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Blazhkina, Anastasia Yu. "Some aspects of the authorship of the treatise “Xiao Jing”." Orientalistica 4, no. 5 (2021): 1279–300. http://dx.doi.org/10.31696/2618-7043-2021-4-5-1279-1300.
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The article deals with the authorship of the Confucian treatise Xiao Jing (“The Classic of Filial Piety”). Xiao Jing is one of the classical treatises that constitutes a part of the Confucian corpus Shisan Jing (“The Thirteen Classics”). This confirms the importance and high significance of this text for the traditional philosophical thought of China. The earliest mention of the title “Xiao Jing” was recorded in the work from the 3rd century BC, Lu shi chun qiu (“Spring and Autumn of Mr Liu”), which indicates the terminus ante quem non for the treatise Xiao Jing. According to some Russian scholars, the treatise Xiao Jing was compiled in the IV-II centuries BC. The Chinese scholarship acknowledges eight main versions of authorship, and therefore dating of Xiao Jing. The author stresses the importance to establish the authorship of the Xiao Jing treatise since this can be a piece of additional information for a comprehensive understanding of the philosophical heritage of the Confucian tradition of this text. After presenting an outline of the main versions of authorship of the Xiao Jing treatise, the author states that this issue can hardly be solved unambiguously. Therefore, this article can be considered as a preliminary essay for further research. The appendix offers a complete Russian translation of the Xiao Jing made by the author of the present article.
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Pejda, Katarzyna. "Xiao Jing 孝經 – wczesne znaczenie pojęcia xiao 孝 i tłumaczenie tekstu". Roczniki Humanistyczne 67, № 9 (2019): 119–38. http://dx.doi.org/10.18290/rh.2019.67.9-6.
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Artykuł zawiera tłumaczenie na język polski klasycznego tekstu konfucjańskiego pt. Xiao Jing oraz analizę wczesnego znaczenia pojęcia xiao, zwykle tłumaczonego na angielski jako „filial piety”, czyli „synowska nabożność” lub „posłuszeństwo synowskie”. Osoba, która nauczyła się słuchać i opiekować się rodzicami, jest w stanie rozszerzyć to uczucie na innych poza rodziną. To sprawia, że xiao jest korzeniem ren, oznaczajacego przykładne zachowania wobec wszystkich ludzi. Dlatego uczenie się, jak zachowywać się zgodnie z xiao, jest pierwszym etapem konfucjańskiego samodoskonalenia. Xiao Jing, tradycyjnie przypisywane uczniowi Konfucjusza — Zengzi, zapewnia krótki, ale ważny wgląd w jedną z podstawowych konfucjańskich koncepcji etycznych.
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OCHIAI, Toshinori. "On the Da-anpan jing and Xiao-anpan jing." JOURNAL OF INDIAN AND BUDDHIST STUDIES (INDOGAKU BUKKYOGAKU KENKYU) 51, no. 1 (2002): 31–36. http://dx.doi.org/10.4259/ibk.51.31.
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FUJITANI, Masanori. "The Yingluo jing and Xiao Ziliang's Fingxing youpose jing." JOURNAL OF INDIAN AND BUDDHIST STUDIES (INDOGAKU BUKKYOGAKU KENKYU) 53, no. 1 (2004): 205–7. http://dx.doi.org/10.4259/ibk.53.205.
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KISHIDA, Yuri. "The Background of the Xiao niepan jing:." Journal of Indian and Buddhist Studies (Indogaku Bukkyogaku Kenkyu) 64, no. 1 (2015): 178–81. http://dx.doi.org/10.4259/ibk.64.1_178.
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Cao, Yang. "A Model of Protection of Intangible Cultural Heritage by Commercial Three-Dimensional Animation - Taking “Little Master of Brocade” as an Example." Asian Culture and History 10, no. 1 (2017): 1. http://dx.doi.org/10.5539/ach.v10n1p1.
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Though China has carried out protection of intangible cultural heritage by three-dimensional animation, to protect intangible cultural heritage by commercial three-dimensional animation still requires further discussion and promotion. “Little Master of Brocade” (Yun Jing Xiao Dang Jia) is a cartoon gaining a good reputation at home and abroad and it has achieved certain economic benefits and social and cultural benefits in respect of protection of intangible cultural heritage. On the basis the status of protection of intangible cultural heritage by three-dimensional animation, this paper discussed a new model and the future trend of protection of intangible cultural heritage by commercial three-dimensional animation by taking “Little Master of Brocade” (Yun Jing Xiao Dang Jia) as an example.
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Croll, Elisabeth J. "Chinese Youth in Transition. Jieying Xi , Yunxiao Sun , Jing Jian Xiao." China Journal 57 (January 2007): 191–93. http://dx.doi.org/10.1086/tcj.57.20066269.
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Liščák, Vladimír. "François Noël (1651–1729) and his Latin translations of Confucian Classical books published in Prague in 1711." Anthropologia integra 6, no. 2 (2015): 45–52. http://dx.doi.org/10.5817/ai2015-2-45.
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První setkání Evropy s konfucianismem se připisuje jesuitům, kteří působili v Číně v 16. až 18. století. Na počátku byl překlad úvodu k Da xue 大學 do latiny, publikovaný v Římě roku 1593. Nicméně, první překlad konfuciánských klasických knih, jenž přitáhl značnou pozornost, byl Confucius Sinarum Philosophus, publikovaný v Paříži v roce 1687. Tato publikace obsahovala komentovaný překlad tří ze Čtyř knih konfuciánského kánonu. Nový překlad uvedených knih byl vydán v Praze v roce 1711. Jeho autorem byl François Noël (1651–1729), belgický (vlámský) básník, dramatik a jezuita v Číně. Jeho Sinensis Imperii Libri Classici Sex obsahovaly nový překlad prvních tří z již dříve přeložených Čtyř knih a byl doplněn o Mencia (Mengzi 孟子). V této své knize rovněž zahrnul i Klasickou knihu synovské úcty (Xiao jing 孝經), jednu z třinácti klasických knih, a Malé či Základní učení (Xiao Xue 小學), sbírku textů pro děti pořízenou Zhu Xim 朱熹. Překlady jsou rozděleny do malých, číslovaných oddílů, stejně jako čínský originál. Pokud jsou uvedeny poznámky, často na konci úseku, jsou obvykle doprovázeny jménem komentátora. Noëlova práce se jeví jako důležitý pokus o vědeckou prezentaci starověkého textu, snad v záměrném kontrastu k cílům jesuitů, kteří sestavili knihu Confucius Sinarum Philosophus o půl století dříve.
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Shen, Francis H. "Reviewer’s comment concerning “Anterior cervical discectomy versus corpectomy for multilevel cervical spondylotic myelopathy: a meta-analysis” (ESJO-D-14-00408R2 by Shan-Wen Xiao, Hua Jiang, Li-Jing Yang and Zeng-Ming Xiao)." European Spine Journal 24, no. 1 (2014): 40. http://dx.doi.org/10.1007/s00586-014-3608-0.
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Hong, Jing Han, Chern Han Yong, Hong Lee Heng, et al. "Abstract LT09: Integrative Multi-Omics Enhancer Activity Profiling Identifies Therapeutic Vulnerabilities in Cholangiocarcinoma of Different Etiologies." Cancer Research 84, no. 8_Supplement (2024): LT09. http://dx.doi.org/10.1158/1538-7445.fcs2023-lt09.
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Abstract Objectives: Cholangiocarcinoma (CCA) is a heterogeneous malignancy with high mortality and dismal prognosis, and an urgent clinical need for new therapies. Knowledge of the CCA epigenome is largely limited to aberrant DNA methylation. Dysregulation of enhancer activities has been identified to affect carcinogenesis and leveraged for new therapies but is uninvestigated in CCA. Our aim is to identify potential therapeutic targets in different subtypes of CCA through enhancer profiling. Design: Integrative multi-omics enhancer activity profiling of diverse CCA was performed. A panel of diverse CCA cell lines, and patient-derived and cell line-derived xenografts were used to study identified enriched pathways and vulnerabilities. NanoString, multiplex immunohistochemistry staining, and single-cell spatial transcriptomics were used to explore immunogenicity of diverse CCA. Results: We identified 3 distinct groups, associated with different etiologies and unique pathways. Drug inhibitors of identified pathways reduced tumor growth in in-vitro and in-vivo models. The first group (ESTRO), with mostly fluke-associated CCAs, displayed activation in estrogen signaling and were sensitive to MTOR inhibitors. Another group (OXPHO), with mostly BAP1 and IDH-mutant CCAs, displayed activated oxidative phosphorylation pathways, and were sensitive oxidative phosphorylation inhibitors. Immune-related pathways were activated in the final group (IMMUN), made up of an immunogenic CCA subtype and CCA with aristolochic acid (AA) mutational signatures. Intra-tumor differences in AA mutation load were correlated to intra-tumor variation of different immune cell populations. Conclusion: Our study elucidates the mechanisms underlying enhancer dysregulation and deepens understanding of different tumorigenesis processes in distinct CCA subtypes, with potential significant therapeutics and clinical benefits. Citation Format: Jing Han Hong, Chern Han Yong, Hong Lee Heng, Jason Yongsheng Chan, Mai Chan Lau, Jianfeng Chen, Jing Yi Lee, Abner Herbert Lim, Zhimei Li, Peiyong Guan, Pek Lim Chu, Sheng Rong Ng, Xiaosai Yao, Peili Wang, Rong Xiao, Xian Zeng, Yichen Sun, Wei Liu, Joanna Koh, Felicia Yu Ting Wee, Jeffrey Chun Tatt Lim, Cedric Chuan Young Ng, Xiu Yi Kwek, Poramate Klanrit, Yaojun Zhang, Jiaming Lai, David Wai Meng Tai, Chawalit Pairojkul, Simona Dima, Irinel Popescu, Sen-Yung Hsieh, Ming-Chin Yu, Joe Yeong, Sarinya Kongpetch, Apinya Jusakul, Watcharin Loilome, Patrick Tan, Jing Tan, Bin Tean Teh. Integrative Multi-Omics Enhancer Activity Profiling Identifies Therapeutic Vulnerabilities in Cholangiocarcinoma of Different Etiologies [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr LT09.
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Moyer, Jessica Dvorak. "The Textual Architecture of Empire in Two Early Qing Anthologies." Journal of Chinese Literature and Culture 8, no. 2 (2021): 371–98. http://dx.doi.org/10.1215/23290048-9299684.
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Abstract During the first half century of the Qing dynasty, Manchu emperors commissioned massive publication projects on the Chinese classics. In early Qing interpretations of classics on the family, negotiations between Manchu and Han family and gender norms furthered the empire-building project. This article compares the spatial form of the Yuding Nei ze yanyi 御定内則衍義 (1656), an expansion of the “Inner Standards” chapter of the Classic of Rites commissioned by the Shunzhi emperor, to that of the Yuding Xiao jing yanyi 御定孝經衍義 (1682), an expansion of the Classic of Filial Piety commissioned by the Kangxi emperor. These works are textual spaces where the cultural and political negotiations of the early Qing empire play out; they use spatial strategies of juxtaposition and hierarchy to balance different messages for different constituencies, creating textual models of empire.
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Yamanaka, Naoki, Md Motaher Hossain, and Yuichi Yamaoka. "Molecular mapping of Asian soybean rust resistance in Chinese and Japanese soybean lines, Xiao Jing Huang, Himeshirazu, and Iyodaizu B." Euphytica 205, no. 2 (2015): 311–24. http://dx.doi.org/10.1007/s10681-015-1377-4.
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LI, GUOLIANG, WENLIANG MA, AIMEI GAO, HONGYU CHEN, DAVID FINLOW, and QIAN-SHU LI. "DENSITY FUNCTIONAL THEORY STUDIES OF CHARGED, COPPER-DOPED, SMALL SILICON CLUSTERS, ${\rm CuSi}_{n}^{+}/{\rm CuSi}_{n}^{-}$ (n = 1–7)." Journal of Theoretical and Computational Chemistry 11, no. 01 (2012): 185–96. http://dx.doi.org/10.1142/s0219633612500125.
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The structures and stabilities of charged, copper-doped, small silicon clusters [Formula: see text] (n = 1–7) have been systematically investigated using the density functional theory method at the B3LYP/6-311+G* level. For comparison, the geometries of neutral CuSi n clusters were also optimized at the same level, although most of them have been reported previously [see Xiao CY, Abraham A, Quinn R, Hagelberg F, Comparative study on the interaction of scandium and copper atoms with small silicon clusters, J Phys Chem A106:11380, 2002; Liu X, Zhao GF, Guo LJ, Wang XW, Zhang J, Jing Q, Luo YH, First-principle studies of the geometries and electronic properties of Cu m Si n (2 ≤ m + n ≤ 7) clusters, Chin Phys16:3359, 2007]. Our results for the ground state structures of neutral CuSi n clusters agree well with those of Liu et al. and Xiao et al. except for CuSi3 and CuSi7 . Removing or adding an electron greatly changes some ground state structures, i.e. for [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text]; others are almost unchanged, e.g. [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text]. The ground states of ionic [Formula: see text] are all singlet, except for the smaller CuSi- and [Formula: see text]. Based on the optimized geometries, various energetic properties, including binding energies, second-order difference energies, the highest occupied molecular orbit and the lowest unoccupied molecular orbital (HOMO–LUMO) energy gaps, ionization potential and electron affinities, were calculated for the most stable isomers of [Formula: see text]. All the results indicate that anionic [Formula: see text] and cationic [Formula: see text] clusters are relatively stable. The higher stability of the latter has been confirmed by Beck's observations.
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QIU, LIHONG, JINGXIU ZHAO, ZHONGDAO WU, ZHIYUE LV, and YI PANG. "Steinernema pui sp. n. (Rhabditida, Steinernematidae), a new entomopathogenic nematode from Yunnan, China." Zootaxa 2767, no. 1 (2011): 1. http://dx.doi.org/10.11646/zootaxa.2767.1.1.
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A new species of entomopathogenic nematode, herein described as Steinernema pui sp. n. was recovered from a soil sample collected from Xiao-jie town, Jing-hong city, Xi-shuang-ban-na district in Yunnan province, the People’s Republic of China in December 2002. Both morphological and molecular evidence show congruently that S. pui sp. n. belongs to the S. glaseri group. It can be separated from all described Steinernema species by a combination of morphological and morphometrical characters of adult and juvenile stages, including spicule and gubernaculum shape of the first generation males (spicule bearing an aperture on the tip and an irregular-shaped concave on ventral side of the lamina close to the tip; gubernaculum with a short needle-shaped cuneus); the tail and vulva shape of the first generation females (tail conoid and pointed with a mucron; vulva with a short double flapped epiptygma) and the body and tail length, distance from anterior end to excretory pore and to the base of pharynx of infective juveniles. The new species can also be distinguished from other Steinernema species by DNA sequences of either a partial 28S rDNA or the internal transcribed spacer (ITS) regions of rDNA, and from the closely related species S. longicaudum and S. guangdongense by cross-breeding tests.
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Xing, Wen. "NEW LIGHT ON THE LI JI 禮記: THE LI JI AND THE RELATED WARRING STATES PERIOD GUODIAN BAMBOO MANUSCRIPTS". Early China 37 (грудень 2014): 519–50. http://dx.doi.org/10.1017/eac.2014.8.
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AbstractThis article starts by examining how “Li ji” was used as a title in early China. In addition to the Li, Li jing, Shi li, Li yi and Yi li, etc., “Li ji” was used as an alternative title for the Li canon, and the “Li” as a title was used to indicate what we now refer to as the Li ji or the Xiao Dai Li ji as well. By discussing how the Guodian bamboo slip texts are related to the transmitted version of the Li ji, this article argues that the writing styles of the related excavated bamboo manuscripts are the particular Li gujing- or Li guji-styles, that the “Li gujing” or “Li guji” is more a description of those ancient retrieved texts than an actual title, and that many of the Guodian bamboo-slip texts are the Li guji- or Li gujing-style writings. According to the Li guji-style Zi yi text, it is evident that the material in the Li ji comes from creditable pre-Qin textual sources. Although the Li ji text came to its current shape as a result of later editing work, it does not mean that the received Li ji sections have higher textual value than the excavated manuscripts do. On the contrary, the excavated manuscripts could have many valuable early textual sources that the transmitted Li ji has lost.
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Mielikainen, Jarno, Melin Huang, Bormin Huang, and Allen H. L. Huang. "Comments on the paper by Huadong Xiao, Jing Sun, Xiaofeng Bian and Zhijun Dai, “GPU acceleration of the WSM6 cloud microphysics scheme in GRAPES model”." Computers & Geosciences 72 (November 2014): 262–63. http://dx.doi.org/10.1016/j.cageo.2013.12.003.
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Wang, Jing, Jun Wang, Yang Liu, et al. "Abstract 1799: BH3120, a bispecific antibody targeting 4-1BB and PD-L1 simultaneously, stimulates T cells in tumor tissue preferred manner." Cancer Research 83, no. 7_Supplement (2023): 1799. http://dx.doi.org/10.1158/1538-7445.am2023-1799.
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Abstract BH3120 is a heterodimeric bispecific antibody, designed to target 4-1BB and PD-L1 simultaneously with Pentambody™ platform, to stimulate anti-tumor immune response in a tumor microenvironment (TME) specific manner. BH3120 showed strong antitumor efficacy in multiple tumor models, and combination of BH3120 with a PD-1 antagonist showed synergic effects eradicating tumor. While BH3120 consistently activates T cells, both as a monotherapy and in combination with a PD-1 antagonist, modulation of immune system in the tumor tissue is clearly de-coupled from that in peripheral blood, suggesting reduced risks of immune related adverse events (irAEs) with BH3120. To verify this hypothesis, BH3120 was compared with reference bispecific antibodies. Combination of BH3120 with a PD-1 antogonist does not result in elevation of transaminase enzymes, while the reference bispecific antibodies, when combined with the same PD-1 antagonist, show significant increase of the enzymes and macrophage in liver. In the toxicology studies conducted so far with cynomolgus monkeys, NOAEL of BH3120 was determined to be 200 mg/kg (QW X 5). Citation Format: Jing Wang, Jun Wang, Yang Liu, Yan Pang, Aihong Zhang, Jie Feng, Aibo Sun, Xiao Ma, Jingmei Cai, Jiangcheng Xu, Jiawang Liu, Kyoungwoo Lee. BH3120, a bispecific antibody targeting 4-1BB and PD-L1 simultaneously, stimulates T cells in tumor tissue preferred manner [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 1799.
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Blazhkina, Anastasia Yur'evna. "Philosophical Value of the Confucian Treatise "Kong-Zi Jia Yu"." RUDN Journal of Philosophy 25, no. 2 (2021): 276–87. http://dx.doi.org/10.22363/2313-2302-2021-25-2-276-287.
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This article reveals the philosophical value of the Confucian treatise "Kong-zi jia yu," it examines issues of the theoretical importance for the history of world sinology. In the historicо-philosophical tradition, this text has long been attributed to the Confucian scientist Van Su (3rd century), however, not so long ago the situation changed significantly. In the modern scientific community, disputes around the authorship and time of writing this treatise continue. The content of "Kong-zi jia yu" is composed of stories from the life of Confucius, his conversations with his closest students, as well as prominent political figures of that time. These conversations are philosophical dialogues, they concern the most important ontological, ethical, aesthetic and epistemological issues, such as: harmonization of the Tianxia on the basis of virtuous management, the philosophical need for ritual practice, cosmological device of the Tianxia, issues traditional for early Confucianism of a pedagogical and educational nature, moral self-improvement. The diverse theme of "Kong-zi jia yu" is a valuable source that reveals the essence of the philosophy of early Confucianism. Individual fragments of "Kong-zi jia yu" coincide with the classic Confucian monuments "Shang shu," "Lun yu," "Xiao jing," etc. Although "Kong-zi jia yu" for a number of reasons, is not considered a classic text of Confucianism, but it carries an enduring philosophical value. The study of "Kong-zi jia yu" seems to the author of this work to be an urgent scientific task, the solution of which can expand the arsenal of world philosophical knowledge, as well as contribute to the dialogue of the philosophical cultures of the East and West.
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申智娟 та 宋在漢. "Contemplation on Fanqie Bottom Words in the Middle of Kunaichoshoryobuzo “Chun qiu jing zhuan ji jie” Kamakura ─ Focusing on the group of Guo(果)･Jia(假)･Xiao(效) ─". Journal of Japanese Studies 49 (30 вересня 2016): 263–84. http://dx.doi.org/10.18841/2016.49.11.
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Lind, Hanne, Alexander Strait, Spencer Hall, et al. "Abstract 6646: Investigating the combination of radiation and subsequent immune checkpoint inhibitor treatment in head and neck squamous cell carcinoma models." Cancer Research 84, no. 6_Supplement (2024): 6646. http://dx.doi.org/10.1158/1538-7445.am2024-6646.
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Abstract Purpose: Head and neck squamous cell carcinoma (HNSCC) is often marked by an immunosuppressive tumor microenvironment, which contributes to the dismal 10-20% response rate to immune checkpoint inhibitor (ICI) therapy in HNSCC patients. Radiotherapy (RT) is a currently standard of care and frontline therapy for HNSCC, yet resistance is common. We sought to examine the combination therapy of RT followed by ICI therapy to test if RT induces an in situ vaccination which enhances the efficacy of subsequent ICI. Methods: We utilized SCC cell lines derived from K15.KrasG12D/Smad4−/− SCCs, which mimic the progression of HPV-unrelated HNSCC, and transplanted SCC cells into immune-competent C57BL/6J mouse recipients. Mice were subjected to RT followed by anti-PD-L1/anti-TGFb therapy. CD8+ splenic T cells of responder or non-responder mice were examined by paired single-cell VDJ sequencing and single cell RNA sequencing (TCR/sc-RNAseq) to look for adaptations of the cytotoxic T cell compartment following combination therapy. Responder and non-responder tumor lines or tumors were treated with RT alone in vitro and in vivo, respectively, to examine major histocompatibility complex I (MHC-I) levels on tumor cells. Results: Responders to this combination therapy exhibited complete tumor eradication while non-responders displayed rapid tumor progression. When re-challenged with same HNSCCs cells, responders rejected implanted tumor cells while naïve recipients rapidly developed HNSCCs. Single-cell TCR sequencing of splenic CD8+ T cells revealed that responders, but not naïve recipients exhibited multiclonal CD8+ T cell expansion specifically of memory cell populations. Responder tumor cells exhibited greater levels of MHC-I protein level presentation than non-responders when stimulated with RT. Conclusions: Our data suggest that 1) elevated MHC-I by SCC tumor cells presentation driven by RT and ICI combination therapy facilitate a systemic expansion of memory CD8+ T cell clonotypes which drive anti-tumor immunity and 2) MHC-I expression at baseline or when induced by RT may serve as a predictive marker for therapeutic response to RT and ICI combination therapy in HNSCCs. Citation Format: Hanne Lind, Alexander Strait, Spencer Hall, Jack B. Goon, John D. Aleman, Samantha Chen, Philip Owens, Jing H. Wang, Christian Young, Xiao-Jing Wang. Investigating the combination of radiation and subsequent immune checkpoint inhibitor treatment in head and neck squamous cell carcinoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6646.
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Xiao, Zhenlong, and Xingjian Jing. "Corrigendum to “Estimation of parametric convergence bounds for Volterra series expansion of nonlinear systems” by Zhenlong Xiao, Xingjian Jing, Li Cheng [Mech. Syst. Signal Process. 45 (1) (2014) 28–48]." Mechanical Systems and Signal Processing 50-51 (January 2015): 784–85. http://dx.doi.org/10.1016/j.ymssp.2014.06.008.
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HOOPER, BEVERLEY. "Chinese Youth in Transition. EDITED BY JING JIAN XIAO, JIEYING XI AND YUNXIAO SUN. Aldershot, Hampshire, and Burlington, VT: Ashgate, 2006. xviii + 273 pp. £60. ISBN 0-7546-4369-7." China Quarterly 189 (March 2007): 202–3. http://dx.doi.org/10.1017/s0305741006001056.
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Zhao, Xiao Hong, Man Man Han, Qian Qian Yan, et al. "Abstract 7052: p53 underpins a dependence on oxidative phosphorylation in glycolysis-competent colorectal cancer." Cancer Research 84, no. 6_Supplement (2024): 7052. http://dx.doi.org/10.1158/1538-7445.am2024-7052.
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Abstract The use of mitochondrial inhibitors to target oxidative phosphorylation (OXPHOS) in cancer treatment presents a challenge due to dose-limiting toxicities. Moreover, while glycolysis-deficient cancers are vulnerable to OXPHOS inhibition in preclinical models, the full extent of phenotypical and mechanistic consequences of inhibiting OXPHOS in cancers capable of glycolysis is not yet well understood. Our results presented here offer promising insights into potential therapeutic gains from combining p53 restoration strategies with OXPHOS inhibitors, even when applied to glycolysis-competent CRC cells. Treatment with mitochondrial complex I inhibitors did not cause energy stress in CRC cells capable of glycolysis. It does, however, induce DNA replication stress, apparent through an observed cell cycle arrest at the S phase, enrichment of the G2/M DNA-damage checkpoint regulation pathway, and replication fork slowdown. Intriguingly, CRC cells harboring wildtype p53 exhibited more severe replication stress than those carrying mutant p53. Furthermore, siRNA knockdown of p53 attenuates replication stress and reduces cell cycle arrest, underlining the important role of p53 in CRC cell responses to OXPHOS inhibition. Our targeted metabolomics analysis reveals that OXPHOS inhibition results in reductions in the purine nucleotides, adenine monophosphate (AMP) and guanine monophosphate (GMP), as well as the pyrimidine nucleotide, uridine monophosphate (UMP), in CRC cells, regardless of their p53 mutational status. By supplementing cell culture mediums with the purine nucleobases adenine and guanine, and the pyrimidine nucleoside uridine, we observed a partial reversal of the replication fork slowdown and reductions in cell viability. This suggests nucleotide deficiencies are involved in the induction of DNA replication stress caused by OXPHOS inhibition. The nucleotide deficiencies were associated with a decrease in the nucleobase precursor aspartate. By adding aspartate at a supraphysiological concentration, to overcome the low expression of the excitatory amino acid transporter 1 required for cellular import of aspartate, we were able to restore the levels of nucleotides. Collectively, our findings suggest broader potential cancer treatment paradigms via OXPHOS targeting, extending beyond glycolysis-deficient cancers. Our data uncovers that CRC cells, which commonly exhibit the glycolytic phenotype, are susceptible to OXPHOS inhibition, with those carrying wildtype p53 showing heightened sensitivity. Therefore, p53 status could serve as a biomarker for predicting CRC responses to OXPHOS inhibitors. Moreover, our findings suggest that combined strategies of restoring p53 function, using small molecules such as APR-246, might enable reduced dosage of OXPHOS inhibitors in CRC treatment, thereby mitigating their dose-limiting toxicities. Citation Format: Xiao Hong Zhao, Man Man Han, Qian Qian Yan, Yi Meng Yue, Kai Hong Ye, Yuan Yuan Zhang, Liu Teng, Liang Xu, Xiao Jing Shi, Ting La, Yu Chen Feng, Ran Xu, Vinod K. Narayana, David P. De Souza, Tao Liu, Mark Baker, Rick F. Thorne, Xu Dong Zhang, Song Chen, Lei Jin. p53 underpins a dependence on oxidative phosphorylation in glycolysis-competent colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7052.
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Sun, Jianming, Xiao Huang, Yurong Qin, et al. "Abstract 2965: LBL-033, a novel bispecific antibody targeting MUC16 and CD3, for the treatment of tumors over-expressing MUC16." Cancer Research 83, no. 7_Supplement (2023): 2965. http://dx.doi.org/10.1158/1538-7445.am2023-2965.
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Abstract Background: MUC16 is a large glycoprotein overexpressed on cell membrane of solid tumors, especially in almost 80% of ovarian cancer. The extracellular part of MUC16 could be cleaved as CA125, which is well known as a diagnosis biomarker for ovarian cancer. Despite recent advances in therapies such as PARP inhibitors, advanced ovarian cancer remains a disease of high unmet need. Herein a novel bispecific antibody targeting MUC16 and CD3, LBL-033, is developed to specifically kill MUC16 positive tumor cells by engaging T cells. Methods: LBL-033 was constructed using our unique T cell engager platform, which is a 2:1 format bispecific antibody with two arms targeting MUC16 membrane-proximal domain with high affinity and one arm targeting CD3 with fine-tuned affinity. The binding affinity of LBL-033 to MUC16 and CD3 was determined with Fortebio, while the activity was measured using several cell based assays including reporter gene and TDCC assays. The anti-tumor activity of LBL-033 was investigated in C57BL/6-huCD3e mice implanted with MC38-huMUC16 cells. GLP-compliant repeat-dose toxicologic study was evaluated in cynomolgus monkeys. Results: The binding affinity of LBL-033 to MUC16 and CD3 protein was 2.67 nM and 29.6 nM, respectively. The epitope that anti-MUC16 binds was identified at the C-terminal of MUC16 extracellular domain; and the activity was not affected in the presence of soluble CA-125. In CD3 reporter gene assay, LBL-033 could activate the NFAT reporter element through MUC16 antigen-dependent CD3 cross-linking with an EC50 value of 1.068 nM. LBL-033 was shown a potent TDCC activity in OVCAR3 cells with T cell activation. In C57BL/6-huCD3e transgenic mice implanted with MC38-huMUC16 tumor cells, LBL-033 was shown a dose dependent anti-tumor activity. In addition, LBL-033 had a significant synergistic effect, when combined with anti-PD-1. LBL-033 was shown favorable pharmacokinetic properties with a good safety profile in cynomolgus monkeys. Conclusion: LBL-033, a novel bispecific antibody targeting CD3 and MUC16 with a unique epitope, which is located at the MUC16 membrane-proximal domain, with affinity differentiation between anti-MUC16 and anti-CD3. It is shown a great anti-tumor efficacy in animal models, with a good safety profile in monkeys. These data support LBL-033 as a novel therapeutic bispecific antibody for ovarian cancer and other MUC16 positive tumors. A dose escalation study in humans will begin in Q1 2023. Citation Format: Jianming Sun, Xiao Huang, Yurong Qin, XingXing Fang, Min Chen, Huan Lin, Jing Guan, Jing Huang, Tongjun Liu, Baohui Wang, Guojin Wu, Shoupeng Lai, Xiaoqiang Kang, Hong Ling. LBL-033, a novel bispecific antibody targeting MUC16 and CD3, for the treatment of tumors over-expressing MUC16 [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 2965.
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Wang, Baohui, Xiao Huang, Mi Ding, et al. "Abstract 1867: LBL-049: A novel neutralizing antibody against GDF15 for the treatment of cachexia." Cancer Research 84, no. 6_Supplement (2024): 1867. http://dx.doi.org/10.1158/1538-7445.am2024-1867.
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Abstract Background: Cachexia is a disorder characterized by loss of body weight with specific losses of skeletal muscle and adipose tissue and occurs in the progression of many diseases, especially in cancer. Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor β (TGFβ) superfamily. GDF15 can bind to the glial cell-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL) protein, which is primarily expressed in the hindbrain. This interaction activates the GFRAL-RET signaling pathway, which transmits anorectic neural signals, leading to weight loss, affecting fat and muscle degradation, and inducing cachexia. Anti-GDF-15/GFRAL antibodies have the potential to reverse this response, making them vital therapeutic targets for cachexia. Herein, a novel humanized GDF-15 neutralizing antibody (LBL-049) was developed with higher efficacy and better specificity than ponsegromab, the same target antibody from Pfizer, in pre-clinical studies. Methods: LBL-049 was generated from mouse hybridoma, humanized by CDR grafting, the Fc region was further engineered to silence Fc effector. The binding affinity and specificity were detected by Fortebio and ELISA respectively. The function of blocking GDF15/GFRAL/RET signaling was examined in the reporter-gene cell assays. The in vivo efficacy of restoring cachexia was demonstrated in both tumor-induced and cisplatin-induced mouse cachexia models, in which preliminary pharmacokinetics (PK) and pharmacodynamics (PD) studies were also conducted. And a single-dose PK study was conducted in rats. Results: LBL-049 had high binding affinities to both human and cynomolgus GDF-15 proteins with high specificity, did not bind with other TGF family members as compared with ponsegromab. In reporter-gene cell assays, LBL-049 blocked GDF15/GFRAL signaling more potently than ponsegromab. In HT1080 tumor-induced or cisplatin-induced mouse cachexia model, LBL-049 prevented weight loss by neutralizing circulating GDF-15 in a dose dependent manner, at low dose of 1 mpk in HT1080 cachexia model, LBL-049 was more efficacious than ponsegromab to restore the body weight loss. The PK profile was excellent after single dosing of LBL-049 in rats. LBL-049 also showed good developability, i.e., low viscosity and good stability. Conclusion: LBL-049, a novel GDF15 neutralizing antibody with high affinity and specificity, showed great potency to inhibit GDF15/GFRAL/RET signaling in vitro and prevent weight loss in various mouse cachexia models, which are encouraging for future development for the treatment of cachexia. Citation Format: Baohui Wang, Xiao Huang, Mi Ding, Jing Huang, Yurong Qin, Fengxia Li, Jing Guan, Jianming Sun, Guojin Wu, Xiaoxiao Liu, Jordan Zhu, Shoupeng Lai, Xiaoqiang Kang, Hong Ling. LBL-049: A novel neutralizing antibody against GDF15 for the treatment of cachexia [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 1867.
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Wu, Yuchuan, Rui Hao, Xi Chen, et al. "Abstract 1821: Discovery of XNW21015, a novel, potent HPK1 inhibitor with excellent immune modulatory activity." Cancer Research 83, no. 7_Supplement (2023): 1821. http://dx.doi.org/10.1158/1538-7445.am2023-1821.
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Abstract Hematopoietic progenitor kinase 1 (HPK1), also known as MAP4K1, is a member of the STE20 family of serine/threonine kinases, and restrictedly expressed in hematopoietic cells. In T cells, HPK1 negatively regulated TCR signaling by phosphorylating the adaptor protein SLP76 on Ser376, which leads to the dissociation of the SLP-76/LAT signalosomes and downregulation of T cell priming and activation. HPK1 knockout (KO) or kinase-inactive (KI) mice spontaneously reject tumors with an enhanced immune response compared to wild-type ones. Thus, HPK1 is a novel immuno-oncology (I/O) target. In this work, we described the discovery of a potent HPK1 inhibitor starting from comprehensive SAR-based design with guidance from X-ray crystallography and computational modeling. These efforts led to identification of the potent azaindole inhibitor XNW21015, with excellent kinase selectivity and promising PK profile of low clearance and sufficient exposure for in vivo animal studies. XNW21015 dose-dependently inhibited phosphorylation of SLP76(Ser376) in vitro and in vivo in response to anti-CD3 agonist antibody, with concomitant enhancement in T cell activation. Oral administration of XNW21015 in mouse syngeneic tumor models showed favorable PK profile and robust anti-tumor activity as both single agent and in combination with immune checkpoint inhibitors. In a humanized PDX (patient-derived xenograft) model, XNW21015 enhanced tumor-infiltrated lymphocytes (TIL). In summary, we have discovered a novel, highly potent and selective HPK1 inhibitor XNW21015 as promising small molecule I/O agent, as monotherapy or in combination with immune checkpoint inhibitors. Citation Format: Yuchuan Wu, Rui Hao, Xi Chen, Xiao Liu, Yonghua Xie, Shihua Wang, Bingquan Gao, Jichun Wen, Zhenwei Wu, Wengui Wang, Haiyang Wei, Yonghan Hu, Xiaojun Liu, Meijie Le, Jing Qiang. Discovery of XNW21015, a novel, potent HPK1 inhibitor with excellent immune modulatory activity [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 1821.
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Zhang, Jie, Feng Gao, Wei Zhu, et al. "Abstract 5727: ISM9682A, a novel and potent KIF18A inhibitor, shows robust antitumor effects against chromosomally unstable cancers." Cancer Research 84, no. 6_Supplement (2024): 5727. http://dx.doi.org/10.1158/1538-7445.am2024-5727.
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Abstract KIF18A belongs to the kinesin-8 subfamily and is a plus-end-directed motor, which regulates kinetochore microtubules dynamics to control mitotic chromosome alignment and spindle tension. Studies have shown that genetic depletion or pharmacological inhibition of KIF18A is a promising therapeutic approach for cancers, exhibiting high chromosomal instability (CIN-high), without having a significant impact on the normal division of euploid cells. Here, we report the discovery and preclinical evaluation of ISM9682A, a novel KIF18A inhibitor with excellent potency and high selectivity. ISM9682A is a potent KIF18A inhibitor with a single-digit nanomolar IC50 value and exhibits high selectivity over other kinesin family members. In addition, ISM9682A demonstrated excellent monotherapy anti-proliferative activity, with single-digit nanomolar IC50 values, in high-grade serous ovarian carcinoma (HGSOC) as well as in triple-negative breast cancer (TNBC) aneuploid cell lines with p53 mutation. Notably, ISM9682A exhibited a prolonged drug-target residence time indicated by both enzymatic and cellular assays. Consistent with the in vitro findings, ISM9682A displayed significant anti-tumor efficacy with a robust pharmacodynamic response (pH3, mitotic marker; γH2AX, DNA damage marker) in OVCAR3 and HCC1806 CDX models in a dose-dependent manner. In addition to its robust biological potency and high selectivity, ISM9682A exhibits favorable drug-like properties, including desirable in vitro ADMET characteristics and excellent in vivo exposure, clearance, as well as good oral bioavailability across multiple preclinical species. Collectively, these findings highlight the potential of ISM9682A as a novel and highly potent KIF18A inhibitor for the treatment of CIN-high cancers. Citation Format: Jie Zhang, Feng Gao, Wei Zhu, Chenxi Xu, Xiaoyu Ding, Jing Shang, Junwen Qiao, Shan Chen, Xin Cai, Xiao Ding, Supriya Bavadekar, Sujata Rao, Man Zhang, Feng Ren, Alex Zhavoronkov. ISM9682A, a novel and potent KIF18A inhibitor, shows robust antitumor effects against chromosomally unstable cancers [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 5727.
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Ma, Hong, Ai Huang, Yong Xiao, et al. "Abstract 1097: Surufatinib improved the radiation sensitivity of biliary cancer growth by reprograming of TAM and anti-angiogenesis." Cancer Research 83, no. 7_Supplement (2023): 1097. http://dx.doi.org/10.1158/1538-7445.am2023-1097.
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Abstract Background: Patients with Biliary tract cancer (BTC) have poor clinical outcomes. Radiation therapy is an adjunct strategy throughout biliary tract cancer treatment. The aim of the study was to explore the efficacy and mechanism of the radiosensitization of surufatinib(SF), an oral tyrosine kinase inhibitor with anti-angiogenic and immunomodulatory activities. Methods: The NOZ and TFK1 human BTC cell lines were treated with SF and/or radiation. Effects on cell viability and cell cycle progression were measured by CCK8, a clonogenic survival assay, and flow cytometry. Finally, the in vivo effect on the growth of NOZ xenografts was assessed in nude mice. F4/80, CD206, Ki67 and CD31 expression were employed in tumor samples. Results: SF inhibited the proliferation and enhanced the radiosensitivity in NOZ and TFK1 cells lines. SF combined with radiation increased cell cycle arrest in the G2/M phase compared to the other treatments in the NOZ cell line (P<0.05). Similarly, cell cycle arrest occurred in the TFK1 cell line, (P<0.05). In vivo, SF plus radiation significantly inhibited the tumor growth compared to either agent independently. Conclusions: SF significantly increased the radiosensitivity of NOZ and TFK1 cells in vitro and in vivo. Radiation combined with SF inhibited tumor proliferation, increased apoptosis, prolonged G2/M arrest. SF decreased the number of blood vessels and reprogrammed the macrophages from M2 to M1. These data support the clinical trials of biologically targeted and conventional therapies in the treatment of cancer. Citation Format: Hong Ma, Ai Huang, Yong Xiao, Jing Yao, Ningyu Wang, Xiangping Mei, Shaoshi Wen, Xing Lv. Surufatinib improved the radiation sensitivity of biliary cancer growth by reprograming of TAM and anti-angiogenesis [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 1097.
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Wang, Ningyu, Hong Ma, Xiangping Mei, Ai Huang, Yong Xiao, and Jing Yao. "Abstract 2127: Enhancing radiosensitivity in biliary tract cancer: The dual role of surufatinib in tumor suppression and macrophage reprogramming." Cancer Research 84, no. 6_Supplement (2024): 2127. http://dx.doi.org/10.1158/1538-7445.am2024-2127.
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Abstract Background: Biliary tract cancer (BTC) is notorious for its unfavorable clinical outcomes. Radiotherapy (RT) is a crucial component in BTC treatment. This study explores the radiosensitizing potential and mechanisms of Surufatinib (SF), an oral tyrosine kinase inhibitor, distinguished by its anti-angiogenic and immunomodulatory effects. Methods: In a NOZ mouse xenograft model, tumor growth and expressions of Ki-67, CD31 were analyzed. NOZ and TFK1 BTC cells treated with SF and/or RT underwent assessments for viability, cycle, and apoptosis using CCK8, colony formation, and flow cytometry. Macrophage polarization in SF/RT-treated tumor cell-macrophage co-cultures was studied using Elisa, qRT-PCR, and flow cytometry. Results: In vivo, SF impeded angiogenesis and bolsters the anti-tumor effect of radiotherapy. SF combined with RT significantly reduced subcutaneous tumor growth in nude mice, and diminished Ki-67 and CD31 expressions. In vitro, SF heightened cholangiocarcinoma cells' radio-sensitivity, causing DNA double-strand breaks and apoptosis. SF and radiotherapy combined notably increased γ-H2A expression and apoptosis levels (P<0.05). SF induced inflammatory response changes, favoring M2 to M1 macrophage polarization. In a tumor cell-macrophage co-culture, the SF-radiotherapy group showed increased IL-6 and decreased TGF-β (P<0.05), with upregulated M1 markers (IL-6, CXCL10) and downregulated M2 markers (TGF-β, CCL22, Arg-1) in macrophages (P<0.05). Both in vivo and in vitro, SF significantly reduced CD206+ M2-type macrophages (P<0.05). Conclusion: Surufatinib alters the immune microenvironment in cholangiocarcinoma, reversing the immunosuppressive macrophage polarization induced by radiotherapy and reprogramming M2-type macrophages into M1-type, thereby enhancing the radiosensitivity of cholangiocarcinoma. Citation Format: Ningyu Wang, Hong Ma, Xiangping Mei, Ai Huang, Yong Xiao, Jing Yao. Enhancing radiosensitivity in biliary tract cancer: The dual role of surufatinib in tumor suppression and macrophage reprogramming [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 2127.
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Brabec, V., O. Vrana, O. Novakova, and J. Kasparkova. "Comment on “Delivering a photosensitive transplatin prodrug to overcome cisplatin drug resistance” by H. Song, W. Li, R. Qi, L. Yan, X. Jing, M. Zheng and H. Xiao, Chem. Commun., 2015, 51, 11493." Chemical Communications 52, no. 21 (2016): 4096–98. http://dx.doi.org/10.1039/c5cc09589a.
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Xiao, Fei, Kailiang Wang, Xinjuan Wang, et al. "Abstract 477: Discovery of RGT-018: A potent, selective and orally bioavailable SOS1 inhibitor for mutant KRAS-driven cancers." Cancer Research 83, no. 7_Supplement (2023): 477. http://dx.doi.org/10.1158/1538-7445.am2023-477.
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Abstract Background: KRAS is the most frequently mutated oncogene with high prevalence in non-small cell lung cancers (NSCLC), colorectal cancers (CRC), and pancreatic cancers (PAC). FDA currently approved sotorasib provides breakthrough therapy for cancer patients with KRASG12C mutation, however there is still high unmet medical need for new agents that target a broader KRAS mutated tumors. A new opportunity emerges to develop a pan KRAS inhibitor by suppressing the upstream guanine nucleotide exchange factor (GEF) protein son of sevenless 1 (SOS1). SOS1 is a key activator of KRAS and facilitates the conversion of GDP-bound KRAS (off) state to GTP-bound KRAS (on) state. Binding to its catalytic domain, small molecule SOS1 inhibitor prevents KRAS activation and suppresses cancer cell proliferation. Material and Methods: Regor’s unique Computer Accelerated Rational Design (CARD) technology platform was applied to identify potent and selective SOS1 inhibitors. Biochemical assays and cellular assays were utilized to drive the structure-activity relationship (SAR). In vitro and in vivo target engagement were confirmed. In vivo efficacy study data were generated using lung and pancreatic cancer xenograft mouse models with KRAS mutation. Results: In vitro, RGT-018 blocked the interaction of KRAS::SOS1 with high selectivity, and inhibited proliferation of a broad spectrum of mutant KRAS-driven cancer cells as a single agent. Robust anti-proliferation activity was observed when RGT-018 was combined with MEK, KRASG12C, EGFR or CDK2/4/6 inhibitors in vitro. Oral administration of RGT-018 inhibited tumor growth and suppressed KRAS signaling pathway activation in tumor xenografts. Furthermore, combination with MEK or KRASG12C inhibitors led to profound tumor regression. Conclusions: The pharmacological properties of RGT-018 represent an attractive drug candidate with oral bioavailability for combination with targeted agents to treat a broader patient population driven by mutant KRAS. Citation Format: Fei Xiao, Kailiang Wang, Xinjuan Wang, Huijuan Li, Zhilong Hu, Wei Huang, Xiaoming Ren, Teng Feng, Lili Yao, Jing Lin, Chunlai Li, Liufeng Mei, Zhuanzhuan Zhang, Yangyang Liu, Xi Chen, Xiaotian Zhu, Wenge Zhong, Zhi Xie. Discovery of RGT-018: A potent, selective and orally bioavailable SOS1 inhibitor for mutant KRAS-driven cancers [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 477.
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Zhou, Yuzhen, Bang Fu, Jie Chen, et al. "Abstract 7583: Discovery of a potent small molecule MALT1 protease inhibitor for the treatment of cancer." Cancer Research 84, no. 6_Supplement (2024): 7583. http://dx.doi.org/10.1158/1538-7445.am2024-7583.
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Abstract The paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), as the core component of CBM complex (CARD9/10/11/14-BCL10-MALT1), plays an essential role in activating the NF-κB pathway and regulating the cell proliferation, differentiation and immunity. Inhibiting of MALT1 is considered a promising therapeutic approach for the treatment of several non-Hodgkin B-cell lymphomas, chronic lymphocytic leukemia (CLL), solid tumors and autoimmune diseases. Herein, we report the discovery of a novel potent MALT1 allosteric inhibitor, BPI-530616, which strongly inhibited MALT1 protease activity with subnanomolar IC50, and low off-target activity on other proteases. BPI-530616 can inhibit the proliferation of B-cell diffuse large B-cell lymphoma (ABC-DLBCL) cell line, OCI-ly3, bearing CD79b and CARD11 mutations. The cell line is intrinsically resistant to covalent and non-covalent Bruton's Tyrosine Kinase (BTK) inhibitors. Meanwhile, BPI-530616 suppressed the cellular cytokine secretion (e.g.IL-10, IL-2) or MALT1 direct substrate cleavage (e.g. CYLD). In vivo, BPI-530616 dose-dependently suppressed tumor growth and inhibited the cleavage of CYLD in OCI-ly3 xenograft mouse model. To address the role of MALT1 inhibitor in the contest of immune-oncology, a CT26 syngeneic mouse model was set up. Oral administration of BPI-530616 exhibited a good antitumor effect comparable to that of the anti-PD1 antibody, with no observable adverse effects. Additionally, BPI-530616 displayed desirable drug-like properties, including low clearance and good oral bioavailability across multiple pre-clinical species. Taken together, our research has led to the discovery of a novel, potent, selective, and orally bioavailable small molecule MALT1 inhibitor, BPI-530616. It demonstrated anti-tumor efficacy in the DLBCL animal model and showed promising effects in an immune-oncology animal model. Citation Format: Yuzhen Zhou, Bang Fu, Jie Chen, Weidong Cai, Xiao Sun, Yinlong Li, Wei Ren, Qichao Shen, Guolong Du, Xiaojun Zhou, Zhengyao Zou, Haibo Chen, Xiaoyun Liu, Cheng Yang, Xiangyong Liu, Jing Guo, Hao Wu, Lieming Ding, Jiabing Wang, Hong Lan. Discovery of a potent small molecule MALT1 protease inhibitor for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7583.
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Li, Qi, Jainfei Wan, Jinxin Liu, et al. "Abstract 1656: ISM6331, a novel and potent pan-TEAD inhibitor, exhibits strong anti-tumor activity in preclinical models of Hippo pathway-dysregulated cancers." Cancer Research 84, no. 6_Supplement (2024): 1656. http://dx.doi.org/10.1158/1538-7445.am2024-1656.
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Abstract The Hippo-YAP/TAZ-TEAD signaling pathway plays critical roles in tumorigenesis and tumor progression. Genetic alterations of Hippo pathway regulators, such as NF2 or LATS1/2, have been shown to induce YAP/TAZ-TEAD transcriptional activity, promoting initiation and progression of many solid tumors. In addition, many studies have shown that YAP/TAZ-TEAD activation mediates resistance to multiple targeted therapies, particularly EGFR-KRas-MAPK pathway inhibitors. The TEAD family of transcription factors (TEAD1/2/3/4) share structural similarity and have overlapping functions in tumor development and TEAD auto-palmitoylation is critical for its interaction with YAP/TAZ and its transcriptional function. Therefore, blocking TEAD palmitoylation and allosterically disrupting YAP/TAZ-TEAD-mediated transcriptional regulation, is emerging as a promising approach for the treatment of tumors with Hippo pathway dysregulation. In this work, ISM6331, a novel and potent TEAD inhibitor with excellent inhibition against TEAD1/2/3/4 was identified leveraging an AI generative model. ISM6331 reversibly binds to the TEAD palmitoylation site and significantly suppresses TEAD transcriptional activity. ISM6331 potently and selectively inhibited the growth of many Hippo pathway-dysregulated tumor cells and dose-dependently suppressed the expression of TEAD target genes in vitro. In NF2-deficient or LATS1/2-mutant in vivo mesothelioma models, ISM6331 exhibited promising anti-tumor efficacy as monotherapy in a dose-dependent manner from 3 to 30mg/kg. ISM6331 also showed synergism with EGFR or KRasG12C inhibitors in inhibiting tumor cell growth and overcame drug resistance in in vitro and in vivo models. In addition, ISM6331 showed excellent pharmacokinetic properties in multiple preclinical species and was well-tolerated in GLP-toxicity studies. In summary, ISM6331 has promising potential to treat Hippo pathway-dysregulated tumors as monotherapy as well as in combination with targeted therapies. Citation Format: Qi Li, Jainfei Wan, Jinxin Liu, Jing Shang, Jiaojiao Yu, Wei Zhu, Celia X.-J. Chen, Junwen Qiao, Ling Wang, Man Zhang, Xiao Ding, Supriya Bavadekar, Sujata Rao, Feng Ren, Alex Zhavoronkov. ISM6331, a novel and potent pan-TEAD inhibitor, exhibits strong anti-tumor activity in preclinical models of Hippo pathway-dysregulated cancers [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 1656.
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Gadwa, Jacob, Maria Amann, Thomas E. Bickett, et al. "Abstract 4158: Selective targeting of CD122 combined with radiotherapy triggers CD8 and NK mediated immunity, abrogating metastasis in head and neck squamous cell carcinoma." Cancer Research 83, no. 7_Supplement (2023): 4158. http://dx.doi.org/10.1158/1538-7445.am2023-4158.
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Abstract The implementation of cancer immunotherapies, while revolutionary in certain cancer types, has seen limited clinical success in head and neck squamous cell carcinomas (HNSCC). This revelation has prompted investigation in alternative targets to invigorate anti-tumor immunity. IL-2 signaling governs the survival and functionality of lymphocytes, thus making IL-2 receptor signaling an attractive target for new immunotherapies. However, therapies to enhance IL-2 signaling are often limited in their efficacy by modulating the activation of regulatory T cells (Tregs), which preferentially binds IL-2 via the high affinity receptor IL-2Rα (CD25). Selectively targeting IL2Rβ (CD122), the intermediate affinity receptor, can be leveraged to induce anti-tumor immune responses in effector T cells and natural killer (NK) cells while limiting negative regulation conferred by Tregs. The novel bispecific immunocytokine PD1-IL2v preferentially activates IL-2 signaling through CD122 on PD-1 expressing cells, activating immune effectors, and preventing immune exhaustion by blockade of PD-1. However, PD-1 blockade can amplify immunosuppression by Tregs, necessitating their depletion using αCD25. Here, we observe that radiation therapy and combination of PD1-IL2v with an Fc-optimized αCD25 antibody induces systemic activation of effector CD4 and CD8 T cells, reducing overall tumor burden. Concordant with improved local tumor control, we also observed a decrease in metastatic spread using a newly developed Kras/smad4/p53 mutated metastatic tumor model. NK cells, which are known to play a central role in the control of tumor cell dissemination though direct cytotoxicity, displayed a phenotypic shift towards an activated state upon treatment with PD1-IL2v, highlighted by enhanced cytotoxicity, NK receptor diversity, and metabolic activity. Although relatively uncommon in comparison to other cancer types, those patients who present with metastases display a substantially poorer outcome, demonstrating the need for therapies which target this axis of cancer disease progression. In summary, we find that radiation therapy and PD1-IL2v imparts potent anti-tumor immunity, reducing local tumor growth and distant tumor spread, which taken together contribute to increased overall survival. Citation Format: Jacob Gadwa, Maria Amann, Thomas E. Bickett, Michael W. Knitz, Laurel B. Darragh, Miles Piper, Benjamin Van Court, Sanjana Bukkapatanam, Tiffany T. Pham, Xiao-Jing Wang, Laura Codarri Deak, Christian Klein, Pablo Umana, Angelo D'Alessandro, Sana Karam. Selective targeting of CD122 combined with radiotherapy triggers CD8 and NK mediated immunity, abrogating metastasis in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4158.
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Dang, Yujia, Xiao Huang, Yurong Qin, et al. "Abstract 6712: LBL-043, a novel LILRB4xCD3 T cell engager, for the treatment of LILRB4 positive leukemia." Cancer Research 84, no. 6_Supplement (2024): 6712. http://dx.doi.org/10.1158/1538-7445.am2024-6712.
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Abstract Background: Acute myeloid leukemia (AML) is a malignant clonal disorder linked to a broad spectrum of molecular alterations. It is still an incurable cancer, the prognosis is even worse in elderly patients, where overall survival (OS) at 1 year is approximately 10-15%. Now, several CD3 bispecific immunotherapies that harness T cells against AML are at various stages of preclinical and clinical development, but most of them are hampered by the lack of specific targets to distinguish tumor cells from normal hematopoietic stem cells (HSC). Leukocyte immunoglobulin-like receptor B4 (LILRB4) is an immune checkpoint inhibitory receptor, which is highly expressed on FAB M4 and M5 AML cells with a lack of expression on normal HSC and progenitor cells. LILRB4 expression level inversely correlates with OS of patients with M4 and M5 AML. All of these indicate that LILRB4 represents a promising target for developing a T cell redirecting bispecific antibody to treat patients with AML, especially for more aggressive M4 and M5 subtype. Herein a novel bispecific antibody targeting LILRB4 and CD3, LBL-043, is developed to specifically kill LILRB4 positive tumor cells by engaging T cells. Methods: LBL-043 was constructed using our proprietary LeadsBodyTM T cell engager platform, which is a 2:1 format bispecific antibody with two VHH arms targeting LILRB4 with high affinity and one scFv arm targeting CD3 with fine-tuned low affinity. The binding affinity of LBL-043 to LILRB4 and CD3 was determined with Fortebio, while the activity was measured using several cell based assays including reporter gene and TDCC assays. The anti-tumor activity of LBL-043 was investigated in B-NDG/hu-PBMC reconstructed mice implanted with MOLM-13 (human AML-M5a) tumor model. Results: The binding affinity of LBL-043 to LILRB4 and CD3 protein was 0.724 nM and 35.7 nM, respectively. In CD3 reporter gene assays, LBL-043 could activate the NFAT reporter signaling through LILRB4 binding dependent CD3 cross-linking with an EC50 value of 2.459 nM. LBL-043 was shown a potent TDCC activity in different LILRB4 expression level MOLM-13 cells and HL-60 cells with T cell activation and cytokine release. In B-NDG/hu-PBMC reconstructed mice implanted with MOLM-13 tumor cells, LBL-043 was shown significant anti-tumor activity. Simultaneously, LBL-043 can effectively improve the survival rate and maintain relatively stable body weight in the study compared to the vehicle group. Conclusion: LBL-043, a novel bispecific antibody targeting CD3 and LILRB4 with affinity differentiation, induces T cell killing of AML cells by simultaneously binding LILRB4 expressed on tumor cells and CD3 on T cells, redirecting T cells to efficiently killing of AML cells. It is also shown a great anti-tumor efficacy in CDX mouse models. These data support LBL-043 as a novel therapeutic bispecific antibody for the treatment of LILRB4 positive AML and CMML leukemia patients. Citation Format: Yujia Dang, Xiao Huang, Yurong Qin, Xiaoya Liu, Min Chen, Duqing Jiang, Guojin Wu, Mi Ye, Jianming Sun, Baohui Wang, Jing Guan, Tingting Li, Jordan Zhu, Shoupeng Lai, Xiaoqiang Kang, Hong Ling. LBL-043, a novel LILRB4xCD3 T cell engager, for the treatment of LILRB4 positive leukemia [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 6712.
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Shan, Chenxiao, Jia Li, Bo Sun, et al. "Identification of absorbed compounds of Xiao Yao San Jia Wei and pharmacokinetic study in depressed rats by force swimming stress." RSC Advances 12, no. 8 (2022): 4455–68. http://dx.doi.org/10.1039/d1ra08778a.
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Wu, Lei, Tian-yu Long, and Chong-ming Li. "The simulation research of dissolved nitrogen and phosphorus non-point source pollution in Xiao-Jiang watershed of Three Gorges Reservoir area." Water Science and Technology 61, no. 6 (2010): 1601–16. http://dx.doi.org/10.2166/wst.2010.852.
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Xiao-jiang, with a basin area of almost 5,276 km2 and a length of 182.4 km, is located in the center of the Three Gorges Reservoir Area, and is the largest tributary of the central section in Three Gorges Reservoir Area, farmland accounts for a large proportion of Xiao-jiang watershed, and the hilly cropland of purple soil is much of the farmland of the watershed. After the second phase of water storage in the Three Gorges Reservoir, the majority of sub-rivers in the reservoir area experienced eutrophication phenomenon frequently, and non-point source (NPS) pollution has become an important source of pollution in Xiao-jiang Watershed. Because dissolved nitrogen and phosphorus non-point source pollution are related to surface runoff and interflow, using climatic, topographic and land cover data from the internet and research institutes, the Semi-Distributed Land-use Runoff Process (SLURP) hydrological model was introduced to simulate the complete hydrological cycle of the Xiao-jiang Watershed. Based on the SLURP distributed hydrological model, non-point source pollution annual output load models of land use and rural residents were respectively established. Therefore, using GIS technology, considering the losses of dissolved nitrogen and phosphorus in the course of transport, a dissolved non-point source pollution load dynamic model was established by the organic coupling of the SLURP hydrological model and land-use output model. Through the above dynamic model, the annual dissolved non-point source nitrogen and phosphorus pollution output as well as the load in different types were simulated and quantitatively estimated from 2001 to 2008, furthermore, the loads of Xiao-jiang Watershed were calculated and expressed by temporal and spatial distribution in the Three Gorges Reservoir Area. The simulation results show that: the temporal changes of dissolved nitrogen and phosphorus load in the watershed are close to the inter-annual changes of rainfall runoff, and the different land-use type distribution has great impacts on the spatial changes of dissolved nitrogen and phosphorus load in the watershed; The nitrogen and phosphorus load of different land-use types in size with descending order is, glebe and mixed land, paddy, grassland, urban land, forestland; however, for the phosphorus load, the unit area output load of glebe and mixed land is almost the same as for paddy fields; The output contribution of nitrogen and phosphorus pollution load from land-use accounts for 78%–85%, while the output contribution from livestock and poultry occupies 13%–20%. The established load model was verified by observation data, simulation results show that the established model is reasonable, simulation accuracy is higher.
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Lim, Bryan Jian Wei, Xiao-Fan Wang, and Qi-Jing Li. "Abstract 5083: Investigating the development and therapeutic potential of intra-tumoral CXCR6+ effector/effector memory T cells (TEFF/EM) in triple-negative breast cancer." Cancer Research 83, no. 7_Supplement (2023): 5083. http://dx.doi.org/10.1158/1538-7445.am2023-5083.
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Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype that makes up 10-20% of all breast cancer cases. Because of the higher risk of metastasis and recurrence post-treatment, there is a need to develop novel therapeutics to address these challenges. In previously published work, we demonstrated that CXCL16 traps CXCR6+PD-1+ effector/effector memory (TEFF/EM) within the primary tumor and that these T cells have anti-metastatic function that can be harnessed when released into peripheral sites with intra-tumoral administration of anti-CXCL16 prior to surgical resection. However, whether CXCL16 blockade can be used in combination with conventional checkpoint targets and the developmental route of this CXCR6+ TEFF/EM is not known. To develop a novel neoadjuvant therapy, we use the spontaneously metastasizing murine TNBC model, 4T1. Here, we report that anti-4-1BB, and not anti-PD-1, when used in combination with blockade of CXCL16 can prolong survival post-surgical resection. Using anti-4-1BB in combination with CRISPR-generated Cxcl16-KO 4T1 model, we show that both deficiency of CXCL16 within the tumor microenvironment (TME) and anti-4-1BB contribute synergistically to survival advantage. To study the development of this population of T cells, we use the Py8119 murine TNBC model. We definitively show that CXCR6+PD-1+ TEFF/EM is uniquely generated within the primary tumor. Co-expression of CXCR6 and PD-1 indicates that T cell receptor (TCR) signaling is a potential regulator of the development of this TEFF/EM sub-population. Analyses of our previously published scRNA-seq dataset reveals Lat2 to be the top gene involved in TCR signaling. Tumors growing on Lat2-KO animals show a significant increase in tumor size accompanied by significant reduction of CD44high/mid CXCR6+PD-1+ TEFF/EM. However, competitive transfer of naïve WT and Lat2-KO T cells into Tcra-KO recipients led to comparable levels of CXCR6+ TEFF/EM. Surprisingly, transferred Lat2-KO T cells failed to engraft within the primary tumor relative to WT T cells. Future work will address if this engraftment defect is due to expansion/survival defects. Therefore, regulation of TCR signaling within the TME via LAT2 potentially represents a mechanism in which primary tumors trap T cells, promoting their exhaustion. Importantly, this can be harnessed through combinatorial activation and blockade of 4-1BB and CXCL16 respectively. Citation Format: Bryan Jian Wei Lim, Xiao-Fan Wang, Qi-Jing Li. Investigating the development and therapeutic potential of intra-tumoral CXCR6+ effector/effector memory T cells (TEFF/EM) in triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5083.
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Guo, Jing, Lijia Liu, Xiangyong Liu, et al. "Abstract 6511: BPI-520105, a highly potent, CNS-penetrant 4th generation EGFR inhibitor overcoming major EGFR resistance mutations in NSCLC." Cancer Research 84, no. 6_Supplement (2024): 6511. http://dx.doi.org/10.1158/1538-7445.am2024-6511.
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Abstract EGFR activating mutations are prevalent in 10-50% of NSCLC patients. The most common EGFR mutations, L858R (L) and Del19 (D), initially respond to first-, second-, or third-generation (1G, 2G and 3G) EGFR-TKIs. However, on-target resistance, primarily by T790M (T) and C797X(C), inevitably emerges post-treatment and leads to disease progression. Different treatment sequence give rise to different complex mutations. In patients resistant to the 3G TKI osimertinib, double mutations L858R/C797X or Del19/C797X (LC or DC) were observed at a frequency of up to 12% after first-line osimertinib, and triple mutations L858R/T790M/C797S or Del19/T790M/C797S (LTC or DTC) were up to 20% after second-line osimertinib. There are no approved targeted therapy options for these complex resistant mutations. In this study, we developed BPI-520105, a 4th generation EGFR inhibitor capable of targeting all aforementioned major forms of EGFR activating and resistance mutations in NSCLC. It might be an optimal way to address this urgent medical need. In vitro, BPI-520105 potently inhibited the activity of a variety of EGFR kinases, as well as inhibited the proliferation and EGFR phosphorylation in cell lines bearing relative mutations, including single (D, L), double (DT, LT, and DC, LC) and triple (LTC, DTC) mutations. Meanwhile, BPI-520105 exhibited relative weakness towards wild type EGFR and IGF1R, demonstrating good selectivity in kinase and cell-based assays. Despite being a reversible EGFR inhibitor, BPI-520105 sustained the inhibition of pEGFR and pERK for up to 24 hours in the western blot assay. In vivo, oral administration of BPI-520105 displayed significant dose-dependent antitumor effect in multiple EGFR mutant xenograft models, including HCC827 (D), NCI-H1975 (LT), BaF3-EGFR-LC/DC, and BaF3-EGFR-LTC models. Remarkably, BPI-520105 significantly prolonged the lifespan of mice with brain orthotropic BaF3-EGFR-DTC-Luc2 allografts, demonstrating its activity towards brain metastasis. Additionally, BPI-520105 exhibited favorable ADME properties, with high oral exposure across various preclinical species. In summary, BPI-520105 is a highly potent, CNS-penetrant, wide type sparing, and orally bioavailable 4th generation EGFR inhibitor, holding promise for the treatment of NSCLC patients with resistance mutations post 3G progression or even at front line. Citation Format: Jing Guo, Lijia Liu, Xiangyong Liu, Bang Fu, Guangcan Bai, Changyong Qiu, Wei Ren, Xiaodong Song, Guolong Du, Xiao Sun, Yongchun Zhang, Weidong Cai, Pingping Wang, Haibo Chen, Xiaoyun Liu, Zhengyao Zou, Jiayu Zhao, Xuepeng Jv, Hong Lan, Lieming Ding, Jiabing Wang. BPI-520105, a highly potent, CNS-penetrant 4th generation EGFR inhibitor overcoming major EGFR resistance mutations in NSCLC [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 6511.
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Aleman, John, Khoa A. Nguyen, Yao Ke, Christian D. Young, and Xiao-Jing Wang. "Abstract 3834: Assessing the role of extracellular matrix-integrins in metastatic squamous cell carcinoma." Cancer Research 82, no. 12_Supplement (2022): 3834. http://dx.doi.org/10.1158/1538-7445.am2022-3834.
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Abstract Purpose: Patients with head and neck squamous cell carcinoma (HNSCC) have a dismal survival rate. The effects of the extracellular matrix (ECM) on cancer progression have been long studied, but the roles of specific integrins in the process of HNSCC metastasis remain to be dissected. This study aims to determine how HNSCC cells affect the production of laminin-binding integrins, and how these integrins participate in the ECM interactions necessary for a metastatic phenotype. Experimental design: Our laboratory has produced syngeneic mouse SCC cell lines, P029 and A223, derived from Keratin15+ stem cells with Smad4 loss and KrasG12D mutation. In syngeneic recipients, SCCs derived from P029 cells transplanted to the flank mouse skin produced spontaneous metastases to the lung while SCCs derived from A223 cells did not form metastases. Having the same genotype, these cell lines serve as models to examine cancer cell interactions with the ECM and resulting effects on invasion and metastasis. Bulk RNA sequencing (RNAseq) was performed to compare cultured metastatic P029 cells versus non-metastatic A223 cells and identify differentially expressed genes that regulate SCC cells and ECM interactions. Immunoassays and functional invasion assays were performed to evaluate ECM-cancer cell signaling and influence on cancer cell invasion in these two cell lines. Results: RNAseq analysis revealed that, relative to A223 cells, P029 cells have increased levels of integrins, the main mechanoreceptors for numerous ECM ligands and matrix proteins. Laminin-binding integrins, including integrins α4 and β6, were greater at the RNA and protein levels. Additionally, P029 cells expressed higher levels of fibronectin and laminin coding genes compared to non-metastatic A223 cells. Correlatively, high expression of these matrix proteins is associated with worse patient survival. Additionally, P029 SCC cells displayed differential gene expression of tight and apical junctions, PI3K signaling components, and regulators of cytoskeletal remodeling. Furthermore, ELISA and western blot analysis revealed that P029 has aberrant TGFβ-Smad signaling as indicated by the elevated release of TGFβ-1 protein and higher levels of phosphorylated Smad2 and Smad3 relative to non-metastatic A223. Treating P029 cells with TGFβ-1 significantly increased their motility and invasion. Conversely, migration and motility of P029 cells were radically reduced by the TGFβ inhibitor galunisertib. Additionally, the mouse cytokine array revealed that mouse plasma bearing P029 tumors had a greater circulation of CXCL16, MMP-9, proliferin, and serpin E1. These proteins are associated with ECM remodeling and metastasis in HNSCC. Conclusions: SCC cells with metastatic properties upregulate integrins which bind to non-collagen matrix proteins and have elevated invasive and migratory capacity contributed from activated TGFβ signaling. Citation Format: John Aleman, Khoa A. Nguyen, Yao Ke, Christian D. Young, Xiao-Jing Wang. Assessing the role of extracellular matrix-integrins in metastatic squamous cell carcinoma [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 3834.
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Ouyang, Quchang, Huihua Xiong, Min Yan, et al. "Abstract P2-13-32: Pyrotinib in combination with letrozole for estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer: A multicenter, single-arm, phase II trial." Cancer Research 82, no. 4_Supplement (2022): P2–13–32—P2–13–32. http://dx.doi.org/10.1158/1538-7445.sabcs21-p2-13-32.
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Abstract Background: HER2-targeted agents combined with endocrine therapy (ET) has been recommended as an optional therapeutic strategy for hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) co-positive metastatic breast cancer (MBC). Pyrotinib is an oral irreversible pan-ErbB receptor tyrosine kinase inhibitor targeting EGFR, HER2 and HER4, with proven efficacy in combination with chemotherapy in HER2-positive MBC. This multicenter, single-arm phase 2 trial aimed to investigate the efficacy and safety of pyrotinib plus letrozole in patients with estrogen receptor (ER)-positive, HER2-positive MBC (NCT04407988). Methods: Pre-/perimenopausal or postmenopausal women with histologically confirmed HER2-positive (immunohistochemistry [IHC] 3+ or 2+ with fluorescence in situ hybridization positive) and ER-positive (the percentage of ER+ cells ≥ 10% by IHC) MBC were enrolled. Prior treatment for metastatic disease was not allowed. Eligible patients received pyrotinib (400 mg, po, qd) plus letrozole (2.5 mg, po, qd) until disease progression or unacceptable toxicity. For pre-/perimenopausal patients, additional treatment with ovarian function suppression (OFS) was required. The primary endpoint was clinical benefit rate (CBR), defined as the rate of patients with complete response (CR), partial response (PR), or stable disease (SD) for at least 24 weeks per RECIST 1.1. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between December 3, 2019 and April 2, 2021, 26 patients were enrolled. As of July 5, 2021, CBR was 76.9% (20 of 26; 95% CI 56.4% to 91.0%) and ORR was 57.7% (15 of 26; 95% CI 36.9% to 76.6%). One of the 26 patients (3.8%) had CR, 14 (53.8%) had PR, 5 (19.2%) had SD, 5 (19.2%) had progressive disease, and 1 (3.8%) had not evaluable disease. The benefits in CBR and ORR were observed across all subgroups. The most common any grade AEs were diarrhea (25 of 26, 96.2%), vomiting (8 of 26, 30.8%), nausea (6 of 26, 23.1%), and oral ulceration (6 of 26, 23.1%). Diarrhea was the only reported grade 3 AE that occurred in 5 patients (19.2%). No grade 4 or 5 AEs occurred during this study. Conclusions: Pyrotinib combined with letrozole showed an encouraging antitumor activity with good tolerance in patients with ER/HER2 co-positive MBC, promising as an alternative treatment option for this disease. The study is ongoing. Citation Format: Quchang Ouyang, Huihua Xiong, Min Yan, Jincai Zhong, Li Ran, Ting Luo, Liping Liu, Jing Li, Xiaohong Yang, Huawu Xiao, Ning Xie, Hui Wu, Jianxiang Gao, Jun Lu, Xuming Hu, Zheyu Hu, Can Tian, Zhengrong Shui, Min Cao. Pyrotinib in combination with letrozole for estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer: A multicenter, single-arm, phase II trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-32.
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Zhong, Jun, Ruxue Xiao, Wenya Xie, et al. "Abstract CT056: Development of a novel next-generation RET inhibitor." Cancer Research 84, no. 7_Supplement (2024): CT056. http://dx.doi.org/10.1158/1538-7445.am2024-ct056.
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Abstract Oncogenic RET alterations confer constitutive activation in multiple types of human cancers. Two first-generation selective RET inhibitors selpercatinib and pralsetinib have been approved for patients with RET-driven solid tumors including non-small cell lung cancer (NSCLC) and thyroid cancer. However, critical unmet medical needs remain due to drug resistance caused by RET mutations in patients treated with the first-generation RET inhibitors. To address this emerging clinical issue, we discovered a highly potent and selective RET inhibitor with novel chemical scaffold through structure-based drug design, APS03118. Preclinical studies showed APS03118 had stronger in vitro and in vivo biological activity than the first-generation RET inhibitors targeting a broad range of RET fusions and mutations. Importantly, APS03118 was highly potent against a series of resistant RET mutations including the solvent front mutations RET G810C/R/S (IC50 0.04-5.72 nM) and gatekeeper mutations RET V804E/L/M (IC50 0.04-1.36 nM). Off-target screen analysis using the 468-kinase panel demonstrated APS03118 was highly selective for RET. APS03118 was orally bioavailable with good ADME and PK properties and markedly suppressed tumor growth in various RET-driven mouse xenograft tumor models (tumor growth inhibition 87-108% at 10-30 mg/kg BID). In addition, APS03118 exhibited excellent brain penetrating properties with strong efficacy in the in vivo orthotopic brain tumor model. GLP toxicity studies showed acceptable safety profiles. APS03118 received IND approval from both US FDA and China NMPA, and was granted the fast-track designation by FDA. We recently achieved First-in-Human milestone for APS03118 and the Ph 1 clinical trial is ongoing. As of January 5, 2024, three dose levels have been tested. Plasma exposure of APS03118 increased proportionally following single and repeated administration of APS03118 at different doses. APS03118 was well tolerated in NSCLC and thyroid cancer patients harboring RET fusions or mutations relapsed on the chemotherapy, multi-kinase inhibitor and first-generation RET inhibitor therapy. In addition to the favorable safety profiles, we observed sign of efficacy in the RET altered cancer patients in response to APS03118 treatment even in the early clinical trial testing. Partial response and stable disease were observed in patients 2-4 months after administration of APS03118 and dose limiting toxicity (DLT) dose has not been reached. Dose escalation for APS03118 is continuing. Taken together, APS03118 is a novel highly potent and selective next-generation RET inhibitor overcoming resistance following treatment with the first-generation RET inhibitors. APS03118 warrants further clinical development. Citation Format: Jun Zhong, Ruxue Xiao, Wenya Xie, Minchun Chen, Xiaohu Chen, Hao Wang, Yongbo Liu, Qin Gao, Xiupeng Wang, Zongbao Wang, Qian Chen, Jing Yang, Yizhe Ji, Yuxun Wang. Development of a novel next-generation RET inhibitor [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 CT056.
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Aleman, John D., Khoa A. Nguyen, Erica Wong, et al. "Abstract 4206: Regional transcriptomic profiling of the head and neck squamous cell carcinoma tumor microenvironment paired with murine models identify extracellular matrix components that mediate tumor progression and immune suppression." Cancer Research 84, no. 6_Supplement (2024): 4206. http://dx.doi.org/10.1158/1538-7445.am2024-4206.
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Abstract Purpose: A substantial contribution to the poor prognosis for head and neck squamous cell carcinoma (HNSCC) patients is the progression to distant metastasis. This occurs in 30% of patients over the course of their disease, and radically reduces the 5-year survival rate to under 50%. Investigations in recent years have begun to unveil the intricate interplay of the extracellular matrix (ECM) in both tumor-intrinsic signaling and immunoregulation. However, studies conducted in the context of metastatic have been limited. Here, we employ spatial transcriptomics on HNSCC patient biopsies to identify ECM components that may contribute to cancer progression and immune suppression. Experimental design: Comprehensive transcriptome profiling of HNSCC patient biopsies was conducted using the GeoMx Digital Spatial Profiler (DSP). This approach allowed us to characterize regions of the tumor microenvironment (TME) by immunofluorescent staining for subsequent bioinformatic analysis. To investigate the biological consequences of associations observed in our dataset, we performed in vivo murine studies. We have produced a series of SCC C57BL/6 murine cell lines derived from Smad4-/-KrasG12D Keratin15+ stem cells, which faithfully mimic the clinical progression of HNSCC tumors, including metastasis. Using these murine models, we applied relevant pharmacologic inhibitors and genetic knockdown of targets identified with our GeoMx DSP analysis. In vitro immune-based and functional assays were conducted to elucidate the underlying mechanisms contributing to SCC progression. Results: GeoMx DSP analysis revealed that laminins were enriched in stage IV HNSCC patient stroma, relative to lower stage patients. This coincided with TGFβ enrichment and inversely associated with signatures of anti-tumor immune infiltration. Analysis of The Cancer Genome Atlas data revealed similar inverse correlations in SCCs, distinct from breast cancer and lung adenocarcinoma. Our metastatic SCC murine lines likewise exhibited elevated levels of these laminin proteins, accompanied by high levels of laminin-binding integrins and TGFβ-Smad signaling. Independent of impacting cell proliferation, shRNA knockdown of laminin decreased tumor volume in an immune-competent setting. Targeting laminin-integrin signaling with the small molecule inhibitors Galunisertnib and Buparlisib also reduced the metastatic capacity of these cells in C57BL/6 mice. Conclusions: Spatial transcriptomic profiling of the HNSCC TME uncovers intricate associations and promising targets not readily discernible in bulk RNAseq analyses. Validation through genetic and pharmacological approaches in immune-competent models underscores their potential as strategies to reduce HNSCC burden. Citation Format: John D. Aleman, Khoa A. Nguyen, Erica Wong, Yao Ke, Hanne T. Lind, Clifford G. Tepper, Andrew C. Birkeland, Christian D. Young, Sana D. Karam, Xiao-Jing Wang. Regional transcriptomic profiling of the head and neck squamous cell carcinoma tumor microenvironment paired with murine models identify extracellular matrix components that mediate tumor progression and immune suppression [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 4206.
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Kumar, Gopendra, D. K. Bhatt, and B. K. Raina. "Skeletal microfauna of Meishucunian and Qiongzhusian (Precambrian–Cambrian boundary) age from the Ganga Valley, Lesser Himalaya, India." Geological Magazine 124, no. 2 (1987): 167–71. http://dx.doi.org/10.1017/s0016756800015995.
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AbstractThe earliest skeletal microfauna of Precambrian-Cambrian age recovered from the ‘Lower Tal’ sequence (Chert-Phosphorite to Calcareous members) of the Tal Formation, exposed in the Ganga Valley, Lesser Himalaya, Uttar Pradesh, India, has been grouped into three assemblages. In ascending order these are: assemblage I, containing Anabarites trisulcatus Missarzhevsky, Tiksitheca korobovi (Miss.). Circotheca sp., Turcutheca sp., Spirellus columnorus Jiang and Olivooides alveus Qian; assemblage II, yielding Allonia erromenosa Jiang, A. sp. cf. A. erromenosa Jiang, Dimidia simpleca Jiang, D. sp. cf. D. simpleca Jiang and Hyolithellus sp.; and assemblage III, comprising Pelagiella lorenzi Kobayashi, Auriculatespira madianensis Zhou & Xiao and A. andunca He & Pei. The assemblages I and II are correlatable to the Meishucunian Zone I and Zone III respectively, and the assemblage III to the Qiongzhusian Stage of China. Thus the ‘Lower Tal’ sequence is assigned to Precambrian–Cambrian age.
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Wang, Xiao-Jing. "Calcium Coding and Adaptive Temporal Computation in Cortical Pyramidal Neurons." Journal of Neurophysiology 79, no. 3 (1998): 1549–66. http://dx.doi.org/10.1152/jn.1998.79.3.1549.
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Wang, Xiao-Jing. Calcium coding and adaptive temporal computation in cortical pyramidal neurons. J. Neurophysiol. 79: 1549–1566, 1998. In this work, we present a quantitative theory of temporal spike-frequency adaptation in cortical pyramidal cells. Our model pyramidal neuron has two-compartments (a “soma” and a “dendrite”) with a voltage-gated Ca2+ conductance ( g Ca) and a Ca2+-dependent K+ conductance ( g AHP) located at the dendrite or at both compartments. Its frequency-current relations are comparable with data from cortical pyramidal cells, and the properties of spike-evoked intracellular [Ca2+] transients are matched with recent dendritic [Ca2+] imaging measurements. Spike-frequency adaptation in response to a current pulse is characterized by an adaptation time constant τadap and percentage adaptation of spike frequency F adap [% (peak − steady state)/peak]. We show how τadap and F adap can be derived in terms of the biophysical parameters of the neural membrane and [Ca2+] dynamics. Two simple, experimentally testable, relations between τadap and F adap are predicted. The dependence of τadap and F adap on current pulse intensity, electrotonic coupling between the two compartments, g AHP as well the [Ca2+] decay time constant τCa, is assessed quantitatively. In addition, we demonstrate that the intracellular [Ca2+] signal can encode the instantaneous neuronal firing rate and that the conductance-based model can be reduced to a simple calcium-model of neuronal activity that faithfully predicts the neuronal firing output even when the input varies relatively rapidly in time (tens to hundreds of milliseconds). Extensive simulations have been carried out for the model neuron with random excitatory synaptic inputs mimicked by a Poisson process. Our findings include 1) the instantaneous firing frequency (averaged over trials) shows strong adaptation similar to the case with current pulses; 2) when the g AHP is blocked, the dendritic g Ca could produce a hysteresis phenomenon where the neuron is driven to switch randomly between a quiescent state and a repetitive firing state. The firing pattern is very irregular with a large coefficient of variation of the interspike intervals (ISI CV > 1). The ISI distribution shows a long tail but is not bimodal. 3) By contrast, in an intrinsically bursting regime (with different parameter values), the model neuron displays a random temporal mixture of single action potentials and brief bursts of spikes. Its ISI distribution is often bimodal and its power spectrum has a peak. 4) The spike-adapting current I AHP, as delayed inhibition through intracellular Ca2+ accumulation, generates a “forward masking” effect, where a masking input dramatically reduces or completely suppresses the neuronal response to a subsequent test input. When two inputs are presented repetitively in time, this mechanism greatly enhances the ratio of the responses to the stronger and weaker inputs, fulfilling a cellular form of lateral inhibition in time. 5) The [Ca2+]-dependent I AHP provides a mechanism by which the neuron unceasingly adapts to the stochastic synaptic inputs, even in the stationary state following the input onset. This creates strong negative correlations between output ISIs in a frequency-dependent manner, while the Poisson input is totally uncorrelated in time. Possible functional implications of these results are discussed.
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Song, Erwei, Herui Yao, Meili Sun, et al. "Abstract PO2-04-03: BL-M07D1, an antibody-drug conjugate directed to HER2 in patients with locally advanced or metastatic Breast Cancer with HER2-positive/low-expression and other solid tumors: Results from a first-in-human phase 1 study." Cancer Research 84, no. 9_Supplement (2024): PO2–04–03—PO2–04–03. http://dx.doi.org/10.1158/1538-7445.sabcs23-po2-04-03.
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Abstract Background: BL-M07D1 is an anti-HER2 antibody-drug conjugate (ADC) comprised of a humanized anti-HER2 antibody, a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor (Ed-04). Methods: This study included subjects with locally advanced or metastatic HER2 expressing (positive/low) breast cancer (BC) and other solid tumors. BL-M07D1 would be administered at doses of 1.0mg/kg Day 1 & Day 8 every 3 weeks (D1D8 Q3W) or 2.6, 3.2, 3.8, 4.4, 5.0, 5.6, 6.2, 6.8 and 7.4 mg/kg Day 1 every 3 weeks (D1Q3W) during dose escalation (D-ESC). A subset of patients (pts) will be enrolled in the dose-expansion phase (D-EXP) at D1 Q3W regimens. Results: As of June 25, a total of 75 pts have been treated with at least one dose of BL-M07D1, with 22 pts in the D-ESC phase and 53 in the D-EXP phase. Among the 75 pts, 1 received 1.0 mg/kg D1D8Q3W and 74 were treated on the D1Q3W schedule. Dose-limiting toxicity (DLT) was observed at 6.2mg/kg (febrile neutropenia and G3 thrombocytopenia lasting >7 days in one patient). The maximum tolerated dose (MTD) has not been reached yet. D-EXP dose levels included 3.8, 4.4, 5.0 and 5.6mg/kg D1 Q3W. This study enrolled 62 patients with BC, 6 with gastric cancer, 4 with colorectal cancer and 3 with non-small cell lung cancer. The most common TEAEs ( >10%, all grade/≥G3) were leukopenia (79%/24%), neutropenia (69%/39%), anemia (63%/11%), nausea (47%/0%), thrombocytopenia (37%/9%), vomiting (37%/1%), decreased appetite (27%/0%), lymphopenia (24%/8%), alopecia (23%/0%), asthenia (19%/0), gamma-glutamyl transferase increased (17%/0%), aspartate aminotransferase increased (17%/0%), constipation (13%/0%), diarrhea (12%/0%), hypertriglyceridemia (12%/0%), urinary tract infection (11%/1%), COVID-19 (11%/0%), occult blood positive (11%/0%), pyrexia (11%/0%). No ILD was observed. Forty-five pts with BC were evaluated for efficacy (i.e., had at least one post-baseline tumor assessment). Updated efficacy and pharmacokinetic (PK) results will be presented at the meeting. Conclusions: BL-M07D1 demonstrated encouraging efficacy in heavily pretreated HER2 expressing cancers, especially in HER2+ BC. The safety profile showed adequate safety and tolerability. Clinical trial identification: NCT05461768. Efficacy in Patients with Breast Cancer a. 8/9 pts received prior HER2-ADC with microtubule inhibitor. 1/9 pts received prior HER2-ADC with TOPI inhibitor. b. 6 pts with tumor shrinkage are still on-going. c. All pts with tumor shrinkage are still on-going. Citation Format: Erwei Song, Herui Yao, Meili Sun, Hong Zong, Rongbo Lin, Wen Zou, Muran Ding, Jing Yu, Sa Xiao, Hongwei Wang, Hai Zhu, Martin Olivo, Yi Zhu. BL-M07D1, an antibody-drug conjugate directed to HER2 in patients with locally advanced or metastatic Breast Cancer with HER2-positive/low-expression and other solid tumors: Results from a first-in-human phase 1 study [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 PO2-04-03.
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Huang, Tao, Kyu Hong, Krista McCutcheon, et al. "Abstract LB217: A novel bispecific LILRB4/CD3 antibody with potent killing of monocytic acute myeloid leukemia cells." Cancer Research 83, no. 8_Supplement (2023): LB217. http://dx.doi.org/10.1158/1538-7445.am2023-lb217.
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Abstract Background: Acute myeloid leukemia (AML) remains one of the highest unmet needs among human cancers. LILRB4 is specifically expressed on M4 myelomonocytic and M5 monocytic AML cells with a lack of expression on normal hematopoietic stem cells and progenitors, making LILRB4 an attractive target for a T-cell redirecting bispecific antibody to treat AML. Using a proprietary bispecific antibody platform, we engineered and optimized a LILRB4/CD3 bispecific antibody demonstrating potent and specific killing of monocytic AML cells in vitro and in vivo. The strong chemistry, manufacturing and control (CMC) attributes and cross-reactivity to non-human primate LILRB4 and CD3 favor this bispecific for rapid advancement to the clinic. Experimental Procedures: Binding EC50 values for LILRB4/CD3 bispecific antibodies were determined by flow cytometry analysis. The selectivity of the anti-LILRB4 modality to other LILRA/B proteins was assessed by ELISA. The potency of T-cell mediated killing of LILRB4-expressing AML cells was determined by co-culturing human peripheral T cells and monocytic AML THP-1 cells. A human peripheral mononuclear cell (PBMC) assay evaluated potency against LILRB4-positive primary cells (CD14+ monocytes), using CD19+ B cells as a negative control. Tumor bioluminescence kinetics was performed in NSG mice administrated intravenously with human T cells and THP-1-luciferase cells to measure T cell-directed killing of AML cells in vivo. Single intravenous dose of 5 mg/kg was used for PK evaluation in human FcRn transgenic mice. Results: Two top candidates were selected using biophysical criteria: 1) A monovalent anti-LILRB4 arm together with a monovalent anti-CD3 (1+1); 2) A bivalent anti-LILRB4 arm together with a monovalent anti-CD3 (2+1). The binding EC50 values of the 2+1 or the 1+1 variants to LILRB4 in the THP-1 cells were 0.7 nM and 1.3 nM, respectively. ELISA showed the anti-LILRB4 arm to be highly selective for LILRB4. Both 2+1 and 1+1 variants demonstrated potent killing of the THP-1 cells with EC50 values of 0.5 pM and 4.3 pM, respectively. In the PBMC assay, both variants induced killing of monocytes while sparing B cells, supporting the specificity in inducing T-cell directed killing of the LILRB4-expressing primary cells. The anti-CD3 arm was designed to have a low affinity for CD3 to mitigate the risk of cytokine release while ensuring sufficient T cell activation. Both variants showed potent tumor-growth inhibition at doses as low as 0.2 mg/kg in the NSG mice with the 2+1 molecule showing superiority in vivo. The PK profile of the 2+1 bispecific in human FcRn-transgenic mice was similar to what is expected of human IgG1 with linear clearance. Conclusions: A novel bispecific LILRB4/CD3 (2+1) has been identified for development to treat AML based on its potency and specificity in killing monocytic AML cells in both in vitro and in vivo preclinical studies. Citation Format: Tao Huang, Kyu Hong, Krista McCutcheon, Jing-Tyan Ma, Ying Zhu, Mi Deng, Cheng Cheng Zhang, Paul Woodard, Hong Xiang, Xiao Min Schebye, X. Charlene Liao. A novel bispecific LILRB4/CD3 antibody with potent killing of monocytic acute myeloid leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB217.
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Cheng, Rui, Hongxiang Han, and Nan Jiang. "A new specie of the genus Phthorarcha Meyrick, 1892 from Gansu, China (Lepidoptera: Geometridae)." SHILAP Revista de lepidopterología 50, no. 200 (2022): 593–97. http://dx.doi.org/10.57065/shilap.251.
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A new species of the genus Phthorarcha Meyrick, 1892 is described from Gansu of China: Phthorarcha pallidia Xian & Jiang, sp. nov. Diagnosis of the new species is provided; illustrations of external features and male genitalia of the new species are also presented.
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Pulleyblank, Edwin G. "Ji 姬 and Jiang 姜: The Role of Exogamic Clans in the Organization of the Zhou Polity". Early China 25 (2000): 1–27. http://dx.doi.org/10.1017/s0362502800004259.
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AbstractsThe rule of surname exogamy, which has been an important feature of Chinese social organization down to recent times, seems to have originated with the Zhou dynasty. Its importance is symbolized in the myth of Jiang Yuan姜媚 or 姜原, the mother of Hou Ji后稷, Lord Millet, the ancestor of the Zhou kings, whose surname was Ji姬. Contrary to a view that has become popular, it is argued that Ji and Jiang could not have been the names of two originally separate peoples with different geographical origins that came together and formed an intermarrying alliance but were the names of the two leading, intermarrying, clans of a single people. After the Zhou conquest of Shang, marriage politics, which required the rulers of originally non-Chinese states to have clan names of the same kind, played an important part in gradually incorporating such states into the Zhou, Hua-Xia華夏, polity. The fact that the surnames Ji and Jiang were also found among peoples known as Rong 戎 who were not recognized as Hua-Xia but were probably also Sino-Tibetan in language seems to be consistent with traditional accounts of Zhou's northwestern origins. The words Ji and Jiang are probably etymologically related and although yang羊 “sheep” plays a phonetic role in the graphs of both the surname Jiang and the ethnic name Qiang 羌, Jiang and Qiang are two separate words and need not have anything to do with one another.
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Rasin, R. S., S M Sunoj, and Rakesh Poduval. "Kernel-based Estimation of Ageing Intensity Function: Properties and Applications." Austrian Journal of Statistics 52, no. 5 (2023): 16–33. http://dx.doi.org/10.17713/ajs.v52i5.1497.
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The notion of ageing plays an important role in reliability and survival analysis as it is an inherent property of all systems and products. Jiang, Ji, and Xiao (2003) proposed a new quantitative measure, known as ageing intensity (AI) function, an alternative measureto study the ageing pattern of probability models. In this paper, we propose a nonparametric estimator for ageing intensity function. Asymptotic properties of the estimator are established under suitable regularity conditions. A set of simulation studies are carriedout based on various probability models to examine the performance of estimator and to establish its efficiency over the classical estimator. The usefulness of the estimator is also examined through a real data set.