table PD-L1 TPS ≥50% PD-L1 TPS ≥20% PD-L1 TPS ≥1% Pembro n = 72 Chemo n = 74 Pembro n = 101 Chemo n = 103 Pembro n = 128 Chemo n = 134 OS, median (95% CI), mo 24.5 (17.4-34.3) 13.8 (10.1-18.3) 21.9 (17.4-27.0) 13.5 (10.1-17.9) 20.2 (17.4-25.3) 13.5 (10.1-17.9) OS, HR (95% CI) 0.66 (0.45-0.95) 0.68 (0.49-0.93) 0.67 (0.51-0.89) OS 4-y rate (95% CI), % 23.4 (13.5-34.8) 13.6 (6.1-24.1) 22.5 (14.2-31.9) 14.4 (8.0-22.6) 21.3 (14.1-29.5) 12.7 (7.2-19.7) ORRa (95% CI), % 41.7 (30.2-53.9) 24.3 (15.1-35.7) 34.7 (25.5-44.8) 24.3 (16.4-33.7) 32.0 (24.1-40.9) 24.6 (17.6-32.8) DOR, median (range), mo 16.5 (1.4+ to 47.1+) 11.7 (1.6+ to 46.9+) 16.5 (1.4+ to 47.1+) 10.9 (1.6+ to 46.9+) 16.0 (1.4+ to 47.1+) 10.9 (1.1+ to 46.9+) DOR ≥2-y, % 36.9 34.0 37.4 25.6 36.7 25.0 DOR, duration of response; HR, hazard ratio; TPS, tumor proportion score. ‘+’ indicates no PD by time of last assessment. aPer RECIST v1.1 by blinded independent central review. Citation Format: Yi-Long Wu, Yun Fan, JianYing Zhou, Li Zhang, Qing Zhou, Wei Li, ChengPing Hu, GongYan Chen, Xin Zhang, CaiCun Zhou, Carmen González Arenas, Wei Fu, Helen Wu, Tony Mok. Pembrolizumab vs chemotherapy in Chinese patients with PD-L1-positive NSCLC: 4-year update from KEYNOTE-042 China 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 CT555.

Abstract Background: The combination of a PD-(L)1 inhibitor plus chemotherapy demonstrated promising anti-tumor activity as first-line therapy for patients (pts) with locally recurrent inoperable or metastatic PD-L1 positive triple-negative breast cancer (TNBC). However, for pts without PD-L1 expression and for those who have failed prior lines of treatment, therapeutic options are still limited. This multi-cohort, phase II trial aimed to evaluate the safety and antitumor activity of 70 mg (cohort A) or 100 mg (cohort B) sitravatinib plus tislelizumab in pts with locally recurrent or metastatic TNBC, and their combination (70 mg sitravatinib plus tislelizumab) with nab-paclitaxel in untreated locally recurrent inoperable or metastatic TNBC pts (cohort C). The efficacy of sitravatinib plus tislelizumab in cohort A and B has been reported with objective response rate (ORR) of 38.1% and 45.0%, respectively. Herein, the preliminary results of cohort C and updated results of cohort A and B were reported. Methods: Pts with untreated locally inoperable or metastatic TNBC were included in cohort C and received 70 mg sitravatinib orally once daily plus 200 mg tislelizumab intravenously on day 1 and 100mg/m2 nab-paclitaxel on days 1 and 8 every three weeks until disease progression or intolerable toxicity. The primary endpoint was ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), 1-year overall survival (OS) rate and safety/tolerability. Based on Simon’s two-stage design, > 9 responders were need in stage 1 (n=18) for the study to continue, and >19 responders were needed by the end of study (n=35) to demonstrate statistical superiority with sitravatinib plus tislelizumab and nab-paclitaxel (assumed to be around 65%) to a historical control of 46% (1-sided alpha of 0.1, power of 80%). Updated analyses were provided for cohort A (Simon’s 2 stage design) and B (Bayesian optimal phase II design). Results: Among the 18 pts in stage 1 of cohort C, 12 of them achieved confirmed response, and therefore the study proceeded to the enrollment in stage 2. As of April 30, 2023, a total of 32 pts were enrolled, with a median age of 51 years. Among the 23 efficacy evaluable pts, unconfirmed ORR was 87.0% (95% CI 66.4-97.2) (including 3 CRs and 17 PRs), with 7 pts not reaching next tumor assessment after reaching CR/PR, and confirmed ORR was 52.2% (95% CI 30.6-73.2). DCR was 95.7%. Any grade of treatment-related adverse events (TRAEs) occurred in 31 (96.9%) pts, and grade ≥3 TRAEs occurred in 5 (15.6%) pts. One (3.1%) patient experienced grade ≥3 immune-related adverse events. SAEs were reported in 3 (9.4%) pts. At the data cut-off date, the median follow-up duration for cohort A and B was 20.4 (range 1.3–24.3) months and 13.3 (range 5.1-19.1) months, respectively. The median PFS in cohort A was 8.2 (95% CI 2.8-12.4) months, and in cohort B was 5.4 (95% CI 4.2-10.9) months. Median OS was not reached in both cohorts. RNA-seq analysis showed that the suppression of immune regulatory pathways and the activation of metabolic pathways promoted early progression. Besides, baseline angiogenesis associated pathway held the potential to predict the favorable response to tislelizumab plus sitravatinib. Conclusion: In the first-line treatment of locally recurrent or metastatic TNBC, preliminary analysis of cohort C showed that sitravatinib combined with tislelizumab and nab-paclitaxel had promising anti-tumor activity with a high ORR, and the combination was generally well tolerated. In TNBC pts with less than three lines of therapy, the chemotherapy-free regimen with sitravatinib plus tislelizumab demonstrated promising PFS after a longer follow-up duration. Citation Format: Lei Fan, Xiyu Liu, Ying Xu, Xinyi Sui, Wenjuan Zhang, Linxiaoxi Ma, Xi Jin, Song-Yang Wu, Han Wang, Yi Xiao, Li Chen, Jiong Wu, Ke-da Yu, Guangyu Liu, Xin Hu, Zhonghua Wang, Yi-Zhou Jiang, Zhi-Ming Shao. Phase II study of sitravatinib plus tislelizumab with or without nab-paclitaxel in patients with locally recurrent or metastatic triple negative breast cancer [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 PO1-06-12.

Abstract Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease and lacks effective treatment. Our previous study classified TNBCs into four subtypes (luminal androgen receptor [LAR], immunomodulatory [IM], basal-like immune-suppressed [BLIS], mesenchymal-like [MES]) with distinct molecular features. We aimed to assess the efficacy and safety of molecular subtype-derived precision treatment in patients with heavily pretreated metastatic TNBC. Methods: This open-label, phase 2, umbrella trial included patients from four centers in China. Participants were women (aged ≥18 years) with histologically confirmed metastatic TNBC with disease progression after multiple lines of standard chemotherapy. Patients were enrolled into seven parallel arms according to their molecular subtypes: LAR with or without ERBB2 somatic mutation/amplification assigned to arm A (pyrotinib with capecitabine) and arm B (androgen inhibitor included therapy); IM assigned to arm C (anti-PD-1 antibody with nab-paclitaxel); BLIS with or without BRCA1/2 germline mutation assigned to arms D (PARP inhibitor included therapy) and E (anti-VEGFR included therapy); MES without or with PI3K-AKT mutation assigned to arms F (anti-VEGFR included therapy) and G (everolimus with nab-paclitaxel). Bayesian predictive probability was adopted to monitor each arm, which can be terminated independently according to a prespecified futility or efficacy boundary. This trial is registered with ClinicalTrials.gov, NCT03805399. Findings: Between October 18, 2018, and February 11, 2022, we enrolled 141 patients. All patients were heavily pretreated and resistant to six categories of the most common chemotherapeutic agents used in breast cancer treatment, with a median of 3 previous lines of therapies in the metastatic setting (Table 1 and 2). The median follow-up was 18.3 months (IQR 11.7-27.7). A confirmed objective response was achieved in 42 (29.8%, 95% CI 22.4-38.1) of the 141 patients. The median PFS was 3.4 months (95% CI 2.7-4.2), and the median OS was 10.7 months (95% CI 9.0-12.3) (Table 3). Arms A, C, E and G achieved efficacy boundaries, with 3 (75.0%) out of 4 patients in arm A, 20 (43.5%) out of 46 patients in arm C, 13 (28.3%) out of 46 patients in arm E, and 3 (33.3%) out of 9 patients in arm G achieving objective responses. Potential predictive biomarkers of efficacy in each arm were explored. Safety data were consistent with the known safety profiles of relevant drugs. Interpretation: We demonstrate the feasibility and clinical utility of a subtyping-based, genomic sequencing-guided strategy which allows the majority of heavily pretreated metastatic TNBCs to benefit from precision treatment. Most arms exhibit promising efficacy and manageable toxicities, providing subtyping schema to optimize personalized treatment. Table 1. The FUTURE trial schema. Patients are stratified into seven arms using the FUSCC 484-gene NGS panel testing and IHC subtyping. Abbreviations: mTNBC, metastatic triple-negative breast cancer; NGS, next-generation sequencing; IHC, immunohistochemistry; FUSCC, Fudan University Shanghai Cancer Center; LAR, luminal androgen receptor; IM, immunomodulatory; BLIS, basal-like immune-suppressed; MES, mesenchymal-like; n, number; AR, androgen receptor; PD-1, programmed cell death-1; PARPi, poly ADP-ribose polymerase inhibitor; VEGF, vascular endothelial growth factor; mTORi, mammalian target of rapamycin inhibitors. Table 2. Patient characteristics in the FUTURE trial. Table 3. Summary of treatment efficacy of TNBC in the FUTURE trial Citation Format: Zhi-Ming Shao, Zhong-Hua Wang, Yi-Zhou Jiang, Yin Liu, Xiu-Zhi Zhu, Yi Xiao, Song-Yang Wu, Wen-Jia Zuo, Qiang Yu, A-Yong Cao, Jun-Jie Li, Ke-Da Yu, Guang-Yu Liu, Jiong Wu, Tao Sun, Jiuwei Cui, Zheng Lv, Hui-Ping Li, Xiao-Yu Zhu. Subtyping-based platform guides precision medicine for heavily pretreated metastatic triple-negative breast cancer: a multicenter, phase 2, umbrella, FUTURE trial [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 OT3-27-01.

Abstract Introduction: Bacillus Calmette-Guérin (BCG) is the standard of care for high-risk non-muscle-invasive bladder cancer (NMIBC) following transurethral resection. However, patients often have heterogeneous responses. Even among those who initially respond well to BCG, 10-20% relapse. Identification of reliable biomarkers predicting the efficacy of BCG remains an unmet need. En bloc resection is a novel technique representing a substantial advancement in the surgical management of NMIBC. We sought to investigate genomic and tumor microenvironmental (TME) profiles in NMIBC and explore potential predictive markers for BCG treatment following en-block resection. Methods: A total of 40 patients with high-risk NMIBC (cTis-T1N0M0) were retrospectively enrolled who underwent en bloc resection followed by BCG instillation. Surgical samples were subjected to NGS sequencing using a 520-gene panel (Burning Rock Biotech, Guangzhou) and multiplex immunofluorescence (mIF) assay. Results: The cohort had a median age of 63 years, and 80% were male. After a median follow-up of 21.8 months, 19/40 patients relapsed with a one-year relapse-free survival (RFS) rate of 57.5%. All tumors were microsatellite stable and showed a median TMB of 7.98muts/Mb. Genomic profiling revealed a high prevalence of alterations in TERT (55%), KDM6A (32.5%), KMT2D (32.5%), FGFR3(30%), PIK3CA (30%), TP53(27.5%), KMT2C (25%), and ARID1A (20%). TME analysis showed higher proportions of M1 macrophages and CD56 dim NK cells in the tumoral compartment and more intense infiltration of CD8+ T cells, exhausted CD8+T, CD56 bright NK cells, and M2 macrophages in the stromal compartment. Multivariate analysis identified TERT C228T mutation (HR=3.28 [95%CI:1.225-8.79], p=0.0181) and alteration in KDM6A (HR=2.94 [95%CI:1.040-8.29], p=0.042) as two independent factors associated with inferior RFS. Patients with concomitant TERT C228T and KDM6A alteration had the shortest RFS (median RFS:5.83months) compared with those who were free of (median RFS: NR) or harbored either one of the two alterations (median RFS:9.13months) (p=0.0022). We also found that tumoral infiltration of CD8+T cells was positively associated with RFS (HR=0.29 [95%CI:0.097-0.885], p=0.0208). Conclusion: The study comprehensively depicted the genomic and TME profiles in NMIBC and identified potential predictive biomarkers for BCG treatment. Our findings may facilitate the stratification of patients and better guide the clinical decision-making on the management of NMIBC. Citation Format: Qi-Dong Xia, Yao-Bing Chen, Jian-Xuan Sun, Chen-Qian Liu, Jin-Zhou Xu, Zhi-Peng Yao, Ye An, Meng-Yao Xu, Si-Han Zhang, Xing-Yu Zhong, Na Zeng, Si-Yang Ma, Hao-Dong He, Heng-Long Hu, Jia Hu, Yi Lu, Lin Shao, Si-Qi Li, Zheng Liu, Shao-Gang Wang. TERT C228T and KDM6A alterations are potential predictive biomarkers in non-muscle-invasive bladder cancer treated with intravesical Bacillus Calmette-Guérin instillation [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 2127.

Abstract Background: CHASE001 (NCT05544123), a prospective, non-interventional multicenter study exploring real-world treatment and referral behavior of Chinese county patients (pts) with HER2+ or HR+/HER2– breast cancer is ongoing since September 2022. A prespecified interim analysis (IA) on 750 HER2+ and HR+/HER2- early breast cancer (eBC) was reported at the ESMO Congress 2023. In the 2nd IA from CHASE001, adjuvant treatment selection for patients with HR+/HER2- eBC will be evaluated. Methods: The study was designed to enroll 2500 pts, including four cohorts (HER2+ eBC, HR+/HER2-eBC, HER2+ advanced BC, and HR+/HER2- aBC). In this IA, HR+/HER2- eBC pts after surgery were included. Descriptive statistics reported patient demographics, clinical and disease characteristics and treatment patterns. To investigate the factors associated with chemotherapy-free regimen, non-anthracycline chemotherapy regimen and ovarian function suppression (OFS), univariate and multivariate logistic regression analyses were conducted. Results: At data cutoff (May 17, 2023), 697 HR+/HER2- eBC pts (median age 52 years, 45.77% pT2, 50.93% pN0, 56.10% G2) were included from 26 institutions in China county areas, 338 (48.49%) were premenopausal. 584 (83.79%) received adjuvant chemotherapy, with a few (47/584, 8.05%) initially developing their treatment plan at a higher level hospital (national or provincial tertiary hospital). AC-T (309/584, 52.91%) was the most commonly used regimen. 181 (30.99%) pts received non-anthracycline chemotherapy regimen (mainly TC), and pts with N0, age≥65 years and ki67 < 20% had the strongest association to this regimen (multivariate OR=0.082, 95%CI [0.037,0.179], OR=0.463, 95%CI [0.250,0.859], and OR=0.642, 95%CI [0.418,0.985], respectively). Interestingly, on univariate analysis pts initially diagnosed in a higher level hospital were significantly associated with non-anthracycline regimen (P=0.0109), however on multivariate analysis it was no longer significant. 483 pts received endocrine therapy, including 234 (48.45%) premenopausal pts. The most commonly used endocrine regimen for premenopausal pts was OFS/OFS+ (122/234, 52.14%) ,of which half (61, 50%) were prescribed OFS+TAM/TOR; followed by TAM/TOR monotherapy (69/234, 29.49%). The proportions of patients classified as low, intermediate, and high clinical risk for recurrence (investigator assessed)were 33.62%, 42.67% and 23.71%. The OFS rate were 39.74% in low, 61.62% in intermediate and 70.91% in high risk pts, respectively. Multivariable analyses found that high clinical risk, age < 45 years and ki67 < 20% were strongly associated with the use of OFS (OR=0.210, 95%CI [0.066,0.674], OR=0.327, 95%CI [0.165,0.649], and OR=0.405, 95%CI [0.194,0.845], respectively). For postmenopausal pts, AI monotherapy (84.74%) was the most commonly used endocrine regimen. Conclusions: To our knowledge, this is the first real-world study evaluating the treatment patterns and referral behavior of BC pts in China counties. The 2nd IA results presented showed the current systemic adjuvant treatment preferences and influence factors from a large sample of HR+/HER2- eBC pts in China counties, which were generally consistent with China BC treatment guidelines. Table 1. Utilization of adjuvant systemic therapy regimens in 697 HR+/HER2− eBC pts, China counties AC-T: (dd)doxorubicin/epirubicin, cyclophosphamide, followed by (dd)paclitaxel/docetaxel; TC: paclitaxel/docetaxel, cyclophosphamide; AC: doxorubicin/epirubicin, cyclophosphamide; TAC: docetaxel, doxorubicin/epirubicin, cyclophosphamide; TAM: tamoxifen; OFS: ovarian function suppression; AI: aromatase inhibitors; TOR: toremifene; CDK4/6i: cyclin-dependent kinase 4/6 inhibitors; “Other” category includes various therapies used in <1% of patients each Citation Format: Yinghua Ji, Honglan Qu, Feidu Zhou, Juan Wang, Qianfu Wu, Guohua Dai, Mengyou Liu, Wenbo He, Wei Liang, Qiuli Meng, Yun Ren, Guoxiang Luo, Hongjian Wang, Hui Liu, Zien Qin, Yingguo Tian, Huali Tang, Hongmei Liu, Jun Luo, Zengfeng Yu, Guinv Hu, Jianzhi Gao, Xiang Tan, Yi Liu, Yuanjiang Zhang, Ming Wang, Min Zhang, Ping Lu. Adjuvant Treatment Selection for County-Level Patients with HR+/HER2- Early Breast Cancer in a Real-Life Setting in China [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 PO2-16-08.

Objetivo: Esse estudo objetivou investigar percepções de estudantes de Odontologia quanto ao medo e à ansiedade em relação ao manejo de pacientes e ao risco de infecção por COVID-19. Materiais e métodos: Esse estudo transversal envolveu todos os alunos regularmente matriculados em Odontologia, no primeiro semestre de 2020, da Universidade Federal de Pelotas. Um questionário foi aplicado, coletando dados demográficos, nível de formação e perguntas relacionadas ao medo e ansiedade frente à pandemia de COVID-19. Quatro comparações de acordo com a fase da graduação (fase pré-clínica ou clínica), nível de graduação e pós-graduação e de acordo com os sexos foram feitas. Análises independentes para as comparações entre os sexos foram realizadas para os alunos de graduação e de pós-graduação (α<5%). Resultados: Foram incluídos 408 estudantes. Na graduação, mulheres relataram sentirem-se mais ansiosas ao realizar tratamento em pacientes com suspeita de COVID-19 (54%) e sentem mais medo ao ouvir que a infecção tem causado mortes (92,4%), na pós-graduação, responderam ser mais nervosas para conversar com pacientes em ambientes fechados em comparações com homens (P<0,05). Alunos em fase pré-clínica possuem significativamente menor receio (65,5%), ansiedade (32,3%) e nervosismo (28,3%) do contágio do COVID-19 quando comparados com aqueles na fase clínica. Conclusões: Mulheres e alunos na fase clínica apresentam maior ansiedade e nervosismo. Descritores: Ansiedade; Estudantes de Odontologia; Medo; Infecções por Coronavírus. Referências Chang J, Yuan Y, Wang D. [Mental health status and its influencing factors among college students during the epidemic of COVID-19]. Nan Fang Yi Ke Da Xue Xue Bao. 2020;40(2):171-176. World Health Organization. WHO Director-General’s opening remarks at the media briefing on COVID-19- 11 March 2020. 2020. Disponível em: https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. Acesso em: 8 de novembro de 2020. Pascarella G, Strumia A, Piliego C, Bruno F, Del Buono R, Costa F, Scarlata S, Agrò FE. COVID-19 diagnosis and management: a comprehensive review. J Intern Med. 2020;288(2):192-206. Chen E, Lerman K, Ferrara E. Tracking Social Media Discourse About the COVID-19 Pandemic: Development of a Public Coronavirus Twitter Data Set. JMIR Public Health Surveill. 2020;6(2):e19273. Iyer P, Aziz K, Ojcius DM. Impact of COVID-19 on dental education in the United States. J Dent Educ. 2020;84(6):718-722. Meng L, Hua F, Bian Z. Coronavirus Disease 2019 (COVID-19): Emerging and Future Challenges for Dental and Oral Medicine. J Dent Res. 2020;99(5):481-487. Peng X, Xu X, Li Y, Cheng L, Zhou X, Ren B. Transmission routes of 2019-nCoV and controls in dental practice. Int J Oral Sci. 2020;12(1):9. Machado RA, Bonan PRF, Perez DEDC, Martelli Júnior H. COVID-19 pandemic and the impact on dental education: discussing current and future perspectives. Braz Oral Res. 2020;34:e083. Ataş O, Talo Yildirim T. Evaluation of knowledge, attitudes, and clinical education of dental students about COVID-19 pandemic. PeerJ. 2020;8:e9575. Deery C. The COVID-19 pandemic: implications for dental education. Evid Based Dent. 2020;21(2):46-47. Basudan S, Binanzan N, Alhassan A. Depression, anxiety and stress in dental students. Int J Med Educ. 2017;8:179-186. Elani HW, Allison PJ, Kumar RA, Mancini L, Lambrou A, Bedos C. A systematic review of stress in dental students. J Dent Educ. 2014; 78(2):226-42. Sahu P. Closure of Universities Due to Coronavirus Disease 2019 (COVID-19): Impact on Education and Mental Health of Students and Academic Staff. Cureus. 2020;12(4):e7541. Ahmed MA, Jouhar R, Ahmed N, Adnan S, Aftab M, Zafar MS, Khurshid Z. Fear and Practice Modifications among Dentists to Combat Novel Coronavirus Disease (COVID-19) Outbreak. Int J Environ Res Public Health. 2020;17(8):2821. Talevi D, Socci V, Carai M, Carnaghi G, Faleri S, Trebbi E, di Bernardo A, Capelli F, Pacitti F. Mental health outcomes of the CoViD-19 pandemic. Riv Psichiatr. 2020;55(3):137-44. Mijiritsky E, Hamama-Raz Y, Liu F, Datarkar AN, Mangani L, Caplan J, Shacham A, Kolerman R, Mijiritsky O, Ben-Ezra M, Shacham M. Subjective Overload and Psychological Distress among Dentists during COVID-19. Int J Environ Res Public Health. 2020;17:5074. Rymarowicz J, Stefura T, Major P, Szeliga J, Wallner G, Nowakowski M, Pędziwiatr M. General surgeons' attitudes towards COVID-19: A national survey during the SARS-CoV-2 virus outbreak. Eur Surg. 2020;1-6. Adams JG, Walls RM. Supporting the Health Care Workforce During the COVID-19 Global Epidemic. JAMA. 2020;323(15):1439-40. Naz N, Iqbal S, Mahmood A. Stress, anxiety and depression among the dental students of university college of medicine and dentistry Lahore; Pakistan. Pak J Med Health Sci. 2017;11(4):1277-81. Waqas A, Iftikhar A, Malik Z, Aedma KK, Meraj H, Naveed S. Association of severity of depressive symptoms with sleep quality, social support and stress among Pakistani medical and dental students: A cross-sectional study. Global Psychiatry. 2019;2(2):211-20. Wang Y, Di Y, Ye J, Wei W. Study on the public psychological states and its related factors during the outbreak of coronavirus disease 2019 (COVID-19) in some regions of China. Psychol Health Med. 2020;1-10. Xiong J, Lipsitz O, Nasri F, Lui LMW, Gill H, Phan L, Chen-Li D, Iacobucci M, Ho R, Majeed A, McIntyre RS. Impact of COVID-19 pandemic on mental health in the general population: A systematic review. J Affect Disord. 2020;277:55-64. Liu N, Zhang F, Wei C, Jia Y, Shang Z, Sun L, Wu L, Sun Z, Zhou Y, Wang Y, Liu W. Prevalence and predictors of PTSS during COVID-19 outbreak in China hardest-hit areas: Gender differences matter. Psychiatry Res. 2020;287;112921. Terán E, Mayta-Tovalino F. Risk Factors, Self-perceived Stress, and Clinical Training among Dentistry Students in Peru: A Cross-sectional Study. J Contemp Dent Pract. 2019;20(5):561-5. Uraz A, Tocak YS, Yozgatligil C, Cetiner S, Bal B. Psychological well-being, health, and stress sources in Turkish dental students. J Dent Educ. 2013:77(10):1345-55. Agius AM, Gatt G, Vento Zahra E, Busuttil A, Gainza-Cirauqui ML, Cortes ARG et al. Self-reported dental student stressors and experiences during the COVID-19 pandemic. J Dent Educ. 2020. doi: 10.1002/jdd.12409. Hu J, Zou H, Dai Y, Feng Z. How to keep students engaged in oral health education during the COVID-19 pandemic. J Dent Educ. 2020. doi: 10.1002/jdd.12420. Liu S, Yang L, Zhang C, Xiang YT, Liu Z, Hu S, Zhang B. Online mental health services in China during the COVID-19 outbreak. 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Abstract Background: Immune checkpoint inhibitors (ICIs) have heralded a new era in breast cancer treatment; however, response rates remain limited, making precision immune-oncology a major unmet need. In addition to T cells, effective immune responses to ICIs rely on coordinated interactions between innate and adaptive immune cells. Mast cells are evolutionarily conserved, tissue-resident cells of importance to human health. Specific subsets of mast cells might be endowed with opposite roles in cancer treatment, yet the extent of mast cell heterogeneity and its clinical merit in immunotherapy remain undefined. Objective: We sought to comprehensively characterize mast cells in breast cancer, investigate their association with immunotherapy response with in-depth mechanistic insights, and identify actionable strategies to modulate mast cell functional states, thereby optimizing immunotherapy efficacy. Methods: We employed single-cell profiling on longitudinal breast cancer samples from three independent clinical trials (NCT04613674, NCT03197389 and GSE169246) to delineate mast cell heterogeneity in anti-PD-(L)1 therapy. By integrating multi-omic analyses, tissue characterization, preclinical experiments, transgenic mice, and high-throughput drug screening, we outlined the molecular features, underlying mechanisms, and clinical relevance of distinct mast cells to elicit ICI-responsive microenvironments. Subsequently, we launched RENAISSANCE (NCT05076682), a proof-of-concept, Bayesian adaptive, phase 2 platform trial, to evaluate the efficacy and safety of combining mast cell therapeutics with anti-PD-1 backbone therapy in metastatic triple-negative breast cancer (TNBC) patients who progressed after immunotherapy. The primary endpoint was the objective response rate (ORR) assessed using RECIST v1.1 criteria. Results: We identified a distinct population of mast cells termed antigen-presenting mast cells (APMCs), constituting approximately 30% of intratumoral mast cells and correlating with improved clinical benefit of anti-PD-(L)1 therapy in TNBC. APMCs displayed MHC-II and costimulatory molecules, and indicated the presence of tumor-reactive T cells and tertiary lymphoid structures. Using three immunocompetent mouse models, we confirmed the immunomodulatory capacity of APMCs in immunotherapy. Mechanistically, by employing Cpa3CreERT2Cd74fl/fl mice, we demonstrated that APMCs potentiate anti-PD-1 efficacy and antitumor T cell immunity through their antigen-presentation machinery. Interestingly, we identified cromolyn, an FDA-approved drug for allergy, as a potential therapeutic agent that elicited APMC-dependent CD8+ T cell cytotoxicity to synergize with anti-PD-1 therapy. Between February 2022 and March 2023, 10 patients with immunotherapy-refractory metastatic TNBC were enrolled to receive cromolyn plus camrelizumab backbone treatment. Given Bayesian predictive probability, this arm was “graduated” due to meeting the pre-specified efficacy boundary, with an ORR of 40.0% (4/10). The treatment was well tolerated with similar safety profiles of relevant drugs. Conclusions: Our findings provide crucial insights into the impact of mast cell heterogeneity on the clinical response to ICIs at a single-cell level, and pave the way for APMC-directed therapeutic interventions in cancer treatment. To our knowledge, this is the first prospective study in breast cancer of cromolyn plus anti-PD-1 backbone regimen after anti-PD-(L)1 immunotherapy failure, demonstrating significant antitumor activity and commendable tolerability. Consequently, we suggest a phase 3 randomized study to consolidate this finding, which might be an effective treatment in patients for whom there are few effective treatment options. Citation Format: Song-Yang Wu, Xi Jin, Yin Liu, Wen-Jia Zuo, Li Chen, Xiyu Liu, Lei Fan, Zhong-Hua Wang, Yan-Fei Liu, Yi-Zhou Jiang, Zhi-Ming Shao. Programme of mast cell subsets to potentiate breast cancer immunotherapy: from bed to bench to bed (the phase 2 platform RENAISSANCE trial) [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 PO1-14-07.

The alkali volcanics and intrusive rocks, dated at around 35-33Ma, are cut by mineralised northeast and east trending faults showing predominant evidence for strike-slip. Mineralisation includes haematite-Au-Cu and is accompanied by iron-rich alteration of the volcanic rocks. Detailed assessment of the geometry of the fault system at Pu Sam Cap suggests that the faults formed as a Riedel shear system during left-lateral slip within the Song Hong-Song Chay shear zone and the numerous contemporaneous northwest trending faults to the south; the northeast trending faults are interpreted as dextral “book-end’’ faults between major northwest trending faults enclosing the Pu Sam Cap massif. As mineralisation is hosted within these faults and is also associated with lamprohyric dykes it confirms a thermal event younger than the alkaline volcanics and syenitic intrusives at Pu Sam Cap, suggesting a hidden, young porphyry system. The age of faulting, and thus the maximum age for this young intrusive event, is attributed to the 23-21Ma period of late-stage left-lateral strike-slip motion across northwest Vietnam.ReferencesAnczkiewicz R., Viola G., Muntener O., Thrirlwall M., Quong N.Q., 2007. Structure and shearing conditions in the Day Nui Con Voi massif: implications for the evolution of the Red River Fault. Tectonics 26: TC2002.Cao Shunyun, Liu Junlai, Leis B., Zhao Chunquiang 2010. New zircon U/Pb geochronology of the post-kinematic granitic plutons in Diancang Shan Massif along the Ailao-Shan-Red River Shear Zone and its geological implications. Acta Geologica Sinica (English Edition), 84, 1474-1487.Chung S.-L., Lee T., Lo C., et al., 1997. Intraplate extension prior to continental extrusion along the Ailao Shan-Red River shear zone.Geology, 25, 311-314.Cloos H., 1928. Experimentezurinnern Tektonik. Zentralblatt fur Mineralogie und Palaeontologie, 1928, 609-621.Findlay R.H., Phan Trong Trinh 1997. The structural setting of the Song Ma region, Vietnam, and the Indochina-South China plate boundary problem. Gondwana Research, 1, 11-33.Jolivet L., Beysasac O., Goffe B., Avigad D., Leprevrier C., Maluski H., Ta Trong Thang, 2001. Oligo-Miocene midcrustal subhorizontal shear in Indochina. Tectonics, 20, 46-57.Khuong The Hung 2010. The complex tectonic events and their influence on formation of mineral deposits in northwest Vietnam. Unpublished PhD Thesis, University of Science and Technology, Cracow, 167p.Leloup P.H., N. Arnau, R. Lacassin, J.R. Kienast, T.M. Harrison, P.T. Trinh, A. Replumaz and P. Tapponnier, 2001. New constraints on the structure, thermochronology and timing of the Ailao Shan - Red river shear zone, SE Asia, J. G. R., 106, 6657-6671.Leloup PH.., R. Lacassin, P. Tapponnier, U. Scharer, Zhong Dalai, Liu Xaohan, Zhangshan, Ji Shaocheng and PT.Trinh, 1995. The Ailao Shan - Red river shear zone (Yunnan, China), Tertiary transform boundary of Indochina, Tectonophysics, 251, 3-84. Leprevier C., Maluski H., Nguyen Van Vuong, Roques D., Axente V., Rangin C., 1996. Indosinian NW-trending shear zones within the Truong Son belt, Vietnam: 40Ar-39Ar Triassic ages and Cretaceous to Cenozoic overprints. Tectonophysics, 283, 105-107.Lien-Sheng Zhang, Scharer U. 1999. Age and origin of magmatism along the Cenozoic Red River shear belt, China. Contributions to Mineralogy and Petrology, 134, 67-85.Nagy E.A., Scharer U., Minh N.T., 2000. Oligo-Miocene granitic magmatismin central Vietnam and implications for continental deformation in Indochina. Terra Nova, 12, 67-76.Nguyen Thi Bich Thuy, 2016. Isotop dating U-Pb Zircon of Syenit Formation, Pu Sam Cap. Journal of Geology, A Serie, 356, 30-36. (In Vietnamese).Pei-Long Wang, Ching-Hua Lo, Tung-Yi Lee, Sun-ling Chun, Ching-Yan Lan, Nguyen Trong Yem 1998. Thermochronological evidence for the movement of the Ailo Shan-Red River shear zone, a perspective from Vietnam. Geology, 26, 887-890.Phan Trong Trinh, Nguyen Trong Yem, Herve L.P., Tapponnier P., 1994. Late Cenozoic stress fields in North Vietnam from microtectonic measurements. Proceedings of the International Workshop on Seismotectonics and Seismic Hazard in Southeast Asia. Geological Survey of SR Vietnam, Hanoi, 182-186.Riedel W., 1929. Zur Mechanikgreologischer Brucherscheinungen. Zentralblatt fur Mineralogie und Palaeontologie, Abhandlung B, 354-368.Scharer U., Tapponnier P., Lacassin R., Leloup P.H., Dalai Z., Shaosheng J., 1990. Intraplate tectonics in Asia: a precise age for large-scale Miocene movement along the Ailao Shan-Red River shear zone, China. Earth and Planetary Science Letters, 97, 65-77.Scharer U., Zhang L.S., Tapponnier P., 1994. Duration of strike-slip movements in large shear zones: the Red River belt, China. Earth and Planetary Science Letters, 126, 379-397.Searle M.P., 2006. Role of the Red River Shear zone, Yunnan and Vietnam, in the continental extrusion of SE Asia. Journal of the Geological Society, London, 163, 1025-1036.Searle M.P., Meng-Wan Yeh, Te-Hsien Lin, Sun-Lin Chung, 2010. Structural constraints on the timing of left-lateral shear along the Red River shear zone in the Ailao Shan and Diancang Shan Ranges, Yunnan, SW China. Geosphere, 6, 316-338.Tapponnier P., Lacassin R., Leloup H., Scharer U., Zhong Dalai, Wu Hawei, Liu Ziaohan, Ji Shaocheng, Zhang Lianshang, Zong Jiayou, 1990. The Ailao Shan/ Red River metamorphic belt: Tertiary left-lateral shear between Indochina and south China. Nature, 342, 431-437.Tchalenko J.S., 1970. Similarities between shear zones of different magnitudes. Bulletin of the Geological Society of America, 81, 1625-1640.Viola G., Anczkiewicz R. 2009. Exhumation history of the Red River shear zone in northern Vietnam: new insights from zircon and apatite fission-track analysis. Journal of Asian Earth Sciences, 33, 78-90.Yang Yiseng, Hong Qun, Hu Huan-ting, Hieu Pham Trung, Nguyen Thi Bich Thuy, Chen Fu-kun, 2013. Geochemical characteristics and genesis of the Cenozoic porphyry in the Laizhou area, northwestern Vietnam. Acta Petrologica Sinica, 29(3), 899-911. (In Chinese with English abstract, full English version through Google Translate).

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.

The 17th book of Lüshi chunqiu 呂氏春秋, compiled by Lü Buwei 呂不韋 inthe 3rd c. B.C., comprises two lists of officials who are credited with initiatingcertain cultural phenomena. In this study, I explore the available informationon these 26 individuals (Da Nao 大橈, Qian Ru 黔如, Rong Cheng 容成, XiHe 羲和, Shang Yi 尚儀, Hou Yi 后益, Hu Cao 胡曹, Yi Yi 夷羿, Zhu Rong祝融, Yi Di 儀狄, Gao Yuan 高元, Yu Xu 虞姁, Bo Yi 伯益, Chi Ji 赤冀, ChengYa 乘雅, Han Ai 寒哀, Wang Hai 王亥, Shi Huang 史皇, Wu Peng 巫彭, WuXian巫咸, Xi Zhong 奚仲, Cang Jie 蒼頡, Houji 后稷, Gao Yao 皋陶, Kunwu昆吾, Gun 鯀), and propose a new interpretation of their presence in this earlysource.

The journal is pleased to publish the abstracts of the six finalists of the 2020 Manufacturing and Service Operations Management Society’s student paper competition. The 2020 prize committee was chaired by Vishal Agrawal (Georgetown), Feryal Erhun (University of Cambridge), and Jun Li (University of Michigan). The judges were Adem Orsdemir, Antoine Desir, Anton Ovchinnikov, Anyan Qi, Arian Aflaki, Arzum Akkas, Ashish Kabra, Bin Hu, Bob Batt, Bora Keskin, Can Zhang, Carri Chan, Chloe Kim Glaeser, Daniel Lin, Eduard Calvo, Ekaterina Astashkina, Elena Belavina, Elodie Adida, Enis Kayış, Ersin Korpeoglu, Fabian Sting, Fang Liu, Fanyin Zheng, Fei Gao, Florin Ciocan, Gah-Yi Ban, Gizem Korpeoglu, Guihua Wang, Guillaume Roels, Guoming Lai, Hessam Bavafa, Hummy Song, Ioannis (Yannis) Stamatopoulos, Ioannis Bellos, Iris Wang, Itir Karaesmen, Jiankun Sun, Jiaru Bai, Jing Wu, Joann de Zegher, Joel Wooten, John Silberholz, Jose Guajardo, Kaitlin Daniels, Karen Zheng, Ken Moon, Kenan Arifoglu, Lennart Baardman, Leon Valdes, Lesley Meng, Linwei Xin, Luyi Gui, Luyi Yang, Mary Parkinson, Mazhar Arikan, Michael Freeman, Ming Hu, Morvarid Rahmani, Mumin Kurtulus, Nan Yang, Necati Tereyagoglu, Nektarios Oraiopoulos, Nikos Trichakis, Nil Karacaoglu, Nitin Bakshi, Niyazi Taneri, Nur Sunar, Olga Perdikaki, Ovunc Yilmaz, Ozan Candogan, Ozge Sahin, Panos Markou, Pascale Crama, Pengyi Shi, Pnina Feldman, Qiuping Yu, Renyu (Philip) Zhang, Robert Bray, Ruslan Momot, Ruxian Wang, Saed Alizamir, Safak Yucel, Samantha Keppler, Santiago Gallino, Serdar Simsek, Seyed Emadi, Shiliang (John) Cui, Shouqiang Wang, Simone Marinesi, So Yeon Chun, Song-Hee Kim, Soo-Haeng Cho, Soroush Saghafian, Stefanus Jasin, Suresh Muthulingam, Suvrat Dhanorkar, Tian Chan, Tim Kraft, Tom Tan, Tugce Martagan, Velibor Misic, Weiming Zhu, Xiaoshan Peng, Xiaoyang Long, Yasemin Limon, Yehua Wei, Yiangos Papanastasiou, Ying-Ju Chen, and Zumbul Atan.

ObjectiveNeuropathic pain (NP) is a common disease that manifests with pathological changes in the somatosensory system. In recent years, the interactions of NP with the epigenetic mechanism have been increasingly elucidated. However, only a few studies have used bibliometric tools to systematically analyze knowledge in this field. The objective of this study is to visually analyze the trends, hotspots, and frontiers in epigenetics and NP research by using a bibliometric method.MethodsStudies related to epigenetics and NP were searched from the Science Citation Index-Expanded of the Web of Science Core Collection database. Search time is from inception to November 30, 2022. No restrictions were placed on language. Only articles and reviews were included as document types. Data on institutions, countries, authors, journal distribution, and keywords were imported into CiteSpace software for visual analysis.ResultsA total of 867 publications met the inclusion criteria, which spanned the period from 2000 to 2022. Over the years, the number of publications and the frequency of citations exhibited a clear upward trend in general, reaching a peak in 2021. The major contributing countries in terms of the number of publications were China, the United States, and Japan. The top three institutions were Rutgers State University, Xuzhou Medical University, and Nanjing Medical University. Molecular Pain, Pain, and Journal of Neuroinflammation contributed significantly to the volume of issues. Among the top 10 authors in terms of the number of publications, Tao Yuan-Xiang contributed 30 entries, followed by Zhang Yi with 24 and Wu Shao-Gen with 20. On the basis of the burst and clusters of keywords, “DNA methylation,” “Circular RNA,” “acetylation,” “long non-coding RNA,” and “microglia” are global hotspots in the field.ConclusionThe bibliometric analysis indicates that the number of publications related to epigenetics and NP is exhibiting a rapid increase. Keyword analysis shows that “DNA methylation,” “Circular RNA,” “acetylation,” “long non-coding RNA” and “microglia” are the most interesting terms for researchers in the field. More rigorous clinical trials and additional studies that explore relevant mechanisms are required in the future.

LANGUAGE NOTE | Document text in Chinese; abstract also in English. 本文考訂楊伯峻《春秋左傳注》（以下簡稱《左傳注》），以《左傳》成公二年爲範圍，討論“無能爲役”“詰朝”、“朝食”、“大户”四則。經詞例分析，“無能爲役”之“役”當爲名詞，應從《左傳》襄公十七年《春秋左傳集解》（以下簡稱《集解》）釋爲“役事”，較《左傳注》解作“僕役”適洽。《左傳》四見“詰朝”，《集解》於三處釋“平旦”、一處釋“明朝”，《左傳注》解作明日早晨。本文讀“詰”爲“佶”而訓爲“正”，先秦典籍“正”字常有“平”義；至於“朝”與“旦”皆有“早”義，故“詰朝”即“平旦”。《左傳注》謂“朝食”爲早上進食，《史記》則將“朝食”寫爲“會食”。然就《左傳》載齊頃公“余姑翦滅此而朝食”語，顯是自認可在早上結束戰争，故“朝食”仍應解爲在早上進食。《集解》釋“大户”爲“閲民户口”而《左傳注》解作“清理户口”，“大户”之“大”應讀爲“汏”。《説文》謂“汏”字本義爲“淅㶕”，即後世所謂淘洗，沙汏、淘汏皆自“汏”字本義引申。從另一角度言，“淅㶕”亦有清理、計算義；且《左傳》“閲”字亦有“計算”義，故《集解》釋“大户”爲“閲民户口”即計算户籍，乃讀“大”爲“汏”。 This article examines four phrases in Yang Bojun’s Commentary on the Zuo Tradition of the Spring and Autumn Annals (hereafter Yang’s Commentary), namely “wu neng wei yi” 無能爲役, “jie chao” 詰朝, “zhao shi” 朝食, and “da hu” 大户, which are found in the second year of Duke Cheng of Lu (589 B.C.) in the Zuozhuan. According to the analysis of a register of example phrases, the word “yi” in the phrase “wu neng wei yi” should be regarded as a noun, which refers to “service matter” as seen in Duke Xiang 17 in Collective Exegeses on the Zuo Tradition of the Spring and Autumn Annals (hereafter, Collective Exegeses). This reading makes more sense than Yang’s Commentary, in which the word is glossed as “servant.” The phrase “jie chao” occurs four times in Zuozhuan. In Collective Exegeses it is glossed as “dawn” three times and as “the next morning” once. In Yang’s Commentary, however, all four occurrences are glossed as “the next morning.” The present article reads “jie” 詰 as “ji” 佶 and glosses it as “zheng” 正 (“the horizon”). In pre-Qin texts, the character “zheng” often carries the meaning of “the horizon.” The characters “chao” and “dan” both mean “dawn.” Therefore, the phrase “jie chao” refers to “dawn.” In Collective Exegeses, the phrase “zhao shi” is glossed as “eating a meal in the morning.” In the Shiji, “zhao shi” is written as “hui shi” 會食; however, the Zuozhuan records a sentence said by Duke Qing of Qi, “Yu gu jian mie ci er zhao shi” 余姑翦滅此而朝食, which clearly refers to a statement to himself that the battle could be over in the morning. Therefore, “zhao shi’ should still be understood as “eating a meal in the morning.” The Collective Exegeses glosses the phrase “da hu” as to “check on” (“yue” 閲) household occupants, while Yang’s Commentary glosses it as “canceling one’s residence registration.” Therefore, “da” should be read as “tai” 汏. According to the Shuowen, the original meaning of “tai” is “to wash in a pan or basket” (“xi jian” 淅㶕); referring to weeding out something/someone in today’s parlance. Moreover, several other phrases such as “sha tai” 沙汰 and “tao tai” 淘汰 were derived from the same original meaning. From another angle, the phrase “xi jian” also carries the meanings of “checking” or “calculating.” In the Zuozhuan, the word “yue” also means “calculating”; therefore, the phrase “da hu” means “checking on (“yue”) the household occupants or, in other words, to calculate household registries. The word “da” should be read as “tai”.

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). 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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus , is causing a serious worldwide COVID-19 pandemic. The emergence of strains with rapid spread and unpredictable changes is the cause of the increase in morbidity and mortality rates. A number of drugs as well as vaccines are currently being used to relieve symptoms, prevent and treat the disease caused by this virus. However, the number of approved drugs is still very limited due to their effectiveness and side effects. In such a situation, medicinal plants and bioactive compounds are considered a highly valuable source in the development of new antiviral drugs against SARS-CoV-2. This review summarizes medicinal plants and bioactive compounds that have been shown to act on molecular targets involved in the infection and replication of SARS-CoV-2. Keywords: Medicinal plants, bioactive compounds, antivirus, SARS-CoV-2, COVID-19 References [1] R. Lu, X. Zhao, J. Li, P. Niu, B. Yang, H. 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Introdução: A transmissão SARS-CoV-2 de humano para humano pode ocorrer e o risco de propagação no ar durante os procedimentos odontológicos geradores de aerossóis permanece uma preocupação. Acredita-se que um enxaguatório bucal antimicrobiano pré-operacional reduza o número de micróbios orais. No entanto, a eficácia do enxaguatório bucal pré-procedimento na redução do número de microrganismos disseminados por meio do aerossol gerado por procedimentos odontológicos ainda não está clara. Objetivo: avaliar através de uma revisão de literatura o uso de enxaguantes bucais na redução da carga viral do SARS-CoV-2. Materiais e Método: O levantamento literário para esta pesquisa foi realizado no período de dezembro de 2019 a 10 de agosto de 2020 nas bases de dados Scielo e Medline/PubMed. Na estratégia de busca, foram utilizadas as palavras “SARS-CoV-2”, “2019-nCoV”, “COVID-19”, “Dentistry”, “Odontologia”, “Odontología”, “Mouthwashes”, “Antissépticos Bucais” e “Antisépticos Bucales”. Resultados: Uma busca sistematizada foi realizada, foram encontrados 661 artigos, após a realização da leitura criteriosa dos artigos completos foram selecionados 42 artigos. 88% dos estudos indicavam o uso de Peróxido de hidrogênio a 1%, 76% indicavam Povidine 0,2% e apenas 19% o uso da Clorexidina a 0,12%. Conclusão: Os estudos presentes na literatura apresentam divergências nas indicações e porcentagens dos enxaguantes indicados. Os protocolos clínicos devem ser avaliados para reduzir o risco de transmissão e proteger pacientes e profissionais.Descritores: Infecções por Coronavírus; Betacoronavirus; Odontologia; Antissépticos Bucais.ReferênciasGe ZY, Yang LM, Xia JJ, Fu XH, Zhang YZ. Possible aerosol transmission of COVID-19 and special precautions in dentistry. J Zhejiang Univ Sci B. 2020;21(5):361-68. Peng X, Xu X, Li Y, Cheng L, Zhou X, Ren B. Transmission routes of 2019-nCoV and controls in dental practice. 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The curtain rose. The howling of desert wind filled the performance hall in the Shanghai Grand Theatre. Into the center stage, where a scenic construction of a mountain cliff and a desert landscape was dimly lit, entered the character of the Daoist priest Wang Yuanlu (1849–1931), performed by Chen Yizong. Dressed in a worn and dusty outfit of dark blue cotton, characteristic of Daoist priests, Wang began to sweep the floor. After a few moments, he discovered a hidden chambre sealed inside one of the rock sanctuaries carved into the cliff.Signaled by the quick, crystalline, stirring wave of sound from the chimes, a melodious Chinese ocarina solo joined in slowly from the background. Astonished by thousands of Buddhist sūtra scrolls, wall paintings, and sculptures he had just accidentally discovered in the caves, Priest Wang set his broom aside and began to examine these treasures. Dawn had not yet arrived, and the desert sky was pitch-black. Priest Wang held his oil lamp high, strode rhythmically in excitement, sat crossed-legged in a meditative pose, and unfolded a scroll. The sound of the ocarina became fuller and richer and the texture of the music more complex, as several other instruments joined in.Below is the opening scene of the award-winning, theatrical dance-drama Dunhuang, My Dreamland, created by China’s state-sponsored Lanzhou Song and Dance Theatre in 2000. Figure 1a: Poster Side A of Dunhuang, My Dreamland Figure 1b: Poster Side B of Dunhuang, My DreamlandThe scene locates the dance-drama in the rock sanctuaries that today are known as the Dunhuang Mogao Caves, housing Buddhist art accumulated over a period of a thousand years, one of the best well-known UNESCO heritages on the Silk Road. Historically a frontier metropolis, Dunhuang was a strategic site along the Silk Road in northwestern China, a crossroads of trade, and a locus for religious, cultural, and intellectual influences since the Han dynasty (206 B.C.E.–220 C.E.). Travellers, especially Buddhist monks from India and central Asia, passing through Dunhuang on their way to Chang’an (present day Xi’an), China’s ancient capital, would stop to meditate in the Mogao Caves and consult manuscripts in the monastery's library. At the same time, Chinese pilgrims would travel by foot from China through central Asia to Pakistan, India, Nepal, Bangladesh, and Sri Lanka, playing a key role in the exchanges between ancient China and the outside world. Travellers from China would stop to acquire provisions at Dunhuang before crossing the Gobi Desert to continue on their long journey abroad. Figure 2: Dunhuang Mogao CavesThis article approaches the idea of “abroad” by examining the present-day imagination of journeys along the Silk Road—specifically, staged performances of the various Silk Road journey-themed dance-dramas sponsored by the Chinese state for enhancing its cultural and foreign policies since the 1970s (Kuang).As ethnomusicologists have demonstrated, musicians, choreographers, and playwrights often utilise historical materials in their performances to construct connections between the past and the present (Bohlman; Herzfeld; Lam; Rees; Shelemay; Tuohy; Wade; Yung: Rawski; Watson). The ancient Silk Road, which linked the Mediterranean coast with central China and beyond, via oasis towns such as Samarkand, has long been associated with the concept of “journeying abroad.” Journeys to distant, foreign lands and encounters of unknown, mysterious cultures along the Silk Road have been documented in historical records, such as A Record of Buddhist Kingdoms (Faxian) and The Great Tang Records on the Western Regions (Xuanzang), and illustrated in classical literature, such as The Travels of Marco Polo (Polo) and the 16th century Chinese novel Journey to the West (Wu). These journeys—coming and going from multiple directions and to different destinations—have inspired contemporary staged performance for audiences around the globe.Home and Abroad: Dunhuang and the Silk RoadDunhuang, My Dreamland (2000), the contemporary dance-drama, staged the journey of a young pilgrim painter travelling from Chang’an to a land of the unfamiliar and beyond borders, in search for the arts that have inspired him. Figure 3: A scene from Dunhuang, My Dreamland showing the young pilgrim painter in the Gobi Desert on the ancient Silk RoadFar from his home, he ended his journey in Dunhuang, historically considered the northwestern periphery of China, well beyond Yangguan and Yumenguan, the bordering passes that separate China and foreign lands. Later scenes in Dunhuang, My Dreamland, portrayed through multiethnic music and dances, the dynamic interactions among merchants, cultural and religious envoys, warriors, and politicians that were making their own journey from abroad to China. The theatrical dance-drama presents a historically inspired, re-imagined vision of both “home” and “abroad” to its audiences as they watch the young painter travel along the Silk Road, across the Gobi Desert, arriving at his own ideal, artistic “homeland”, the Dunhuang Mogao Caves. Since his journey is ultimately a spiritual one, the conceptualisation of travelling “abroad” could also be perceived as “a journey home.”Staged more than four hundred times since it premiered in Beijing in April 2000, Dunhuang, My Dreamland is one of the top ten titles in China’s National Stage Project and one of the most successful theatrical dance-dramas ever produced in China. With revenue of more than thirty million renminbi (RMB), it ranks as the most profitable theatrical dance-drama ever produced in China, with a preproduction cost of six million RMB. The production team receives financial support from China’s Ministry of Culture for its “distinctive ethnic features,” and its “aim to promote traditional Chinese culture,” according to Xu Rong, an official in the Cultural Industry Department of the Ministry. Labeled an outstanding dance-drama of the Chinese nation, it aims to present domestic and international audiences with a vision of China as a historically multifaceted and cosmopolitan nation that has been in close contact with the outside world through the ancient Silk Road. Its production company has been on tour in selected cities throughout China and in countries abroad, including Austria, Spain, and France, literarily making the young pilgrim painter’s “journey along the Silk Road” a new journey abroad, off stage and in reality.Dunhuang, My Dreamland was not the first, nor is it the last, staged performances that portrays the Chinese re-imagination of “journeying abroad” along the ancient Silk Road. It was created as one of many versions of Dunhuang bihua yuewu, a genre of music, dance, and dramatic performances created in the early twentieth century and based primarily on artifacts excavated from the Mogao Caves (Kuang). “The Mogao Caves are the greatest repository of early Chinese art,” states Mimi Gates, who works to increase public awareness of the UNESCO site and raise funds toward its conservation. “Located on the Chinese end of the Silk Road, it also is the place where many cultures of the world intersected with one another, so you have Greek and Roman, Persian and Middle Eastern, Indian and Chinese cultures, all interacting. Given the nature of our world today, it is all very relevant” (Pollack). As an expressive art form, this genre has been thriving since the late 1970s contributing to the global imagination of China’s “Silk Road journeys abroad” long before Dunhuang, My Dreamland achieved its domestic and international fame. For instance, in 2004, The Thousand-Handed and Thousand-Eyed Avalokiteśvara—one of the most representative (and well-known) Dunhuang bihua yuewu programs—was staged as a part of the cultural program during the Paralympic Games in Athens, Greece. This performance, as well as other Dunhuang bihua yuewu dance programs was the perfect embodiment of a foreign religion that arrived in China from abroad and became Sinicized (Kuang). Figure 4: Mural from Dunhuang Mogao Cave No. 45A Brief History of Staging the Silk Road JourneysThe staging of the Silk Road journeys abroad began in the late 1970s. Historically, the Silk Road signifies a multiethnic, cosmopolitan frontier, which underwent incessant conflicts between Chinese sovereigns and nomadic peoples (as well as between other groups), but was strongly imbued with the customs and institutions of central China (Duan, Mair, Shi, Sima). In the twentieth century, when China was no longer an empire, but had become what the early 20th-century reformer Liang Qichao (1873–1929) called “a nation among nations,” the long history of the Silk Road and the colourful, legendary journeys abroad became instrumental in the formation of a modern Chinese nation of unified diversity rooted in an ancient cosmopolitan past. The staged Silk Road theme dance-dramas thus participate in this formation of the Chinese imagination of “nation” and “abroad,” as they aestheticise Chinese history and geography. History and geography—aspects commonly considered constituents of a nation as well as our conceptualisations of “abroad”—are “invariably aestheticized to a certain degree” (Bakhtin 208). Diverse historical and cultural elements from along the Silk Road come together in this performance genre, which can be considered the most representative of various possible stagings of the history and culture of the Silk Road journeys.In 1979, the Chinese state officials in Gansu Province commissioned the benchmark dance-drama Rain of Flowers along the Silk Road, a spectacular theatrical dance-drama praising the pure and noble friendship which existed between the peoples of China and other countries in the Tang dynasty (618-907 C.E.). While its plot also revolves around the Dunhuang Caves and the life of a painter, staged at one of the most critical turning points in modern Chinese history, the work as a whole aims to present the state’s intention of re-establishing diplomatic ties with the outside world after the Cultural Revolution. Unlike Dunhuang, My Dreamland, it presents a nation’s journey abroad and home. To accomplish this goal, Rain of Flowers along the Silk Road introduces the fictional character Yunus, a wealthy Persian merchant who provides the audiences a vision of the historical figure of Peroz III, the last Sassanian prince, who after the Arab conquest of Iran in 651 C.E., found refuge in China. By incorporating scenes of ethnic and folk dances, the drama then stages the journey of painter Zhang’s daughter Yingniang to Persia (present-day Iran) and later, Yunus’s journey abroad to the Tang dynasty imperial court as the Persian Empire’s envoy.Rain of Flowers along the Silk Road, since its debut at Beijing’s Great Hall of the People on the first of October 1979 and shortly after at the Theatre La Scala in Milan, has been staged in more than twenty countries and districts, including France, Italy, Japan, Thailand, Russia, Latvia, Hong Kong, Macao, Taiwan, and recently, in 2013, at the Lincoln Center for the Performing Arts in New York.“The Road”: Staging the Journey TodayWithin the contemporary context of global interdependencies, performing arts have been used as strategic devices for social mobilisation and as a means to represent and perform modern national histories and foreign policies (Davis, Rees, Tian, Tuohy, Wong, David Y. H. Wu). The Silk Road has been chosen as the basis for these state-sponsored, extravagantly produced, and internationally staged contemporary dance programs. In 2008, the welcoming ceremony and artistic presentation at the Olympic Games in Beijing featured twenty apsara dancers and a Dunhuang bihua yuewu dancer with long ribbons, whose body was suspended in mid-air on a rectangular LED extension held by hundreds of performers; on the giant LED screen was a depiction of the ancient Silk Road.In March 2013, Chinese president Xi Jinping introduced the initiatives “Silk Road Economic Belt” and “21st Century Maritime Silk Road” during his journeys abroad in Kazakhstan and Indonesia. These initiatives are now referred to as “One Belt, One Road.” The State Council lists in details the policies and implementation plans for this initiative on its official web page, www.gov.cn. In April 2013, the China Institute in New York launched a yearlong celebration, starting with "Dunhuang: Buddhist Art and the Gateway of the Silk Road" with a re-creation of one of the caves and a selection of artifacts from the site. In March 2015, the National Development and Reform Commission (NDRC), China’s top economic planning agency, released a new action plan outlining key details of the “One Belt, One Road” initiative. Xi Jinping has made the program a centrepiece of both his foreign and domestic economic policies. One of the central economic strategies is to promote cultural industry that could enhance trades along the Silk Road.Encouraged by the “One Belt, One Road” policies, in March 2016, The Silk Princess premiered in Xi’an and was staged at the National Centre for the Performing Arts in Beijing the following July. While Dunhuang, My Dreamland and Rain of Flowers along the Silk Road were inspired by the Buddhist art found in Dunhuang, The Silk Princess, based on a story about a princess bringing silk and silkworm-breeding skills to the western regions of China in the Tang Dynasty (618-907) has a different historical origin. The princess's story was portrayed in a woodblock from the Tang Dynasty discovered by Sir Marc Aurel Stein, a British archaeologist during his expedition to Xinjiang (now Xinjiang Uygur autonomous region) in the early 19th century, and in a temple mural discovered during a 2002 Chinese-Japanese expedition in the Dandanwulike region. Figure 5: Poster of The Silk PrincessIn January 2016, the Shannxi Provincial Song and Dance Troupe staged The Silk Road, a new theatrical dance-drama. Unlike Dunhuang, My Dreamland, the newly staged dance-drama “centers around the ‘road’ and the deepening relationship merchants and travellers developed with it as they traveled along its course,” said Director Yang Wei during an interview with the author. According to her, the show uses seven archetypes—a traveler, a guard, a messenger, and so on—to present the stories that took place along this historic route. Unbounded by specific space or time, each of these archetypes embodies the foreign-travel experience of a different group of individuals, in a manner that may well be related to the social actors of globalised culture and of transnationalism today. Figure 6: Poster of The Silk RoadConclusionAs seen in Rain of Flowers along the Silk Road and Dunhuang, My Dreamland, staging the processes of Silk Road journeys has become a way of connecting the Chinese imagination of “home” with the Chinese imagination of “abroad.” Staging a nation’s heritage abroad on contemporary stages invites a new imagination of homeland, borders, and transnationalism. Once aestheticised through staged performances, such as that of the Dunhuang bihua yuewu, the historical and topological landscape of Dunhuang becomes a performed narrative, embodying the national heritage.The staging of Silk Road journeys continues, and is being developed into various forms, from theatrical dance-drama to digital exhibitions such as the Smithsonian’s Pure Land: Inside the Mogao Grottes at Dunhuang (Stromberg) and the Getty’s Cave Temples of Dunhuang: Buddhist Art on China's Silk Road (Sivak and Hood). 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