Journal articles on the topic 'Ying,Han'

Han Ying-Shan is the managing director of Han Consultants. He specializes in providing Chinese business and marketing information in English. He has published several English-language directories, and also offers market studies, direct marketing and database services, translation, literature design and printing.

This study explores the question of how ethnic groups were assimilated by the Imperial State to be placed under the administration of the central government and how their ethnicity changed during this process of nationalization. This paper studies the case of the Yi ethnic group in Bailu Ying of Mianning county, Sichuan Province in China. The ancestors of Yi people in Bailu Ying lived on Mount Daliang before the Wanli reign of the Ming Dynasty. In the early period of the Ming Dynasty, the government had set up Ningfan Garrison on the river valley on the west side of Mount Daliang. By the late Wanli Period, the garrison was consistently being attacked by the indigenous people in the area. In order to quell the resistance, the Imperial Court recruited Yi people as soldiers to guard the garrison. Afterwards, a new settlement of the Yi tribe in the Bailu Ying River valley emerged, and in the process the Yi people’s livelihood was transformed from herding and fishing to agriculture. In the early Qing, the Yi people in Bailu Ying were further integrated into the Imperial system with the inclusion of chieftains in the imperial governing body. However, up until the later years of the Qianlong reign, the Yi maintained relative autonomy in terms of its tribal settlement, power structure and cultural integrity. Later, with the arrival of new Han migrants, the introduction of the Baojia system, and the promotion of Han culture and education, the Yi group in Bailu Ying gradually lost its independence and began to be assimilated into the national identity, leading to the formation of Shuitian (rice field) Yi ethnicity. The case of the Shuitian Yi shows that the survival strategy of tribal minorities from the mountains did not necessarily follow the pattern of ‘avoiding becoming part of empires’, as suggested by James C. Scott, nor were these ethnic people always slow and passive in integrating with empires. On the contrary, the acceptance of the imperial rule was a survival strategy that helped to creating new ethnic groups while also consolidating frontiers for the Ming and Qing Empires.

Abstract Hei Ying 黑嬰 (1915–1992) wrote prolifically about the “southern isles,” where he—a Hakka from Sumatra—was born. Written for a sophisticated urban readership in China that was curious about the exotic and erotic Nanyang, Hei Ying's 1930s fiction foregrounds questions of Chinese ethnicity and nation. Ethnicity interacts with gender against sultry and desultory backgrounds, with improper patriotic or sexual tendencies attracting narrative punishment. Drawing on three pieces of his short fiction from the 1930s, this article argues that Hei Ying's theme of sexual temptation in the tropics rehearses European colonial (or Han majority) views of the impulsive, sultry native, an image that is contrasted with Republican Chinese primness. The bourgeois woman awakening to Chinese ethnonationalism and rejecting sensuality in favor of patriotism makes her an ancestor to the sexless heroines of Chinese revolutionary culture, including some Hei Ying would write later. The sensuality of the tropics thus operates as a foil for passions correctly channeled—toward nation (and eventually also party-state).

The location of the Chu core area during the reign of King Wu (740-690) is a question rendered uncertain by two issues: 1) the date of the move from Danyang to Ying, and 2) the locations of these capitals. In the traditional literature, both were considered to have been situated along the Yangzi, in southwest Hubei. Recent suggestions, on the other hand, place Danyang in either the Dan Valley (southwest Henan) or west-central Hubei (Nanzhang or Yicheng counties); and arguments have been offered that Ying was also in the Yicheng area.In the arguments both for and against these hypotheses, a commonly employed assumption is that Chu military activities under King Wu hold the potential for indicating the area from which the campaigns were launched. The present paper analyzes one of these campaigns, the military encounter at Pusao between Chu and Yun, east of the Han River (Handong), in 701. This episode is noteworthy for the number of states and placenames that occur in the Zuozhuan account of it.The present study suggests that in plotting the states and placenames appearing in this account, geographical sources dating from the sixth century through the early Qing that are frequently cited in defense of the Southern School (Yangzi Valley) view exhibit several deficiencies. Correcting these leads to the conclusion that regardless of whether Danyang or Ying was the capital at the time, in 701 the Chu force could well have set forth from the Nanzhang/Yicheng region.

Film the Karate Kid yang dibintangi oleh Dre Parker dan tuan Han, telah memberikan banyak pelajaran kepada para pemirsanya, secara tidak langsung cerita film ini mengangkat konsep pragmatisme Amerika dan konsep Yin Yang yang ada di negara China. Kedua konsep ini dicoba untuk disatukan meskipun memiliki latar belakang budaya yang berbeda. Dre Parker sebagai pemeran utama dalam film ini telah berhasil memahami dengan baik konsep Yin Yang dalam budaya China, hal ini bisa terlihat dari bagaimana Dre Parker berlatih bersama tuan Han untuk bisa mempelajari Kung Fu sekaligus mempelajari konsep Yin Yang. Konsep Ying Yang yang diajarkan kepada Dre Parker adalah melalui pelatihan mengambil jaket dengan cara berulang-ulang, di sini jelas bahwa tuan Han ingin mengajarkan kepad Dre parker tentang konsep alam semesta yang penuh engan ketengangan, cinta, disiplin, toleransi dan harmoni serta keseimbangan, semua itu dapat dipelajari melalui alam semesta. Pada tahap selanjutnya konsep pragmatisme the tough minded soul dicoba disatukan oleh tuan Han, dengan mengajak Dre Parker ke gunung Wudang untuk berlatih kung fu. Di sinilah Dre Parker belajar konsep Yin Yang dengan baik, sehingga Dre Parker bisa belajar Kungfu dengan cepat, bisa mengambil keputusan dengan tepat pada saat dia mengalami tekanan dari lawannya. Penelitian ini mempergunakan metode kualitaitf dengan mencoba mengekplorasi konsep pragmatism Amerika dan konsep Yin Yang China. Pada akhirnya bahwa setiap bangsa memiliki konsep dan pandangan hidup mereka sendiri-sendiri yang hrus dihormati dan dihargai oleh bangsa lainnya.

"Huainanzi" is a work edited by the Huainan king Liu An in the early Western Han Dynasty, and it is also called "Huainan Honglie". There are many discourses on the relationship between emotion and artistic aesthetics in the book, which have been related to the nature of artistic generation, creative process, and aesthetic appreciation. They are systematic.“Huainanzi” puts forward some profound and important viewpoints around emotion and art, such as a deep understanding of natural emotions, Fen zhong ying wai" "Zhong you ben zhu" "Jun xing zhe" . Such propositions are elaborated in-depth in the creation and appreciation of literary and artistic aesthetics, so they have a strong aesthetic meaning. Although the original intention of the writers talking about feelings is not aimed at aesthetic appreciation, the aesthetic consciousness they reveal when talking about literature and art has a profound influence on aesthetics that cannot be ignored.

"Huainanzi" is a work edited by the Huainan king Liu An in the early Western Han Dynasty, and it is also called "Huainan Honglie". There are many discourses on the relationship between emotion and artistic aesthetics in the book, which have been related to the nature of artistic generation, creative process, and aesthetic appreciation. They are systematic.“Huainanzi” puts forward some profound and important viewpoints around emotion and art, such as a deep understanding of natural emotions, Fen zhong ying wai" "Zhong you ben zhu" "Jun xing zhe" . Such propositions are elaborated in-depth in the creation and appreciation of literary and artistic aesthetics, so they have a strong aesthetic meaning. Although the original intention of the writers talking about feelings is not aimed at aesthetic appreciation, the aesthetic consciousness they reveal when talking about literature and art has a profound influence on aesthetics that cannot be ignored.

Abstract The article centers on the celebration of Wenzhou Prefect He Wenyuan (1385–1457)’s moral integrity in a building called the “Lodge of Spurned Gold.” Building on historian Ying Zhang’s conception of late-Ming Confucian image politics, in which gentrymen and officials faced an “authenticity crisis,” the article introduces a new concept, the “authenticity dilemma.” A person faces an authenticity dilemma when his or her virtue is questioned precisely because it has been celebrated. The article shows that He rejected an illegal gift intended as a bribe, in a way that may have gone against social norms. The monument to his act accorded with orthodox encouragement of honesty in others, being based on celebrations of Han and Tang exemplars. Despite having clashed with bureaucratic colleagues and emperors, He won state recognition for his excellent service to the people of Wenzhou prefecture and until he was promoted to high office at court there was no question about his honesty. Yet his biographer worked hard to argue that He deserved the honors he won in Wenzhou, because changes in personnel policies and factional fighting meant that He was impeached at court for having “stolen a reputation,” based on the building of the Lodge. On the model of the Lodge, a number of other officials, beginning with envoys sent overseas, were honored for their honesty with “Spurned-Gold Pavilions” (que jin ting 卻金亭). Their multiplication and painter Wen Zhengming’s involvement further undermined He’s reputation, sharpening the authenticity dilemma. As a result, earlier stories of He’s life were reshaped to insist on his deep honesty, at the expense of historical details of the incident.

Abstract Chimeric antigen receptor (CAR)-engineered cell therapy, which leverages genetically modified immune cells to generate a tailored immune response, has revolutionized cancer treatment (Dougan et al., 2021; Hong et al., 2020). The number, type and indications of clinical trials for CAR-engineered cell therapies have increased rapidly in recent years (MacKay et al., 2020). However, serious and potentially life-threaten toxicities, such as on-target, off-tumor effects, remain a major limitation of CAR-engineered cell therapies (Dougan et al., 2021; MacKay et al., 2020). To better understand the effects of CAR-directed immunotherapy, a systematic single-cell-level dissection of the expression of divergent CAR targets in various cell types across different normal tissues is urgently required. We analyzed the expression of 591 CAR targets, including 71 that were employed in clinical trials up to January 2021 and 520 that were predicted to have favorable safety profiles (MacKay et al., 2020), in two independent single-cell cohorts, including 342,755 adult cell scRNA-seq data from human cell landscape (HCL) based on Microwell-seq (Han et al., 2020), and 84,363 adult cell scRNA-seq data from adult human cell atlas (AHCA) based on 10× Genomics (He et al., 2020). We used a stringent cutoff by defining a CAR target as a potentially risky gene (PRG) if it was measurable in more than 100 non-immune cells and more than 2% of the total cells in at least three normal tissues. We identified 92 and 88 PRGs from HCL and AHCA by employing this criterion, with 57 PRGs shared in both HCL and AHCA datasets (hypergeometric test p = 7.17×10-29), suggesting the robustness of our analysis. To aid the research community in the design of CAR targets, we developed a user-friendly data portal, CAR target gene toxicity at single-cell level (CARTSC) (https://hanlab.tamhsc.edu/CARTSC/), to allow for browsing and searching the single target and logical ‘and’ design switch expressions at the single-cell level. Citation Format: Ying Jing, Yuan Liu, Qiang Li, Leng Han. Expression of chimeric antigen receptor therapy targets in subpopulations detected by single-cell sequencing of normal cells may contribute to off-tumor toxicity [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 4082.

Abstract Bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs) are among the most promising and fastest growing classes of next-generation antibody therapeutics for cancer therapy. The strategy of targeting dual tumor-associated antigens (TAAs) with a BsAb offers several advantages, such as improved efficacy due to synergistic effects, increased target cross-linking and internalization, increased tumor cell specificity and reduced side effects in normal tissues. HER2 is an established therapeutic target for approximately 20% of breast cancers, and its overexpression has been observed in a variety of other solid tumors. Trop-2 is another ideal tumor-associated target overexpressed on a wide variety of solid tumors. Co-expression of HER2 and TROP2 has been found in a number of tumors including gastric, colorectal, bladder and breast cancers. Therefore, co-targeting these TAAs using bispecific antibodies has clinical potential. YH012 is a novel first-in-class bispecific antibody-drug conjugate targeting HER2-TROP2 (HER2-TROP2-ADC), which contains a novel fully human bispecific anti-HER2/TROP2 antibody conjugated with Monomethyl auristatin E (MMAE) via a protease-cleavable linker. The anti-HER2/TROP2 BsAb showed increased endocytosis activity compared with its parental mAbs in tumor cells co-expressing HER2/TROP2, whereas the monovalent HER2 or TROP2 antibodies showed reduced internalization. As expected, YH012 showed increased in vitro potency of cell killing compared to the monovalent HER2/TROP2-ADC. These results suggest that YH012 increases the selectivity of payload delivery demonstrating the beneficial effects of targeting dual TAAs using BsAb-ADC. Moreover, YH012 showed robust anti-tumor efficacy in multiple cell line-derived none-small cell lung cancer (NSCLC) and gastric xenografts. Treatment with YH012 showed sustained tumor growth inhibition, which is more pronounced than the effects of the parental mAb-ADCs and monovalent ADCs. These preclinical data suggest that YH012 could potentially benefit patients with tumors co-expressing HER2 and TROP2 through improved drug selectivity and efficacy. Further investigations on the antitumor activity and safety profile of YH012 are ongoing in dogs. Citation Format: Chengzhang Shang, Liu Yang, Jiyong Zhang, Yanfei Han, Zhuolin Li, Zhenyan Han, Jun Li, Ying Meng, Gao An, Hao Yang, Wenqian An, Lei Chen, John Charpentier. YH012, a novel bispecific anti-HER2 and TROP2 antibody-drug conjugate, exhibits potent antitumor efficacy [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 4256.

Abstract Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), which induce DNA damage by inhibiting PARP1 enzymatic activity and trapping PARP on the damaged DNA, are used to eliminate BRCA1/2-mutated (BRCAm) cancer. However, clinical observations suggest that BRCAm tumors develop PARPi resistance. Current strategies to overcome PARPi resistance include impeding multiple DNA repair pathways to induce excessive DNA damage. Here, we propose a novel strategy targeting oncogenic receptor tyrosine kinases to enhance PARP trapping. By developing triple-negative breast cancer (TNBC) cells with acquired talazoparib resistance, we observed a high prevalence of activated fibroblast growth factor receptor 3 (FGFR3) kinase in these cells through kinase antibody array analysis. Mass spectrometry analysis and in vitro kinase assay suggested that FGFR3 phosphorylated PARP1 at tyrosine residues 158 and 176. Biochemistry studies suggested that only PARP1 tyrosine 158 phosphorylation contributes to PARPi resistance in the cells we developed. We then developed a monoclonal antibody against tyrosine 158 phosphorylated PARP1, and found that high-level PARP1 tyrosine 158 phosphorylation positively correlated with PARPi resistance in breast cancer patient-derived xenograft models. We further demonstrated that the combination of FGFR inhibitor and PARPi delayed DNA repair with prolonged PARP trapping. Moreover, synergy between PARPi and FGFR inhibition was observed in multiple TNBC cell lines with PARPi resistance in vitro. The combination of PARPi and FGFR inhibitor also showed synergism in vivo, and treatment with the combination of PARPi and FGFR inhibitor was tolerated in mouse models. These findings reveal that PARP1 tyrosine 158 phosphorylation facilitates resolving of the PARPi-induced PARP-trapping, and that the tyrosine 158 phosphorylated PARP1 may be an effective biomarker to indicate FGFR3 mediated PARPi resistance. Citation Format: MeiKuang Chen, Yuan Gao, Weiya Xia, Yu-Han Wang, Jennifer K. Litton, Yu-Yi Chu, Funda Meric-Bernstam, Helen Piwnica-Worms, Banu Arun, Jordi Rodon Ahnert, Yongkun Wei, Wei-Chao Chang, Hung-Ling Wang, Coya Tapia, Constance T. Albarracin, Shao-Chun Wang, Ying-Nai Wang, Gabriel N. Hortobagyi, Chunru Lin, Liuqing Yang, Dihua Yu, Mien-Chie Hung. FGFR3 mediated PARP1 tyrosine 158 phosphorylation promotes PARP inhibitor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1792.

The following is the abstract of the article discussed in the subsequent letter: Portman, Michael A., Yun Xiao, Ying Song, and Xue-Han Ning. Expression of adenine nucleotide translocator parallels maturation of respiratory control in heart in vivo. Am. J. Physiol. 273 ( Heart Circ. Physiol. 42): H1977–H1983, 1997.—Changes in the relationship between myocardial high-energy phosphates and oxygen consumption in vivo occur during development, implying that the mode of respiratory control undergoes maturation. We hypothesized that these maturational changes in sheep heart are paralleled by alterations in the adenine nucleotide translocator (ANT), which are in turn related to changes in the expression of this gene. Increases in myocardial oxygen consumption (MV˙o 2) were induced by epinephrine infusion in newborn (0–32 h, n = 6) and mature sheep (30–32 days, n = 6), and high-energy phosphates were monitored with 31P nuclear magnetic resonance. Western blot analyses for the ANT1 and the β-subunit of F1-adenosinetriphosphatase (ATPase) were performed in these hearts and additional ( n = 9 total per group) as well as in fetal hearts (130–132 days of gestation, n = 5). Northern blot analyses were performed to assess for changes in steady-state RNA transcripts for these two genes. Kinetic analyses for the31P spectra data revealed that the ADP-MV˙o 2 relationship for the newborns conformed to a Michaelis-Menten model but that the mature data did not conform to first- or second-order kinetic control of respiration through ANT. Maturation from fetal to mature was accompanied by a 2.5-fold increase in ANT protein (by Western blot), with no detectable change in β-F1-ATPase. Northern blot data show that steady-state mRNA levels for ANT and β-F1-ATPase increased ∼2.5-fold from fetal to mature. These data indicate that 1) respiratory control pattern in the newborn is consistent with a kinetic type regulation through ANT, 2) maturational decreases in control through ANT are paralleled by specific increases in ANT content, and 3) regulation of these changes in ANT may be related to increases in steady-state transcript levels for its gene.

Abstract STUDY QUESTION Are fructose levels altered in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER Elevated serum fructose levels are associated with PCOS in Chinese Han women with overweight/obesity and hyperinsulinemia, and fructose levels are higher in follicular fluids from PCOS patients than from control subjects. WHAT IS KNOWN ALREADY Both fructose levels and PCOS are closely linked to obesity and insulin resistance. However, the relationship between fructose and PCOS remains largely unknown. STUDY DESIGN, SIZE, DURATION A total of 157 Chinese Han women (67 controls and 90 PCOS patients) were recruited at Shengjing Hospital of China Medical University. To systematically study the relationship between serum fructose levels and PCOS, the study population of control subjects and PCOS patients was divided into overweight/obese and lean subgroups, and hyper-fasting serum insulin (FSI) and normal-FSI subgroups, respectively. PARTICIPANTS/MATERIALS, SETTING, METHODS Fructose levels were measured in serum samples collected from 80 patients with PCOS (32 lean, 48 overweight/obese) and 59 control subjects (27 lean, 32 overweight/obese) and in follicular fluid samples collected from mature follicles (17–22 mm) and matched immature follicles (8–13 mm) from 10 patients with PCOS and 8 control subjects. MAIN RESULTS AND THE ROLE OF CHANCE Serum fructose levels were increased in overweight/obese and hyper-FSI PCOS patients compared with the control subjects. Fructose had an area under the curve (AUC) of 79.7% at a cutoff value of 10.13 pmol/μl, with a sensitivity of 91.7% and a specificity of 59.3% for the prediction of PCOS in overweight/obese patients. In the hyper-FSI group, fructose had an AUC of 72% at a cutoff value of 10.49 pmol/μl, with a sensitivity of 71.1% and a specificity of 64.4% for the prediction of PCOS. There were no differences between fructose, total testosterone, free testosterone or dehydroepiandrosterone sulfate levels with respect to the reliability of predicting PCOS in the overweight/obese or hyper-FSI groups using the method outlined by Hanley and McNeil. Notably, the combination of fructose and total testosterone levels resulted in the highest AUC of 86.0% and high sensitivity (85.4%) and specificity (83.1%) for the prediction of PCOS in overweight/obese patients. The positive predictive value (PPV) and negative predictive value (NPV) were 80.4 and 87.5%, respectively. Similarly, the combination of fructose and total testosterone levels also resulted in a high AUC of 80.2% and moderate sensitivity (73.3%) and high specificity (84.7%) for the prediction of PCOS in hyper-FSI patients. The PPV and NPV were 78.6 and 80.6%, respectively. Furthermore, fructose levels were significantly higher in follicular fluids from PCOS patients than from control subjects, regardless of whether the follicles were mature or immature. LIMITATIONS, REASONS FOR CAUTION It remains unclear whether fructose levels contribute directly to follicular development and the pathogenesis of PCOS or are merely a biomarker of these processes. WIDER IMPLICATIONS OF THE FINDINGS The results of the present study, together with our previous study, show that monosaccharide status may be a novel marker for PCOS, highlighting the importance of further investigation into the role of monosaccharides, especially fructose, in the pathogenesis of PCOS. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Natural Science Foundation of China (No. 81671423 and No. 81402130), the National Key Research and Development Program of China (No. 2018YFC1003100), Liaoning Provincial Key Research and Development Program (No. 2018225090), the Fok Ying Tung Education Foundation (No. 151039), Distinguished Talent Program of Shengjing Hospital (No. ME76) and Distinguished Teacher Program of China Medical University (No. QGZ2018079). No competing interests were declared.

Abstract Metastatic triple negative breast cancer (TNBC) patients have a 5-year survival rate of just 12%. Therefore, there is an urgent need to discover novel molecular mechanisms that contribute to TNBC metastasis such as N6-methyladenosine (m6A) RNA modification. To do this, we conducted a selective CRISPR-cas9 screen of 14 m6A-regulators and identified an m6A reader protein, YTHDC1, as an essential gene for the survival of MDA-MB-231 cells. The Cancer Genome Atlas (TCGA) dataset showed that patients with poorer prognosis had elevated YTHDC1 expression, which supports a tumor-promoting role of YTHDC1. In vitro, genetic depletion of YTHDC1 significantly impaired Transwell migration and invasion of human TNBC (MDA-MB-231 and SUM159) cells. In vivo, YTHDC1 overexpressing TNBC cells engrafted into the mammary fat pad of NSG mice formed greater numbers and larger sizes of lung metastatic nodules compared to control. Conversely, YTHDC1 knockout (KO) cells produced fewer and smaller lung metastatic nodules compared to control. Together, our in vitro and in vivo data demonstrate YTHDC1’s role in promoting TNBC metastasis. To identify high confidence YTHDC1 targets, we conducted three layers of transcriptome-wide sequencing with MDA-MB-231 cells: RNA-seq (profiling differential gene expression and nuclear export), m6A-seq (profiling m6A methylation in mRNA), and RIP-seq (profiling YTHDC1 binding sites in mRNA). Pathway analysis of differentially expressed genes in MDA-MB-231 YTHDC1 KO cells identified pathways related to metastasis and TGF-β signaling, which is consistent with our phenotypic observations. Overlapping the three sequencing datasets identified SMAD3 as a YTHDC1 target mRNA. Mechanistically, YTHDC1 KO impairs the nuclear export of SMAD3 mRNA, resulting in reduced protein levels of this critical effector of TGF-β signaling. YTHDC1 KO significantly reduced Transwell migration and invasion of TGF-β induced TNBC cells and the expression of TGF-β responsive genes such as SNAIL, IL11, FN, and CTGF. Overexpression of SMAD3 was able to rescue the impaired migration and invasion of YTHDC1 KO TNBC cells and restore the expression of TGF-β responsive genes following TGF-β treatment. We also demonstrated that the oncogenic role of YTHDC1 is mediated through its recognition of m6A, as m6A-binding defective mutants of YTHDC1 were unable to rescue impaired Transwell migration and invasion of YTHDC1 KO TNBC cells. In summary, our study reveals that TNBC metastasis is mediated at least in part through YTHDC1’s function in promoting SMAD3 expression to augment the TGF-β signaling cascade. Citation Format: Brandon Tan, Wei Liu, Keren Zhou, Emily Prince, Lu Yang, Yangchan Li, Ying Qing, Li Han, Zhicong Zhao, Rui Su, Chun-Wei Chen, Jianjun Chen. The N6-methyladenosine reader YTHDC1 is essential for TGF-beta-mediated metastasis of triple negative breast cancer [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 2188.

Abstract Background: As the most prevalent internal decorations in mammalian mRNA, N6-methyladenosine (m6A) has been reported to be involved in many physiological and pathological processes, including acute myeloid leukemia (AML). METTL3 and METTL14, the well-recognized m6A methyltransferase complex, contribute to AML. METTL16 is a recently identified m6A methyltransferase that has been reported to deposit m6A in a few targets. While, unlike METTL3/14, the biological functions of METTL16 are largely unknown. Here, we explored the function and mechanism of METTL16 in AML pathogenesis and evaluated its therapeutic potential for AML treatment. Methods: We performed CRISPR-Cas9 screen to evaluate the dependency of METTL16 in AML cells. We created METTL16 knockout (KO) cells and conditional KO mice to evaluate its role in leukemogenesis and normal hematopoiesis. We employed bone marrow transplantation (BMT), xenograft, and AML patient-derived xenograft (PDX) models to determine its role in AML development and progression. To identify the targets of METTL16, we performed m6A-seq and RNA-seq, followed m6A-qPCR, CLIP-qPCR, in vitro methyltransferase assays and RNA stability assays. To examine the effect of METTL16 on branched chain amino acid (BCAA) metabolism, we performed metabolic profiling with 13C, 15N-leucine. Results: CRISPR-Cas9 screen showed METTL16 is one of the most essential genes for the survival of AMLs. The AML cells display more robust dependency on METTL16 than METTL3/14. We found METTL16 is highly expressed in AML patients compared to healthy controls. METTL16 KO significantly inhibited AML cell proliferation, promoted cell apoptosis and myeloid differentiation in vitro, which could be totally reversed by forced expression of wild-type METTL16, but not catalytic-dead mutant. METTL16 depletion dramatically inhibited AML progression and prolonged survival of recipient mice in the BMT, xenograft and PDX models. In addition, METTL16 is highly expressed in LSCs contrast to leukemic bulk cells and METTL16 KO significantly attenuates LSC self-renewal in vitro and in vivo. By contrast, the role of METLL16 is largely spared in normal hematopoietic cells. Via integrated analysis of m6A-seq data and RNA-seq data, we identified two bona fide targets of METTL16, BCAT1 and BCAT2, which encode two critical BCAA transaminases in BCAA biosynthesis pathway. METTL16 promotes the expression of BCAT1 and BCAT2 via an m6A dependent manner. Metabolomics with 13C, 15N-leucine tracing showed that METTL16 KO results in suppressed pools of TCA cycle intermediates, some non-essential amino acids and nucleotides. Conclusion: We uncover a tumor-promoting role of METTL16 in AML and LSC self-renewal via reprogramming BCAA metabolism, in which METTL16 functions as an m6A methyltransferase to regulate expression of BCAT1 and BCAT2. Our data suggest that METTL16 is an attractive target for AML therapy. Citation Format: Li Han, Lei Dong, Keith Leung, Zhicong Zhao, Yangchan Li, Ying Qing, Jianhuang Xue, Chao Shen, Zhenhua Chen, Lei Gao, Kitty Wang, Keren Zhou, Wei Li, Brandon Tan, Zheng Zhang, Xi Qin, Rui Su, Xiaolan Deng, Jianjun Chen. METTL16 drives leukemogenesis and maintains leukemia stem cell self-renewal via reprogramming BCAA metabolism [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 3617.

Abstract Introduction: Albeit that over 170 types of chemical modifications have been identified in RNAs, the biological functions of most of those decorations are still elusive. N7-methylguanosine (m7G), routinely occurring at the 5’ cap of mRNA or within tRNA and rRNA, also exists in internal mRNA. However, the “reader” proteins that recognize internal mRNA m7G and regulate the metabolism and fate of target mRNAs have yet to be identified. Here, we aim to identify the reader(s) of internal mRNA m7G and elucidate the biological function. Methods: To identify internal m7G reader(s), we utilized RNA-pull down, mass spectrometry (MS), RNA immunoprecipitation (RIP)-seq, and m7G-seq. To evaluate the interaction between QKI and G3BP1, we used Co-IP, immunofluorescence (IF) and proximity ligation assay (PLA). To investigate the function of QKI in stress granule (SG), we performed polyA & m7G RNA fluorescence in situ hybridization (FISH), triple quadrupole MS (QQQ-MS), and Ribo-seq. To assess the role of QKI in drug resistance, we carried out both in vitro cell survival assays and in vivo xenograft mouse model. Results: Our QQQ-MS results suggest cytoplasmic mRNA, in contrast to nuclei mRNA, are highly enriched with internal m7G modification. Quaking proteins (QKI), especially QKI7, can selectively recognize the internal mRNA m7G decoration in the cytosol of various cell types. Our high-throughput sequence data revealed over 1000 confident m7G-modified and QKI-binding RNA targets with a conserved motif, “GANGAN (N=A/U/G)”. Those transcripts are functionally enriched in the “pathways in cancer” and “Hippo signaling pathway”. More strikingly, internal m7G reader QKI7 directly interacts with the SG core protein G3BP1 and can shuttle a subset of m7G-modified transcripts into SG mRNA pool under oxidative stress condition. Additionally, we identified 314 confident m7G-modified & QKI7-binding & SG-enriched target genes in U2OS cells. Ribo-seq indicated that QKI7 modulates the translation efficiency of a set of m7G-modified transcripts via sequestering and silencing them in SGs. Moreover, in line with the observation that many chemotherapy drugs could trigger the assembly of SGs, QKI7 increases the sensitivity of cancer cells to drug treatment (e.g., doxorubicin) in vitro and in vivo in a m7G-dependent manner. Consistently, by analyzing the hepatocellular carcinoma (HCC) pharmacogenomic landscape study dataset, we found that HCC cell lines with higher QKI expression levels are more sensitive to a variety of chemotherapy or targeted therapeutic drugs. Conclusion: Our study identifies QKI as the first internal mRNA m7G reader, provides insights into the biological function of internal mRNA m7G modification in remodeling stress granules transcriptome, and highlights the therapeutic potential of targeting the QKI7/m7G axis in overcoming drug resistance. Citation Format: Zhicong Zhao, Lei Dong, Li Han, Yangchan Li, Jianhuang Xue, Keren Zhou, Wei Li, Xiaolan Deng, Ying Qing, Brandon Tan, Zhenhua Chen, Chao Shen, Andrew Small, Kitty Wang, Keith Leung, Zheng Zhang, Xi Qin, Qiang Xia, Rui Su, Jianjun Chen. Recognition of internal mRNA N7-methylguanosine by QKI shuttles transcripts into stress granules and modulates drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5685.

Abstract Background: Somatic oncogenic fusions of NTRK with other genes, such as ETV6, LMNA, TPM3, PAN3, etc. occur in a wide range of adult and pediatric tumors. Clinical application of 1st generation TRK inhibitors, i.e., larotrectinib and entrectinib, for the treatment of NTRK fusion-positive cancer patients has achieved high response rates regardless of tumor types. However, prolonged treatment often leads to acquired drug resistance attributed to various mutations in TRK kinase domains. Here we report the development of a 2nd generation pan-TRK inhibitor, ICP-723, potently inhibits activities of wild-type and some mutant forms of TRK. Results: ICP-723 effectively inhibits kinase activities of TRKA, TRKB, TRKC with IC50 values < 1 nM. In the KINOMEscan, at a concentration of 100 nM, ICP-723 competitively binds to TRKA/B/C with 100% of inhibition rate, indicating high selectivity for pan-TRK. To evaluate the anti-proliferative activity of ICP-723 in TRK-driven tumor cells, KM12 colorectal cancer cell line bearing TPM3-NTRK1 fusion, as well as a panel of 19 Ba/F3 pro-B murine cell lines over-expressing wild-type or mutant forms of NTRK fusions are tested. ICP-723 demonstrates robust in vitro efficacy in all wild-type TRK-driven tumors. It also overcomes solvent front mutations (e.g., TRKA G595R, TRKC G623R/E) often developed following 1st generation TRK inhibitor treatment. Amongst other TRK mutations, ICP-723 exerts reduced activity in gatekeeper mutations (e.g., TRKA F589L, TRKB F633L, TRKC F617L) and some xDFG mutations (e.g., TRKA G667C/S, TRKB G709C); but retains activity in other xDFG mutations (e.g., TRKA G667A, TRKC G696A/C) and unclassified mutations (e.g., TRKA V573M, TRKA A608D, TRKB V689M). In vivo efficacy studies further demonstrate its robust anti-tumor effects in xenograft models. Treatment with 1 mg/kg of ICP-723 results in 89.5% TGI of KM12 tumors, similar to the efficacies of larotrectinib or selitrectinib at 30 mg/kg dose levels. Treatment with 1 or 3 mg/kg of ICP-723 leads to 100% survival of mice bearing Ba/F3 LMNA-NTRK1 G595R tumors, confirms the effectiveness of ICP-723 against solvent front mutant TRKA. The in vivo efficacy of ICP-723 is also well accompanied by pharmacodynamic modulation of TRK phosphorylation, where ICP-723 exposure levels correlate with the inhibition of TRK phosphorylation. The pharmacokinetic parameters of ICP-723 are overall favorable, with high oral bioavailability. Preclinical safety evaluations also exhibit acceptable drug tolerance in SD rats and Beagle dogs. Conclusions: ICP-723 is a novel, 2nd generation pan-TRK inhibitor with broad-spectrum anti-tumor activities against wild-type and various acquired drug-resistant mutations of NTRK gene fusions. ICP-723 is now in phase I clinical trial in China and United States. Citation Format: Ruixia Liang, Chao Zhou, Yingrui Han, Prince Lu, Charles Ying Wang, Zuopeng Wang, Richard Liu, Norman Kong, Jason Bing Zhang, Jasmine Jisong Cui, Davy Xuesong Ouyang. ICP-723 is a potent pan-TRK Inhibitor with robust anti-tumor activities against wild-type and acquired drug-resistant mutations of NTRK fusions [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 6187.

Abstract Background: Real-world evidence (RWE) studies for surveillance patterns following lung cancer (LC) diagnosis can inform optimizing recommendations on surveillance and practice. One major obstacle in RWE studies for LC surveillance is the lack of radiologic imaging indication for surveillance vs. other reasons (e.g., symptoms). To enable RWE studies for surveillance to detect second primary lung cancer among LC survivors, we developed a hybrid modelling approach that integrates structured data from electronic health records (EHRs) with natural language processing (NLP) from radiology reports for abstracting computed tomography (CT) imaging indications in LC survivors. Methods: We manually reviewed and abstracted CT imaging indications, i.e., surveillance vs. others (e.g., symptoms and metastatic disease follow-up) to create a gold standard from 200 randomly selected radiology reports among 1,952 LC patients (i) who were diagnosed in 2000-2017 at Stanford Health Care (SHC) and (ii) survived ≧5 years after the diagnosis. We abstracted medically relevant key-phrases using the part-of-speech grammar and PageRank algorithms. Hierarchical clustering identified context-specific key-phrase clusters as follows: “surveillance”, “stable”, “nodule”, “symptom”, and “metastasis”. The text-based radiology reports were vectorized to generate NLP features using phrase occurrence frequencies. The structured variables from EHRs included: (i) diagnosis of lung diseases or chest symptoms in previous 6 months, (ii) ordering provider-type (oncology vs. others [e.g. emergency and internal medicine]), and (iii) time from previous CT (≧6 months). A hybrid model was then fitted using logistic regression including both structured and NLP features and validated using a 10-fold cross-validation. The model’s performance was compared to those solely based on NLP or structured data. Results: The dataset of 200 radiology reports included 141 LC survivors (49% White, 72% adenocarcinoma). The proposed hybrid model showed high discrimination (AUC: 0.92), outperforming those based solely on NLP (AUC: 0.88) or structured data (AUC: 0.87). The proposed model demonstrated higher sensitivity (SN: 0.73) and specificity (SP: 0.96) versus those solely based on NLP (SN: 0.53; SP: 0.96) or structured data (SN: 0.53; SP: 0.90). The hybrid model showed that the following variables were positively associated with a higher likelihood that the given CT imaging indication is “surveillance”: (i) a longer time interval (≧6 months) from the previous CT (odds ratio [OR]: 4.63; p=0.01) and key-phrases of (ii) “nodule” (OR: 1.55; p=0.004) and (iii) “stable” (OR: 1.37; p=0.03). On the other hand, the following were negatively associated with the likelihood of surveillance: the key-phrases of “symptom” (OR: 0.17; p=0.02) and “metastasis” (OR: 0.26; p=0.02). Conclusion: A hybrid modeling approach combining text-based NLP and structured EHRs has the potential for abstracting CT imaging indications for LC surveillance. Future directions include validation using other EHR systems and extension using larger data. Citation Format: Aparajita Khan, Julie Wu, Eunji Choi, Anna Graber-Naidich, Solomon Henry, Heather A. Wakelee, Allison W. Kurian, Su-Ying Liang, Ann Leung, Curtis Langlotz, Leah M. Backhus, Summer S. Han. A hybrid modelling approach for abstracting CT imaging indications by integrating natural language processing from radiology reports with structured data from electronic health records. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P068.

Background:Limited information is available on the impact of target disease-modifying anti-rheumatic drugs (tDMARD) on patients with rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM).Objectives:The objective was to compare T2DM-related healthcare resource utilization (HCRU) and cost for TNF inhibitors (TNFi)-naive patients pooled from two commercial databases with RA and T2DM receiving abatacept, other non-TNFi, or TNFi.Methods:A retrospective, observational study was conducted with MarketScan and PharMetrics (January 2008-September 2018). The study population included TNFi-naïve adult patients with RA and T2DM newly initiating abatacept, TNFi (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) or other non-TNFi (tocilizumab, anakinra, sarilumab, rituximab, tofacitinib). Date of tDMARD initiation was the index date. Patients had ≥2 RA diagnoses separated by ≥7 days, ≥1 T2DM diagnosis, and had ≥12 months of pre-index continuous enrollment. Follow-up ended at the end of patient insurance enrollment, study period or index treatment. T2DM-related HCRU and costs including inpatient stay, outpatient visits, ER visits, and pharmacy use were measured on a per-patient-per-month (PPPM) basis (2018 USD). Patients treated with abatacept were matched to TNFi and non-TNFi cohorts separately by propensity score adjusted with patients baseline comorbidities, HCRU, and costs.Results:A total of 16,236 patients meeting criteria were identified. Most patients were female (74.3%), and the overall average age of 55.4 years (Table 1). After matching, 850 pairs of abatacept vs non-TNFi patients, and 1,096 pairs of abatacept vs TNFi patients were included in the adjusted results. Patients initiating abatacept had $144 lower adjusted T2DM-related costs as compared to non-TNFi and $79 lower costs than TNFi cohorts (Table 2).Table 1.Patient CharacteristicsAbataceptn=1,134Non-TNFin=1,353TNFin=13,749TotalN=16,236Age, mean years (SD)58.5 (11.3)57.7 (11.2)54.9 (10.6)55.41 (10.7)Gender, female, n (%)936 (82.5)993 (73.4)10,142 (73.8)12,071 (74.3)CCI, mean (SD)2.2 (1.4)2.3 (1.4)1.8 (1.1)1.89 (1.14)DCSI, n (%) Cardiovascular361 (31.8)406 (30.0)2,500 (18.2)3,267 (20.1) Neuropathy294 (25.9)374 (27.6)3,161 (23.0)3,829 (23.6) Nephropathy146 (12.9)193 (14.3)1,151 (8.4)1,490 (9.2) PVD131 (11.6)155 (11.5)874 (6.4)1,160 (7.1) Retinopathy103 (9.1)119 (8.8)922 (6.7)1,144 (7.0) Cerebrovascular74 (6.5)102 (7.5)620 (4.5)796 (4.9) Metabolic9 (0.8)20 (1.5)141 (1.0)170 (1.0)CCI: Charlson comorbidity index; DCSI: diabetes complications severity index; PVD: peripheral vascular disease.Table 2.Adjusted T2DM-related HCRU and Costs after Propensity Score MatchingAbataceptn=850Non-TNFin=850Diff (ABA- Non-TNF)Abataceptn=1,096TNFin=1,096Diff (ABA- TNF)T2DM-related HCRU (per 1000 Patients per Month)Number of Hospitalizations13.920.4-6.5*12.614.9-2.3*Number ofER Visits22.016.15.9*18.416.32.0*Number ofOutpatient Visits311334.8-23.7*299.3286.912.4T2DM-related Costs (PPPM $)Inpatient Costs507535-28413475-62ER Costs271710*2225-3Outpatient Costs190323-13318617016*Pharmacy Costs1071007*97128-31Total Costs831975-144719798-79**P<0.05Conclusion:TNFi-naive RA patients with T2DM newly initiating abatacept had lower adjusted rates of T2DM-related hospitalizations compared to patients who initiated a non-TNFi or a TNFi. Total costs were lower among patients initiating abatacept vs. patients who initiated a non-TNFi or a TNFi. Findings suggest that initial abatacept among TNFi-naïve patients may be able to reduce healthcare utilization arising from T2DM complications and reduce T2DM-related costs in RA patients.Disclosure of Interests:Xue Han Employee of: BMS, Qian Xia Shareholder of: I own shares of Bristol-Myers Squibb Company, Employee of: I am a paid employee of Bristol-Myers Squibb Company, Ying Bao Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Vardhaman PATEL Employee of: Bristol Myers Squibb, Amrina Roy Employee of: Mu-Sigma, Varshini Rajagopalan Employee of: Mu-Sigma, Francis Lobo Shareholder of: Bristol-Myers Squibb (US), Employee of: Bristol-Myers Squibb (US)

Background:Psoriatic arthritis (PsA) is a chronic inflammatory condition in which a delayed diagnosis will have health impacts including physical and psychological aspects. Thus, identification of risk factors and early diagnosis are crucial in clinical practice. In Malaysia, 13.7% of patients with underlying psoriasis develop PsA 1. However, there are limited data on the risk factors in developing PsA in these patients, not just in Malaysia but also in the Southeast Asia region.Objectives:To analyse sex, clinical features, comorbidities in patients with psoriasis and PsA, and the predictive factors of developing PsA in patients with underlying psoriasis.Methods:A retrospective study was carried out involving patients with a physician-verified diagnosis of psoriasis who were attending the dermatology and/or rheumatology clinics at the University of Malaya Medical Centre, Kuala Lumpur between 2015 to 2020. Data were retrieved from electronic medical records. Data collected included sex, age, body mass index (BMI), duration of psoriasis, socio-demographics, comorbidities, body area affected, severity of skin involvement, presence of nail involvement and systemic therapy used in treating psoriasis. Systemic therapy is defined as methotrexate, sulfasalazine and/or acitretin used before diagnosis of PsA. Patients with psoriasis who developed PsA had information collected on tender joint count, swollen joint count and erythrocyte sedimentation rate (ESR) at their initial visit to the rheumatologist. Logistic regression analyses were performed to identify the possible risk factors of developing PsA.Results:A total of 330 psoriasis patients which included 54.5% male and a mean age of 53 (standard deviation, SD 18.85) years were included. Eighty-three (25.0%) patients were diagnosed with PsA. Among patients with PsA, 39.8% were males with a mean age of 54 (SD 15.79) years. Majority of the PsA patients were ethnic Malay (45.8%), followed by 28.9% Chinese and 25.3% Indian. The median duration of developing PsA was at 36 (IQR 3.5 - 114) months after the diagnosis of psoriasis. 12.3% presented with active polyarthritis at the initial diagnosis of PsA. There was a significant difference in the use of systemic therapy in females, in which there was a higher rate of systemic therapy used in female PsA patients prior to developing PsA as compared to females with psoriasis who did not develop PsA (n=24, 48% vs n=16, 16%; p < 0.001). There was no significant association between ethnicity, education level, comorbidities, BMI, body area affected and family history of psoriasis with development of PsA. The predictive factors in developing PsA are females (OR = 3.14, 95% CI 1.77,5.58), presence of nail involvement (OR = 3.72, 95% CI 1.91,7.26) and the use of systemic therapy (OR = 3.04, 95% CI 1.70,5.43), (all p values <0.001).Conclusion:This study highlighted that female sex, presence of nail involvement and use of systemic therapy prior to PsA diagnosis are predictive risk factors in developing PsA among patients with underlying psoriasis. Further prospective studies with larger cohorts are needed to better delineate these risk factors.References:[1]Mohd Affandi A, Khan I, Ngah Saaya N. Epidemiology and Clinical Features of Adult Patients with Psoriasis in Malaysia: 10-Year Review from the Malaysian Psoriasis Registry (2007-2016). Dermatology research and practice. 2018;2018:4371471.Figure 1.Comorbidities among Patients with underlying Psoriasis and Psoriatic Arthritis (n=330)Chi-square test revealed that there was no significant difference between psoriasis and psoriatic arthritis (p > 0.05)Disclosure of Interests:WAI YANG LOO: None declared, FARIZ YAHYA Speakers bureau: speaker for Novartis, Gilead, AbbVie, Janssen, Eli Lilly, Zuellig-Pharma and Pfizer., Consultant of: consultancy work with Novartis, Gilead, AbbVie, Eli Lilly, Zuellig-Pharma and Pfizer., Grant/research support from: research grants from Novartis, Gilead, AbbVie, Boehringer-Ingelheim and Pfizer., WINN HUI HAN: None declared, NIK AIMEE AZIZAH FAHEM: None declared, SHIN SHEN YONG: None declared, Lydia Say Lee Pok: None declared, Zhenli Kwan Speakers bureau: Novartis, Zuellig, YING CHEW TEE: None declared.

Abstract Background MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) with an extended half-life in late development to prevent RSV infection in infants. Neutralizing mAbs, like MK-1654, have great potential for prophylaxis against viral infection. However, well-validated approaches for clinical dose and efficacy predictions are lacking. Methods Summary-level literature data from RSV prevention studies were used in a model-based meta-analysis (MBMA) to describe the relationship between RSV incidence rates and serum neutralizing antibody (SNA) titer. The model was validated using viral challenge experiments in cotton rats and phase 3 RSV-A efficacy results in infants for an anti-RSV F mAb, REGN-2222. A phase 2b human RSV challenge study (HCS) in adults was also conducted with MK-1654. Participants (N=70) received 100, 200, 300, or 900 mg of MK-1564 or placebo and were challenged intranasally with RSV 29 days later. RSV viral load and symptomatic infection were monitored. Data from the HCS were compared to model predictions. The MBMA was used to predict efficacy of MK-1654 in a virtual population of pre- and full- term infants. Results The relationship between SNA titer and RSV incidence rate defined using the viral load data from the cotton rat approximated the relationship identified for infants from the clinical MBMA. The MBMA was quantitatively consistent with the phase 3 efficacy results against RSV A for REGN-2222. In the HCS, RSV nasal viral load measured by RT-qPCR and quantitative culture as well as symptomatic infections were decreased in MK-1654 recipients compared to placebo. Incidence rates of RSV infection in the HCS were also consistent with MBMA predictions. The model-based clinical trial simulations for MK-1654 indicated a high probability of substantial efficacy against RSV-associated medically attended lower respiratory tract infection ( &gt;75% for 5 months) for doses ≥75 mg. Conclusion Our MBMA successfully quantified the relationship between RSV SNA and clinically relevant endpoints, including lower respiratory tract infection in infants. MBMA-based efficacy predictions support continued development of the MK-1654 antibody for the prevention of RSV in infants. Disclosures Brian M. Maas, PharmD, Merck & Co., Inc. (Employee, Shareholder) Jos Lommerse, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Nele Plock, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Radha Railkar, PhD, Merck & Co., Inc. (Employee, Shareholder) S. Y. Amy Cheung, PhD, Certara (Employee, Shareholder) Luzelena Caro, PhD, Merck & Co., Inc. (Employee, Shareholder) Jingxian Chen, PhD, Merck & Co., Inc. (Employee, Shareholder) Wen Liu, MPH, Merck & Co., Inc. (Employee, Shareholder) Ying Zhang, PhD, Merck & Co., Inc. (Employee, Shareholder) Qinlei Huang, MS, Merck & Co., Inc. (Employee, Shareholder) Wei Gao, PhD, Merck & Co., Inc. (Employee, Shareholder) Li Qin, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Jie Meng, MSc, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Han Witjes, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Emilie Schindler, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Benjamin Guiastrennec, PharmD, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Francesco Bellanti, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Daniel Spellman, PhD, Merck & Co., Inc. (Employee, Shareholder) Brad Roadcap, MS, Merck & Co., Inc. (Employee, Shareholder) Amy Espeseth, PhD, Merck & Co., Inc. (Employee, Shareholder) S. Aubrey Stoch, MD, Merck & Co., Inc. (Employee, Shareholder) Eseng Lai, MD, PhD, Merck & Co., Inc. (Employee, Shareholder) Kalpit A. Vora, PhD, Merck & Co., Inc. (Employee, Shareholder) Antonios O. Aliprantis, MD, PhD, Merck & Co., Inc. (Employee, Shareholder) Jeffrey R. Sachs, PhD, Merck & Co., Inc. (Employee, Shareholder)

Background:RA is more responsive to treatment in the early stages of disease, and early treatment may lead to better long-term outcomes.1,2 Data on the effectiveness of specific drugs as first or later lines of therapy will help inform treatment sequencing.Objectives:Data from patients enrolled in the Corrona RA Registry were used to compare the effectiveness of abatacept across lines of therapy overall (primary cohort) and in a subset of patients who were anti-citrullinated protein antibody positive (ACPA+).Methods:Patients with RA who initiated abatacept (January 2006 to October 2020), had 6 months’ follow-up (within 4−9 months of starting abatacept), had baseline (BL) and follow-up CDAI scores available, and had BL CDAI >2.8 were included. Outcomes were compared for first-, second- and third or higher-line therapy: 0, 1 or ≥2 prior biologic DMARDs or Janus kinase inhibitors, respectively. Continuous outcomes included change from BL to 6 months in mean CDAI and patient-reported pain, fatigue, and HAQ. Binary outcomes included rate of achieving minimal clinically important difference (MCID) in CDAI or modified ACR20/50/70 at 6 months. Continuous and binary outcomes were analysed using multiple linear and logistic regression, respectively. The models included line of therapy, age, sex, disease duration, work status, SC nodules, history of hypertension and depression, BL CDAI, BL patient-reported pain and BL fatigue. Additional subgroup analyses were carried out in patients with moderate/high disease activity (CDAI >10) at BL.Results:In total, 2876 patients (2327 with BL CDAI >10; 890 ACPA+) were included; 442, 911, and 1523 patients initiated first-, second- or third/higher-line abatacept, respectively. Compared with patients on second/third/higher-line abatacept therapy, those on first-line abatacept were significantly older, had shorter disease duration, and had lower BL CDAI, pain and fatigue (all p<0.001). In adjusted analyses, patients receiving abatacept as earlier lines of therapy had significantly greater improvement from BL in mean CDAI and in patient-reported fatigue and HAQ (Table 1). There was no significant difference between lines of therapy in change in patient-reported pain. Patients receiving first-line abatacept had significantly higher odds of achieving a MCID in CDAI or modified ACR20/50/70 response (Figure 1). Similar patterns were seen when the sample was limited to patients with moderate/high disease activity or in patients who were ACPA+.Conclusion:There were significant differences in improvement in clinical disease activity and patient-reported outcomes across lines of therapy. Better treatment responses were observed with earlier lines of abatacept therapy in the overall population, in patients who were ACPA+ and in those with moderate/high BL disease activity.References:[1]Harrold LR, et al. Clin Rheumatol 2017;36:1215−1220.[2]Monti S, et al. RMD Open 2015;1(Suppl 1):e000057.Table 1.Adjusted mean change in CDAI and patient-reported outcomes from BL to 6 months after initiation of abatacept by line of therapy (primary cohort)Adjusted outcome, mean change (SE)First-line (n=440)Second-line (n=898)Third/higher-line (n=1515)p valueaCDAI−7.96 (0.33)−7.49 (0.27)−5.74 (0.19)<0.001Patient-reported pain (VAS 0–100)−9.43 (0.69)−7.98 (0.47)−7.70 (0.35)0.074Patient-reported fatigue (VAS 0–100)−7.49 (0.71)−5.87 (0.51)−4.81 (0.36)0.002Patient-reported HAQ−0.16 (0.01)−0.12 (0.01)−0.08 (0.01)<0.001aEstimated by multiple linear regression model adjusted for age, sex, disease duration, work status, SC nodules, history of hypertension and depression, BL CDAI, BL patient-reported pain and BL fatigue (factors that were identified a priori based on clinical experience or that differed significantly by line of therapy); p values reflect ANOVA overall test of differences across lines of therapy.VAS=visual analogue scale.Acknowledgements:Professional medical writing and editorial assistance was provided by Claire Line, PhD, at Caudex and was funded by Bristol Myers Squibb. The poster was a collaborative effort between Corrona and Bristol Myers Squibb, with financial support provided by Bristol Myers Squibb. This study was sponsored by Corrona, LLC. Corrona is supported through contracted subscriptions with multiple pharmaceutical companies.Disclosure of Interests:Leslie Harrold Consultant of: AbbVie, Bristol Myers Squibb, Genentech/Roche, Grant/research support from: Pfizer, Keith Wittstock Employee of: Bristol Myers Squibb, Sheila Kelly Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Sang Hee Park Employee of: Bristol Myers Squibb, Xue Han Employee of: Bristol Myers Squibb, Ying Shan: None declared, Carla Roberts-Toler: None declared, Nicole Middaugh: None declared, Vadim Khaychuk Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb

Abstract Background: With more endocrine therapies- (ET) based treatment (tx) available, genomic markers that could assist in the prediction of tx outcome is critical. The role of ctDNA mutations in ER+/HER2- metastatic breast cancer (MBC) after prior ET is based on retrospective study results. Methods: ER+/HER2- MBC patients (pts) starting ET-based salvage tx were eligible (NCT04212702). Cell-free DNA (cfDNA) was extracted from plasma before tx, and prepared for next-generation sequencing (NGS) analysis. The targeted NGS for ctDNA included regions of the ESR1 ligand-binding domain, PIK3CA hotspot mutations, and TP53 DNA-bonding domain mutations. 96% of the samples were sequenced at an average depths &gt;10000x using the Ion Torrent platform. Progression-free survival (PFS) was defined from the start of the salvage tx to the date of progression. Results: From 2015/08 to 2020/05, a total of 163 pts treated with ET-based tx were prospectively enrolled. The median age was 60 (32-92). 13%, 15%, 48%, and 17% of pts received ET only, ET + CDK4/6 inhibitor, ET + everolimus, and ET + metronomic chemotherapy, respectively. Only 14 patients received fulvestrant as ET. The median level of recovered cfDNA was 38.5 ng (range 4.4-1935) and the level of cfDNA was significantly and inversely correlated with PFS (p = 0.0032). With mutation ctDNA ≥ 0.5% as a threshold for positive calling, 100 (61.3%), 41 (25.1%), and 25 (15.3) pts have at least one ESR1, PIK3CA, and TP53 mutation, respectively and 61 (37.4%) pts had &gt;1 ESR1 mutation genotypes. The median PFS of the cohort (n=163) was 8.3 mos (95% CI 5.7 – 11.1 mos). PIK3CA mutation (MT) in ctDNA was associated with a worse outcome in all patients (HR 1.91, 95% CI 1.20 to 3.04, p = 0.0064) and the subgroups of ET + everolimus (HR 2.20, 95% CI 1.10 – 4.39, p = 0.025) and ET + metronomic chemotherapy (HR 5.34, 95% CI 1.63- 17.54, p = 0.006). The presence of TP53 MT ctDNA was also associated with worse PFS (HR 1.81, p = 0.043, n = 163) but also exerted a poor prognostic impact in pts with wild type (WT) PIK3CA (HR 3.28, 95% CI 1.44 – 7.48, p = 0.0048). However, the variant allelic frequency (VAF) of PIK3CA MT (p = 0.0421), but not TP53 MT (p = 0.7723), had a inverse linear correlation with PFS. Surprisingly, pts with ESR1 MT had a better PFS as compared to ESR1 WT pts (HR 0.68 95% CI 0.46 – 0.99, p = 0.049). However, if the threshold for. variant calling was raised to 2%, then ESR1 MT (n= 52, 31.9%) vs WT pts had similar PFS (median PFS 8.6 vs 7.8 mos, HR 0.92, 95% CI 0.62-1.37, p = 0.69), suggesting that defining different VAF threshold of MT ESR1 may have divergent PFS impact. How ERS1 MT ctDNA affected PFS was dependent on PIK3CA/TP53 status. When either PIK3CA or TP53 MT ctDNA was present, the ESR1 MT ctDNA did not have any impact on PFS, regardless of VAF. In pts with WT PIK3CA/TP53, pts with ESR1 MT ctDNA VAF 0.5 – 2.0% had a significant better PFS as compared with triple WT pts (HR 1.9, p = 0.0035). Conclusion: Using a 3-gene panel for ctDNA testing with MT ctDNA ≥ 0.5% as a threshold for positive calling in ER+/HER2- MBC pts treated with ET-based tx, the presence of PIK3CA and TP53 mut in ctDNA conferred a worse prognosis. The positive prognostic impact of ESR1 was only noticeable in pts with PIK3CA and TP53 WT ctDNA, and the presence of a low VAF ESR1 MT ctDNA, which may suggest an ER denpendency, was significantly correlated with a better outcome. Table 1.Median PFS of pts with and without PIK3CA, TP53 and ESR in ctDNAPopulation (n)Genotype(s)Median PFS (mos)Hazard Ratiop-valueAll (163)PIK3CA MT (41) vs. WT (122)(VAF ≥ 0.5%)5.4 vs. 10.31.910.0064TP53 MT (25) vs. WT (143)(VAF ≥ 0.5%)4.1 vs. 8.91.810.0439ESR1 MT vs. WT(VAF ≥ 0.5%)9.8 vs. 5.80.680.0493ET + everolimus (82)PIK3CA MT vs. WT(VAF ≥ 0.5%)2.8 vs. 5.92.200.0254PIK3CA and TP53 WT (106)WT vs ESR1 MT (VAF ≥ 0.5% - &lt; 2%)6 vs 15.61.910.0035WT vs ESR1 MT (VAF ≥ 2%)6 vs 121.360.355 Citation Format: Tom Wei-Wu Chen, Wen Hsiao, Ming-Shen Dai, Ching-Hung Lin, Dwang-Ying Chang, I-Chun Chen, Ming-Yang Wang, Ling-Yi Huang, Shu-Han Chang, Shu-Min Huang, Ann-Lii Cheng, Kien Thiam Tan, Yen-Shen Lu. Clinical impact of ESR1 mutation ctDNA on survival outcome is dependent on PI3KCA/TP53 ctDNA mutation status [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-01-09.

OBJECTIVES/SPECIFIC AIMS: Stigma has been recognized as a major impediment to accessing mental health care among Vietnamese and Asian Americans (Leong and Lau, 2001; Sadavoy et al., 2004; Wynaden et al., 2005; Fong and Tsuang, 2007). The underutilization of mental health care, and disparities in both access and outcomes have been attributed to a large extent to stigma and cultural characteristics of this population (Wynaden et al., 2005; Jang et al., 2009; Leung et al., 2010; Spencer et al., 2010; Jimenez et al., 2013; Augsberger et al., 2015). People with neurotic or behavioral disorders may be considered “bad” as many Vietnamese people believe it is a consequence of one’s improper behavior in a previous life, for which the person is now being punished (Nguyen, 2003). Mental disorders can also been seen as a sign of weakness, which contributes to ambivalence and avoidance of help-seeking (Fong and Tsuang, 2007). Equally important is the need to protect family reputation; having emotional problems often implies that the person has “bad blood” or is being punished for the sins of his/her ancestors (Herrick and Brown, 1998; Leong and Lau, 2001), which disgraces the entire family (Wynaden et al., 2005). In these cases, public stigma (as opposed to internal stigma) is the primary reason for delays in seeking help (Leong and Lau, 2001). Other research has also highlighted the influences of culture on how a disorder may be labeled in different settings, although the presentation of symptoms might be identical (see Angel and Thoits, 1987). In Vietnamese culture, mental disorders are often labeled điên (literally translated as “madness”). A điên person and his or her family are often severely disgraced; consequently the individuals and their family become reluctant to disclose and seek help for mental health problems for fear of rejection (Sadavoy et al., 2004). Despite the critical role of stigma in accessing mental health care, there has been little work in trying to understand how stigmatizing attitudes towards mental illness among Vietnamese Americans manifest themselves and the influences of acculturation on these attitudes. Some previous work indicated a significant level of mental illness stigma among Vietnamese Americans, and experiences of living in the United States might interact with the way stigma manifests among this population (Do et al., 2014). Stigma is a complex construct that warrants a deeper and more nuanced understanding (Castro et al., 2005). Much of the development of stigma-related concepts was based on the classic work by Goffman (1963); he defined stigma as a process by which an individual internalizes stigmatizing characteristics and develops fears and anxiety about being treated differently from others. Public stigma (defined by Corrigan, 2004) includes the general public’s negative beliefs about specific groups, in this case individuals and families with mental illness concerns, that contribute to discrimination. Public stigma toward mental illness acts not only as a major barrier to care, but can also exacerbate anxiety, depression, and adherence to treatment (Link et al., 1999; Sirey et al., 2001; Britt et al., 2008; Keyes et al., 2010). Link and Phelan (2001) conceptualized public stigma through four major components. The first component, labeling, occurs when people distinguish and label human differences that are socially relevant, for example, skin color. In the second component, stereotyping, cultural beliefs link the labeled persons to undesirable characteristics either in the mind or the body of such persons, for example people who are mentally ill are violent. The third component is separating “us” (the normal people) from “them” (the mentally ill) by the public. Finally, labeled persons experience status loss and discrimination, where they are devalued, rejected and excluded. Link and Phelan (2001) emphasized that stigmatization also depends on access to social, economic, and political power that allows these components to unfold. This study aims to answer the following research questions: (1) how does public stigma related to mental illness manifest among Vietnamese Americans? and (2) in what ways does acculturation influence stigma among this population? We investigate how the 4 components of stigma according to Link and Phelan (2001) operationalized and how they depend on the level of acculturation to the host society. Vietnamese Americans is the key ethnic minority group for this study for several reasons. Vietnamese immigration, which did not start in large numbers until the 1970s, has features that allow for a natural laboratory for comparisons of degree of acculturation. Previous research has shown significant intergenerational differences in the level of acculturation and mental health outcomes (e.g., Shapiro et al., 1999; Chung et al., 2000; Ying and Han, 2007). In this study, we used age group as a proxy indicator of acculturation, assuming that those who were born and raised in the United States (the 18–35 year olds) would be more Americanized than those who were born in Vietnam but spent a significant part of their younger years in the United States (the 36–55 year olds), and those who were born and grew up in Vietnam (the 56–75 year olds) would be most traditional Vietnamese. The language used in focus group discussions (FGDs) reflected some of the acculturation, where all FGDs with the youngest groups were done in English, and all FGDs with the oldest groups were done in Vietnamese. METHODS/STUDY POPULATION: Data were collected through a set of FGDs and key informant interviews (KIIs) with experts to explore the conceptualization and manifestation of mental illness public stigma among Vietnamese Americans in New Orleans. Six FGDs with a total of 51 participants were conducted. Participants were Vietnamese American men and women ages 18–75. Stratification was used to ensure representation in the following age/immigration pattern categories: (1) individuals age 56–75 who were born and grew up in Vietnam and immigrated to the United States after age 35; (2) individuals age 36–55 who were born in Vietnam but spent a significant part of their youth in the United States; and (3) individuals age 18–35 who were born and grew up in the United States. These groups likely represent different levels of acculturation, assuming that people who migrate at a younger age are more likely to assimilate to the host society than those who do at a later age. Separate FGDs were conducted with men and women. Eleven KIIS were conducted with 6 service providers and 5 community and religious leaders. In this analysis, we focused on mental illness public stigma from the FGD participants’ perspectives. FGDs were conducted in either English or Vietnamese, whichever participants felt more comfortable with, using semistructured interview guides. All interviews were audio recorded, transcribed and translated into English if conducted in Vietnamese. Data coding and analysis was done using NVivo version 11 (QSR International, 2015). The analysis process utilized a Consensual Qualitative Research (CQR) approach, a validated and well-established approach to collecting and analyzing qualitative data. CQR involves gathering textual data through semistructured interviews or focus groups, utilizing a data analysis process that fosters multiple perspectives, a consensus process to arrive at judgments about the meaning of data, an auditor to check the work of the research team, and the development of domains, core-ideas, and cross-analysis (Hill et al., 2005). The study was reviewed and approved by Tulane University’s Internal Review Board. RESULTS/ANTICIPATED RESULTS: Components of public stigma related to mental illness. The 4 components of public stigma manifest to different extents within the Vietnamese Americans in New Orleans. Labeling was among the strongest stigma components, while the evidence of the other components was mixed. Across groups of participants, Vietnamese Americans agreed that it was a common belief that people with mental disorders were “crazy,” “acting crazy,” or “madness.” “Not normal,” “sad,” and “depressed” were among other words used to describe the mentally ill. However, there were clear differences between younger and older Vietnamese on how they viewed these conditions. The youngest groups of participants tended to recognize the “craziness” and “madness” as a health condition that one would need to seek help for, whereas the oldest groups often stated that these conditions were short term and likely caused by family or economic problems, such as a divorce, or a bankruptcy. The middle-aged groups were somewhere in between. The evidence supporting the second component, stereotyping, was not strong among Vietnamese Americans. Most FGD participants agreed that although those with mental disorders may act differently, they were not distinguishable. In a few extreme cases, mentally ill individuals were described as petty thefts or being violent towards their family members. Similarly to the lack of strong evidence of stereotyping, there was also no evidence of the public separating the mentally ill (“them”) from “us”. It was nearly uniformly reported that they felt sympathetic to those with mental disorders and their family, and that they all recognized that they needed help, although the type of help was perceived differently across groups. The older participants often saw that emotional and financial support was needed to help individuals and families to pass through a temporary phase, whereas younger participants often reported that professional help was necessary. The last component, status loss and discrimination, had mixed evidence. While nearly no participants reported any explicit discriminatory behaviors observed and practiced towards individuals with mental disorders and their families, words like “discrimination” and “stigma” were used in all FGDs to describe direct social consequences of having a mental disorder. Social exclusion was common. Our older participants said: “They see less of you, when they see a flaw in you they don’t talk to you or care about you. That’s one thing the Vietnamese people are bad at, spreading false rumors and discrimination” (Older women FGD). One’s loss of status seemed certain if their or their loved one’s mental health status was disclosed. Shame, embarrassment, and being “frowned upon” were direct consequences of one’s mental health status disclosure and subsequently gossiped about. Anyone with mental disorders was certain to experience this, and virtually everyone in the community would reportedly do this to such a family. “You get frowned upon. In the Vietnamese culture, that’s [a family identified as one with mental health problems] the big no-no right there. When everybody frowns upon your family and your family name, that’s when it becomes a problem” (Young men FGD). This is tied directly to what our participants described as Vietnamese culture, where pride and family reputation were such a high priority that those with mental disorders needed to go to a great extent to protect—“We all know what saving face means” as reported by our young participants. Even among young participants, despite their awareness of mental illness and the need for professional help, the desire to avoid embarrassment and save face was so strong that one would think twice about seeking help. “No, you just don’t want to get embarrassed. I don’t want to go to the damn doctor and be like ‘Oh yeah, my brother got an issue. You can help him?’ Why would I do that? That’s embarrassing to myself…” (Young men FGD). Our middle-aged participants also reported: “If I go to that clinic [mental health or counseling clinic], I am hoping and praying that I won’t bump into somebody that I know from the community” (Middle-aged women FGD). Vietnamese people were also described as being very competitive among themselves, which led to the fact that if a family was known for having any problem, gossips would start and spread quickly wherever they go, and pretty soon, the family would be looked down by the entire community. “I think for Vietnamese people, they don’t help those that are in need. They know of your situation and laugh about it, see less of you, and distant themselves from you” (Older women FGD). Culture and mental illness stigma, much of the described stigma and discrimination expressed, and consequently the reluctance to seek help, was attributed to the lack of awareness of mental health and of mental health disorders. Many study participants across groups also emphasized a belief that Vietnamese Americans were often known for their perseverance and resilience, overcoming wars and natural disasters on their own. Mental disorders were reportedly seen as conditions that individuals and families needed to overcome on their own, rather than asking for help from outsiders. This aspect of Vietnamese culture is intertwined with the need to protect one’s family’s reputation, being passed on from one generation to the next, reinforcing the beliefs that help for mental disorders should come from within oneself and one’s family only. Consequently persons with mental health problems would be “Keeping it to themselves. Holding it in and believing in the power of their friends” (Middle-aged FGD) instead of seeking help. Another dimension of culture that was apparent from FGDs (as well as KIIs) was the mistrust in Western medicine. Not understanding how counseling or medicines work made one worry about approaching service providers or staying in treatment. The habit of Vietnamese people to only go see a doctor if they are sick with physical symptoms was also a hindrance to acknowledging mental illness and seeking care for it. Challenges, including the lack of vocabulary to express mental illness and symptoms, in the Vietnamese language, exaggerated the problem, even among those who had some understanding of mental disorders. It was said in the young men FGD that: “when you classify depression as an illness, no one wants to be sick,… if you call it an illness, no one wants to have that sort of illness, and it’s not an illness that you can physically see…” (Young men FGD). Another young man summarized so well the influence of culture on mental illness stigma: “Us Southeast Asian, like, from my parents specifically has Vietnam War refugees. I think the reason why they don’t talk about it is because it’s a barrier that they have to overcome themselves, right? As refugees, as people who have been through the war… [omitted]They don’t want to believe that they need help, and so the trauma that they carry when they give birth to us is carried on us as well. But due to the language barrier and also the, like, they say with the whole health care, in Vietnam I know that they don’t really believe in Western and Eurocentric medicine. So, from their understanding of how, like from their experience with colonization or French people, and how medicine works, they don’t believe in it” (Young men FGD). One characteristic of the Vietnamese culture that was also often mentioned by our FGD participants (as well as KIIs) was the lack of sharing and openness between generations, even within a family. Grandparents, parents, and children do not usually share and discuss each other’s problems. Parents and grandparents do not talk about problems because they need to appear strong and good in front of their children; children do not talk about problems because they are supposed to do well in all aspects, particularly in school. The competitiveness of Vietnamese and high expectations of younger generations again come into play here and create a vicious cycle. Young people are expected to do well in school, which put pressure on them and may result in mental health problems, yet, they cannot talk about it with their parents because they are not supposed to feel bad about school, and sharing is not encouraged. The Asian model minority myth and the expectations of parents that their children would do well in school and become doctors and lawyers were cited by many as a cause of mental health problems among young people. “Our parents are refugees, they had nothing and our parents want us to achieve this American Dream…. [omitted] It set expectations and images for us…. It was expected for all the Asians to be in the top 10, and for, like a little quick minute I thought I wasn’t going to make it, I was crying” (Yong men FGD). As a result, the mental health problems get worse. “If you’re feeling bad about something, you don’t feel like you can talk about it with anyone else, especially your family, because it is not something that is encouraged to be talked about anyway, so if you are feeling poorly and you don’t feel like you could talk to anybody, I think that just perpetuates the bad feelings” (Middle-aged women FGD). Acculturation and mental illness stigma Acculturation, the degree of assimilation to the host society, has changed some of the understanding of mental illness and stigmatizing attitudes. Differences across generations expressed in different FGDs indicated differences in perceptions towards mental illness that could be attributed to acculturation. For example, the young generation understood that mental illness was a health problem that was prevalent but less recognized in the Vietnamese community, whereas a prominent theme among the older participants was that mental illness was a temporary condition due to psychological stress, that it was a condition that only Caucasians had. Some of the components of public stigma related to mental illness seemed to vary between generations, for example the youngest participants were less likely to put a label on a person with mental health problems, or to stereotype them, compared to the oldest and middle-aged participants. This was attributed to their education, exposure to the media and information, and to them “being more Americanized.” However, there was no evidence that acculturation played an important role in changing the other components of public stigma, including stereotyping, separating, and status loss and discrimination. For example, the need to protect the family reputation was so important that our young participants shared: “If you damage their image, they will disown you before you damage that image” (Young men FGD). Young people, more likely to recognize mental health problems, were also more likely to share within the family and to seek help, but no more likely than their older counterparts to share outside of the family—“maybe you would go to counseling or go to therapy, but you wouldn’t tell people you’re doing that” (Young women FGD). The youngest participants in our study were facing a dilemma, in which they recognized mental health problems and the need for care, yet were still reluctant to seek care or talk about it publicly because of fears of damaging the family reputation and not living up to the parents’ expectations. Many young participants reported that it actually made it very difficult for them to navigate mental health issues between the 2 cultures, despite the awareness of the resources available. “I think it actually makes it harder. Only because you know to your parents and the culture, and your own people, it’s taboo, and it’s something that you don’t talk about. Just knowing that you have the resources to go seek it… You want advice from your family also, but you can’t connect the appointment to your family because you’re afraid to express that to your parents, you know? So I think that plays a big part, and knowing that you are up and coming, but you don’t want to do something to disappoint your family because they are so traditional” (Young men FGD). Some participants felt more comfortable talking about mental health problems, like depression, if it was their friend who experienced it and confided in them, but they would not necessarily felt open if it was their problem. Subtle cultural differences like this are likely overlooked by Western service providers. One older participant summarized it well “They [the young generation] are more Americanized. They are more open to other things [but] I think that mental health is still a barrier.” DISCUSSION/SIGNIFICANCE OF IMPACT: This study investigated how different components of public stigma related to mental illness manifest among Vietnamese Americans, a major ethnic group in the United States, and how acculturation may influence such stigma. The findings highlighted important components of public stigma, including labeling and status loss, but did not provide strong evidence of the other components within our study population. Strong cultural beliefs underlined the understanding of mental health and mental illness in general, and how people viewed people with mental illness. Several findings have been highlighted in previous studies with Asian immigrants elsewhere; for example, a study from the perspectives of health care providers in Canada found that the unfamiliarity with Western biomedicine and spiritual beliefs and practices of immigrant women interacted with social stigma in preventing immigrants from accessing care (O’Mahony and Donnelly, 2007). Fancher et al. (2010) reported similar findings regarding stigma, traditional beliefs about medicine, and culture among Vietnamese Americans. Acculturation played a role in changing stigmatizing attitudes as evidenced in intergenerational differences. However, being more Americanized did not equate to being more open, having less stigmatizing attitudes, or being more willing to seek care for mental health issues. Consistent with previous studies (Pedersen and Paves, 2014), we still found some level of stigma among young people aged 18–35, although some components were lessened with an increased level of acculturation. There was also a conflict among the younger generation, in which the need for mental health care was recognized but accessing care was no easier for them than for their parent and grandparent generations. The study’s findings are useful to adapt existing instruments to measure stigma to this population. The findings also have important program implications. One, they can be directly translated into basic supports for local primary and behavioral health care providers. Two, they can also be used to guide and inform the development and evaluation of an intervention and an additional study to validate the findings in other immigrant ethnic groups in the United States. Finally, based on results of the study, we can develop a conceptual framework that describes pathways through which social, cultural, and ecological factors can influence stigma and the ways in which stigma acts as a barrier to accessing mental health care among Vietnamese Americans. The guiding framework then can be validated and applied in future programs aimed to improve mental health care utilization among ethnic minorities.

This paper is meant to study the apocalyptic scenario of the at the perspectives of the Great Acceleration. the apocalyptic scenario is not a pure imagination of the literature works. Instead, scientific evidences are in favour of dramatic change in the climatic conditions related to the climax of Man actions. the modelling of the future climate leads to horrible situations including intolerable temperatures, dryness, tornadoes, and noticeable sear level rise evading coastal regions. Going far from these scientific claims, Homo Sapiens Sapiens extended his imagination through the Climate-Fiction (cli-fi) to propose a dramatic end. Climate Fiction is developed into a recording machine containing every kind of fictions that depict environmental condition events and has consequently lost its true significance. Introduction The Great Acceleration may be considered as the Late Anthropocene in which Man actions reached their climax to lead to dramatic climatic changes paving the way for a possible apocalyptic scenario threatening the existence of the humanity. So, the apocalyptic scenario is not a pure imagination of the literature works. Instead, many scientific arguments especially related to climate change are in favour of the apocalypse1. As a matter of fact, the modelling of the future climate leads to horrible situations including intolerable temperatures (In 06/07/2021, Kuwait recorded the highest temperature of 53.2 °C), dryness, tornadoes, and noticeable sear level rise evading coastal regions. These conditions taking place during the Great Acceleration would have direct repercussions on the human species. Considering that the apocalyptic extinction had really caused the disappearance of many stronger species including dinosaurs, Homo Sapiens Sapiens extended his imagination though the Climate-Fiction (cli-fi) to propose a dramatic end due to severe climate conditions intolerable by the humankind. The mass extinction of animal species has occurred several times over the geological ages. Researchers have a poor understanding of the causes and processes of these major crises1. Nonetheless, whatever the cause of extinction, the apocalyptic scenario has always been present in the geological history. For example, dinosaurs extinction either by asteroids impact or climate changes could by no means denies the apocalyptic aspect2.At the same time as them, many animal and plant species became extinct, from marine or flying reptiles to marine plankton. This biological crisis of sixty-five million years ago is not the only one that the biosphere has suffered. It was preceded and followed by other crises which caused the extinction or the rarefaction of animal species. So, it is undeniable that many animal groups have disappeared. It is even on the changes of fauna that the geologists of the last century have based themselves to establish the scale of geological times, scale which is still used. But it is no less certain that the extinction processes, extremely complex, are far from being understood. We must first agree on the meaning of the word "extinction", namely on the apocalyptic aspect of the concept. It is quite understood that, without disappearances, the evolution of species could not have followed its course. Being aware that the apocalyptic extinction had massacred stronger species that had dominated the planet, Homo Sapiens Sapiens has been aware that the possibility of apocalyptic end at the perspective of the Anthropocene (i.e., Great Acceleration) could not be excluded. This conviction is motivated by the progressive defaunation in some regions3and the appearance of alien species in others related to change of mineralogy and geochemistry4 leading to a climate change during the Anthropocene. These scientific claims fed the vast imagination about climate change to set the so-called cli-fi. The concept of the Anthropocene is the new geological era which begins when the Man actions have reached a sufficient power to modify the geological processes and climatic cycles of the planet5. The Anthropocene by no means excludes the possibility of an apocalyptic horizon, namely in the perspectives of the Great Acceleration. On the contrary, two scenarios do indeed seem to dispute the future of the Anthropocene, with a dramatic cross-charge. The stories of the end of the world are as old as it is, as the world is the origin of these stories. However, these stories of the apocalypse have evolved over time and, since the beginning of the 19th century, they have been nourished particularly by science and its advances. These fictions have sometimes tried to pass themselves off as science. This is the current vogue, called collapsology6. This end is more than likely cli-fi driven7and it may cause the extinction of the many species including the Homo Sapiens Sapiens. In this vein, Anthropocene defaunation has become an ultimate reality8. More than one in eight birds, more than one in five mammals, more than one in four coniferous species, one in three amphibians are threatened. The hypothesis of a hierarchy within the living is induced by the error of believing that evolution goes from the simplest to the most sophisticated, from the inevitably stupid inferior to the superior endowed with an intelligence giving prerogative to all powers. Evolution goes in all directions and pursues no goal except the extension of life on Earth. Evolution certainly does not lead from bacteria to humans, preferably male and white. Our species is only a carrier of the DNA that precedes us and that will survive us. Until we show a deep respect for the biosphere particularly, and our planet in general, we will not become much, we will remain a predator among other predators, the fiercest of predators, the almighty craftsman of the Anthropocene. To be in the depths of our humanity, somehow giving back to the biosphere what we have taken from it seems obvious. To stop the sixth extinction of species, we must condemn our anthropocentrism and the anthropization of the territories that goes with it. The other forms of life also need to keep their ecological niches. According to the first, humanity seems at first to withdraw from the limits of the planet and ultimately succumb to them, with a loss of dramatic meaning. According to the second, from collapse to collapse, it is perhaps another humanity, having overcome its demons, that could come. Climate fiction is a literary sub-genre dealing with the theme of climate change, including global warming. The term appears to have been first used in 2008 by blogger and writer Dan Bloom. In October 2013, Angela Evancie, in a review of the novel Odds against Tomorrow, by Nathaniel Rich, wonders if climate change has created a new literary genre. Scientific basis of the apocalyptic scenario in the perspective of the Anthropocene Global warming All temperature indices are in favour of a global warming (Fig.1). According to the different scenarios of the IPCC9, the temperatures of the globe could increase by 2 °C to 5 °C by 2100. But some scientists warn about a possible runaway of the warming which can reach more than 3 °C. Thus, the average temperature on the surface of the globe has already increased by more than 1.1 °C since the pre-industrial era. The rise in average temperatures at the surface of the globe is the first expected and observed consequence of massive greenhouse gas emissions. However, meteorological surveys record positive temperature anomalies which are confirmed from year to year compared to the temperatures recorded since the middle of the 19th century. Climatologists point out that the past 30 years have seen the highest temperatures in the Northern Hemisphere for over 1,400 years. Several climatic centres around the world record, synthesize and follow the evolution of temperatures on Earth. Since the beginning of the 20th century (1906-2005), the average temperature at the surface of the globe has increased by 0.74 °C, but this progression has not been continuous since 1976, the increase has clearly accelerated, reaching 0.19 °C per decade according to model predictions. Despite the decline in solar activity, the period 1997-2006 is marked by an average positive anomaly of 0.53 °C in the northern hemisphere and 0.27 °C in the southern hemisphere, still compared to the normal calculated for 1961-1990. The ten hottest years on record are all after 1997. Worse, 14 of the 15 hottest years are in the 21st century, which has barely started. Thus, 2016 is the hottest year, followed closely by 2015, 2014 and 2010. The temperature of tropical waters increased by 1.2 °C during the 20th century (compared to 0.5 °C on average for the oceans), causing coral reefs to bleach in 1997. In 1998, the period of Fort El Niño, the prolonged warming of the water has destroyed half of the coral reefs of the Indian Ocean. In addition, the temperature in the tropics of the five ocean basins, where cyclones form, increased by 0.5 °C from 1970 to 2004, and powerful cyclones appeared in the North Atlantic in 2005, while they were more numerous in other parts of the world. Recently, mountains of studies focused on the possible scenario of climate change and the potential worldwide repercussions including hell temperatures and apocalyptic extreme events10 , 11, 12. Melting of continental glaciers As a direct result of the global warming, melting of continental glaciers has been recently noticed13. There are approximately 198,000 mountain glaciers in the world; they cover an area of approximately 726,000 km2. If they all melted, the sea level would rise by about 40 cm. Since the late 1960s, global snow cover has declined by around 10 to 15%. Winter cold spells in much of the northern half of the northern hemisphere are two weeks shorter than 100 years ago. Glaciers of mountains have been declining all over the world by an average of 50 m per decade for 150 years. However, they are also subject to strong multi-temporal variations which make forecasts on this point difficult according to some specialists. In the Alps, glaciers have been losing 1 meter per year for 30 years. Polar glaciers like those of Spitsbergen (about a hundred km from the North Pole) have been retreating since 1880, releasing large quantities of water. The Arctic has lost about 10% of its permanent ice cover every ten years since 1980. In this region, average temperatures have increased at twice the rate of elsewhere in the world in recent decades. The melting of the Arctic Sea ice has resulted in a loss of 15% of its surface area and 40% of its thickness since 1979. The record for melting arctic sea ice was set in 2017. All models predict the disappearance of the Arctic Sea ice in summer within a few decades, which will not be without consequences for the climate in Europe. The summer melting of arctic sea ice accelerated far beyond climate model predictions. Added to its direct repercussions of coastal regions flooding, melting of continental ice leads to radical climatic modifications in favour of the apocalyptic scenario. Fig.1 Evolution of temperature anomaly from 1880 to 2020: the apocalyptic scenario Sea level rise As a direct result of the melting of continental glaciers, sea level rise has been worldwide recorded14 ,15. The average level of the oceans has risen by 22 cm since 1880 and 2 cm since the year 2000 because of the melting of the glaciers but also with the thermal expansion of the water. In the 20th century, the sea level rose by around 2 mm per year. From 1990 to 2017, it reached the relatively constant rate of just over 3mm per year. Several sources contributed to sea level increase including thermal expansion of water (42%), melting of continental glaciers (21%), melting Greenland glaciers (15%) and melting Antarctic glaciers (8%). Since 2003, there has always been a rapid rise (around 3.3 mm / year) in sea level, but the contribution of thermal expansion has decreased (0.4 mm / year) while the melting of the polar caps and continental glaciers accelerates. Since most of the world’s population is living on coastal regions, sea level rise represents a real threat for the humanity, not excluding the apocalyptic scenario. Multiplication of extreme phenomena and climatic anomalies On a human scale, an average of 200 million people is affected by natural disasters each year and approximately 70,000 perish from them. Indeed, as evidenced by the annual reviews of disasters and climatic anomalies, we are witnessing significant warning signs. It is worth noting that these observations are dependent on meteorological survey systems that exist only in a limited number of countries with statistics that rarely go back beyond a century or a century and a half. In addition, scientists are struggling to represent the climatic variations of the last two thousand years which could serve as a reference in the projections. Therefore, the exceptional nature of this information must be qualified a little. Indeed, it is still difficult to know the return periods of climatic disasters in each region. But over the last century, the climate system has gone wild. Indeed, everything suggests that the climate is racing. Indeed, extreme events and disasters have become more frequent. For instance, less than 50 significant events were recorded per year over the period 1970-1985, while there have been around 120 events recorded since 1995. Drought has long been one of the most worrying environmental issues. But while African countries have been the main affected so far, the whole world is now facing increasingly frequent and prolonged droughts. Chile, India, Australia, United States, France and even Russia are all regions of the world suffering from the acceleration of the global drought. Droughts are slowly evolving natural hazards that can last from a few months to several decades and affect larger or smaller areas, whether they are small watersheds or areas of hundreds of thousands of square kilometres. In addition to their direct effects on water resources, agriculture and ecosystems, droughts can cause fires or heat waves. They also promote the proliferation of invasive species, creating environments with multiple risks, worsening the consequences on ecosystems and societies, and increasing their vulnerability. Although these are natural phenomena, there is a growing understanding of how humans have amplified the severity and impacts of droughts, both on the environment and on people. We influence meteorological droughts through our action on climate change, and we influence hydrological droughts through our management of water circulation and water processes at the local scale, for example by diverting rivers or modifying land use. During the Anthropocene (the present period when humans exert a dominant influence on climate and environment), droughts are closely linked to human activities, cultures, and responses. From this scientific overview, it may be concluded apocalyptic scenario is not only a literature genre inspired from the pure imagination. Instead, many scientific arguments are in favour of this dramatic destiny of Homo Sapiens Sapiens. Fig.2. Sea level rise from 1880 to 2020: a possible apocalyptic scenario (www.globalchange.gov, 2021) Apocalyptic genre in recent writing As the original landmark of apocalyptic writing, we must place the destruction of the Temple of Jerusalem in 587 BC and the Exile in Babylon. Occasion of a religious and cultural crossing with imprescriptible effects, the Exile brought about a true rebirth, characterized by the maintenance of the essential ethical, even cultural, of a national religion, that of Moses, kept as pure as possible on a foreign land and by the reinterpretation of this fundamental heritage by the archaic return of what was very old, both national traditions and neighbouring cultures. More precisely, it was the place and time for the rehabilitation of cultures and the melting pot for recasting ancient myths. This vast infatuation with Antiquity, remarkable even in the vocabulary used, was not limited to Israel: it even largely reflected a general trend. The long period that preceded throughout the 7th century BC and until 587, like that prior to the edict of Cyrus in 538 BC, was that of restorations and rebirths, of returns to distant sources and cultural crossings. In the biblical literature of this period, one is struck by the almost systematic link between, on the one hand, a very sustained mythical reinvestment even in form and, on the other, the frequent use of biblical archaisms. The example of Shadday, a word firmly rooted in the Semites of the Northwest and epithet of El in the oldest layers of the books of Genesis and Exodus, is most eloquent. This term reappears precisely at the time of the Exile as a designation of the divinity of the Patriarchs and of the God of Israel; Daily, ecological catastrophes now describe the normal state of societies exposed to "risks", in the sense that Ulrich Beck gives to this term: "the risk society is a society of catastrophe. The state of emergency threatens to become a normal state there1”. Now, the "threat" has become clearer, and catastrophic "exceptions" are proliferating as quickly as species are disappearing and climate change is accelerating. The relationship that we have with this worrying reality, to say the least, is twofold: on the one hand, we know very well what is happening to us; on the other hand, we fail to draw the appropriate theoretical and political consequences. This ecological duplicity is at the heart of what has come to be called the “Anthropocene”, a term coined at the dawn of the 21st century by Eugene Stoermer (an environmentalist) and Paul Crutzen (a specialist in the chemistry of the atmosphere) in order to describe an age when humanity would have become a "major geological force" capable of disrupting the climate and changing the terrestrial landscape from top to bottom. If the term “Anthropocene” takes note of human responsibility for climate change, this responsibility is immediately attributed to overpowering: strong as we are, we have “involuntarily” changed the climate for at least two hundred and fifty years. Therefore, let us deliberately change the face of the Earth, if necessary, install a solar shield in space. Recognition and denial fuel the signifying machine of the Anthropocene. And it is precisely what structures eco-apocalyptic cinema that this article aims to study. By "eco-apocalyptic cinema", we first mean a cinematographic sub-genre: eco-apocalyptic and post-eco-apocalyptic films base the possibility (or reality) of the end of the world on environmental grounds and not, for example, on damage caused by the possible collision of planet Earth with a comet. Post-apocalyptic science fiction (sometimes abbreviated as "post-apo" or "post-nuke") is a sub-genre of science fiction that depicts life after a disaster that destroyed civilization: nuclear war, collision with a meteorite, epidemic, economic or energy crisis, pandemic, alien invasion. Conclusion Climate and politics have been linked together since Aristotle. With Montesquieu, Ibn Khaldûn or Watsuji, a certain climatic determinism is attributed to the character of a nation. The break with modernity made the climate an object of scientific knowledge which, in the twentieth century, made it possible to document, despite the controversies, the climatic changes linked to industrialization. Both endanger the survival of human beings and ecosystems. Climate ethics are therefore looking for a new relationship with the biosphere or Gaia. For some, with the absence of political agreements, it is the beginning of inevitable catastrophes. For others, the Anthropocene, which henceforth merges human history with natural history, opens onto technical action. The debate between climate determinism and human freedom is revived. The reference to the biblical Apocalypse was present in the thinking of thinkers like Günther Anders, Karl Jaspers or Hans Jonas: the era of the atomic bomb would mark an entry into the time of the end, a time marked by the unprecedented human possibility of 'total war and annihilation of mankind. The Apocalypse will be very relevant in describing the chaos to come if our societies continue their mad race described as extra-activist, productivist and consumerist. In dialogue with different theologians and philosophers (such as Jacques Ellul), it is possible to unveil some spiritual, ethical, and political resources that the Apocalypse offers for thinking about History and human engagement in the Anthropocene. What can a theology of collapse mean at a time when negative signs and dead ends in the human situation multiply? What then is the place of man and of the cosmos in the Apocalypse according to Saint John? Could the end of history be a collapse? How can we live in the time we have left before the disaster? Answers to such questions remain unknown and no scientist can predict the trajectory of this Great Acceleration taking place at the Late Anthropocene. When science cannot give answers, Man tries to infer his destiny for the legend, religion and the fiction. Climate Fiction is developed into a recording machine containing every kind of fictions that depict environmental condition events and has consequently lost its true significance. Aware of the prospect of ecological collapse additionally as our apparent inability to avert it, we tend to face geology changes of forceful proportions that severely challenge our ability to imagine the implications. Climate fiction ought to be considered an important supplement to climate science, as a result, climate fiction makes visible and conceivable future modes of existence inside worlds not solely deemed seemingly by science, however that area unit scientifically anticipated. 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Chinese Pi Ying and Indonesian Wayang Kulit as known as the crystal of folklore from two different countries. This article is aim to make a comparison between these two traditional folklore.Pi Ying and Wayang Kulit both are made from wood and paper or animal skin. The function of these two folklore is giving a show or performance to audiences based on traditional stories or mythological stories. Compared with Wayang Kulit, Chinese Pi Ying was originated from Han Dynasty, earlier than Wayang Kulit. As traditional arts, coming with improvement of digital technology, Chinese Pi Ying and Wayang Kulit are losing their influence now, these two traditional folklore only can be seen more frequently in theater or rural area. Through this article, Pi Ying and Wayang Kulit will be analyzed, compared and found out the same and different aspects from these two traditional folklore, furthermore, this article will also give certain solutions to solve the problems these two folklore are facing.

Object segmentation is an important task which is widely employed in many computer vision applications such as object detection, tracking, recognition, and retrieval. It can be seen as a two-phase process: object detection and segmentation. Object segmentation becomes more challenging in case there is no prior knowledge about the object in the scene. In such conditions, visual attention analysis via saliency mapping may offer a mean to predict the object location by using visual contrast, local or global, to identify regions that draw strong attention in the image. However, in such situations as clutter background, highly varied object surface, or shadow, regular and salient object segmentation approaches based on a single image feature such as color or brightness have shown to be insufficient for the task. This work proposes a new salient object segmentation method which uses a depth map obtained from the input image for enhancing the accuracy of saliency mapping. 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Introduction Although our postmodern (media) society should provide room for diversity and otherness (Greer and Jewkes), some people are not integrated but rather excluded. Social exclusion can be defined as the discrepancy of the wish of being part of a society and its possibilities to be part of it and contains feelings or experiences of physically or emotionally exclusion from others (Burchardt et al.; Riva and Eck). It is not really known what or who is responsible for social exclusion (Hills et al.), but it is certain that it is not that rare phenomenon — especially in social media. Here, digital engagement characteristics (likes, follows, shares, and comments) are important to build up, renew, and strengthen different forms of relationships. But if users do not receive any feedback, the risk of feeling social excluded increases. In this context, adolescents and young adults as the primary audience are the focus of interest. They seem to be especially vulnerable when it comes to social ostracism within social media and its potential negative psychological effects (Timeo et al.). The variety of social exclusion allows multiple perspectives on the topic. Hereafter we focus on young people with cancer. This life-threatening disease can increase the risk of being excluded. Cancer as a chronic illness and its negative effects on people’s lives, such as potential death, long-term and late effects, private and social burdens (Hilgendorf et al.), show an obvious otherness compared to the healthy peer, which might push ostracism effects and social exclusion of young people within social media to a new level. We actually can see a large number of (included) young cancer patients and survivors using social media for information sharing, exchanging ideas, networking, and addressing their unmet needs of the real world (Chou et al.; Chou and Moskowitz; Ruckenstuhl et al.; Perales et al.). Especially Instagram is becoming more present in social cancer communication (Stage et al.), though it actually increasingly represents cheerful, easy-going content (Hu et al.; Waterloo et al.). Judging by the number of cancer-related hashtags, we can see more and more public cancer bloggers thematise cancer illness on Instagram. But less is known about the actual content posted by cancer bloggers on Instagram. This leads us to the question, to what extent is cancer content found and included or excluded on public Instagram profiles of German speaking cancer bloggers? And is there a difference between biography descriptions with visible cancer references and posted motifs, captions and hashtags? Chronic Illnesses, Identities, and Social Networks Chronic illnesses such as cancer not only affect the body, but also impact on the identity of those affected. It is understood as life-changing with both short-term and long-term effects on the identity-forming process and on the already developed identity (Bury; Charmaz; Leventhal et al.). With their diagnosis, adolescents and young adults face a double challenge: they have to cope with the typical developmental changes of this age group and they have to negotiate these changes against the background of a life-threatening illness (Makros and McCabe; Zebrack and Isaacso). Miller shows three levels of identity for young cancer patients (pre-cancer identity, patient identity, and post-cancer identity), which are used regularly and flexibly by those affected in their interaction with the social network in order to maintain relationships and to minimise communicative misunderstandings. Moreover, the negotiation of the self within the social network and its expectations, especially towards convalescent people, can lead to paradoxical situations and identities of young people with cancer (Jones et al.). Although therapeutic measures are completed and patients may be discharged as cured, physical, cognitive, and emotional challenges with regard to the illness (e.g. fatigue, loss of performance, difficulty concentrating) still have to be overcome. These challenges, despite recovery, cause those affected to feel they still belong to a cancer group which they have actually largely outgrown medically and therapeutically, and also continually remind them of their present difference from the healthy peer group. To minimise these differences, narratives are the means for those affected to negotiate their new illness-related identity with their network (Hyde). These processes can be digitally transformed on blogs or to age-appropriate social network sites (SNS), which enable users to record and communicate experiences and emotions in an uncomplicated, situational manner and with fewer inhibitions (Kim and Gilham). Cancer contents on SNS are called autopathography and can serve as a means of self-expression, whilst at the same time stimulating communication and networking and thus significantly influencing identity and identity development in the chronic disease process (Rettberg; Ressler et al.; Abrol et al.; Stage). The possibility of recording and archiving private moments in a digital environment through photos and texts creates a visual diary. Here, illness recordings are not just motifs, but also part of an identity process by accepting the self as being ill (Nesby and Salamonsen; Tembeck). Instagram-Exclusive Positivity Instagram is the most popular social media network amongst 14-29 year olds in Germany (Beisch et al.). It presents itself as a highly visual structured platform. Furthermore, both posts and stories are dominated by content with innocuous motifs (Hu et al.). Additionally, the visual culture on Instagram is supported by integrated image optimisations such as filters and therefore often associated with high aesthetic standards (Waterloo et al.). This encourages the exchange of idealised self-presenting and self-advertising content (Lee et al.; Lup et al.; Sheldon and Bryant). The positive tone of the shared motifs and captions can also be explained by larger, sometimes anonymous networks on Instagram. The principle of non-reciprocal following of public accounts increasingly creates weak ties, which can additionally encourage the sharing of positively connoted content due to the anonymity (Lin et al.; Waterloo et al.). The posting of negative moods or image motifs to anonymous followers does not seem to be socially standardised, due to the associated intimate thoughts and feelings (Bazarova). In addition, users are aware of the public framework in which they address intimate topics and discourses (Bazarova and Choi). Internal platform standards and technical possibilities thus create a particular posting culture: an environment that is—due to its strong visual-aesthetic structure and anonymous follower-based networks—almost exclusively positive. However, these assumptions and findings are based on a general posting culture, which is usually not focussed on niche topics like cancer. Previous studies show that SNS are used for exchange and networking, especially by young cancer patients (Chou and Moskowitz; Perales et al.). Studies from online SNS disease-related self-help groups show that weak ties in illness situations are considered beneficial when it comes to self-disclosure, seeking help, and support (Wright et al.; Love et al.; Donovan et al.). In addition, Instagram is part of the so-called “vital media” (Stage et al.), which means it is very important for young cancer patients to share cancer-related material. But despite these research findings less is known about the content shared by German-speaking bloggers who have visible cancer references in their Instagram biography. Do they include a serious, even life-threatening illness on a platform that actually stands for positivity, or do they follow the invisible platform regulations in their posted content and statements and exclude it by themselves? The specific objectives of this explorative study were (a) to obtain a descriptive analysis of the manner in which cancer bloggers post content on Instagram, and (b) to determine the extent to which most applied practices exclude the posting of certain negatively connoted motives and emotions associated with cancer. Methodology For the study, 142 German-speaking cancer bloggers (14–39 years of age) with public accounts and visible cancer references in their biography were researched on Instagram. The sample was divided into posts (7,553) and stories (4,117). The content was examined using a standardised content analysis and a code book with relevant categories (motifs, body presences, emotions, captions, emojis; ICR Cronbach’s alpha = 0.85). Measured by the value of the content posted, the story users, at 23 years of age, were comparatively much younger than the post users, at 30 years of age. The sample was predominantly female in both posts (81%) and stories (99%). The most common form of cancer was breast cancer (posts: 28%; stories: 29%), followed by brain tumors (posts: 19%; stories: 16%) and leukaemia (posts: 4%; stories: 19%). Most content was shared by people who were actively involved in treatment – 46% of posts and 54% of stories. Completed treatments were more common in posts (39%) than in stories (19%). At the time of data collection, the Instagram entries were explicitly open to the public, and no registration was required. The content, not the individual, was analysed to minimise the risk for the bloggers and to prevent them from violations of privacy and autonomy by third parties. Furthermore, the entries were assigned unidentifiable numbers to ensure that no tracing is possible (Franzke et al.). Results The sample consists of public cancer blogger accounts who document everyday experiences for their network in images and videos. The following results are shown for posts (P) and stories (S). Motifs and Bodies Looking at the evaluation of the image motifs, the selfie predominates both in posts, with 20.7 per cent, and stories, with 32.8 per cent. Other popular photo motifs are pictures of food (P: 10.2%; S: 11.0%), activities (P: 7.2%; S: 7.7%), landscapes (P: 6.3%; S: 7.1%), and of/with family and friends (P: 12.5%; S: 6.0%). Photos in medical or clinical settings are rare, with one per cent in the posts and three per cent in the stories. Looking at the bodies and faces displayed, a comparatively normal to positive image of the bloggers that were studied can be observed. Most of the people in the posts present themselves with hair (81.3%), wear make-up (53.3%) and smile at the camera (64.1%). A similar trend can also be seen in the stories. Here 63.8 per cent present themselves with hair, 62.7 per cent with make-up and 55.3 per cent with happy facial expressions. In contrast, scars (P: 1.6%; S: 4.4%) or amputations (P: 0.2%; S: 0.1%) are hardly ever shown. Thus, possible therapy-accompanying symptoms, such as alopecia, ports for chemotherapy, or amputations (e.g. mastectomy in the case of breast cancer) are rarely or hardly ever made visible by cancer bloggers. Captions, Hashtags, and Emojis Similar to the motifs, everyday themes dominate in the captions of the images, such as the description of activities (P: 23.2%; S: 18.0%), food (P: 8.2%; S: 9.3%), or beauty/fashion (P: 6.2%; S: 10.2%). However, information on the current health status of the person affected can be found under every tenth photo, both in the stories and in the posts. Hashtags are mainly found amongst the posts with 81.5 per cent. In keeping with the caption, normal themes were also chosen here, divided into the categories of activities (17.7%), beauty/fashion (7.6%), food (5.8%), and family/friends (4.8%). Illness-specific hashtags (e.g. #cancer, #survivor, or #chemo) were chosen in 15.6 per cent. In addition, the cancer bloggers in this study used emojis in 74 per cent of their posts. In the stories, however, only 28.2 per cent of the content was tagged with emojis. The most common category is smileys & people (P: 46.8%; S: 52.8%), followed by symbols (e.g. hearts, ribbons) (P: 21.1%; S: 26.5%), and animals & nature (P: 17.0%; S: 14.2%). Emotions In captions, hashtags and emojis, emotions were divided into positive (e.g. joy, fighting spirit), neutral (e.g. simple narration of the experience), and negative (e.g. fear, anger). It is noticeable that in all three categories predominantly and significantly positive or neutral words and images were used to describe emotional states or experiences. In the case of captions, 40.4 per cent of the posts and 43.9 per cent of the stories could be classified as positive. For the hashtags, the values were 18.7 per cent (P) and 43 per cent (S), and for the emojis 60 per cent (P) and 65.7 per cent (S). In contrast, there were hardly any negative moods (captions P: 5.7%, S: 5.8%; hashtags P: 4.4%, S: 0.7%; emojis P: 8.7%, S: 6.4%). Although the disease status (e.g. active in therapy or completed) had less impact on emotional messages, a significant connection with the applied thematic areas could be observed. Thus, it is apparent that medical and/or therapeutic aspects tend to be described with positive and negative words and hashtags, e.g. the current health status (χ²(3) = 795.44, p =.000, φ = 0.346) or the topics of illness/health via hashtag (χ²(3) = 797.67, p =.000, φ = 0.361). Topics such as food (χ²(3) = 20.49, p =.000, φ = 0.056) or beauty/fashion (χ²(3) = 51.52, p =.000, φ = 0.092) are recognisably more impersonal from an emotional perspective. Discussion A Digital Identity Paradox Drugs, chemotherapy, setbacks, physical impairments, or anxiety are issues that usually accompany cancer patients during treatment and also in remission. Looking at the content posted by German-speaking cancer bloggers on Instagram, illness-related images and words are comparatively rare. The bloggers show their normal, mostly cancer-free world, in which negative and illness-related content does not seem to fit. Although they clearly draw attention to their illness through their biography, this is not or only rarely addressed. Therefore, it can be stated that cancer as a topic is excluded by choice by the bloggers examined. Neither motifs, captions, nor hashtags make the illness visible. This seems paradoxical because the content and biography appear to contradict each other. And yet, the content studied only shows what Jones et al. and Miller have already described: their identity paradox, or multiple identities. The digital acceptance of one's own illness and solidarity with (anonymous) fellow sufferers is clearly given through the disclosure in the biography, but yet a normal and healthy online ego—comparable to the peer group and equal to their own illness identity—is aspired to. It seems as if those affected have to switch their identity back and forth. The awareness that they are already different in real life (in this case, ill) encourages the users examined to show a normal, age-appropriate life—at least online, which is why we speak of an identity paradox 2.0. Based on our data, the obvious otherness of being ill—and in this context the potential higher risk of digital ostracism effects (Greer and Jewkes; Timeo et al.)—can be a reason for self-exclusion of the cancer topic, in order not to be excluded by a healthy peer. The Standard Creates the Content The positive tone that can be found in almost every second post can be explained by the platform standards and practices themselves (Waterloo et al.). Thus, smiling faces in a public environment correspond more to this than sadness, anger, or despair. Although disease-related topics in captions are also provided with negatively connoted language, they do not have a determining influence on the public self-image of the blogger and their life and the illness. The strong visual culture on Instagram does not leave much scope for "other", perhaps more authentic serious content. The fact that published content has the potential to talk about cancer and to make one’s own experience with the disease transparent is proven by blogs (Kim and Gilham). Instagram does not currently seem to be particularly suitable for public profiles to make serious illness narratives about cancer. Conclusion It remains to be noted that public cancer blogs attempt to include a serious topic on Instagram. But with regard to the data, we can see a form of (maybe unconsciously) self-chosen exclusion of illness narratives. The reasons might vary. On the one hand, cancer bloggers want to belong to a healthy peer group, and expressing a visible otherness would exclude them. Therefore, they try to reduce the higher risk potential of ostracism effects. On the other hand, internal Instagram regulations and standards create an environment which can strengthen the bloggers' posting behaviours: young people, especially, post life-affirming and life-related content. This also helps them to cope with crisis situations and to avoid being dominated by a life-threatening disease. Further research on cancer on Instagram is needed to determine to what extent this is desired, and whether an awareness of this paradox exists or develops intuitively. 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Introduction The first “Aquarius Festival” came together in Canberra, at the Australian National University, in the autumn of 1971 and was reprised in 1973 in the small rural town of Nimbin, in northern New South Wales. Both events reflected the Zeitgeist in what was, in some ways, an inchoate expression of the so-called “counterculture” (Roszak). Rather than attempting to analyse the counterculture as a discrete movement with a definable history, I enlist the theory of cultural memes to read the counter culture as a Dawkinsian cluster meme, with this paper offered as “testimonio”, a form of quasi-political memoir that views shifts in the culture through the lens of personal experience (Zimmerman, Yúdice). I track an evolving personal, “internal” topography and map its points of intersection with the radical social, political and cultural changes spawned by the “consciousness revolution” that was an integral part of the counterculture emerging in the 1970s. I focus particularly on the notion of “consciousness raising”, as a Dawkinsian memetic replicator, in the context of the idealistic notions of the much-heralded “New Age” of Aquarius, and propose that this meme has been a persistent feature of the evolution of the “meme cluster” known as the counterculture. Mimesis and the Counterculture Since evolutionary biologist Richard Dawkins floated the notion of cultural memes as a template to account for the evolution of ideas within political cultures, a literature of commentary and criticism has emerged that debates the strengths and weaknesses of his proposed model and its application across a number of fields. I borrow the notion to trace the influence of a set of memes that clustered around the emergence of what writer Marilyn Ferguson called The Aquarian Conspiracy, in her 1980 book of that name. Ferguson’s text, subtitled Personal and Social Transformation in Our Time, was a controversial attempt to account for what was known as the “New Age” movement, with its late millennial focus on social and personal transformation. That focus leads me to approach the counterculture (a term first floated by Theodore Roszak) less as a definable historical movement and more as a cluster of aspirational tropes expressing a range of aspects or concerns, from the overt political activism through to experimental technologies for the transformation of consciousness, and all characterised by a critical interrogation of, and resistance to, conventional social norms (Ferguson’s “personal and social transformation”). With its more overtly “spiritual” focus, I read the “New Age” meme, then, as a sub-set of this “cluster meme”, the counterculture. In my reading, “New Age” and “counterculture” overlap, sharing persistent concerns and a broad enough tent to accommodate the serious—the combative political action of Students for a Democratic Society (SDS), say, (see Elbaum)—to the light-hearted—the sport of frisbee for example (Stancil). The interrogation of conventional social and political norms inherited from previous generations was a prominent strategy across both movements. Rather than offering a sociological analysis or history of the ragbag counterculture, per se, my discussion here focuses in on the particular meme of “consciousness raising” within that broader set of cultural shifts, some of which were sustained in their own right, some dropping away, and many absorbed into the dominant mainstream culture. Dawkins use of the term “meme” was rooted in the Greek mimesis, to emphasise the replication of an idea by imitation, or copying. He likened the way ideas survive and change in human culture to the natural selection of genes in biological evolution. While the transmission of memes does not depend on a physical medium, such as the DNA of biology, they replicate with a greater or lesser degree of success by harnessing human social media in a kind of “infectivity”, it is argued, through “contagious” repetition among human populations. Dawkins proposed that just as biological organisms could be said to act as “hosts” for replicating genes, in the same way people and groups of people act as hosts for replicating memes. Even before Dawkins floated his term, French biologist Jacques Monod wrote that ideas have retained some of the properties of organisms. Like them, they tend to perpetuate their structure and to breed; they too can fuse, recombine, segregate their content; indeed they too can evolve, and in this evolution selection must surely play an important role. (165, emphasis mine) Ideas have power, in Monod’s analysis: “They interact with each other and with other mental forces in the same brain, in neighbouring brains, and thanks to global communication, in far distant, foreign brains” (Monod, cited in Gleick). Emblematic of the counterculture were various “New Age” phenomena such as psychedelic drugs, art and music, with the latter contributing the “Aquarius” meme, whose theme song came from the stage musical (and later, film) Hair, and particularly the lyric that runs: “This is the dawning of the Age of Aquarius”. The Australian Aquarius Festivals of 1971 and 1973 explicitly invoked this meme in the way identified by Monod and the “Aquarius” meme resonated even in Australia. Problematising “Aquarius” As for the astrological accuracy of the “Age of Aquarius meme”, professional astrologers argue about its dating, and the qualities that supposedly characterise it. When I consulted with two prominent workers in this field for the preparation of this article, I was astonished to find their respective dating of the putative Age of Aquarius were centuries apart! What memes were being “hosted” here? According to the lyrics: When the moon is in the seventh house And Jupiter aligns with Mars Then peace will guide the planets And love will steer the stars. (Hair) My astrologer informants assert that the moon is actually in the seventh house twice every year, and that Jupiter aligns with Mars every two years. Yet we are still waiting for the outbreak of peace promised according to these astrological conditions. I am also informed that there’s no “real” astrological underpinning for the aspirations of the song’s lyrics, for an astrological “Age” is not determined by any planet but by constellations rising, they tell me. Most important, contrary to the aspirations embodied in the lyrics, peace was not guiding the planets and love was not about to “steer the stars”. For Mars is not the planet of love, apparently, but of war and conflict and, empowered with the expansiveness of Jupiter, it was the forceful aggression of a militaristic mind-set that actually prevailed as the “New Age” supposedly dawned. For the hippified summer of love had taken a nosedive with the tragic events at the Altamont speedway, near San Francisco in 1969, when biker gangs, enlisted to provide security for a concert performance by The Rolling Stones allegedly provoked violence, marring the event and contributing to a dawning disillusionment (for a useful coverage of the event and its historical context see Dalton). There was a lot of far-fetched poetic licence involved in this dreaming, then, but memes, according to Nikos Salingaros, are “greatly simplified versions of patterns”. “The simpler they are, the faster they can proliferate”, he writes, and the most successful memes “come with a great psychological appeal” (243, 260; emphasis mine). What could be retrieved from this inchoate idealism? Harmony and understanding Sympathy and trust abounding No more falsehoods or derisions Golden living dreams of visions Mystic crystal revelation And the mind’s true liberation Aquarius, Aquarius. (Hair) In what follows I want to focus on this notion: “mind’s true liberation” by tracing the evolution of this project of “liberating” the mind, reflected in my personal journey. Nimbin and Aquarius I had attended the first Aquarius Festival, which came together in Canberra, at the Australian National University, in the autumn of 1971. I travelled there from Perth, overland, in a Ford Transit van, among a raggedy band of tie-dyed hippie actors, styled as The Campus Guerilla Theatre Troupe, re-joining our long-lost sisters and brothers as visionary pioneers of the New Age of Aquarius. Our visions were fueled with a suitcase full of potent Sumatran “buddha sticks” and, contrary to Biblical prophesies, we tended to see—not “through a glass darkly” but—in psychedelic, pop-, and op-art explosions of colour. We could see energy, man! Two years later, I found myself at the next Aquarius event in Nimbin, too, but by that time I inhabited a totally different mind-zone, albeit one characterised by the familiar, intense idealism. In the interim, I had been arrested in 1971 while “tripping out” in Sydney on potent “acid”, or LSD (Lysergic acid diethylamide); had tried out political engagement at the Pram Factory Theatre in Melbourne; had camped out in protest at the flooding of Lake Pedder in the Tasmanian wilderness; met a young guru, started meditating, and joined “the ashram”—part of the movement known as the Divine Light Mission, which originated in India and was carried to the “West” (including Australia) by an enthusiastic and evangelical following of drug-toking drop-outs who had been swarming through India intent on escaping the dominant culture of the military-industrial complex and the horrors of the Vietnam War. Thus, by the time of the 1973 event in Nimbin, while other festival participants were foraging for “gold top” magic mushrooms in farmers’ fields, we devotees had put aside such chemical interventions in conscious awareness to dig latrines (our “service” project for the event) and we invited everyone to join us for “satsang” in the yellow, canvas-covered, geodesic dome, to attend to the message of peace. The liberation meme had shifted through a mutation that involved lifestyle-changing choices that were less about alternative approaches to sustainable agriculture and more about engaging directly with “mind’s true liberation”. Raising Consciousness What comes into focus here is the meme of “consciousness raising”, which became the persistent project within which I lived and worked and had my being for many years. Triggered initially by the ingestion of those psychedelic substances that led to my shocking encounter with the police, the project was carried forward into the more disciplined environs of my guru’s ashrams. However, before my encounter with sustained spiritual practice I had tried to work the shift within the parameters of an ostensibly political framework. “Consciousness raising” was a form of political activism borrowed from the political sphere. Originally generated by Mao Zedong in China during the revolutionary struggle to overthrow the vested colonial interests that were choking Chinese nationalism in the 1940s, to our “distant, foreign brains” (Monod), as Western revolutionary romantics, Chairman Mao and his Little Red Book were taken up, in a kind of international counterculture solidarity with revolutionaries everywhere. It must be admitted, this solidarity was a fairly superficial gesture. Back in China it might be construed as part of a crude totalitarian campaign to inculcate Marxist-Leninist political ideas among the peasant classes (see Compestine for a fictionalised account of traumatic times; Han Suyin’s long-form autobiography—an early example of testimonio as personal and political history—offers an unapologetic account of a struggle not usually construed as sympathetically by Western commentators). But the meme (and the processes) of consciousness raising were picked up by feminists in the United States in the late 1960s and into the 1970s (Brownmiller 21) and it was in this form I encountered it as an actor with the politically engaged theatre troupe, The Australian Performing Group, at Carlton’s Pram Factory Theatre in late 1971. The Performance Group I performed as a core member of the Group in 1971-72. Decisions as to which direction the Group should take were to be made as a collective, and the group veered towards anarchy. Most of the women were getting together outside of the confines of the Pram Factory to raise their consciousness within the Carlton Women’s Liberation Cell Group. While happy that the sexual revolution was reducing women’s sexual inhibitions, some of the men at the Factory were grumbling into their beer, disturbed that intimate details of their private lives—and their sexual performance—might be disclosed and raked over by a bunch of radical feminists. As they began to demand equal rights to orgasm in the bedroom, the women started to seek equal access within the performance group, too. They requested rehearsal time to stage the first production by the Women’s Theatre Group, newly formed under the umbrella of the wider collective. As all of the acknowledged writers in the Group so far were men—some of whom had not kept pace in consciousness raising—scripts tended to be viewed as part of a patriarchal plot, so Betty Can Jump was an improvised piece, with the performance material developed entirely by the cast in workshop-style rehearsals, under the direction of Kerry Dwyer (see Blundell, Zuber-Skerritt 21, plus various contributors at www.pramfactory.com/memoirsfolder/). I was the only male in the collective included in the cast. Several women would have been more comfortable if no mere male were involved at all. My gendered attitudes would scarcely have withstood a critical interrogation but, as my partner was active in launching the Women’s Electoral Lobby, I was given the benefit of the doubt. Director Kerry Dwyer liked my physicalised approach to performance (we were both inspired by the “poor theatre” of Jerzy Grotowski and the earlier surrealistic theories of Antonin Artaud), and I was cast to play all the male parts, whatever they would be. Memorable material came up in improvisation, much of which made it into the performances, but my personal favorite didn’t make the cut. It was a sprawling movement piece where I was “born” out of a symbolic mass of writhing female bodies. It was an arduous process and, after much heaving and huffing, I emerged from the birth canal stammering “SSSS … SSSS … SSMMMO-THER”! The radical reversioning of culturally authorised roles for women has inevitably, if more slowly, led to a re-thinking of the culturally approved and reinforced models of masculinity, too, once widely accepted as entirely biologically ordained rather than culturally constructed. But the possibility of a queer re-versioning of gender would be recognised only slowly. Liberation Meanwhile, Dennis Altman was emerging as an early spokesman for gay, or homosexual, liberation and he was invited to address the collective. Altman’s stirring book, Homosexual: Oppression and Liberation, had recently been published, but none of us had read it. Radical or not, the Group had shown little evidence of sensitivity to gender-queer issues. My own sexuality was very much “oppressed” rather than liberated and I would have been loath to use “queer” to describe myself. The term “homosexual” was fraught with pejorative, quasi-medical associations and, in a collective so divided across strict and sometimes hostile gender boundaries, deviant affiliations got short shrift. Dennis was unsure of his reception before this bunch of apparent “heteros”. Sitting at the rear of the meeting, I admired his courage. It took more self-acceptance than I could muster to confront the Group on this issue at the time. Somewhere in the back of my mind, “homosexuality” was still something I was supposed to “get over”, so I failed to respond to Altman’s implicit invitation to come out and join the party. The others saw me in relationship with a woman and whatever doubts they might have carried about the nature of my sexuality were tactfully suspended. Looking back, I am struck by the number of simultaneous poses I was trying to maintain: as an actor; as a practitioner of an Artaudian “theatre of cruelty”; as a politically committed activist; and as a “hetero”-sexual. My identity was an assemblage of entities posing as “I”; it was as if I were performing a self. Little gay boys are encouraged from an early age to hide their real impulses, not only from others—in the very closest circle, the family; at school; among one’s peers—but from themselves, too. The coercive effects of shaming usually fix the denial into place in our psyches before we have any intellectual (or political) resources to consider other options. Growing up trying to please, I hid my feelings. In my experience, it could be downright dangerous to resist the subtle and gross coercions that applied around gender normativity. The psychoanalyst D. W. Winnicott, of the British object-relations school, argues that when the environment does not support the developing personality and requires the person to sacrifice his or her own spontaneous needs to adapt to environmental demands, there is not even a resting-place for individual experience and the result is a failure in the primary narcissistic state to evolve an individual. The “individual” then develops as an extension of the shell rather than that of the core [...] What there is left of a core is hidden away and is difficult to find even in the most far-reaching analysis. The individual then exists by not being found. The true self is hidden, and what we have to deal with clinically is the complex false self whose function is to keep this true self hidden. (212) How to connect to that hidden core, then? “Mind’s true liberation...” Alienated from the performative version of selfhood, but still inspired by the promise of liberation, even in the “fuzzy” form for which my inchoate hunger yearned (sexual liberation? political liberation? mystical liberation?), I was left to seek out a more authentic basis for selfhood, one that didn’t send me spinning along the roller-coaster of psychedelic drugs, or lie to me with the nostrums of a toxic, most forms of which would deny me, as a sexual, moral and legal pariah, the comforts of those “anchorage points to the social matrix” identified by Soddy (cited in Mol 58). My spiritual inquiry was “counter” to these institutionalised models of religious culture. So, I began to read my way through a myriad of books on comparative religion. And to my surprise, rather than taking up with the religions of antique cultures, instead I encountered a very young guru, initially as presented in a simply drawn poster in the window of Melbourne’s only vegetarian restaurant (Shakahari, in Carlton). “Are you hungry and tired of reading recipe books?” asked the figure in the poster. I had little sense of where that hunger would lead me, but it seemed to promise a fulfilment in ways that the fractious politics of the APG offered little nourishment. So, while many of my peers in the cities chose to pursue direct political action, and others experimented with cooperative living in rural communes, I chose the communal lifestyle of the ashram. In these different forms, then, the conscious raising meme persisted when other challenges raised by the counterculture either faded or were absorbed in the mainstream. I finally came to realise that the intense disillusionment process I had been through (“dis-illusionment” as the stripping away of illusions) was the beginning of awakening, in effect a “spiritual initiation” into a new way of seeing myself and my “place” in the world. Buddhist teachers might encourage this very kind of stripping away of false notions as part of their teaching, so the aspiration towards the “true liberation” of the mind expressed in the Aquarian visioning might be—and in my case, actually has been and continues to be—fulfilled to a very real extent. Gurus and the entire turn towards Eastern mysticism were part of the New Age meme cluster prevailing during the early 1970s, but I was fortunate to connect with an enduring set of empirical practices that haven’t faded with the fashions of the counterculture. A good guitarist would never want to play in public without first tuning her instrument. In a similar way, it is now possible for me to tune my mind back to a deeper, more original source of being than the socially constructed sense of self, which had been so fraught with conflicts for me. I have discovered that before gender, and before sexuality, in fact, pulsing away behind the thicket of everyday associations, there is an original, unconditioned state of beingness, the awareness of which can be reclaimed through focused meditation practices, tested in a wide variety of “real world” settings. For quite a significant period of time I worked as an instructor in the method on behalf of my guru, or mentor, travelling through a dozen or so countries, and it was through this exposure that I was able to observe that the practices worked independently of culture and that “mind’s true liberation” was in many ways a de-programming of cultural indoctrinations (see Marsh, 2014, 2013, 2011 and 2007 for testimony of this process). In Japan, Zen roshi might challenge their students with the koan: “Show me your original face, before you were born!” While that might seem to be an absurd proposal, I am finding that there is a potential, if unexpected, liberation in following through such an inquiry. As “hokey” as the Aquarian meme-set might have been, it was a reflection of the idealistic hope that characterised the cluster of memes that aggregated within the counterculture, a yearning for healthier life choices than those offered by the toxicity of the military-industrial complex, the grossly exploitative effects of rampant Capitalism and a politics of cynicism and domination. The meme of the “true liberation” of the mind, then, promised by the heady lyrics of a 1970s hippie musical, has continued to bear fruit in ways that I could not have imagined. References Altman, Dennis. Homosexual Oppression and Liberation. Sydney: Angus & Robertson, 1972. Blundell, Graeme. The Naked Truth: A Life in Parts. 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