Journal articles on the topic 'Xia family'
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V. P., Thomas, M. SABU, and E. SANOJ. "Amomum meghalayense (Zingiberaceae): a new species from northeast India." Phytotaxa 245, no. 2 (January 25, 2016): 178. http://dx.doi.org/10.11646/phytotaxa.245.2.9.
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Amomum Roxburgh (1820: 75) is the second largest genus in the ginger family with about 150–180 species, widely distributed in Southeast Asia (Xia et al. 2004). The genus is characterized by having radical inflorescences, an absence of involucre of sterile bracts, reduced lateral staminodes and well-developed anther crests.
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Zhang, Pingfan. "“A More Personal Look at Her Life”: Family Narrative, Gender, and Transnational Memories in The Girl and the Picture." Camera Obscura: Feminism, Culture, and Media Studies 37, no. 2 (September 1, 2022): 91–117. http://dx.doi.org/10.1215/02705346-9787028.
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Abstract Recent decades have witnessed a booming film industry portraying the Nanjing Massacre, both within and outside Mainland China, which is closely related to contemporary Chinese political, socioeconomic, and cultural transformations. This article examines the USC Shoah Foundation's 2018 documentary film The Girl and the Picture, featuring the well-known Nanjing Massacre female survivor Xia Shuqin. It argues that the cinematic rendition of Xia's family stories serves as a piercing incision into Nanjing Massacre historical memories and weaves together the personal with the national, and transgenerational with transnational memories. The Girl and the Picture radicalizes cinematic discourses on the Nanjing Massacre from multiple angles and not only sheds light on the emerging field of Nanjing Massacre studies but also contributes to our understanding of the ongoing memory boom of the Nanjing Massacre in the context of globalization. By delivering the stories of Xia along both family and transnational lines, The Girl and the Picture points out a new way to cope with the memory crisis of the Nanjing Massacre, and to take responsibility for transmitting the memories across generational, national, gender, and ethnic boundaries.
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Trappes-Lomax, John. "Trappes of Nidd: A Family History by Richard Trappes-Lomax." Recusant History 27, no. 2 (October 2004): 151–216. http://dx.doi.org/10.1017/s0034193200031319.
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In Ripon Liberty only one [Catholic] gentry family survived this period [the eighteenth century] (the Trappes of Nidd) and in their case the main line died out and a cadet branch from Carlton succeeded them’; this fact of mere survival both justifies and permits setting this account before the reader. Christopher Trappes (XIa), the founder of the Carlton branch, would probably have remained single, if he had not found an heiress with just sufficient income for marriage; had he remained single, the Trappes family would have died out in 1761, and this history would have remained unwritten. As it is, there survives just enough material to show something of how one recusant family contrived to retain its identity through and after the penal times.
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Nestell, Galina P., and Merlynd K. Nestell. "Late Capitanian (latest Guadalupian, Middle Permian) radiolarians from the Apache Mountains, West Texas." Micropaleontology 56, no. 1-2 (2010): 7–68. http://dx.doi.org/10.47894/mpal.56.1.02.
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A diverse radiolarian fauna is described from strata of a road cut section of the uppermost part of the Bell Canyon Formation (Capitanian, Guadalupian, Middle Permian), Apache Mountains, West Texas. Fifteen new species are described: Campanulithus insuetus, Pseudoalbaillella apachensis, Astroentactinia capitanensis, Polyedroentactinia guadalupensis, Afanasievella apachensis, Copicyntra erinacea, Paracopicyntra snyderi, Klaengspongus planus, Copiellintra orbiculata, C. fastuosa, Shangella capitanensis, Rectotormentum wardlawi, Tetratormentum ormistoni, Quadrilobata? blomei, and Nazarovispongus globosum. The diagnoses of the species Follicucullus sphaericus Takemura in Takemura et al. 1999 and the genus Raciditor Sugiyama 2000 are emended. The rank of the subspecies Raphidociclicus gemellus americanus Nazarov and Ormiston 1985a is raised to species level. The genus Nazarovispongus Kozur 1980 is considered to be a valid genus and is reinstated. Established are one new genus, Afanasievella (assigned to the family Spongentactiniidae), one new subfamily Polyedroentactiniinae (in the composition of the family Orosphaeridae), and one new family Tetratormentidae (in the composition of the order Pyramidata). The radiolarian assemblage from the described section in the Apache Mountains is at least partly coeval with the radiolarian assemblage from the Reef Trail Member of the Bell Canyon Formation in the Guadalupe Mountains, allowing a straight correlation of this age strata between the Apache and Guadalupe mountains. This correlation is supported by the conodont species that define the latest Guadalupian conodont zones and that occur together with radiolarians in both areas. The radiolarian species Albaillella yamakitai in sense of Xia et al. (2005) present in the late Guadalupian J. altudaensis conodont Zone cannot be a marker for the Guadalupian – Lopingian boundary as was proposed by Xia et al. (2005).
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VU, QUANG NAM, NIAN-HE XIA, THI THO NGUYEN, and THI HAI NINH KHUAT. "Magnolia quangninhensis (Magnoliaceae), a new species from northern Vietnam." Phytotaxa 464, no. 2 (October 16, 2020): 188–92. http://dx.doi.org/10.11646/phytotaxa.464.2.7.
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A new species of the family Magnoliaceae, Magnolia quangninhensis Q.N. Vu & N.H. Xia from Yen Tu National Forest, in the Quang Ninh Province, north of Vietnam is described and illustrated. It is most closely related to M. bawangensis and M. shangsiensis, but differs by having all parts of tree glabrous (except for dense brown sericeous tomentose to tomentulose brachyblasts), larger elliptic-obovate leaves, creamy-white to pink–purple tepals and stamens, and (6–)9–11 tepals.
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XIA, BIN. "A review of progress on the systematics and biology of the family Cheyletidae in China, with a checklist of the Chinese cheyletids." Zoosymposia 4, no. 1 (June 30, 2010): 158–64. http://dx.doi.org/10.11646/zoosymposia.4.1.11.
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This paper reviews the taxonomic research on the family Cheyletidae in China, with an updated checklist of 48 species belonging to 24 genera. The most important contributions to the Chinese fauna of these mites were made by Tseng Yi-Hsiung, who recognized and described ten species from Taiwan, Lin Jianzhen, who described seven species from Fujian, and Xia Bin, who added five new species. A few studies on the biology and ecology of Cheyletidae in China are briefly reviewed.
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Hamaguchi, Motohiro, Tadashi Matsushita, Mitsune Tanimoto, Isao Tekahashi, Kohji Yamamoto, Isamu Sugiura, Junki Takamatsu, Kanji Ogata, Tadashi Kamiya, and Hidehiko Saito. "Three Distinct Point Mutations in the Factor IX Gene of Three Japanese CRM+ Hemophilia B Patients (Factor IX BMNagoya 2, Factor IX Nagoya 3 and 4)." Thrombosis and Haemostasis 65, no. 05 (1991): 514–20. http://dx.doi.org/10.1055/s-0038-1648182.
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SummaryEnzymatic DNA amplification and complete sequence analysis were used to investigate human factor IX coding sequences in three CRM+ hemophilia B patients. In a patient with severe hemophilia B and a markedly prolonged ox-brain prothrombin time, a C to T transition in exon VI changed the codon for Argl80 to Trp (factor IX BMNagoya 2). This mutation would impair the cleavage by factor XIa required for activation of the zymogen. In a patient with mild hemophilia B, a G to A transition in exon VI changed the codon for Argl45 to His (factor IX Nagoya 3). This substitution also would be predicted to preclude the cleavage of factor IX by factor XIa at this peptide bond (Argl45-Alal46). Furthermore, this point mutation creates a new NlaIII restriction site which provides a quick and reliable method for carrier detection in the affected family members. A patient with severe hemophilia B (factor IX Nagoya 4) had a G to A transition in exon II changing the codon for Glu21 to Lys. This novel point mutation is assumed to impair the function of factor IX by disrupting the calcium binding of factor IX.
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Vázquez-García, J. Antonio, David A. Neill, and Mercedes Asanza. "Magnolia vargasiana (Magnoliaceae), a new Andean species and a key to Ecuadorian species of subsection Talauma, with notes on its pollination biology." Phytotaxa 217, no. 1 (June 22, 2015): 26. http://dx.doi.org/10.11646/phytotaxa.217.1.2.
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Magnoliaceae Jussieu (1789: 280) consist of ca. 330 species worldwide, nearly half of them in the New World (Vázquez-García et al. 2014). There is no agreement on the internal classification, including the number of sections (0–11), genera (1–13), subgenera (0–9) and subfamilies (0–2) (Figlar & Nooteboom 2004; Xia et al. 2008, Romanov & Dilcher 2013) and despite various phylogenetic studies of Magnoliaceae in the last two decades, classification of the family has not reached a consensus (Qiu et al. 1993, 1995; Kim et al. 2001; Azuma et al. 2001, Li & Conran 2003, Nie et al. 2008, Kim & Suh 2013). Here we follow the classification of Figlar & Nooteboom (2004).
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Williams -Wheeler, Meeshay, Jawan M. Burwell, Gabrielle S. Gravely, and Raleta Summers-Dawkins. "Experiential Learning in a Family Systems Course: Integrating the FCSfit KIDS Curriculum." Journal of Family & Consumer Sciences 114, no. 1 (March 1, 2022): 38–40. http://dx.doi.org/10.14307/jfcs114.1.38.
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Experiential learning is a pedagogical tool that aligns with the mission of family and consumer sciences (FCS) university programs because it emphasizes the role of formal education in the development of individuals, family members, and global citizens (Brooks & Simpson, 2014). College students benefit from experiential learning and field-based experiences through enhanced integration of course materials and enhanced perceptions of learning and actual learning (Langlais, 2018). There are many positive outcomes of experiential learning activities in the college classroom including high retention rates of students during and after these semesters (Darling & Cassidy, 2014), improved employability (Brooks & Simpson, 2014), and a broader global perspective (Smith & Yang, 2017). Within FCS courses, experiential learning often provides skills that prepare college students to succeed in their work with children, youth, and families (Brooks & Simpson, 2014; Taylor & Xia, 2018). This paper highlights an experiential activity provided in a Family Systems course in which students learn about family dynamics and the systematic approach of familial well-being. With its focus on the application, creativity, and linking theory to practice, the FCSfit KIDS curriculum was implemented in a Family Systems course to provide varied interactive learning activities to enhance students' understanding of the role of families on preschoolers' health and well-being.
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朱, 书艳. "The Development Dilemma and Promotion Path of Filial Piety in the Family with “En Wang Xia Liu”." Advances in Social Sciences 11, no. 09 (2022): 3933–41. http://dx.doi.org/10.12677/ass.2022.119539.
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SHI, JIAN-PING, YAN DANG, and ZHAN YIN. "A new species of the genus Mongolotettix Rehn, 1928 from Inner Mongolia, China (Acrididae, Acridoidea, Orthoptera)." Zootaxa 4319, no. 2 (September 12, 2017): 368. http://dx.doi.org/10.11646/zootaxa.4319.2.5.
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The grasshopper genus Mongolotettix Rehn, 1928 is a median genus of family Acrididae. It contains 10 species that are distributed in Far Eastern Asian countries, including China, Japan, Korea, Mongolia, and Russia (Bolívar, 1898; Uvarov, 1914; Caudell, 1921; Bei-Bienko & Mishchenko, 1951; Chogsomzhav,1974; Li & Lian, 1994; Yin et al, 1996; Wan et al. 1998, Xie & Li 2000, Yin, Xia et al, 2003; Yin, Zhang et al, 2003; Yin et al, 2004; Kim & Kim, 2005; Huang et al, 2010; Shi et al. 2016; Storozhenko, 2016; Eades et al. 2017; Zhang et al, 2017 and Zheng et al, 2017). In the present paper, we describe a new species of the genus from Inner Mongolia, China. Type specimens are deposited in the Natural Museum of Hebei University, Baoding, Hebei, China.
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Zamalieva, Zarina I., and Elena I. Nesterenko. "LEGAL STATUS OF WOMEN IN TANGUT SOCIETY (based on materials of the Tangut Code)." Vestnik of Kostroma State University 29, no. 3 (December 21, 2023): 68–73. http://dx.doi.org/10.34216/1998-0817-2023-29-3-68-73.
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This article examines the legal status of women in the Tangut society based on the materials of the “Amended and Approved New Code of Regnal Era of Heavenly Prosperityˮ, as well as the basic laws that establish the rights and obligations of women in the state of Xi Xia. The articles of the code that define women by social status, are raised. The women’s status is analysed in the whole variety of their social roles in the Tangut state – mother, wife, daughter, widow, concubine, nun, slave. Laws, indicating restrictions on marriage and divorce, and establishing a distinction between a lawful wife and a concubine were also considered. Serious attention is paid to female victims of family crimes. Topicality of the theme is due to the high interest in the culture of the peoples inhabiting the territory of China in the past, since the development of their culture had a lot of influence on the development of China itself, which today is a multinational state.
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Ding, Boyu. "The opera “Mulan psalm” by Guan Xia in the modern musical culture of China." Culture of Ukraine, no. 82 (December 13, 2023): 67–76. http://dx.doi.org/10.31516/2410-5325.082.08.
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The purpose of the article is to identify and systematize a complex of historical, cultural and musical factors that caused the great popularity of the opera “Mulan Psalm” in China and the interest in this work of viewers from many countries on different continents.
The methodology combines elements of the musicological complex (music-historical, music-performance methods) with historical, cultural and comparative methods, which allows us to analyze and compare the ancient text with the opera libretto, characterize the main means of expression used by the composer, define the historical and cultural background on which the opera was created, and describe the specifics of the opera’s portrayal of the main character, around whose fate the entire plot of the work is built.
The results. Even the initial analysis of the opera by the prominent contemporary artist Guan Xia shows the multivariate interpretation of the image of the main character — one of the most famous characters of the ancient folk epic, as well as the possibility of finding hidden meaning in this masterpiece of modern Chinese opera, because with each new viewing or with each new production of “Mulan Psalm” and new actors performing the main roles, in particular, the three leading singers performing the role of Mulan, different facets of this heroine and the deeper meaning of the opera, which quickly crossed national borders and gained universal significance due to the involvement of its authors, directors and performers in the values that are eternally important to humanity, are revealed: patriotism, sacrifice for the sake of the homeland, and at the same time, sincere love, natural feelings, love for family, brothers in arms, and a loved one. Almost all of the characters are endowed with all of these traits, as there are virtually no negative characters in the opera, since the image of the enemy as such, as well as the enemy army, is not individualized but presented as a common evil that the characters fight and defeat.
The practical significance of the article consists in understanding the significance of the opera “Mulan Psalm” in the operatic art of modern China and identifying the prospects of presenting the best achievements of Chinese artists in this genre on the world academic concert stage.
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Liu, Xiaohui, Ying Wang, Dongliang Xia, Wei Zhang, Shijie Tian, Yan He, Xuerong Feng, et al. "Abstract 1834: Discovery of a novel and highly selective PARP7 inhibitor for cancer immunotherapy." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1834. http://dx.doi.org/10.1158/1538-7445.am2024-1834.
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Abstract Poly-ADP-ribose polymerase 7 (PARP7) is a member of the wider PARP enzyme family that modulate protein function by using nicotinamide adenine dinucleotide (NAD+) as a substrate to transfer an ADP-ribose monomer onto specific amino acid acceptor residues of target proteins. PARP7 acts as a key repressor of type I interferon (IFN) signaling. Its inhibition combats tumor regression by enhancing antitumor immunity that depends on STING pathway. Therefore, PARP7 is emerging as a promising drug target for new immunotherapy. Using structure-based drug design and optimization, we discovered a novel PARP7 inhibitor, HSN002066, with high inhibitory potency (Enzyme assay IC50 = 0.96 nM) and high selectivity for PARP7 over PARP1/2/12/5A/5B/10 (IC50 =163.4/4.7/345.2/1790/110.2/>10000 nM, respectively). In addition, HSN002066 has excellent ADMET profiles with CYPs inhibition, IC50 >10 μM, human LMS T1/2 > 60 min, hERG inhibition, IC50 > 30 μM,mouse oral bioavailability (F) 98.1%. Notably, HSN002066 and RBN-2397, the only PARP7 inhibitor currently in Ph 1/2 clinical development, displayed differentiated antiproliferative activities in cell line NCI-H1373 (IC50 are 387.8 nM and 15.2 nM, respectively). However, HSN002066 revealed remarkable antitumor effects as monotherapy (TGI 77% at 100 mg/kg) or combination with PD-1 antibody in CT-26 allograft model. The structure of HSN002066 was not presented and will not be disclosed at the time of presentation at AACR meeting. Citation Format: Xiaohui Liu, Ying Wang, Dongliang Xia, Wei Zhang, Shijie Tian, Yan He, Xuerong Feng, Xia Yang, Qi Zhang, Shiyi Jiang, Meifeng Wu, Jianfeng Deng, Yeye Wang, Yuxi Su, Min Yao, Weijiao Yuan, Xuedan You. Discovery of a novel and highly selective PARP7 inhibitor for cancer immunotherapy [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 1834.
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Lorthiois, Edwige, James Roache, David Barnes-Seeman, Eva Altmann, Ulrich Hassiepen, Gordon Turner, Rohit Duvadie, et al. "Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach." Journal of Medicinal Chemistry 63, no. 15 (June 17, 2020): 8088–113. http://dx.doi.org/10.1021/acs.jmedchem.0c00279.
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Hd., J. "Cui-Xia Zhawg, Farcey John E. — Gender and the distribution of house-family studies.hold work. Female college faculty in the United States and China." Population Vol. 51, no. 2 (February 1, 1996): 496–97. http://dx.doi.org/10.3917/popu.p1996.51n2.0497.
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Ikels, Charlotte. "Handbook on the Family and Marriage in China, edited by Xiaowei Zang and Lucy Xia Zhao. Cheltenham: Edward Elgar, 2017. v+452 pp. £170.00 (cloth)." China Journal 81 (January 2019): 157–59. http://dx.doi.org/10.1086/700347.
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Yoo, Jongsoo. "Northern Song’s Policies on the Tribes of Cheng and Hui Prefectures during Emperor Zhezong’s Period: Rethinking the “Land Abandonment” and “Opening of the Frontier” Issues." Institute of History and Culture Hankuk University of Foreign Studies 90 (May 31, 2024): 191–216. http://dx.doi.org/10.18347/hufshis.2024.90.191.
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This study builds on existing research to verify the existing interpretation of the policy towards the tribes of Cheng and Hui prefectures during Emperor Zhezong’s reign. The results show that the abolition of several fortresses near the Cheng prefecture actually occurred in the third year of Yuanyou (1088), not in the third year of Yuanfu (1100). However, in the first year of Yuanfu, the Cheng prefecture was still not rebuilt, suggesting that “opening of the frontier” was not carried out in the Cheng and Hui prefectures during the Shaosheng and Yuanfu eras. In comparison with the northwestern border area, “land abandonment” appeared in both areas during the Yuanyou period, but unlike the northwest border, there was no “opening of the frontier” in the Cheng and Hui prefectures between the Shaosheng and Yuanfu periods. While the concept “land abandonment” may appear to be an ideological thesis, its implementation in practice may vary depending on factors such as strategic judgments about the region, historical events, and the degree of Sinicization. Moreover, the impeachment of Yuanyou’s “abandoning the land” theorists can also be seen as a reflection of the New Policies Party’s attitude towards “opening of the frontier” in the early Shaosheng period. However, the cases of the Tangut Xia and Qingtang show that the “opening of the frontier” could not only be a unilateral intention, but also had to take into account the counterpart’s attitude towards the Song dynasty and its internal situation. Since the Yang family of the Cheng and Hui prefectures maintained a pro-Song stance, at least during the Shaosheng and Yuanfu years, the Song dynasty expected them to become another Zhe family of the Fu prefecture, and thus the “opening of the frontier” did not occur.
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Huang, Jianbo, Xiaogang Bao, Wenjun Xia, Lingjun Zhu, Jin Zhang, Jing Ma, Nan Jiang, et al. "Functional analysis of a de novo mutation c.1692 del A of the PHEX gene in a Chinese family with X-linked hypophosphataemic rickets." Bone & Joint Research 8, no. 8 (August 2019): 405–13. http://dx.doi.org/10.1302/2046-3758.88.bjr-2018-0276.r1.
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Objectives X-linked hypophosphataemic rickets (XLHR) is a disease of impaired bone mineralization characterized by hypophosphataemia caused by renal phosphate wasting. The main clinical manifestations of the disorder are O-shaped legs, X-shaped legs, delayed growth, and bone pain. XLHR is the most common inheritable form of rickets, with an incidence of 1/20 000 in humans. It accounts for approximately 80% of familial cases of hypophosphataemia and serves as the prototype of defective tubular phosphate (PO43+) transport, due to extra renal defects resulting in unregulated FGF23 activity. XLHR is caused by loss-of-function mutations in the PHEX gene. The aim of this research was to identify the genetic defect responsible for familial hypophosphataemic rickets in a four-generation Chinese Han pedigree and to analyze the function of this mutation. Methods The genome DNA samples of all members in the pedigree were extracted from whole blood. We sequenced all exons of the PHEX and FGF23 genes, as well as the adjacent splice site sequence with Sanger sequencing. Next, we analyzed the de novo mutation c.1692 del A of the PHEX gene with an online digital service and investigated the mutant PHEX with SWISS-MODEL, immunofluorescence, and protein stability detection. Results Through Sanger sequencing, we found a de novo mutation, c.1692 del A, in exon 16 of the PHEX gene in this pedigree. This mutation can make the PHEX protein become unstable and decay rapidly, which results in familial XLHR. Conclusion We have found a de novo loss-of-function mutation, c.1692 del A, in exon 16 of the PHEX gene that can cause XLHR. Cite this article: J. Huang, X. Bao, W. Xia, L. Zhu, J. Zhang, J. Ma, N. Jiang, J. Yang, Q. Chen, T. Jing, J. Liu, D. Ma, G. Xu. Functional analysis of a de novo mutation c.1692 del A of the PHEX gene in a Chinese family with X-linked hypophosphataemic rickets. Bone Joint Res 2019;8:405–413. DOI: 10.1302/2046-3758.88.BJR-2018-0276.R1.
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Lingle, Christopher J., Xu-Hui Zeng, J. P. Ding, and Xiao-Ming Xia. "Inactivation of Bk Channels Mediated by the Nh2 Terminus of the β3b Auxiliary Subunit Involves a Two-Step Mechanism." Journal of General Physiology 117, no. 6 (May 29, 2001): 583–606. http://dx.doi.org/10.1085/jgp.117.6.583.
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A family of auxiliary β subunits coassemble with Slo α subunit to form Ca2+-regulated, voltage-activated BK-type K+ channels. The β subunits play an important role in regulating the functional properties of the resulting channel protein, including apparent Ca2+ dependence and inactivation. The β3b auxiliary subunit, when coexpressed with the Slo α subunit, results in a particularly rapid (∼1 ms), but incomplete inactivation, mediated by the cytosolic NH2 terminus of the β3b subunit (Xia et al. 2000). Here, we evaluate whether a simple block of the open channel by the NH2-terminal domain accounts for the inactivation mechanism. Analysis of the onset of block, recovery from block, time-dependent changes in the shape of instantaneous current-voltage curves, and properties of deactivation tails suggest that a simple, one step blocking reaction is insufficient to explain the observed currents. Rather, blockade can be largely accounted for by a two-step blocking mechanism () in which preblocked open states (O*n) precede blocked states (In). The transitions between O* and I are exceedingly rapid accounting for an almost instantaneous block or unblock of open channels observed with changes in potential. However, the macroscopic current relaxations are determined primarily by slower transitions between O and O*. We propose that the O to O* transition corresponds to binding of the NH2-terminal inactivation domain to a receptor site. Blockade of current subsequently reflects either additional movement of the NH2-terminal domain into a position that hinders ion permeation or a gating transition to a closed state induced by binding of the NH2 terminus.
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Tian, Felicia F., and Lin Chen. "Unequal at the college door." International Journal of Sociology and Social Policy 38, no. 11/12 (October 8, 2018): 1041–56. http://dx.doi.org/10.1108/ijssp-03-2018-0050.
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Purpose The purpose of this paper is to investigate the inequality in career constructions among freshmen in an elite university in Shanghai, China. The authors first investigated whether rural students and those from municipalities (zhi xia shi) and provincial capitals differ in their career awareness when arriving at college. After finding the difference, the authors explored how this initial difference in career awareness evolves and influences the career construction process in the freshman year. Design/methodology/approach This study used a complementary mixed-methods approach to monitor a cohort of students’ career construction process and the evolvement of their career awareness throughout the freshman year (n=210). Data collection included two surveys: students’ self-reflections and in-depth interviews to capture a holistic story. Findings The findings revealed that students differed in career awareness when arriving at college. This initial difference further evolved in the first year of college: students from municipalities and provincial capitals considered college a part of their career paths and began timely to construct their careers, whereas students from rural areas lagged behind. This study suggests that college maintains inequality, reinforcing the initial gap in career construction based on students’ family background. Originality/value College students differ in career prospects and associated skills when transitioning from school to work. Only a few studies have explored the role of college in shaping the career construction process during the college years. By exploring the process of career construction among freshmen, this study contributes to the growing literature on school-to-work transition and educational inequality in China.
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Safin, Timur. "Kinship ties of the ancient Huaxia: correcting one historiographical inaccuracy." Исторический журнал: научные исследования, no. 6 (June 2023): 145–52. http://dx.doi.org/10.7256/2454-0609.2023.6.69324.
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The study focuses on Huaxia's beliefs regarding their kinship from the seventh to sixth century BC. One theory holds that the people living in the many ancient Chinese states at that time came together to form an ethnic group known as the Hua, Xia, or Huaxia, based on concepts of shared ancestry among other things. Citations from ancient Chinese texts are provided as confirmation, drawing a comparison between the "barbarians" and the foreign and unconnected polities and the "fraternal" and "related" states of the Huaxia. There are issues with this interpretation, though, as genealogical kinship between certain individuals is seen as evidence of the ethnic identity among the Huaxia, while translations of ancient texts are sometimes erroneous and the statement's context is disregarded. This work offers revised translations and interpretations of certain sections from Chun Qiu Zuo Zhuan (Commentary by Zuo [Qiuming to the] Chun Qiu). The author concludes that these statements refute any notion of a shared ancestry among the ancient Chinese as a whole. Rather, they deal only with the family links that existed between the several governing dynasties. Moreover, even in cases where there were no significant linguistic or cultural divide, the principalities ruled by unrelated monarchs or those whose relationship was deemed too remote could be left out of the list of "related," "fraternal" states. The question is raised as to whether the commoners were part of the emerging community of Huaxia, or whether this term still referred to representatives of the elite. It is obvious that the Huaxia are opposed to "barbarians", but it is not entirely clear whether the commoners were taken into account in the context of this comparison.
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Branch, Donald R., Payman Baradar Bokaei, Darinka Sakac, and Xue-Zhong Ma. "HIV-1 Proviral Integration Is Blocked by Agonists to the VpPAC2 Neuroendocrine Receptor." Blood 106, no. 11 (November 16, 2005): 1427. http://dx.doi.org/10.1182/blood.v106.11.1427.1427.
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Abstract VPAC1 is a 7-transmembrane G-protein-coupled neuroendocrine receptor previously shown to transduce a facilitation signal for HIV-1 infection (Branch DR, et al., AIDS.2002;16:309–319). VPAC2, a related receptor, has been reported to have opposing function when compared to VPAC1 (Xia M, et al., J Immunol.1996;157:1132–1138; Tsutsumi M, et al., Diabetes.2002;51:1453–1460). We therefore examined whether stimulation of VPAC2, in contrast to VPAC1, may act to inhibit HIV-1 infection. Using three different and specific agonists of VPAC2, helodermin, RO 25-1553, and R3P55, daily treatment with low concentrations (10−9M) resulted in ~75% to 95% inhibition of either X4 or R5 HIV-1 productive infection in cell lines or primary peripheral blood mononuclear cells. The agonists VIP, PACAP, and secretin, that stimulate the two other VPAC receptor family members VPAC1 and PAC1, did not inhibit HIV-1 infection. Also, Hut78 cells, that lack VPAC2 and are infected by HIV-1, show no effect of VPAC2 agonists on HIV-1 infection. However, Hut78 cells transfected with human VPAC2 cDNA to overexpress this receptor become resistant to HIV-1 infection when treated with VPAC2 agonists. VPAC2-mediated inhibition of productive HIV-1 infection was not due to effects on CD4 or chemokine co-receptor expression, cell growth, or apoptosis. Treatment with VPAC2 agonists also did not inhibit HIV-1 entry into the host cell. However, compared to untreated or cells treated with VPAC1-specific agonists, VPAC2 stimulation profoundly inhibits HIV-1 proviral DNA integration into the host genome. The block in integration was found to be due to the ability of agonists to VPAC2 to inhibit formation of 2-LTR circles, required for HIV-1 integration within the nucleus. We conclude that VPAC2-specific agonists are strongly inhibitory for productive HIV-1 infection. Furthermore, this inhibition is mediated by suppression of 2-LTR circle formation preventing proviral integration. Agonists of VPAC2 appear to be excellent candidates for future development as possible drugs for the amelioration of treatments aimed at the prevention of HIV/AIDS.
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Zeng, Xu-Hui, J. P. Ding, Xiao-Ming Xia, and Christopher J. Lingle. "Gating Properties Conferred on Bk Channels by the β3b Auxiliary Subunit in the Absence of Its Nh2- and Cooh Termini." Journal of General Physiology 117, no. 6 (May 29, 2001): 607–28. http://dx.doi.org/10.1085/jgp.117.6.607.
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Both β1 and β2 auxiliary subunits of the BK-type K+ channel family profoundly regulate the apparent Ca2+ sensitivity of BK-type Ca2+-activated K+ channels. Each produces a pronounced leftward shift in the voltage of half-activation (V0.5) at a given Ca2+ concentration, particularly at Ca2+ above 1 μM. In contrast, the rapidly inactivating β3b auxiliary produces a leftward shift in activation at Ca2+ below 1 μM. In the companion work (Lingle, C.J., X.-H. Zeng, J.-P. Ding, and X.-M. Xia. 2001. J. Gen. Physiol. 117:583–605, this issue), we have shown that some of the apparent β3b-mediated shift in activation at low Ca2+ arises from rapid unblocking of inactivated channels, unlike the actions of the β1 and β2 subunits. Here, we compare effects of the β3b subunit that arise from inactivation, per se, versus those that may arise from other functional effects of the subunit. In particular, we examine gating properties of the β3b subunit and compare it to β3b constructs lacking either the NH2- or COOH terminus or both. The results demonstrate that, although the NH2 terminus appears to be the primary determinant of the β3b-mediated shift in V0.5 at low Ca2+, removal of the NH2 terminus reveals two other interesting aspects of the action of the β3b subunit. First, the conductance-voltage curves for activation of channels containing the β3b subunit are best described by a double Boltzmann shape, which is proposed to arise from two independent voltage-dependent activation steps. Second, the presence of the β3b subunit results in channels that exhibit an anomalous instantaneous outward current rectification that is correlated with a voltage dependence in the time-averaged single-channel current. The two effects appear to be unrelated, but indicative of the variety of ways that interactions between β and α subunits can affect BK channel function. The COOH terminus of the β3b subunit produces no discernible functional effects.
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Sun, Qiaoling, Yunfei Chen, Maojiang Wu, Jing Lv, Hongyue Jin, Peng Zeng, Xia Song, et al. "Abstract 7147: ASN-3186 is a potent and selective inhibitor of USP1 for the treatment of BRCA1/2 mut and HRD+ cancers." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7147. http://dx.doi.org/10.1158/1538-7445.am2024-7147.
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Abstract Ubiquitin-specific protease 1 (USP1), a well-characterized member of the deubiquitinating enzyme family, selectively cleaves ubiquitin from various target proteins, including DNA repair protein PCNA. USP1 contributes to oncogenesis by playing critical roles in DNA damage repair processes including translesion synthesis and the Fanconi anemia pathway. Despite the clinical benefit achieved with PARP inhibitors (PARPi) in BRCA-mutated (BRCAm) or homologous recombination deficient (HRD+) populations, some patients either do not respond to therapy or develop resistance. USP1 inhibitors may have the potential to address this unmet clinical need as USP1 functions in distinct DNA damage repair pathway as compared to PARP. ASN-3186 is a novel, potent, and selective USP1 inhibitor with enzyme IC50 value of single digit nanomolar and selectivity >1000-fold against other family members. ASN-3186 demonstrated potent anti-proliferative activity in the BRCA1m triple negative breast cancer (TNBC) cell line, MDA-MB-436 (IC50 <30 nM). MDA-MB-436 CDX mouse model confirmed dose-dependent, single-agent inhibitory activity of ASN-3186 in vivo with higher potency than KSQ4279, possibly due to ASN-3186’s higher oral bioavailability. Efficacy is consistent with increase of pharmacodynamic biomarker ub-PCNA. The combination of ASN-3186 and PARPi Olaparib yielded a more robust and durable anti-tumor response, with near-complete tumor regression demonstrated at higher combination dose. Moreover, addition of ASN-3186 significantly sensitized Olaparib’s minimal anti-tumor activity in CAOV3 (ovarian, HRD high) and MX-1 (TNBC, BCRA1/2 mut) models, which are resistant to PAPRi, indicating that it has the potential to overcome PARPi resistance. Synthetic lethal activity was also observed when ASN-3186 was combined with DNA damage drug Gemcitabine. Furthermore, ASN-3186 displayed desirable ADME and PK profiles with high oral bioavailabilities (>75%) across species. These data support further clinical development of ASN-3186 as a potential best-in-class USP1 inhibitor, both as a single agent as well as in combination with PARPi, for treatment of BRCA1/2 mut and HRD+ cancers. Citation Format: Qiaoling Sun, Yunfei Chen, Maojiang Wu, Jing Lv, Hongyue Jin, Peng Zeng, Xia Song, Wenfeng Hou, Qi Huang, Wei Niu, Mengyao Zhang, Tie-Lin Wang, Alice Chen. ASN-3186 is a potent and selective inhibitor of USP1 for the treatment of BRCA1/2 mut and HRD+ 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 7147.
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Tu, Peng, Chen Zhang, Biao Lu, Yuanfeng Xia, and Fanglong Yang. "Abstract 664: GSC000190, a highly potent inhibitor of KIF18A, for tumors with chromosome instability." Cancer Research 84, no. 6_Supplement (March 22, 2024): 664. http://dx.doi.org/10.1158/1538-7445.am2024-664.
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Abstract Chromosome instability (CIN) and Genetic instability is a common feature of malignant tumor cells, which may contribute to tumor progression and lead to drug resistance and tumor metastasis. KIF18A, a member of the kinesin-8 family, is an ATP dependent plus end microtubule motor protein. Studies have found that genetic depletion of KIF18A greatly impacts the chromosome alignment, elongation of mitotic spindles, activation spindle assembly checkpoint of CIN+ tumor cell and leads to cell death, while have little impact towards the survival of normal cells, making KIF18A an attractive therapeutic target for targeting the vulnerability of CIN related tumors. Here we report the pharmacology characterization of a “best in class” potential KIF18A inhibitor for CIN+ tumors. In vitro, GSC000190 inhibited KIF18A ATPase activity with a single nM potency and has great potency inhibiting growth of a wide range of TP53 mutant/CIN+ tumor cells. In vivo, GSC000190, at approximately one tenth of systematic exposure comparing to that of AMG650, the leading clinical KIF18A inhibitor, causes tumor shrinkage in multiple CDX models including ovarian, colon and lung cancers. In an HGSOC PDX model which is resistant to platinum and olaparib, GSC000190 induced strong tumor regression both as single agent and through combination without significant body weight reduction. PD study confirms a more elevated mitotic phosphorylated histone 3 (PH3) staining in GSC000190 treated tumor tissues, correlating with a better in vivo efficacy than that of AMG650. GSC000190 has a favorable ADME profile in rodents, dogs and NHPs, as well as a much better safety profile. GSC000190 is now under IND-enabling study and P1 study is planned in the second quarter of 2024. Legal entity responsible for the study: The authors. Disclosure: All authors have declared no conflicts of interest. Citation Format: Peng Tu, Chen Zhang, Biao Lu, Yuanfeng Xia, Fanglong Yang. GSC000190, a highly potent inhibitor of KIF18A, for tumors with chromosome instability [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 664.
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Luo, Qiuyun, Zengfei Xia, Jing Yang, Wentao Pan, Fan Luo, Jiaxin Cao, Yuting Sun, et al. "Abstract 6140: Caspase-3 mediated cleavage of GSDME enhances the antitumor efficacy of HER2-targeted therapy in HER2-positive gastric cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6140. http://dx.doi.org/10.1158/1538-7445.am2023-6140.
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Abstract Background: Gasdermin E (GSDME) is one of the gasdermin family proteins, which induces a new type of programmed cell death - pyroptosis after cleavage by caspase-3. Previous researches have shown that the overexpression of GSDMB, another gasdermin family protein, is associated with poor prognosis in HER2 breast cancer and attributed to HER2-targeted therapy resistance through mediating protective autophagy. However, the role of GSDME in the anti-HER2 treatment of HER2-positive gastric cancer remains unclear. In this study, we sought to explore the function of GSDME in response to anti-HER2 treatment of HER2-positive gastric cancer and investigate the combination treatment strategies. Methods: GSDME overexpressed vector and siRNA interference were applied to evaluate the function of GSDME in HER2-positive gastric cancer. The correlation between the expression of GSDME and survival in HER2-positive and negative gastric cancer was analyzed in the Kaplan Meier plotter database. Flow cytometry, LDH release assay and western blotting were used to determine apoptosis and pyroptosis. Moreover, the phospho-tyrosine kinase array was applied to explore the synergistic mechanism of combination therapy. GSDME overexpressed NCI-N87 xenograft model was established to evaluate the synergistic antitumor effect in vivo. Results: We found that anti-HER2 agents upregulated the expression level of GSDME in a dose- and time-dependent manner. The bioinformatics analysis showed that a higher level of GSDME was correlated with poor overall survival both in HER2-negative and HER2-positive gastric cancer. We further demonstrated that GSDME upregulation in response to anti-HER2 treatment is associated with anti-HER2 therapy resistance. In order to validate whether cleavage of GSDME may render the cancer cells more sensitive to anti-HER2 agents, we applied a novel BCL-2/BCL-XL dual target inhibitor APG-1252 to test the combination antitumor effect with anti-HER2 agents. We found that APG-1252 could enhance the antitumor effect of lapatinib by promoting cell apoptosis and pyroptosis. Mechanistically, the combination treatment synergistically inhibited the phosphorylation of AKT/GSK-3β, subsequently inducing depolarization of the mitochondrial membrane and caspase-3-dependent cleavage of GSDME, which consequently triggered cell apoptosis and pyroptosis. Finally, in the HER2-positive GC cells xenotransplantation models, both lapatinib and APG-1252 monotherapy could delay tumor growth, while the combination therapy significantly suppressed tumor growth. Conclusions: Taken together, our data indicated that anti-HER2 agents could upregulate the expression of GSDME, and the combination of lapatinib and APG-1252 showed a synergistic antitumor effect against HER2-positive gastric cancer through inducing caspase-3/GSDME mediated apoptosis and pyroptosis. Citation Format: Qiuyun Luo, Zengfei Xia, Jing Yang, Wentao Pan, Fan Luo, Jiaxin Cao, Yuting Sun, Liqiong Yang, Lin Zhang, Miaozhen Qiu, Dajun Yang. Caspase-3 mediated cleavage of GSDME enhances the antitumor efficacy of HER2-targeted therapy in HER2-positive gastric 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 6140.
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Błasiok, Jarosław, Venkatesan Guruswami, Preetum Nakkiran, Atri Rudra, and Madhu Sudan. "General Strong Polarization." Journal of the ACM 69, no. 2 (April 30, 2022): 1–67. http://dx.doi.org/10.1145/3491390.
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Arıkan’s exciting discovery of polar codes has provided an altogether new way to efficiently achieve Shannon capacity. Given a (constant-sized) invertible matrix M , a family of polar codes can be associated with this matrix and its ability to approach capacity follows from the polarization of an associated [0, 1]-bounded martingale, namely its convergence in the limit to either 0 or 1 with probability 1. Arıkan showed appropriate polarization of the martingale associated with the matrix ( G 2 = ( 1 1 0 1) to get capacity achieving codes. His analysis was later extended to all matrices M that satisfy an obvious necessary condition for polarization. While Arıkan’s theorem does not guarantee that the codes achieve capacity at small blocklengths (specifically in length, which is a polynomial in ( 1ε ) where (ε) is the difference between the capacity of a channel and the rate of the code), it turns out that a “strong” analysis of the polarization of the underlying martingale would lead to such constructions. Indeed for the martingale associated with ( G 2 ) such a strong polarization was shown in two independent works (Guruswami and Xia (IEEE IT’15) and Hassani et al. (IEEE IT’14)), thereby resolving a major theoretical challenge associated with the efficient attainment of Shannon capacity. In this work we extend the result above to cover martingales associated with all matrices that satisfy the necessary condition for (weak) polarization. In addition to being vastly more general, our proofs of strong polarization are (in our view) also much simpler and modular. Key to our proof is a notion of local polarization that only depends on the evolution of the martingale in a single time step. We show that local polarization always implies strong polarization. We then apply relatively simple reasoning about conditional entropies to prove local polarization in very general settings. Specifically, our result shows strong polarization over all prime fields and leads to efficient capacity-achieving source codes for compressing arbitrary i.i.d. sources, and capacity-achieving channel codes for arbitrary symmetric memoryless channels. We show how to use our analyses to achieve exponentially small error probabilities at lengths inverse polynomial in the gap to capacity. Indeed we show that we can essentially match any error probability while maintaining lengths that are only inverse polynomial in the gap to capacity.
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Yang, Mo, Fu qun Wu, Min Zhou, Jie yu Ye, Xiao jing Li, Beng Chong, and Chang Liu. "Tanshinone IIA has anti-platelet effect and induces apoptosis in megakaryocytes via TNFR and Caspases." Blood 122, no. 21 (November 15, 2013): 3635. http://dx.doi.org/10.1182/blood.v122.21.3635.3635.
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Abstract Tanshinone IIA (TIIA) isolated from Danshen (Radix Salviae Miltiorrhiza Bge) is a derivative of phenanthrenequinone, which has been used for centuries to treat hypercoagulation related diseases. Our previous study showed that TIIA has neural protective effect (Xia et al, Pediatric Research, 2005). In this study, we investigated the effect of TIIA on platelets and megakaryocytes in a rabbit model, and its molecular mechanisms. Rabbit immune vasculitis model was established by intravenous injection of bovine serum albumin with TIIA treatment (5 mg/kg/day, iv). The platelet count, platelet aggregation, and inflammatory cytokine IL-1β level were significantly increased in vasculitis model compared with normal group at day 7. There were positive correlations between platelet count and IL-1β level. The number of megakaryocytes and CFU-MK formation in bone marrow were significantly increased in this model. Treatment with TIIA significantly decreased all these parameters, and also significantly reduced the injury vessel in immune vasculitis. Furthermore, the effect of IIA on in-vitro megakaryopoiesis was investigated. TIIA at 10-30 ug/ml significantly inhibited CFU-MK formation (p<0.05, n=6). TIIA also induced the apoptosis of megakaryocytic cell line CHRF. The cell viability was reduced to 81% after 72hrs of TIIA treatment. Using Annexin V/PI staining, TIIA induced apoptosis on CHRF cells in a dose dependent manner. This was verified by Caspase 3 assay which showed the activation of Caspase 3 increased from 5% to 16% after TIIA treatment. Using JC-1 assay, we found that the depolarized cells increased from 9% to 17% after TIIA treatment suggesting the involvement of intrinsic apoptotic pathway. To further determine the molecular mechanisms involved in the pro-apoptosis effect, Microarray studies using Affymetrix 133 plus genechips were conducted to identify the genes that were differentially expressed after TIIA treatment. Several groups of genes involved in apoptosis, calcium regulation and cell cycle checkpoints were found to be differentially expressed after the treatment. The differential expressions of these genes were validated using quantitative PCR. The most significantly upregulated gene (6.0±0.333 folds) was TNF Receptor Super-Family 9 (TNFRSF9). In addition, Receptor Interacting Protein Kinase (RIPK), a protein that likely interacts with TNFRSF9, was up-regulated to 2.0±0.167 folds. These results suggest that TIIA has an anti-platelet effect in this model. Its mechanism may be related to its inhibiting megakaryopoiesis and inducing apoptosis of megakaryocytes via TNFR and caspases. Disclosures: No relevant conflicts of interest to declare.
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Bai, Chang, Danqi Chen, Zilei Xia, Shujuan Huang, LIshan Lin, Zhaopie Zeng, Jing Su, and Yongkui Sun. "Abstract 7277: Discovery of INV-9956, an orally available and highly selective Cyp11A1 inhibitor for the treatment of castration-resistant prostate cancer with drug resistant AR mutations." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7277. http://dx.doi.org/10.1158/1538-7445.am2024-7277.
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Abstract Androgen Receptor (AR) signaling plays a profound role in prostate cancer and development. Efforts in harnessing androgen and AR axis for castration-resistant prostate cancer treatment have led to discovery of several therapeutics, including AR antagonists and Cyp17 inhibitors. However, resistance to these approved therapeutics has emerged, and remained a significant unmet medical need. Among the prominent resistance mechanisms of action are restored androgen signaling via AR amplification and overexpression, and gain-of-function mutations occurring at AR ligand binding domain that can be agonized by existing AR antagonists and/or non-androgenic steroids such as glucocorticoids. Targeting Cyp11A1 that catalyzes the formation of pregnenolone is effective to ablate biosynthesis of androgens and all steroids and thus holds promise to deliver coverage of a significant percentage of drug resistant AR mutations and benefit CRPC patients post treatment with AR antagonists or Cyp17 inhibitors. Here we present discovery and characterization of INV-9956, an orally available, selective, and potent Cyp11A1 inhibitor with well-acceptable pharmacokinetic properties. INV-9956 potently inhibits biosynthesis of pregnenolone and other androgens in H295R cells with IC50 at single-digit nanomolar, suppresses proliferation of prostate cancer cell lines harboring major clinically acquired drug resistant AR LBD mutations, such as AR L702H using coculture assays. Orally administered INV-9956 showed consistent dose dependent PK/PD correlations across animal species. Particularly, INV-9956 displayed pronounced tumor inhibition superior to known competitors in a CRPC VCaP xenograft model and in a “humanized” animal model. Furthermore, INV-9956 displayed a good tox profile in 14-day repeated dosing rat and dog studies, supported by a high selectivity to Cyp11A1 over other Cyp family members, clean hERG and mini-Ames, and no significant off-target activity in a safety panel screen. The promising preclinical profiles of INV-9956 lend strong support to its potentials in addressing unmet needs in CRPC treatments and warrant clinical development. Citation Format: Chang Bai, Danqi Chen, Zilei Xia, Shujuan Huang, LIshan Lin, Zhaopie Zeng, Jing Su, Yongkui Sun. Discovery of INV-9956, an orally available and highly selective Cyp11A1 inhibitor for the treatment of castration-resistant prostate cancer with drug resistant AR mutations [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 7277.
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Shang, Yushuan, Junzhuan Qiu, Yanfei Xin, Min Zhao, Qiang Liu, Zhengsheng Wang, Xiaojing Gong, et al. "Abstract 5087: ILB-3101, a novel B7H3-targeting ADC with Eribulin as payload, demonstrates strong tumor killing activities and favorable PK/TOX profile in preclinical evaluation." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5087. http://dx.doi.org/10.1158/1538-7445.am2024-5087.
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Abstract B7H3, a B7 family member of immune checkpoint proteins, is overexpressed in a broad spectrum of malignant tumors. It has become an attractive target for cancer therapies in recent years. ILB-3101, a potential best-in-class ADC, was constructed by conjugating a potent mitotic inhibitor Eribulin to a proprietary anti-B7H3 mAb through a proprietary linker. This ADC molecule has been developed and preclinically evaluated as both the 1st line ADC treatment with B7H3 expressed patients in Eribulin sensitive cancer types and the later line treatment for patients whose cancer are B7H3 positive but TopoI inhibitor resistant. The humanized antibody of ILB-3101 is IgG1 type and shows high affinity to both human and monkey B7H3 proteins. It also shows better internalization than benchmark antibodies such as that of DS-7300 analog. The DAR value of ILB-3101 is 3.5. ILB-3101 has potent and dose-dependent cytotoxicity to B7H3-positive tumor cells and shows better activities than DS-7300 analog as positive control. In vivo studies based on xenograft tumor models reveal that ILB-3101 has potent anti-tumor activities in various tumor types including TNBC, sarcoma, ovarian cancer and AML etc., which are superior or comparable to DS-7300 analog. Furthermore, ILB-3101 shows strong anti-tumor activity on Dxd based ADC resistant tumors in xenograft tumor models. The PK study of ILB-3101 in cynomolgus monkeys shows dose-dependent exposure and desirable PK profile. ILB-3101 was well tolerated in cynomolgus monkeys with HNSTD at 6 mg/kg. No serious adverse events were observed, and the main safety findings were limited and reversible hematological and immunological effects, which are consistent with the safety profile of Eribulin as an approved chemotherapy. The in vitro and in vivo preclinical results above demonstrate that ILB-3101 has good efficacy and safety profile and it is a promising and potentially best-in-class B7H3 targeting ADC drug candidate. ILB-3101 is worthy of further translational research and clinical trials. Its IND application has been submitted in China, followed by US FDA filing soon. Citation Format: Yushuan Shang, Junzhuan Qiu, Yanfei Xin, Min Zhao, Qiang Liu, Zhengsheng Wang, Xiaojing Gong, Yan Xu, Yan Li, Mingde Xia, Rulei Chen. ILB-3101, a novel B7H3-targeting ADC with Eribulin as payload, demonstrates strong tumor killing activities and favorable PK/TOX profile in preclinical evaluation [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 5087.
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Harlin, Helena, Stephanie Birkey Reffey, Colin S. Duckett, Tullia Lindsten, and Craig B. Thompson. "Characterization of XIAP-Deficient Mice." Molecular and Cellular Biology 21, no. 10 (May 15, 2001): 3604–8. http://dx.doi.org/10.1128/mcb.21.10.3604-3608.2001.
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ABSTRACT The inhibitor of apoptosis protein (IAP) family consists of a number of evolutionarily conserved proteins that function to inhibit programmed cell death. X-linked IAP (XIAP) was cloned due to its sequence homology with other family members and has previously been shown to prevent apoptosis by binding to active caspases 3, 7, and 9 in vitro. XIAP transcripts can be found in a variety of tissues, and the protein levels are regulated both transcriptionally and posttranscriptionally. To better understand the function of XIAP in normal cells, we generated mice deficient in XIAP through homologous gene targeting. The resulting mice were viable, and histopathological analysis did not reveal any differences between XIAP-deficient and wild-type mice. We were unable to detect any defects in induction of caspase-dependent or -independent apoptosis in cells from the gene-targeted mice. One change was observed in cells derived from XIAP-deficient mice: the levels of c-IAP1 and c-IAP2 protein were increased. This suggests that there exists a compensatory mechanism that leads to upregulation of other family members when XIAP expression is lost. The changes in c-IAP1 and c-IAP2 expression may provide functional compensation for loss of XIAP during development or in the induction of apoptosis.
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Chaudagar, Kiranj, Srikrishnan Rameshbabu, Shenglin Mei, Taghreed Hirz, Ya-Mei Hu, Anna Argulian, Brian Labadie, et al. "Abstract 5270: Androgen receptor blockade in macrophages primes NLRP3 inflammasome-mediated phagocytosis and tumor clearance in advanced prostate cancer." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5270. http://dx.doi.org/10.1158/1538-7445.am2024-5270.
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Abstract Immune-based therapies induce durable remissions in subsets of patients across multiple malignancies. However, there is limited efficacy of immunotherapy in metastatic castrate-resistant prostate cancer (mCRPC), manifested by an enrichment of immunosuppressive (M2) tumor-associated macrophages (TAM) in the tumor immune microenvironment (TME). Therefore, therapeutic strategies to overcome TAM-mediated immunosuppression are critically needed in mCRPC. Our single-cell RNA sequencing analysis in human tumors revealed that NLR family pyrin domain containing 3 (NLRP3), an innate immune sensing protein, is differentially expressed in TAM from metastatic PC patients treated with standard-of-care androgen deprivation therapy (ADT), relative to other tumor types and untreated primary PC. Furthermore, bulk RNA sequencing analysis in human mCRPC samples revealed an inverse relationship between NLRP3 expression and AR activity, with high NLRP3 expression associated with an M1 signature and a favorable clinical response to ICI in mCRPC. Based on these findings, we hypothesized that androgen axis blockade could enhance NLRP3 expression and potentiate innate immune tumor control in advanced PC. Critically, we discovered that blockade of TAM-intrinsic androgen receptor (AR) activity enhanced NLRP3 expression, but not inflammasome activity in the immunosuppressive (M2) TAM. In contrast, anti-tumor (M1) TAM exhibited high de novo NLRP3 expression, regardless of AR activity. The combination of AR blockade and NLRP3 agonism significantly enhanced phagocytosis of cancer cells by M2 TAM, whereas NLRP3 agonist treatment alone was sufficient to induce phagocytosis in M1 TAM. Following AR blockade/NLRP3 agonist combination treatment, all TAM acquired a distinct phenotype with high PD-L1 and CD86 expression, indicative of phagocytic TAM. Critically, NLRP3 agonism in combination with ADT resulted in significant tumor control in an aggressive c-myc driven advanced PC model, with 55% of mice achieving complete tumor clearance, which was abrogated by concurrent clodronate treatment (which systemically depletes phagocytic macrophages), thus demonstrating TAM-mediated phagocytosis enhancement as a major driver of the observed anti-tumor response. Collectively, our results identify NLRP3 as an AR-regulated “macrophage phagocytic checkpoint” that can be inducibly expressed and activated in TAM following ADT and NLRP3 agonist treatment, respectively, the combination resulting in TAM-mediated phagocytosis and tumor control. Citation Format: Kiranj Chaudagar, Srikrishnan Rameshbabu, Shenglin Mei, Taghreed Hirz, Ya-Mei Hu, Anna Argulian, Brian Labadie, Kunal Desai, Sam Grimaldo, Doga Kahramangil, Rishikesh Nair, Sabina DSouza, Dylan Zhou, Raymond Chen, Jordan Shafran, Mayme Loyd, Zheng Xia, David Sykes, Amy Moran, Akash Patnaik. Androgen receptor blockade in macrophages primes NLRP3 inflammasome-mediated phagocytosis and tumor clearance in advanced prostate 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 5270.
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Bahnak, B. R., J. M. Lavergne, C. L. Verweij, C. Rothschild, H. Pannekoek, M. J. Larrieu, and D. Meyer. "Carrier Detection in Severe (Type III) von Willebrand Disease Using Two Intragenic Restriction Fragment Length Polymorphisms." Thrombosis and Haemostasis 60, no. 02 (1988): 178–81. http://dx.doi.org/10.1055/s-0038-1647025.
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SummaryDNA from a family with a female member affected with severe (type III) vWD was analysed using three restriction enzymes and a partial vWF cDNA probe. Two restriction fragment length polymorphisms (RFLPs) detected with the enzymes Bgl II and Xba I proved to be informative in this family. A 36.0 Kb allele, demonstrated with the enzyme Xba I was rare in the general population but very important in this family for segregation analysis of the alleles and their association with the putative defective chromosome. The propositus was homozygous for the 36.0 Kb Xba I polymorphic band and heterozygous for the Bgl II polymorphism. She was the only member of the family showing this allelic pattern. The linkage of the alleles could be determined because her mother was homozygous for the 9.0 Kb Bgl II polymorphism but heterozygous for the Xba I polymorphism. The segregation of the alleles could be traced to the proband’s son and a niece. The genotypic analysis revealed that her niece could be considered as carrying a defective gene for severe vWD.
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Schimmer, Aaron D., and Shadi Dalili. "Targeting the IAP Family of Caspase Inhibitors as an Emerging Therapeutic Strategy." Hematology 2005, no. 1 (January 1, 2005): 215–19. http://dx.doi.org/10.1182/asheducation-2005.1.215.
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The IAPs (inhibitor of apoptosis proteins) are a family of caspase inhibitors that block the execution phase of apoptosis. Overexpression of IAPs confers chemoresistance and, in some groups of patients, is associated with a poor prognosis. Given their role in the development and progression of solid tumors and hematologic malignancies, efforts are underway to develop therapeutic IAP inhibitors, with a focus on X-linked IAP (XIAP) and survivin. Antisense oligonucleotides that target XIAP and survivin have been developed and are currently in phase I clinical trial. Small-molecules that bind and inhibit XIAP have also been identified and are in the process of clinical development. This review focuses on the preclinical data that support the development of IAP-targeted therapies.
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Schimmer, Aaron D., and Shadi Dalili. "Targeting the IAP Family of Caspase Inhibitors as an Emerging Therapeutic Strategy." Hematology 2005, no. 1 (January 1, 2005): 215–19. http://dx.doi.org/10.1182/asheducation.v2005.1.215.215.
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Abstract The IAPs (inhibitor of apoptosis proteins) are a family of caspase inhibitors that block the execution phase of apoptosis. Overexpression of IAPs confers chemoresistance and, in some groups of patients, is associated with a poor prognosis. Given their role in the development and progression of solid tumors and hematologic malignancies, efforts are underway to develop therapeutic IAP inhibitors, with a focus on X-linked IAP (XIAP) and survivin. Antisense oligonucleotides that target XIAP and survivin have been developed and are currently in phase I clinical trial. Small-molecules that bind and inhibit XIAP have also been identified and are in the process of clinical development. This review focuses on the preclinical data that support the development of IAP-targeted therapies.
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Chai, Ruipeng, Jinyan Wang, Xing Wang, Jianqiang Wen, Zhijian Liang, Xuemei Ye, Yaling Zhang, et al. "The Pid Family Has Been Diverged into Xian and Geng Type Resistance Genes against Rice Blast Disease." Genes 13, no. 5 (May 17, 2022): 891. http://dx.doi.org/10.3390/genes13050891.
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Rice blast (the causative agent the fungus Magnaporthe oryzae) represents a major constraint on the productivity of one of the world’s most important staple food crops. Genes encoding resistance have been identified in both the Xian and Geng subspecies genepools, and combining these within new cultivars represents a rational means of combating the pathogen. In this research, deeper allele mining was carried out on Pid2, Pid3, and Pid4 via each comprehensive FNP marker set in three panels consisting of 70 Xian and 58 Geng cultivars. Within Pid2, three functional and one non-functional alleles were identified; the former were only identified in Xian type entries. At Pid3, four functional and one non-functional alleles were identified; once again, all of the former were present in Xian type entries. However, the pattern of variation at Pid4 was rather different: here, the five functional alleles uncovered were dispersed across the Geng type germplasm. Among all the twelve candidate functional alleles, both Pid2-ZS and Pid3-ZS were predominant. Furthermore, the resistance functions of both Pid2-ZS and Pid3-ZS were assured by transformation test. Profiting from the merits of three comprehensive FNP marker sets, the study has validated all three members of the Pid family as having been strictly diverged into Xian and Geng subspecies: Pid2 and Pid3 were defined as Xian type resistance genes, and Pid4 as Geng type. Rather limited genotypes of the Pid family have been effective in both Xian and Geng rice groups, of which Pid2-ZS_Pid3-ZS has been central to the Chinese rice population.
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Pinho, M. B., J. Sellos, F. Costas, D. Herchenhorn, F. A. Peixoto, R. Diengsmann, I. A. Small, H. Cardoso, D. P. Guimarães, and C. G. Ferreira. "XIAP mRNA levels but not XAF1 or XIAP/XAF1 mRNA levels predict pathological response in bladder cancer patients treated with neoadjuvant chemotherapy." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 20030. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.20030.
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20030 Background: The relation between apoptosis-related molecules and chemosensitivity has been extensively studied. In recent years, attention has shifted to a new family of inhibitor of apoptosis proteins (IAPs). XIAP (X- linked inhibitor of apoptosis) is the most versatile and potent member of the IAP family. To date, the overexpression of XIAP has been detected in various cancers. XAF1 (X-linked inhibitor of apoptosis associated factor 1) is a new protein identified for its ability to interact with XIAP. Neither XIAP nor XAF1 or XIAP/XAF1 mRNA expression have been studied in bladder cancer patients. Methods: The expression of XIAP and XAF1 mRNA was analyzed by a real time quantitative fluorogenic PCR method in a group of 17 patients with locally advanced bladder cancer treated with a combination of neoadjuvant Gemcitabine and Cisplatin. The prognostic significance of XIAP and XAF1 mRNA expression and the correlation with several clinicopathological variables was evaluated. Results: XIAP and XAF1 mRNA expression was detected in all 17 (100%) case samples. The levels of XIAP mRNA expression showed a moderate variation among samples. In contrast, XAF1 and XIAP/XAF1 mRNA levels showed significant variation among samples. Bivariate correlation analyses revealed a significant positive Spearman direct correlation coefficient between the XIAP expression and the pathological response. No significant correlation was found for XAF1 expression as well as for the XIAP/XAF1 ratio and clinical and pathological response. Conclusions: This is first study to address the role of XIAP, its negative regulator XAF1, and the XIAP/XAF1 ratio in bladder cancer patients. The positive correlation between the XIAP mRNA expression and the pathological response is in line with a previous study from our group in which a correlation was found between XIAP expression and survival. All these observations point to a complex role of XIAP in tumor biology. XAF1 mRNA expression in bladder carcinomas did not achieve significance as an independent predictive and prognostic factor in a bivariate analysis. Further studies are necessary in order to better assess a possible clinical value for XIAP and XAF1 as predictive and prognostic markers in cancer patients. No significant financial relationships to disclose.
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Wesołowski, Zbigniew. "The Virtues of Xiao (Filial Piety) and Ti (Brotherly Obedience) as Two Pillars of Confucian Familism." Studia Warmińskie 59 (December 31, 2022): 315–36. http://dx.doi.org/10.31648/sw.8336.
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In imperial China (221 BC – 1911), filial piety (xiao) and brotherly obedience (ti) were two core values of family life. Confucian familism made filial piety a cornerstone of the entire social order. The original use of the word xiao from the Western Zhou dynasty (ca. 1045–771 BC) refers primarily to ritual services to deceased parents and ancestors. Later, the Confucians of the Warring States (475–221 BC) thought of xiao particularly as showing obedience and displaying respect towards parents. After the late Warring States, the Confucians again reinterpreted xiao extending it to a political dimension, i.e., obedience and respect to one’s lord. Since then, xiao as the dutiful submission of children to their parents has become the basis for both self-cultivation and the political order. Filial sons were also understood as loyal retainers to meet the needs of the emerging bureaucratic state in imperial China. Down through the centuries, parents constantly taught their children to treat elders with filial piety and brotherly obedience, this behavior being a central measure of the children’s moral worth. Although Confucian thought on the family still has its value and relevance in present-day China, it is increasingly exposed to many challenges. This situation is a consequence of the profound transformation of traditional family ethics, values and institutions brought about by the processes of modernization and globalization.
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Peng, Zeyu, Jinyu Liu, Wenwen Dai, Xiaodong F. Liu, Shukai Xia, Hongyan Li, Lei Shi, Hugh M. Davis, Mingjiu Chen, and Mark Z. Ma. "Abstract 5312: BSI-082, a fully human anti-SIRPα antibody with both high specificity and broad coverage of SIRPα variant populations." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5312. http://dx.doi.org/10.1158/1538-7445.am2022-5312.
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Abstract Background: SIRPα is an inhibitory immunoreceptor, expressed on macrophages that interacts with CD47 expressed on tumor cells to release a “don't eat me” signal, resulting in immune evasion of tumor cells. Antibodies targeting CD47 or SIRPα are expected to block the CD47/SIRPα signaling pathway, thereby stimulating macrophage-based phagocytosis of tumor cells. Anti-CD47 antibodies usually have side effects related to anemia and thrombocytopenia since CD47 is expressed on normal cells, including red blood cells and platelets. Targeting SIRPα on the macrophage is an alternative approach to blocking CD47/SIRPα signaling without the side effects observed in anti-CD47 antibody treatment. In addition to SIRPα there are two other members of the SIRP family - SIRPβ and SIRPγ. These isoforms share high sequence homology with SIRPα but have very different functionality. Moreover, SIRPα is polymorphic in humans, among which SIRPαV1, SIRPαV2 and SIRPαV8 are the main SIRPα variants in diverse ethnic groups. Together, the key challenge of anti-SIRPα antibody discovery is to identify lead candidates that specifically bind to SIRPα and block the SIRPα/CD47 interaction while also recognizing the majority of SIRPα variants. Experimental procedures: Humanized mice were used for immunization and the proprietary H3 (High-throughput, High-content and High-efficiency) antibody screening platform was used to identify a lead candidate - BSI-082. Affinity was measured by SPR while specificity of antibodies to SIRPα and blocking activity of CD47/SIRPα were evaluated by ELISA and FACS. Functional activity of antibodies was investigated using monocyte-derived macrophages and Raji cells in the presence of Rituximab with and without anti-SIRPα antibody. Antibody internalization was evaluated by using the Biosion SynTracer™ antibody discovery platform. Results: BSI-082 is a fully human IgG1/κ mAb that binds to SIRPα and blocks the SIRPα/CD47-mediated signaling pathway. BSI-082 is a highly selective SIRPα binder with very weak or no binding to SIRPβ and no binding to SIRPγ. In addition, BSI-082 binds three main SIRPα variants (V1, V2 and V8) with high affinity. Through antibody engineering, BSI-082 harbors an engineered Fc domain that prevents FcγR binding and enhances FcRn binding, thus significantly reducing ADCC while also extending half-life. In the presence of rituximab, BSI-082 promotes macrophage-mediated phagocytosis. BSI-082 exhibits effective internalization, which would deplete SIRPα on macrophages and enhance immune response. Conclusion: BSI-082 exhibits best-in-class biophysical properties, SIRPα specificity, broad SIRPα variant binding and superior functional characteristics, supporting the initiation of development activities including manufacturing and IND-enabling studies. Citation Format: Zeyu Peng, Jinyu Liu, Wenwen Dai, Xiaodong F. Liu, Shukai Xia, Hongyan Li, Lei Shi, Hugh M. Davis, Mingjiu Chen, Mark Z. Ma. BSI-082, a fully human anti-SIRPα antibody with both high specificity and broad coverage of SIRPα variant populations [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 5312.
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Pluta, Agnieszka, Agata Wrzesien-Kus, Barbara Cebula-Obrzut, Konrad Stepka, Anna Wolska, Olga Grzybowska-Izydorczyk, Magdalena Czemerska, Piotr Smolewski, Tadeusz Robak, and Agnieszka Wierzbowska. "The Role of Inhibitor of Apoptosis Proteins Family Expression In Acute Myeloid Leukemia Patients." Blood 116, no. 21 (November 19, 2010): 2728. http://dx.doi.org/10.1182/blood.v116.21.2728.2728.
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Abstract Abstract 2728 Background: IAPs (Inhibitor of Apoptosis Proteins) family acts as an inhibitor of both external and internal apoptosis pathways by binding to specific caspases. These proteins also participate in intracellular signal transduction. Seven human IAPs have been identified: XIAP, cIAP-1, cIAP-2, survivin, livin, NAIP and BRUCE/Apollon. IAPs family can be inhibited by Smac/DIABLO (second mitochondrial derived activator of caspase/direct IAP binding protein with low pI) protein. The role, pathway of action and prognostic significance of IAPs family is not clearly determined in acute myeloid leukemia (AML) patients. Aims: The main objective of this study was to verify whether expressions of selected IAPs as XIAP, cIAP-1, cIAP-2 and survivin proteins have a prognostic impact on response to induction chemotherapy of adult AML patients. Additionally, to analyse the correlation between members of IAPs family and their inhibitor, Smac/DIABLO protein in leukemic blasts. Material and Methods: Intracellular expression of XIAP, cIAP-1, cIAP-2, survivin and Smac/DIABLO proteins were examined in leukemic blasts isolated from bone marrow or peripheral blood of 56 de novo AML patients with median age 57 (range 21–82). All measurements were carried out using multi-colour flow cytometry. In parallel, the isotype controls were performed for all measurements. Protein expression was assessed by percentage of XIAP, cIAP-1, cIAP-2, survivin and Smac/DIABLO positive cells. Expression above 20% of cells was recognized as positive. Results: The median of intracellular expression of XIAP, cIAP-1, cIAP-2, survivin and Smac/DIABLO proteins were 1% (ranged 0,1–16,7%), 3,2% (ranged 0,1–67,0%), 1,7% (ranged 0–41%), 29,9% (ranged 0,3–71,1%) and 65,9% (ranged 3,8–99,9%); respectively. Correlation of cIAP-1 with cIAP-2 and XIAP was observed (p<0.001, p<0.01; respectively). Trend of correlation between cIAP-1 and survivin was also noticed (p=0.07). Similarly to cIAP-1, cIAP-2 was strongly correlated with XIAP (p<0.01). Neither cIAP-2 nor XIAP showed correlation with survivin. Additionally, all of investigated IAPs family members except survivin showed reverse correlation with Smac/DIABLO protein (p<0.01). Thirty three out of 56 AML patients received standard induction chemotherapy with daunorubicine and cytarabine (Ara-C) (3+7), 23/56 received non-intensive chemotherapy. Twenty (60.7%) of intensively treated patients achieved complete remission (CR). We examined influence of presence of cIAPs family members in leukemic blast on response to chemotherapy in intensively treated patients. It was found that probability of CR with absence of cIAP-1, cIAP-2 and survivin was 83%. CR rate with presence of one of IAPs member was 68%. Patients with expressions of three IAPs members did not respond to the induction therapy. Conclusions: Strong correlations between members of IAPs family may bear the evidence for cooperation between these proteins in leukemic blasts. Additionally, reverse correlation between members of IAPs family and their antagonist Smac/DIABLO protein confirm intracellular interaction between them. These data also demonstrate that lack of IAPs family members expressions is associated with higher sensitivity to standard chemotherapy. However, further investigations evaluating the relationship between all known IAPs family members and their inhibitors should be undertaken to better demonstrate its pathways of action as well as prognostic and potentially therapeutic value. Disclosures: Robak: Johnson & Johnson: Research Funding.
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Abbas, Ruqaia, and Sarit Larisch. "Targeting XIAP for Promoting Cancer Cell Death—The Story of ARTS and SMAC." Cells 9, no. 3 (March 9, 2020): 663. http://dx.doi.org/10.3390/cells9030663.
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Inhibitors of apoptosis (IAPs) are a family of proteins that regulate cell death and inflammation. XIAP (X-linked IAP) is the only family member that suppresses apoptosis by directly binding to and inhibiting caspases. On the other hand, cIAPs suppress the activation of the extrinsic apoptotic pathway by preventing the formation of pro-apoptotic signaling complexes. IAPs are negatively regulated by IAP-antagonist proteins such as Smac/Diablo and ARTS. ARTS can promote apoptosis by binding and degrading XIAP via the ubiquitin proteasome-system (UPS). Smac can induce the degradation of cIAPs but not XIAP. Many types of cancer overexpress IAPs, thus enabling tumor cells to evade apoptosis. Therefore, IAPs, and in particular XIAP, have become attractive targets for cancer therapy. In this review, we describe the differences in the mechanisms of action between Smac and ARTS, and we summarize efforts to develop cancer therapies based on mimicking Smac and ARTS. Several Smac-mimetic small molecules are currently under evaluation in clinical trials. Initial efforts to develop ARTS-mimetics resulted in a novel class of compounds, which bind and degrade XIAP but not cIAPs. Smac-mimetics can target tumors with high levels of cIAPs, whereas ARTS-mimetics are expected to be effective for cancers with high levels of XIAP.
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Kane, Alexander, Jinhu Yin, Erping Long, James Feng, Cathrin Gräwe, Harsh Patel, Jinyoung Byun, et al. "Abstract 7327: Investigating the cell-type specific regulation of IRF4 and its role in lung cancer via a lung cancer risk-associated pleiotropic variant." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7327. http://dx.doi.org/10.1158/1538-7445.am2024-7327.
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Abstract Although smoking is a main risk factor for lung cancer, genetic factors also contribute to the risk, as shown by over 50 genomic loci identified by genome-wide association studies (GWAS). A recent cross-ancestry lung cancer GWAS identified a common germline variant, rs12203592 (C/T), in chr6p25.3 as a new signal, and quantitative trait loci (eQTL) colocalization analysis using lung and blood tissues (GTEx v8) identified IRF4 as a likely target of rs12203592. rs12203592 has previously been linked with diverse traits, including pigmentation phenotypes, smoking cessation, lymphoblastic leukemia, melanoma, and other skin cancers. rs12203592 also appears to have varied allelic effects in different cell types. Namely, the lung cancer risk-associated T allele is correlated with higher IRF4 expression in lung tissue and blood cells (GTEx v8) but lower expression in primary melanocytes (n = 106; Zhang et al). Since previous studies established the melanocyte-specific allelic function of this SNP through lineage-specific transcription factors (TFs), we hypothesized that cell-type-specific TFs mediate the observed allelic effect in different tissue/cell types and further contribute to the unique role of IRF4 in lung tumorigenesis. To identify these potential cell-type-specific regulators, we performed mass spectrometry using the nuclear extracts from three cell lines representing lung, blood, and melanocyte lineage. The results nominated the NF-kB and ZEB protein families as the most prominent T-specific binders in the A549 lung cancer cell line, which was validated by electromobility shift assays. Consistent with these findings, tissue-based SNP-gene interaction analysis demonstrated that the mRNA levels of NF-kB and ZEB family members (4 of 7 genes) were correlated with IRF4 expression with a significant interaction with rs12203592 in GTEx lung tissue (P < 0.017), where the correlation is mainly observed with the T allele. Notably, the SNP interaction was less pronounced in whole blood or melanocytes, and the correlation of these TFs and IRF4 expression was mainly observed with the C allele in melanocytes. To begin to establish the roles of these TFs and IRF4 in lung tumorigenesis and given that IRF4 was shown to promote endogenous DNA damage and proliferation of lung-lineage cell lines, we will investigate the roles of NF-kB and ZEB in IRF4 regulation in these contexts using knockdown and overexpression of these TFs. To further investigate lung cancer-specific IRF4 function, we will identify potential targets of IRF4 among lung cancer-associated functional variants established through our previous studies. This data will help elucidate the context-specific roles of IRF4 in lung cancer development and provide clues to gene regulation in a pleiotropic GWAS locus. Citation Format: Alexander Kane, Jinhu Yin, Erping Long, James Feng, Cathrin Gräwe, Harsh Patel, Jinyoung Byun, Christopher Amos, Kevin Brown, Jun Xia, Michiel Vermeulen, Jiyeon Choi. Investigating the cell-type specific regulation of IRF4 and its role in lung cancer via a lung cancer risk-associated pleiotropic variant [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 7327.
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Lotocki, George, Ofelia F. Alonso, Beata Frydel, W. Dalton Dietrich, and Robert W. Keane. "Monoubiquitination and Cellular Distribution of XIAP in Neurons after Traumatic Brain Injury." Journal of Cerebral Blood Flow & Metabolism 23, no. 10 (October 2003): 1129–36. http://dx.doi.org/10.1097/01.wcb.0000086938.68719.e0.
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XIAP is a member of the inhibitor of apoptosis (IAP) gene family that, in addition to suppressing cell death by inhibition and polyubiquitination of caspases, is involved in an increasing number of signaling cascades. Moreover, the function and regulation of XIAP in the central nervous system (CNS) is poorly understood. In this study, the authors investigated the cell-type expression, the subcellular distribution, ubiquitination of XIAP, and levels of Smac/DIABLO in the normal adult rat brain and in brains subjected to moderate traumatic brain injury (TBI). In the normal brain, XIAP was predominantly expressed in the perinuclear region of neurons. Traumatized brains showed dramatic alterations in cellular and regional expression of XIAP early after injury. Stereologic analyses of the number of XIAP-positive cells within the hippocampus of both hemispheres showed a biphasic response. Immunoprecipitation and immunoblots of extracts derived from different brain regions demonstrated that a single ubiquitin modifies XIAP. Normal cortex contained significantly higher levels of monoubiquitinated XIAP than hippocampus. TBI induced alterations in levels of monoubiquitinated XIAP that correlated with changes in XIAP distribution and immunoreactivity, suggesting that monoubiquitination of XIAP may be a regulator of XIAP location or activity. Similar levels of Smac/DIABLO were present in lysates of normal and traumatized brains. These data demonstrate for the first time a region-specific regulation of XIAP monoubiquitination in the normal adult rat brain, and after TBI, that may be a key event in the regulation of XIAP function contributing to the pathogenesis following injury.
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FERRARI, David M., and Hans-Dieter SÖLING. "The protein disulphide-isomerase family: unravelling a string of folds." Biochemical Journal 339, no. 1 (March 25, 1999): 1–10. http://dx.doi.org/10.1042/bj3390001.
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The mammalian protein disulphide-isomerase (PDI) family encompasses several highly divergent proteins that are involved in the processing and maturation of secretory proteins in the endoplasmic reticulum. These proteins are characterized by the presence of one or more domains of roughly 95–110 amino acids related to the cytoplasmic protein thioredoxin. All but the PDI-D subfamily are composed entirely of repeats of such domains, with at least one domain containing and one domain lacking a redox-active -Cys-Xaa-Xaa-Cys- tetrapeptide. In addition to their known roles as redox catalysts and isomerases, the last few years have revealed additional functions of the PDI proteins, including peptide binding, cell adhesion and perhaps chaperone activities. Attention is now turning to the non-redox-active domains of the PDIs, which may play an important role in all of the known activities of these proteins. Thus the presence of both redox-active and -inactive domains within these proteins portends a complexity of functions differentially accommodated by the various family members.
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KIMURA, Taiji, Ai NISHIDA, Nobutoshi OHARA, Daisuke YAMAGISHI, Tomohisa HORIBE, and Masakazu KIKUCHI. "Functional analysis of the CXXC motif using phage antibodies that cross-react with protein disulphide-isomerase family proteins." Biochemical Journal 382, no. 1 (August 10, 2004): 169–76. http://dx.doi.org/10.1042/bj20040116.
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Polyclonal antibodies that had been raised against particular PDI (protein disulphide-isomerase) family proteins did not cross-react with other PDI family proteins. To evade immune tolerance to the important self-motif Cys-Xaa-Xaa-Cys, which is present in PDI family proteins, we used the phage display library [established by Griffiths, Williams, Hartley, Tomlinson, Waterhouse, Crosby, Kontermann, Jones, Low, Allison et al. (1994) EMBO J. 13, 3245–3260] to isolate successfully the phage antibodies that can cross-react with human and bovine PDIs, human P5, human PDI-related protein and yeast PDI. By measuring the binding of scFv (single-chain antibody fragment of variable region) to synthetic peptides and to mutants of PDI family proteins in a surface plasmon resonance apparatus, we identified clones that recognized sequences containing the CGHC motif or the CGHCK sequence. By using the isolated phage antibodies, we demonstrated for the first time that a lysine residue following the CXXC motif significantly increases the isomerase activities of PDI family proteins. Moreover, we demonstrated that the affinity of isolated scFvs for mutant PDI family proteins is proportional to the isomerase activities of their active sites.
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Bergmann, Christina, Ludwig Hallenberger, Sara Chenguiti Fakhouri, Benita Merlevede, Amelie Brandt, Clara Dees, Honglin Zhu, et al. "X-linked inhibitor of apoptosis protein (XIAP) inhibition in systemic sclerosis (SSc)." Annals of the Rheumatic Diseases 80, no. 8 (April 26, 2021): 1048–56. http://dx.doi.org/10.1136/annrheumdis-2020-219822.
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ObjectiveX-linked inhibitor of apoptosis protein (XIAP) is a multifunctional protein with important functions in apoptosis, cellular differentiation and cytoskeletal organisation and is emerging as potential target for the treatment of various cancers. The aim of the current study was to investigate the role of XIAP in the pathogenesis of systemic sclerosis (SSc).MethodsThe expression of XIAP in human skin samples of patients with SSc and chronic graft versus host disease (cGvHD) and healthy individuals was analysed by quantitative PCR, immunofluorescence (IF) and western blot. XIAP was inactivated by siRNA-mediated knockdown and pharmacological inhibition. The effects of XIAP inactivation were analysed in cultured fibroblasts and in the fibrosis models bleomycin-induced and topoisomerase-I-(topoI)-induced fibrosis and in Wnt10b-transgenic mice.ResultsThe expression of XIAP, but not of other inhibitor of apoptosis protein family members, was increased in fibroblasts in SSc and sclerodermatous cGvHD. Transforming growth factor beta (TGF-β) induced the expression of XIAP in a SMAD3-dependent manner. Inactivation of XIAP reduced WNT-induced fibroblast activation and collagen release. Inhibition of XIAP also ameliorated fibrosis induced by bleomycin, topoI and overexpression of Wnt10b in well-tolerated doses. The profibrotic effects of XIAP were mediated via WNT/β-catenin signalling. Inactivation of XIAP reduces binding of β-catenin to TCF to in a TLE-dependent manner to block WNT/β-catenin-dependent transcription.ConclusionsOur data characterise XIAP as a novel link between two core pathways of fibrosis. XIAP is overexpressed in SSc and cGvHD in a TGF-β/SMAD3-dependent manner and in turn amplifies the profibrotic effects of WNT/β-catenin signalling on fibroblasts via transducin-like enhancer of split 3. Targeted inactivation of XIAP inhibits the aberrant activation of fibroblasts in murine models of SSc.
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Feng, S. H., and K. E. Stein. "VH gene family expression in mice with the xid defect." Journal of Experimental Medicine 174, no. 1 (July 1, 1991): 45–51. http://dx.doi.org/10.1084/jem.174.1.45.
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Preferential use of particular VH gene families in the response to specific antigens has been demonstrated in several systems. The lack of responses to certain types of antigens, therefore, could be the result of deletion of or failure to express some VH genes. Because CBA/N mice, which carry the X-linked immunodeficiency (xid) gene defect, have been shown to be unresponsive to thymus-independent polysaccharide antigens, it was of interest to examine if this unresponsiveness could be accounted for by abnormal expression of particular VH gene families. Using in situ hybridization on B cell colonies, we determined the expression of nine VH gene families in CBA/CaHN females (genotypically normal), CBA/N males (xid) and females (xid), and (CBA/N x CBA/CaHN)F1 males (xid) and females (phenotypically normal). Our results indicate that VH gene family expression, including the S107 family, in CBA/N males and F1 males, is similar to that of CBA/CaHN and F1 females with predominant expression of J558, the largest gene family, in all individuals. Interestingly, CBA/N female mice, which carry two defective X chromosomes, as a group expressed significantly reduced levels of the J558 gene family, and as individuals showed variation in which family was predominantly expressed. We conclude that the unresponsiveness of mice with the xid defect to polysaccharide antigens can not attributed to a failure to express the nine VH gene families that we examined. Our findings do not support previous studies (Primi, D., and P.-A. Cazenave 1986. J. Exp. Med. 165:357), which found an absence of expression of the S107 family in xid mice.
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Cheung, Donald W. "El bastón Niulang: una vara de pastor como arma." Revista de Artes Marciales Asiáticas 2, no. 4 (July 18, 2012): 74. http://dx.doi.org/10.18002/rama.v2i4.334.
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<p class="MsoNormal" style="text-align: justify; margin: 0cm 0cm 6pt;"><span style="mso-ansi-language: EN-US;" lang="EN-US"><span style="font-size: small;"><span style="font-family: Calibri;">Yu Qi created the Niulang staff system about 300 years ago. He taught Xiao Side and the art was passed down within the Xiao family to the current grandmaster, Xiao Mingkui. The staff is about 1-meter long and incorporates techniques from both long and short weapons. The concept of yin and yang is central to Niulang staff practice, requiring a proper balance between defense and attack as well as softness and power. The staff always moves in a spiral motion and short explosive power is generated from the waist/kua of the body. Yi (intent) and shen (spirit) are central elements guiding the external movements. The Niulang staff art is designated in China as a major traditional wushu discipline for preservation and research.</span></span></span></p>
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Sanna, M. Germana, Jean da Silva Correia, Odile Ducrey, Jongdae Lee, Ken Nomoto, Nicolas Schrantz, Quinn L. Deveraux, and Richard J. Ulevitch. "IAP Suppression of Apoptosis Involves Distinct Mechanisms: the TAK1/JNK1 Signaling Cascade and Caspase Inhibition." Molecular and Cellular Biology 22, no. 6 (March 15, 2002): 1754–66. http://dx.doi.org/10.1128/mcb.22.6.1754-1766.2002.
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ABSTRACT The antiapoptotic properties of the inhibitor of apoptosis (IAP) family of proteins have been linked to caspase inhibition. We have previously described an alternative mechanism of XIAP inhibition of apoptosis that depends on the selective activation of JNK1. Here we report that two other members of the IAP family, NAIP and ML-IAP, both activate JNK1. Expression of catalytically inactive JNK1 blocks NAIP and ML-IAP protection against ICE- and TNF-α-induced apoptosis, indicating that JNK1 activation is necessary for the antiapoptotic effect of these proteins. The MAP3 kinase, TAK1, appears to be an essential component of this antiapoptotic pathway since IAP-mediated activation of JNK1, as well as protection against TNF-α- and ICE-induced apoptosis, is inhibited when catalytically inactive TAK1 is expressed. In addition, XIAP, NAIP, and JNK1 bind to TAK1. Importantly, expression of catalytically inactive TAK1 did not affect XIAP inhibition of caspase activity. These data suggest that XIAP's antiapoptotic activity is achieved by two separate mechanisms: one requiring TAK1-dependent JNK1 activation and the second involving caspase inhibition.