Artykuły w czasopismach na temat „Han ye (Ba, Jin)”

The pattern “NP1, NP2 + shi ye”, as found in the Chinese translations of Buddhist texts in the Han Dynasty, is not a direct imitation of, or derivation from, the pattern “NP1, NP2 (Subj) + shi (Pron) ye” of the pre-Qin era. Rather, it comes from the pattern “NP1, NP2 (Predicate N) + shi (Copula)” of the Western Han, Eastern Han, Wei, Jin, and Northern and Southern Dynasties periods. In the Chinese Buddhist translations of the Han Dynasty, “NP1, NP2 + shi” is a variant of “NP1, NP2 + shi ye”. The copious use of the two grammatical patterns in the Chinese translations is not intended to render the sentence-final copula in the original Sanskrit texts. Rather, when narrating stories that tell “the NP1 in the previous existence is in fact the NP2 in the present existence”, the Buddhist writings place a specific emphasis on the NP2 of the present existence. The Predicate NP appearing before the copula in these two patterns serves precisely that purpose. Hence, the use is most suitable for stories of this nature.

Since the 1930s, Chinese archaeologists have discovered a number of inscribed wooden tablets from the early Han to the Western Jin, which were identified as “greeting tablets” of two types, ci 刺 and ye 謁. As attested in transmitted accounts, these tablets played an important role in the communicative etiquette of early imperial and early medieval officialdom; during a meeting ceremony, they were presented by the guest to the host. The present article offers a systematic survey of the available corpus of excavated greeting tablets and explores their wider socio-cultural implications. As a component of the communicative etiquette of the bureaucracy, greeting tablets were instrumental in the adaptation of elements of aristocratic culture to the needs of mass officialdom—a new social stratum that in terms of cultural background differed fundamentally from the hereditary aristocracy of the pre-imperial era but occupied a comparable position as a social and political elite. Depuis les années 1930 les archéologues chinois ont découvert de nombreuses tablettes de bois inscrites datant du début des Han jusqu’aux Jin occidentaux, qui ont été identifiées comme étant des « tablettes de salutation ». Il en existe deux types, les ci 刺 et les ye 謁. Comme l’attestent les textes transmis, ces tablettes jouaient un rôle important dans l’étiquette régissant les communications entre fonctionnaires dans la période impériale ancienne et au début de l’époque médiévale: l’hôte les présentait à l’invité au cours du cérémonial marquant leur rencontre. Cet article propose un inventaire systématique du corpus des tablettes de salutation découvertes dans les fouilles et s’intéresse plus généralement à leurs implications socio-culturelles. Partie intégrante de l’étiquette des communications, ces tablettes ont joué leur rôle dans l’adaptation de certains éléments de la culture aristocratique aux besoins de la masse des fonctionnaires, autrement dit d’un groupe social nouveau dont le fonds culturel différait fondamentalement de celui de l’aristocratie héréditaire mais dont la position en tant qu’élite sociale et politique était comparable.

Baekje showed mature Chinese literature, such as writing poetry and literature using Chinese characters, no different from China, in the Sabi era. And document administration was thoroughly implemented. However, The period of Baekje's acceptance of Chinese characters and administration of documents cannot be specified due to a lack of related historical and archaeological materials, or it tends to be considered too late as the period of King Geunchogo, so I wrote this article to look into it. Baekje's acceptance of Chinese characters was examined through whether and when the Baekje constituent group accepted Chinese characters. Baekje was composed of the ruling class of the Buyeo and Goguryeo migrant groups and the under-dominated class of the Han tribes and Ye tribes. The Baekje ruling group split from Goguryeo, which accepted Chinese characters from the time of its founding and started document administration. The Baekje ruling group also knew about Chinese characters and document administration as the ruling group of Goguryeo at one time. Moreover, the Baekje ruling group established a site in the Han River basin after passing through the Chinese county area, where thorough document administration was implemented. The Baekje ruling group had an understanding of Chinese characters and document administration. In addition, the Han and Ye tribes, which were the dominant class of Baekje, were at the center of the Han River basin, and the Jin and Han societies, which were first located in the Han River basin, also accepted Chinese characters through the influence of Chinese residents and exchanges with Hansa-gun during each period of chaos in Chinese history, and knew or participated in the document administration of Chinese county. Baekje accepted and used Chinese characters from the beginning of its foundation because both the ruling and under-dominated groups of Baekje accepted Chinese characters. Since there was no direct record of the beginning of the administration of documents in Baekje, the beginning of the administration of documents was inferred by reviewing historical facts that presuppose the beginning of the administration of documents in Baekje. The establishment of educational institutions and the compilation of history books took place during the reign of King Geunchogo. In addition, Archaeological materials related to inscriptions from the Hanseong period are generally considered to be from the 4th century or later. This can be said to have begun the administration of documents from the time of King Geuncho's reign, as previous understanding. However, looking at the floor stone of the 道(直) name, the period of implementation of Baekje's ritual system and official ranking system, and diplomatic relations with China and counties, there is room to place the beginning of Baekje's document administration in the reign of King Goi. If we limit the period, Baekje document administration began at least from 260, the 27th year of King Goi's reign, when the official rank system was implemented. If interpreted more positively, document administration may have been implemented from the 7th year of King Goi's reign (240), when the military commander was established and the military authority of the central and local regions was reorganized. The reorganization of central and local military authority was carried out by the military command and control of all Baekje armies. This means unification of military government, and this can only be achieved through clear document administration.

Abstract Abnormal expression and activation of Epidermal Growth Factor Receptor (EGFR) contribute to malignancy development, especially in non-small cell lung cancers (NSCLCs). Although the first- to third-generation EGFR small molecule inhibitors have made significant progress in the treatment of EGFR mutant NSCLC patients, acquired mutations have been developed rapidly, resulting in drug resistance. Targeted protein degradation (TPD) technologies including PROteolysis Targeting Chimeras (PROTACs) have recently emerged as a promising alternative modality to address the confronting issues of small molecule inhibitors such as drug resistance. Recently, we have developed a series of heterobifunctional degraders of EGFR mutant proteins, which showed strong degradation ability against a variety of mutant EGFRs including triple mutants with C797S. DC50 (half-maximal degradation concentrations) values of the degraders were obtained using HiBiT assay in NCI-H1975 (EGFR L858R/T790M), HCC827 (EGFR Del19), and H1299 (EGFR WT) cells. Our lead compounds demonstrated excellent EGFR degradation potency with high selectivity against EGFR wild type. Moreover, C-09045, C-09066, and C-13951 strongly inhibited the cell growth of Ba/F3 cells harboring one of the EGFR mutations including L858R/C797S, Del19/C797S, L858R/T790M/C797S, Del19/T790M/C797S, and Exon20 NPH insertion. By contrast, these compounds showed much weaker potency in normal lung fibroblast (HFL-1) and Ba/F3 cells harboring EGFR wild-type. In PK analysis, C-09066 showed good oral bioavailability in mice (F%=41.4) with desirable pharmacokinetic parameters and robust tumor growth inhibition efficacy in the NCI-H1975 EGFR L858R/T790M/C797S xenograft and the Ba/F3 Del19/C797S allograft mouse models. In summary, we have identified selective, potent, and orally bioavailable degraders of various EGFR mutant proteins with broad spectrum anti-tumor efficacy both in vitro and in vivo. Citation Format: Dong Hyuk Ki, Min Sung Joo, Joonwoo Nam, Hunmi Choi, Kyoungwan Seo, Eun-Jung Kim, Jiyeon Kim, Chulwon Kim, Jimmy Taiguang Jin, Wooseok Han. Discovery of novel heterobifunctional degraders of mutant EGFR proteins for NSCLCs harboring various EGFR mutations. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5006.

Abstract Accurate diagnosis of breast cancer using circulating biomarkers present in plasma remains an important challenge. In particular, protein changes in tumor-derived extracellular vesicles (tdEVs) have emerged as potential biomarkers for breast cancer diagnosis because they accurately reflect dynamic changes in tumors. In this study, we compared the proteomes of extracellular vesicle (EV) isolated from the plasma of 100 breast cancer patients and 30 healthy individuals who visited Severance Hospital between Mar 2010 and Dec 2015. Microfluidic chip-based protocol that facilitates the removal of contaminants such as albumin and immunoglobulins was used for the extraction of enriched tdEVs with small amounts of plasma. Comparative analysis of the proteomes identified 26 significant biomarkers that could indicate differences between breast cancer patients and healthy individuals. Using the LsBoost-CNN-SVM hybrid machine learning algorithm, we especially identified key EV protein biomarkers for detecting triple-negative breast cancer (TNBC), a breast cancer subtype with a poor prognosis and a high recurrence rate, as well as lacking therapeutic and diagnostic targets. Remarkably, a signature consisting of three EV proteins, specifically extracellular matrix protein 1 (ECM1), mannose-binding lectin 2 (MBL2), and biotinidase (BTD), effectively distinguished TNBC patients from healthy individuals. In our proteomic analysis set (n=73), this signature exhibited impressive performance, achieving a sensitivity of 93.3% and specificity of 93% in the accurate discrimination of TNBC from the control group. The validation set (n=40) confirmed these findings, with 100% sensitivity and 80% specificity. This signature not only served as a diagnostic tool but also provided valuable insights into the risk of recurrence and patient prognosis. We found a novel diagnostic approach that holds the potential to revolutionize breast cancer diagnostics by enhancing the reliability of tumor-related information obtained from blood samples. Citation Format: Min Woo Kim, Jee Ye Kim, Young Kim, Suji Lee, Sol Moon, Ju-yong Hyon, Kyung-A Hyun, Yeji Yang, Seongmin Ha, Sunyoung Park, Hogyeong Gawk, Haeji Lee, Eun Hee Han, Jin Young Kim, Hyo-Il Jung, Young-Ho Chung, Seung Il Kim. Integrating machine learning with microfluidic technologies for proteomic profiling of extracellular vesicles in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1843.

Lithium-metal electrodes are of particular interest for next-generation rechargeable batteries because of their high specific capacity and low redox potential. Therefore, Li-metal-based batteries may afford higher energy densities than commercially available Li-ion batteries with graphite anodes. However, various bottlenecks have hampered the commercial development of these batteries, including uncontrolled Li dendrite formation and huge volume changes during cycling. Consequently, Li-metal batteries suffer from low Coulombic efficiency and poor cycling stability. In recent years, there has been extensive research on the design and construction of three-dimensional (3D) porous electrodes that can host metallic Li. However, the low pore utilization and uneven Li plating remain crucial issues. This can be understood in terms of electronic and ionic transport through the framework electrode. The carbon frameworks exhibit high electronic conductance; however, large resistance to Li+ migration in the electrolytes of internal and interparticle pores inhibits the penetration of Li+ deep into the electrode. In this work, we demonstrate that a strong interaction between Li and a lithiophilic nanolayer on a substrate plays a critical role in enhancing pore utilization in carbon framework electrodes. As a model architecture, we examine a Li storage process in a framework electrode consisting of porous carbon derived from metal-organic frameworks (MOFs) and a galvanically displaced Ag layer on a Cu substrate (Cu@Ag). The electrochemical experiments combined with operando XRD measurements and microstructural characterizations suggest that a lithiophilic Ag on the Cu substrate preferentially reacts with Li+ to form Li x Ag during the initial stage of Li plating. This Li x Ag phase acts as a seed that can regulate the subsequent Li plating, promoting confined Li storage in the carbon framework electrode while suppressing top plating. Because of these advantages, the MOF-C framework electrode on Cu@Ag exhibits better cycling stability (>250 cycles) than the MOF-C framework electrode on Cu (140cycles). However, when the thickness of the MOF-C framework is increased to 90 μm, the diffraction peak for Ag remains dominant throughout Li plating-stripping, and the formation of Li x Ag alloys is not clearly detectable in the diffraction patterns, suggesting that only a limited amount of Ag is involved in the alloying reaction with Li+. Based on the computational studies, the efficacy of lithiophilic layers toward improving pore utilization is discussed in terms of the kinetic competition between Li+ transport through porous channels and the interfacial reaction of Li+ with the substrate. This study conveys an important message that the Li-substrate interaction plays a vital role in promoting the confined Li storage; hence, it should be considered a key design factor for porous carbon frameworks with high capacity and long cycle lifetime. References Yun, H. R. Shin, E.-S. Won, H. C. Kang, J.-W. Lee, Confined Li metal storage in porous carbon frameworks promoted by strong Li-substrate interaction, Chem. Eng. J. 430 (2022) 132897. Jin, Y. Ye, Y. Niu, Y. Xu, H. Jin, J. Wang, Z. Sun, A. Cao, X. Wu, Y. Luo, H. Ji, L. J. Wan, Solid-solution-based metal alloy phase for highly reversible lithium metal anode, J. Am. Chem. Soc. 142 (2020) 8818–8826. Kim, J. Lee, J. Yun, S.H. Choi, S.A. Han, J. Moon, J.H. Kim, J.-W. Lee, M.-S. Park, Functionality of dual-phase lithium storage in a porous carbon host for lithium-metal anode, Adv. Funct. Mater. 30 (2020) 1910538.

Abstract RON is a receptor tyrosine kinase of the MET proto-oncogene family, known as macrophage stimulating 1 receptor (MST1R) that recognizes macrophage-stimulating protein (MSP). RON has been known to be highly expressed in several epithelial tumors, promoting tumor progression and metastasis, and on macrophages surface, facilitating M2-like phenotype polarization of tumor-associated macrophages (TAM) to impair anti-tumor functions of CD8+ T cells. Although pharmacological inhibition of RON kinase has received attention from many research groups, monoclonal antibody drug showed a limited clinical efficacy due to RON variant of receptor region. Because the structure homology of kinase domain between RON and MET is 80%, discovery of RON-specific small molecule inhibitor is considered to be highly challenging to achieve. At first, we discovered a lead compound with about 50-fold of RON selectivity against MET kinase. Our medicinal chemistry efforts elevated RON/MET selectivity up to 500~10,000-fold (IC50 = 1~50 nM in RON enzyme assay), and the target specificity was proved through a panel assay of 372 kinases (Reaction Biology Corp.). A series of compounds effectively modulated p-RON and downstream signals (e.g. p-ERK and p-AKT) in MDA-MB-453, and inhibited cell proliferation of Ba/F3 cell-line engineered with human RON kinase. Significant anti-tumor effects were shown in syngeneic mouse models compared to a control group after oral administration, and studies related to immuno-oncology are ongoing in in-vitro or ex-/in-vivo assay systems. In conclusion, we have identified RON selective small molecule inhibitors that will be useful to figure out the biology following RON selective inhibition against MET kinase, and to validate the translational potential of RON kinase as a therapeutic target for human diseases including cancer. Citation Format: Young Jin Ham, GyeongHwan Kim, Juhyun Lee, Jaeyoung Lee, Min Kyung Kim, Sunhong Kim, Woosook Kim, Han Byoul Kim, Sung Woong Jang, Hee Dong Park, Seonguk Jeon, Seok-Joo Kim, Joongheui Cho, Jungjoon Kim, Hong bin Yoon, Youngshin Kwak. Discovery of highly selective RON kinase inhibitors [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 LB524.

Abstract Introduction: Bacillus Calmette-Guérin (BCG) is the standard of care for high-risk non-muscle-invasive bladder cancer (NMIBC) following transurethral resection. However, patients often have heterogeneous responses. Even among those who initially respond well to BCG, 10-20% relapse. Identification of reliable biomarkers predicting the efficacy of BCG remains an unmet need. En bloc resection is a novel technique representing a substantial advancement in the surgical management of NMIBC. We sought to investigate genomic and tumor microenvironmental (TME) profiles in NMIBC and explore potential predictive markers for BCG treatment following en-block resection. Methods: A total of 40 patients with high-risk NMIBC (cTis-T1N0M0) were retrospectively enrolled who underwent en bloc resection followed by BCG instillation. Surgical samples were subjected to NGS sequencing using a 520-gene panel (Burning Rock Biotech, Guangzhou) and multiplex immunofluorescence (mIF) assay. Results: The cohort had a median age of 63 years, and 80% were male. After a median follow-up of 21.8 months, 19/40 patients relapsed with a one-year relapse-free survival (RFS) rate of 57.5%. All tumors were microsatellite stable and showed a median TMB of 7.98muts/Mb. Genomic profiling revealed a high prevalence of alterations in TERT (55%), KDM6A (32.5%), KMT2D (32.5%), FGFR3(30%), PIK3CA (30%), TP53(27.5%), KMT2C (25%), and ARID1A (20%). TME analysis showed higher proportions of M1 macrophages and CD56 dim NK cells in the tumoral compartment and more intense infiltration of CD8+ T cells, exhausted CD8+T, CD56 bright NK cells, and M2 macrophages in the stromal compartment. Multivariate analysis identified TERT C228T mutation (HR=3.28 [95%CI:1.225-8.79], p=0.0181) and alteration in KDM6A (HR=2.94 [95%CI:1.040-8.29], p=0.042) as two independent factors associated with inferior RFS. Patients with concomitant TERT C228T and KDM6A alteration had the shortest RFS (median RFS:5.83months) compared with those who were free of (median RFS: NR) or harbored either one of the two alterations (median RFS:9.13months) (p=0.0022). We also found that tumoral infiltration of CD8+T cells was positively associated with RFS (HR=0.29 [95%CI:0.097-0.885], p=0.0208). Conclusion: The study comprehensively depicted the genomic and TME profiles in NMIBC and identified potential predictive biomarkers for BCG treatment. Our findings may facilitate the stratification of patients and better guide the clinical decision-making on the management of NMIBC. Citation Format: Qi-Dong Xia, Yao-Bing Chen, Jian-Xuan Sun, Chen-Qian Liu, Jin-Zhou Xu, Zhi-Peng Yao, Ye An, Meng-Yao Xu, Si-Han Zhang, Xing-Yu Zhong, Na Zeng, Si-Yang Ma, Hao-Dong He, Heng-Long Hu, Jia Hu, Yi Lu, Lin Shao, Si-Qi Li, Zheng Liu, Shao-Gang Wang. TERT C228T and KDM6A alterations are potential predictive biomarkers in non-muscle-invasive bladder cancer treated with intravesical Bacillus Calmette-Guérin instillation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2127.

Abstract The use of mitochondrial inhibitors to target oxidative phosphorylation (OXPHOS) in cancer treatment presents a challenge due to dose-limiting toxicities. Moreover, while glycolysis-deficient cancers are vulnerable to OXPHOS inhibition in preclinical models, the full extent of phenotypical and mechanistic consequences of inhibiting OXPHOS in cancers capable of glycolysis is not yet well understood. Our results presented here offer promising insights into potential therapeutic gains from combining p53 restoration strategies with OXPHOS inhibitors, even when applied to glycolysis-competent CRC cells. Treatment with mitochondrial complex I inhibitors did not cause energy stress in CRC cells capable of glycolysis. It does, however, induce DNA replication stress, apparent through an observed cell cycle arrest at the S phase, enrichment of the G2/M DNA-damage checkpoint regulation pathway, and replication fork slowdown. Intriguingly, CRC cells harboring wildtype p53 exhibited more severe replication stress than those carrying mutant p53. Furthermore, siRNA knockdown of p53 attenuates replication stress and reduces cell cycle arrest, underlining the important role of p53 in CRC cell responses to OXPHOS inhibition. Our targeted metabolomics analysis reveals that OXPHOS inhibition results in reductions in the purine nucleotides, adenine monophosphate (AMP) and guanine monophosphate (GMP), as well as the pyrimidine nucleotide, uridine monophosphate (UMP), in CRC cells, regardless of their p53 mutational status. By supplementing cell culture mediums with the purine nucleobases adenine and guanine, and the pyrimidine nucleoside uridine, we observed a partial reversal of the replication fork slowdown and reductions in cell viability. This suggests nucleotide deficiencies are involved in the induction of DNA replication stress caused by OXPHOS inhibition. The nucleotide deficiencies were associated with a decrease in the nucleobase precursor aspartate. By adding aspartate at a supraphysiological concentration, to overcome the low expression of the excitatory amino acid transporter 1 required for cellular import of aspartate, we were able to restore the levels of nucleotides. Collectively, our findings suggest broader potential cancer treatment paradigms via OXPHOS targeting, extending beyond glycolysis-deficient cancers. Our data uncovers that CRC cells, which commonly exhibit the glycolytic phenotype, are susceptible to OXPHOS inhibition, with those carrying wildtype p53 showing heightened sensitivity. Therefore, p53 status could serve as a biomarker for predicting CRC responses to OXPHOS inhibitors. Moreover, our findings suggest that combined strategies of restoring p53 function, using small molecules such as APR-246, might enable reduced dosage of OXPHOS inhibitors in CRC treatment, thereby mitigating their dose-limiting toxicities. Citation Format: Xiao Hong Zhao, Man Man Han, Qian Qian Yan, Yi Meng Yue, Kai Hong Ye, Yuan Yuan Zhang, Liu Teng, Liang Xu, Xiao Jing Shi, Ting La, Yu Chen Feng, Ran Xu, Vinod K. Narayana, David P. De Souza, Tao Liu, Mark Baker, Rick F. Thorne, Xu Dong Zhang, Song Chen, Lei Jin. p53 underpins a dependence on oxidative phosphorylation in glycolysis-competent colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7052.

Abstract Background Previous studies proposed low-pass whole genome sequencing (LP-WGS)-based circulating tumor DNA (ctDNA) analysis as a versatile tool for genomic profiling and therapeutic monitoring of cancer patients. Here we demonstrate LP-WGS ctDNA genomic profiles and its clinical significance in metastatic breast cancer patients. Patients and methods This prospective exploratory study enrolled 207 treatment-naïve metastatic breast cancer patients from Feb 2017 to September 2020 in Yonsei Cancer Center. The median follow-up duration of patients was 35 months. The baseline (n=207) and post-progression (n=48) plasma samples were prospectively collected on first-line systemic therapy, and LP-WGS was employed for ctDNA somatic copy number alteration (CNA) analysis. The CNA burden of ctDNA was scored by “I-score” method, which was developed to measure genome-wide chromosomal instabilities, to be matched with therapy response. The unsupervised molecular clustering and homologous recombination deficiency (HRD) estimation by shallowHRD algorithm were performed using locus-level CNA profiles with 1 mega base pair resolution. Results The baseline I-score ctDNA CNA burden was highest in triple-negative breast cancer (TNBC) patients among subtypes, and the patients were dichotomized by median I-score level 5.54 (range 2.55 to 12.98). The high baseline ctDNA I-score was independently associated with poor overall survival (hazard ratio [HR] = 3.98, p < 0.001) with adjustment of tumor subtype, visceral metastasis, and disease status (de novo stage IV versus recurrent). The progression-free survival (PFS) on endocrine plus CDK4/6 inhibitors (HR = 2.75, p = 0.005), anti-HER2 therapy (HR = 2.52, p = 0.032), and cytotoxic chemotherapy (HR = 2.33, p = 0.012) was also shorter in high baseline I-score patients than in low I-score patients. The locus-level CNA profile was analyzed in high I-score patients (n=103), and the patients were classified into five molecular clusters with distinct overall survival by unsupervised k-means clustering of CNA profile: basal-like, EGFR-high basal-like, CCND1-high, luminal, and HER2-enriched clusters. Patients with BCL6 (p = 0.009) and PIK3CA amplification (p < 0.001) on baseline ctDNA showed significantly shorter PFS on CDK4/6 inhibitor treatment. The matched baseline and post-progression ctDNA analysis found emergence of FGFR1 amplification and MYC amplification after CDK4/6 inhibitor treatment (n=1, each). The ctDNA shallowHRD score was highest in TNBC patients among subtypes, and TNBC patients with high shallowHRD score (≥10) showed high response rate on (58.3% versus 28.6%) on platinum-based chemotherapy. Conclusion LP WGS-based ctDNA analysis provides a robust tool for non-invasive genomic clustering, therapy response prediction, and HRD estimation in metastatic breast cancer patients. All patients (n=207)Low I-score (n=104)High I-score (n=103)N (%)N (%)N (%)Age, Median (Interquartile range)54 (46-62)53 (47-60)54(44-62)GenderFemale205 (99)102 (98.1)103Male2 (1)2 (1.9)0SubtypeHR+ HER2-106 (51.2)61 (58.7)45 (43.7)HR- HER2+33 (15.9)14 (13.5)19 (18.4)HR+ HER2+22 (10.6)11 (10.6)11 (10.7)HR- HER2- (TNBC)46 (22.2)18 (17.3)28 (27.2)Disease statusDe novo stage IV74 (35.7)31 (29.8)43 (41.7)Recurrent133 (64.3)73 (70.2)60 (58.3)Primary therapyEndocrine + CDK 4/6 inhibitor97 (46.9)55 (52.9)42 (40.8)Anti-HER2 based therapy54 (26.1)24 (23.1)30 (29.1)Chemotherapy45 (21.7)16 (15.4)29 (28.2)Others11 (5.3)9 (8.7)2 (1.9)Visceral metastasisYes142 (68.6)60 (57.7)82 (79.6)No65 (31.4)44 (42.3)21 (20.4)Metastasis SitesLung89 (43)43 (41.3)46 (44.7)Brain19 (9.2)4 (3.8)15 (14.6)Liver59 (28.5)13 (12.5)46 (44.7)Bone120 (58)47 (45.2)73 (70.9)Lymph node90 (43.7)32 (30.8)58 (56.9)Pleura33 (15.9)17 (16.3)16 (15.5) Citation Format: Joohyuk Sohn, Min Hwan Kim, Jin Mo Ahn, Won-Ji Ryu, Seul-Gi Kim, Jee Hung Kim, Tae Yeong Kim, Hyun Ju Han, Jee Ye Kim, Hyung Seok Park, Seho Park, Byeong Woo Park, Seung Il Kim, Eun Hae Cho, Gun Min Kim. Whole genome sequencing-based circulating tumor DNA profiling of metastatic breast cancer patients for molecular characterization and therapy response prediction [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 PD6-07.

Energy and environment are the key global challenges in the 21st century. Solar energy is considered the most promising clean and sustainable energy resource due to its university, inexhaustible and environmental friendliness. One of the most viable means of solar energy conversion and utilization is artificially converting solar energy into chemical energy as natural photosynthesis does. H2 produced from water splitting and CO2 reduction, are the major research topics of artificial photosynthesis. However, the effective conversion of solar energy into chemical energy by cost-effective artificial means on a large scale remains elusive. Metal oxide-based photocatalysts are the most studied materials for photocatalytic water splitting and CO2 reduction. Particularly, perovskite oxides with the chemical formula of ABO3 have been intensively studied as semiconductor photocatalysts. However, overwhelmingly of the perovskite oxides are only active under UV-light-irradiation, which limited their potential in solar energy application. Therefore, breakthrough technology and step-change materials, particularly, visible-light-responsive photocatalysts are highly desirable for the development of photocatalytic systems. In recent years, copious progress has been made in designing materials that function under visible-light-irradiation. So far, the most successful strategy is anion doping of oxide semiconductors, such as nitrogen or sulfur dope to form oxynitrides and oxysulfides, respectively. For example, nitrogen-doped oxynitrides such as (Ga1-xZnx)(N1-xOx) and ANbO2N (A=Sr, Ba, and La)1, and sulfur-doped oxysulfides such as Sm2Ti2S2O5 2 showed efficient photocatalytic overall water splitting activities under visible-light-irradiation. Particularly, oxynitrides (Ga1-xZnx)(N1-xOx) based photocatalyst sheet, showed remarkable photocatalytic overall water splitting activity with AQE of more than 30% at l»420 nm3. However, these oxynitrides and oxysulfides suffer stability problems due to photocorrosion, hindering their potential practical application in photocatalytic applications. Recently, it has been theorized that double perovskite oxides (DPOs) with the chemical formula of A2BʹB"O6 can function as efficient and stable visible-light-responsive photocatalysts for photocatalytic water splitting and CO2 reduction. However, DPOs have been rarely studied for photocatalytic water splitting and CO2 reduction due to the difficulty of obtaining pure phase materials and the paucity of exposed active sites. Thus, developing efficient and stable visible-light-responsive DPOs photocatalysts for photocatalytic water splitting and CO2 reduction becomes important. In this regard, recently, we have demonstrated a series of efficient and stable visible-light-responsive DPOs photocatalysts for photocatalytic water splitting. For instance, Sr2CoWO6 and Sr2CoTaO6 can serve as an efficient and stable bifunctional photocatalyst for both photocatalytic oxygen evolution reaction (OER) and hydrogen evolution reaction(HER)4, 5, and Sr2NiWO6 can efficiently drive the photocatalytic OER6. Even though these DPOs have been demonstrated as visible-light-responsive photocatalysts with suitable CB and VB positions that straddle the theoretical potentials for overall water splitting, however, one-step overall water splitting has not been achieved so far, and their potential for photocatalytic CO2 reduction has not been studied yet. Overall water splitting under visible-light-irradiation based on particulate photocatalysts is a challenging reaction, which is regarded as one of the “Holy Grail” of sciences. And oxide semiconductors showing both photocatalytic OER and HER activities are rare. Nevertheless, bifunctional photocatalytic OER and HER were successfully demonstrated based on Sr2CoWO6 and Sr2CoTaO6. Further improvement of the material designs and developing appropriate cocatalysts may play a key role in achieving one-step overall water splitting under visible-light-irradiation based on DPOs photocatalysts. This work is mainly to explore the possibility of utilizing DPOs materials as visible-light-responsive photocatalysts for photocatalytic water splitting and CO2 reduction reaction, which is challenging work but has great potential value in advancing science and technology in photocatalysis. We anticipated that this work will provide a novel and rational strategy for improving the light absorption, charge separation and charge utilization in DPOs photocatalysts. References Maeda, K.; Teramura, K.; Masuda, H.; Takata, T.; Saito, N.; Inoue, Y.; Domen, K. The Journal of Physical Chemistry B 2006, 110 (26), 13107-13112. Ma, G.; Kuang, Y.; Murthy, D. H.; Hisatomi, T.; Seo, J.; Chen, S.; Matsuzaki, H.; Suzuki, Y.; Katayama, M.; Minegishi, T. The Journal of Physical Chemistry C 2018, 122 (25), 13492-13499. Kato, H.; Asakura, K.; Kudo, A. Journal of the American Chemical Society 2003, 125 (10), 3082-3089. Idris, A. M.; Liu, T.; Shah, J. H.; Zhang, X.; Ma, C.; Malik, A. S.; Jin, A. Solar RRL 2020, 4 (3), 1900456. Idris, A. M.; Liu, T.; Hussain Shah, J.; Han, H.; Li, C. ACS Sustainable Chemistry&Engineering 2020, 8 (37), 14190-14197. Idris, A. M.; Liu, T.; Hussain Shah, J.; Malik, A. S.; Zhao, D.; Han, H.; Li, C. ACS Applied Materials&Interfaces 2020, 12 (23), 25938-25948.

The achievement of children's quality of life is undoubtedly linked to the development of positive habits that will continue to be practiced in future lives. This can be done by developing awareness and behavior of a balanced clean and healthy lifestyle. The purpose of this study was to determine the increase in the PHBS ability of children. Various efforts have been made so that children with intellectual disabilities can maintain their cleanliness. The efforts made by the teacher are still not maximal so that the delivery of information about PHBS must be completed by another method, namely demonstration. This research was conducted at SDLB 127710 Pematangsiantar5 with an action research method that refers to the Kurt Lewin model. Data collection techniques used purposive sampling and data analysis with the Wilcoxon test. The results showed an increase in understanding of the PHBS of children with intellectual disabilities able to learn SDLB 127710 Pematangsiantar through the demonstration method. This is evidenced by the increase in the score, where the initial assessment was obtained (59%), while in the first cycle, the average score was good (69.9%). In short, the understanding of children with intellectual disabilities being able to learn about PHBS is increased by using the demonstration method. Keywords: Intellectual Disability Children, PHBS program, Demonstration methods References Agarwal, R. (2017). Importancia de la atención primaria de salud en la sociedad. International Journal of Health Sciences, 1(1), 5–9. Aiello, A. E., Coulborn, R. M., Perez, V., & Larson, E. L. (2008). Effect of hand hygiene on infectious disease risk in the community setting: A meta-analysis. American Journal of Public Health, 98(8), 1372–1381. https://doi.org/10.2105/AJPH.2007.124610 Arip, M. pdfo., & Emilyani, D. (2018). Strategy to improve knowledge, attitude, and skill toward clean and healthy life behaviour. International Journal of Social Sciences and Humanities, 2(3), 125–135. https://doi.org/10.29332/ijssh.v2n3.222 Basheer, A., Hugerat, M., Kortam, N., & Hofstein, A. (2017). The effectiveness of teachers’ use of demonstrations for enhancing students’ understanding of and attitudes to learning the oxidation-reduction concept. Eurasia Journal of Mathematics, Science and Technology Education, 13(3), 555–570. https://doi.org/10.12973/eurasia.2017.00632a Bloomfield, S. F., Aiello, A. E., Cookson, B., O’Boyle, C., & Larson, E. L. (2007). The effectiveness of hand hygiene procedures in reducing the risks of infections in home and community settings including handwashing and alcohol-based hand sanitizers. American Journal of Infection Control, 35(10 SUPPL. 1). https://doi.org/10.1016/j.ajic.2007.07.001 Cavanaugh, L. K. (n.d.). Intellectual Disabilities (D. L. Porretta (Ed.); 6 th). Human Kinetics. Chang, Y. J., Lee, M. Y., Chou, L. Der, Chen, S. F., & Chen, Y. C. (2011). A Mobile Wetness Detection System Enabling Teachers to Toilet Train Children with Intellectual Disabilities in a Public School Setting. Journal of Developmental and Physical Disabilities, 23(6), 527–533. https://doi.org/10.1007/s10882-011-9243-3 Cummings, S., Bridgman, T., & Brown, K. G. (2016). Unfreezing change as three steps: Rethinking Kurt Lewin’s legacy for change management. Human Relations, 69(1), 33–60. https://doi.org/10.1177/0018726715577707 Dirjen P2P Kemkes RI. (2019). Rencana Aksi Program Pencegahan Dan Pengendalian Penyakit 2015-2019 ( Revisi I - 2018 ). Rencana AKSI Program P2P 2015-2019, 2019, 86. Flanagan, D. P., Alfonso, V. C., & Hale, J. B. (2010). The Wechsler Intelligence Scale for Children - Fourth Edition in Neuropsychological Practice. Handbook of Pediatric Neuropsychology, January, 397–414. Giridharan, K., & Raju, R. (2017). Impact of Teaching Strategies: Demonstration and Lecture Strategies and Impact of Teacher Effect on Academic Achievement in Engineering Education. International Journal of Educational Sciences, 14(3), 174–186. https://doi.org/10.1080/09751122.2016.11890491 Hooman, N., Safaii, A., Valavi, E., & Amini-Alavijeh, Z. (2013). Toilet training in Iranian children: A cross-sectional study. Iranian Journal of Pediatrics, 23(2), 154–158. Hung, J.-W., Chang, Y.-J., & Han, W.-Y. (2016). Game technology to increase range of motion for adolescents with cerebral palsy: a feasibility study. International Journal on Disability and Human Development, 16(3). https://doi.org/10.1515/ijdhd-2016-0026 Kang, Y. S., & Chang, Y. J. (2019). Using a motion-controlled game to teach four elementary school children with intellectual disabilities to improve hand hygiene. Journal of Applied Research in Intellectual Disabilities, 32(4), 942–951. https://doi.org/10.1111/jar.12587 Kementerian, & Indonesia, R. (2011). Profil Kesehatan Indonesia. Kemenenterian Kesehatan RI. Kesehatan, K. (2011). PHBS di Sekolah. Kementerian Kesehatan Republik Indonesia. Ketut Sudiana, I., Adiputra, N., & Budi Adnyana, P. (2020). Integrative Health Thematic Strategy Increases Learning Outcomes and Students ’Clean and Healthy Living Behaviors. Journal of Physics: Conference Series, 1503(1). https://doi.org/10.1088/1742-6596/1503/1/012050 Koh, W. M., Bogich, T., Siegel, K., Jin, J., Chong, E. Y., Tan, C. Y., Chen, M. I. C., Horby, P., & Cook, A. R. (2016). The epidemiology of hand, foot and mouth disease in Asia: A systematic review and analysis. Pediatric Infectious Disease Journal, 35(10), e285–e300. https://doi.org/10.1097/INF.0000000000001242 Kroeger, K., & Sorensen, R. (2010). A parent training model for toilet training children with autism. Journal of Intellectual Disability Research, 54(6), 556–567. https://doi.org/10.1111/j.1365-2788.2010.01286.x Laporan Akuntabilitas Kinerja Kementerian Kesehatan tahun 2014. (n.d.). Lee, R. L. T., & Lee, P. H. (2014). To evaluate the effects of a simplified hand washing improvement program in schoolchildren with mild intellectual disability: A pilot study. Research in Developmental Disabilities, 35(11), 3014–3025. https://doi.org/10.1016/j.ridd.2014.07.016 Lee, R. L. T., Leung, C., Tong, W. K., Chen, H., & Lee, P. H. (2015). Comparative efficacy of a simplified handwashing program for improvement in hand hygiene and reduction of school absenteeism among children with intellectual disability. American Journal of Infection Control, 43(9), 907–912. https://doi.org/10.1016/j.ajic.2015.03.023 Levato, L. E., Aponte, C. A., Wilkins, J., Travis, R., Aiello, R., Zanibbi, K., Loring, W. A., Butter, E., Smith, T., & Mruzek, D. W. (2016). Use of urine alarms in toilet training children with intellectual and developmental disabilities: A review. Research in Developmental Disabilities, 53–54, 232–241. https://doi.org/10.1016/j.ridd.2016.02.007 Noah Ekeyi, D. (2013). Effect of Demonstration Method of Teaching on Students’ Achievement in Agricultural Science. World Journal of Education, 3(6), 1–7. https://doi.org/10.5430/wje.v3n6p1 Pedoman Umum Program Indonesia Sehat dengan Pendekatan Keluarga. (2015). Kementerian Kesehatan Republik Indonesia. Purba, N., Handini, M. C. H., & Yetti, E. (2018). Development of Media Vocabulary Cards to Improve the Speech Competence of Children with Intellectual Disabilities. 6. Puspita, W. A., Sulistyorini, M. P., & Wibowo, B. (2020). Learning Clean, Healthy and Safe Life Behavior in Inclusive Early Childhood Education. 454(Ecep 2019), 270–274. https://doi.org/10.2991/assehr.k.200808.053 Putri, R. M., Rosdiana, Y., & Nisa, A. C. (2019). Application of Clean and Healthy Living Behavior (PHBS) From The Household Knowledge and Attitude Study. Journal Of Nursing Practice, 3(1), 39–49. https://doi.org/10.30994/jnp.v3i1.64 Rosenberg, N. E., Schwartz, I. S., & Davis, C. A. (2010). Evaluating the utility of commercial videotapes for teaching hand washing to children with autism. Education and Treatment of Children, 33(3), 443–455. https://doi.org/10.1353/etc.0.0098 Ruan, F., Yang, T., Ma, H., Jin, Y., Song, S., Fontaine, R. E., & Zhu, B. P. (2011). Risk factors for hand, foot, and mouth disease and herpangina and the preventive effect of hand-washing. Pediatrics, 127(4). https://doi.org/10.1542/peds.2010-1497 Shen, K., Yang, Y., Wang, T., Zhao, D., Jiang, Y., Jin, R., Zheng, Y., Xu, B., Xie, Z., Lin, L., Shang, Y., Lu, X., Shu, S., Bai, Y., Deng, J., Lu, M., Ye, L., Wang, X., Wang, Y., & Gao, L. (2020). Diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts’ consensus statement. World Journal of Pediatrics, 16(3), 223–231. https://doi.org/10.1007/s12519-020-00343-7 Steenkamp, L., Williams, M., Ronaasen, J., Feeley, A., Truter, I., & Melariri, P. (2020). Handwashing knowledge and practices among caregivers of pre-school children in underprivileged areas of Nelson Mandela Bay. South African Journal of Clinical Nutrition, 0(0), 1–5. https://doi.org/10.1080/16070658.2020.1769336 van Nunen, K., Kaerts, N., Wyndaele, J. J., Vermandel, A., & van Hal, G. V. (2015). Parents’ views on toilet training (TT): A quantitative study to identify the beliefs and attitudes of parents concerning TT. Journal of Child Health Care, 19(2), 265–274. https://doi.org/10.1177/1367493513508232 Walpole, R. E. (1955). Pengantar Statistika. Gramedia.

Проведено изучение возможной роли рецепторов дофамина DOP-1, DOP-2 и DOP-3 в модуляции чувствительности почвенной нематоды Caenorhabditis elegans к токсическому действию нитрата свинца. Эксперименты проводили с нематодами четырех линий: линия дикого типа N2 и мутантные линии LX636 (dop-1(vs101)X), LX702 (dop-2(vs105)V), LX703 (dop-3(vs106)X) с нуль-мутациями одного из генов рецепторов дофамина (dop-1, dop-2 и dop-3 соответственно). Нуль-мутации генов рецепторов дофамина DOP-2 и DOP-3 не вызывали достоверных изменений устойчивости поведения C. elegans к действию Pb(NO3)2 в концентрации 0.25–1.0 мМ. Нуль-мутация гена рецептора DOP-1 повышала чувствительность поведения C. elegans к ионам Pb2+ в течение 30–120-минутной экспозиции к токсиканту. Введение в среду инкубации дофамина в концентрации 8 мМ не оказывало существенного влияния на поведение C. elegans, но снижало чувствительность нематод линий с мутациями генов dop-1 и dop-3 к Pb(NO3)2. Дофамин в концентрации 4 мМ не оказывал достоверного влияния на локомоцию C. elegans всех четырех линий как сам по себе, так и при добавлении в среду с нитратом свинца. Нарушения моторной программы плавания у dop-1 мутантов могут быть следствием пониженного содержания эндогенного ацетилхолина в моторных нейронах в результате недостаточной DOP-1 дофаминергической трансмиссии. Снижение чувствительности dop-1 и dop-3 мутантов к Pb(NO3)2 при введении в среду инкубации 8мМ дофамина свидетельствует о том, что у C. elegans этих линий чувствительность к дофамину сохраняется. Список литературы Егорова А.В., Гатиятуллина А.Ф., Калинникова Т.Б. Токсическое действие нитрата свинца на дофаминергическую систему Caenorhabditis elegans линий N2 и CB1112 // Тенденции развития науки и образования. 2022. №91, ч. 6. С. 148–154. doi: 10.18411/trnio-11-2022-318. Калинникова Т.Б., Колсанова Р.Р., Белова Е.Б., Хакимова Д.М., Гайнутдинов М.Х., Шагидуллин Р.Р. 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Metal-induced neurodegeneration in C. elegans // Frontiers in aging neuroscience. 2013. Vol. 5. P. 1–11. https://doi.org/10.3389/fnagi.2013.00018. Han B., Bellemer A., Koelle M.R. An evolutionary conserved switch in response to GABA affects development and behavior of the locomotor circuit of Caenorhabditis elegans // Genetics. 2015. V. 199. P. 1159–1172. https://doi.org/10.1534/genetics.114.173963. Jaishankar M., Tseten T., Anbalagan N., Mathew B.B., Beeregowda K.N. Toxicity, mechanism and health effects of some heavy metals // Interdisciplinary toxicology. 2014. Vol. 7. P. 60–72. doi: 10.2478/intox-2014-0009. Jospin M., Qi Y.B., Stawicki T.M., Boulin T., Schuske K R., Horvitz H.R., Bessereau J.-L., Jorgensen E.M., Jin Y. A neuronal acetylcholine receptor regulates the balance of muscle excitation and inhibition in Caenorhabditis elegans // PLoS Biology. 2009. Vol. 7. P. e1000265. https://doi.org/10.1371/journal.pbio.1000265. Kimura K.D., Fujita K., Katsura I. 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BackgroundRecently, TIGIT+PD1 blockade was shown to confer additive survival benefits in orthotopic glioblastoma and colon cancer mouse models1 2—notably, this included experiments3 that used the 1G9 TIGIT monoclonal antibody (mAb) that has potentially agonistic effects.1 Herein we investigated the TIGIT/CD226/CD155 axis and effects of combining clinically analogous PD-1/PD-L1 mAbs with TIGIT-targeting 1G9 mAb in murine glioblastoma models.MethodsThe overall survival (OS) associated with TIGIT (non-depleting IG9; 200μg every 3days for 4 doses),1 PD-1 (8H3; initial 500μg followed by 250μg every 3days for 7 doses), PD-L1 (6A2; initial 500μg followed by 250μg every 3days for 7 doses), and/or IgG mAbs was assessed in immunocompetent C57BL/6 albino mice intracranially implanted with syngeneic GL261-luc2 or CT2A-luc.4 5 The roles of T cells and NK cells were examined using depletion with CD8a, CD4, or NK1.1 mAbs. Expression of TIGIT/CD226/CD155 and PD-1/PD-L1/PD-L2 by tumor and tumor-infiltrating immune cells was evaluated using flow cytometry and RT-qPCR.ResultsIn vitro, GL261-luc2 and CT2A-luc tumor cells moderately expressed PD-L1, PD-1, and TIGIT; but strongly expressed TIGIT’s inhibitory ligand CD155.(Figure1A-B) Ex vivo, >83% of CD8+ and CD4+TILs in GL261-luc2 co-expressed TIGIT+/CD226+: ≥2x the proportions in CT2A-luc.(Figure 2A) CD155 and PD-L1 were highly co-expressed on tumor-infiltrating macrophages: greater in GL261-luc2 than CT2A-luc tumors.(Figure 2B)In GL261-luc2 mice, anti-TIGIT monotherapy displayed minimal OS improvement; whereas anti-PD-1 and anti-PD-L1 monotherapies demonstrated robust OS responses.(Figure 3A) Adding anti-TIGIT to PD-1/PD-L1 blockade demonstrated synergism with anti-PD-1. Anti-TIGIT plus anti-PD-1 displayed nominally improved OS in CT2A-luc compared to anti-PD-1 monotherapy (p=0.11).(Figure 3B).Given robust T-cell expression of TIGIT and PD-1, we examined how CD4+ or CD8+ depletion affected responses in GL261-luc2 mice: depletion completely abrogated anti-PD-1’s benefits.(Figure 4) Although CD4/CD8 depletion also reduced anti-TIGIT+anti-PD1’s efficacy, the resulting OS matched that of non-depleted anti-PD-1 monotherapy. Additionally, NK cell depletion had no effect on anti-TIGIT+anti-PD1’s efficacy.Abstract 256 Figure 1TIGIT/CD155 axis and PD-1/PD-L1/PD-L2 axis expression in murine glioblastoma model tumor cells. Protein and RNA expression of the TIGIT and PD-1 immune checkpoints — and their ligands CD155 and PDL-1/PD-L2 respectively — on GL261-luc2 and CT2A-luc tumor cells using (A) flow cytometry (blue=samples, red=unstained controls) and (B) RT-qPCR (grey=GL261-luc2, black=CT2A-luc). Pdcd1 encodes PD-1, Cd274 encodes PD-L1, Pvr encodes CD155Abstract 256 Figure 2TIGIT/CD155 axis and PD-1/PD-L1/PD-L2 axis expression in murine glioblastoma model tumor-infiltrating immune cells. (A) Flow cytometry analysis of protein expression for TIGIT (y-axis) and CD226 (x-axis; a competitor of TIGIT) on CD8+, CD4+/FOXP3+ Treg, and CD4+/FOXP3- Teff tumor-infiltrating lymphocytes (TILs) from GL261-luc2 and CT2A-luc tumor-bearing mice. (B) Flow cytometry analysis of protein expression for CD155 (TIGIT’s ligand; bottom) and PD-L1 (PD-1’s ligand; top) on tumor-infiltrating myeloid populations from GL261-luc2 and CT2A-luc tumor-bearing mice. Mean fluorescent intensity (MFI) was compared between cell lines, *indicates statistical significance. Myeloid populations included CD45+/CD11b+/CD11c+/F4-80+ macrophages, CD11b+/CD11c+ and CD11b-/CD11c+ dendritic cells (DCs), CD11b+/CD11c-/Ly6C+/Ly6G- monocytes, CD11b+/CD11c-/Ly6Cmid/Ly6G+ granulocytes, and CD45dim/CX3CR1+ microglia. Tumors were dissociated and leukocytes were enriched for using Percoll gradient. n=5 mice per group.Abstract 256 Figure 3The survival associated with TIGIT-targeting mAb therapy with/without clinically-analogous PD-1/PD-L1 blockade. (A) Kaplan-Meier estimated overall survival (measured from day of intracranial tumor implantation) of GL261-luc2 mice treated with TIGIT (1G9), PD-1 (8H3), PD-L1 (6A2), TIGIT + PD-1, TIGIT + PD-L1 mAbs, or IgG control. (B) A) Kaplan-Meier estimated overall survival (measured from day of intracranial tumor implantation) of CT2A-luc mice treated with TIGIT (1G9), PD-1 (8H3), TIGIT + PD-1 mAbs, or IgG control. For both experiments, all treatments were started on day 6 following implantation, with the following dosing: anti-TIGIT was given as 200μg every 3days for 4 doses. Both anti-PD-1 and anti-PD-L1 were given as an initial 500μg dose followed by 250μg every 3days for 7 doses.4 The n per group and number at risk table is included underneath each graph, along with the corresponding Cox regression analysis. Treatment groups with significantly different OS from the combination TIGIT + PD-1 combination-treated reference group were highlighted in yellow. HR = hazard ratio, CI = confidence interval.Abstract 256 Figure 4How depletion of CD8+ T cells, CD4+ T cells, or NK cells affects survival associated with TIGIT-targeting mAb therapy with/without clinically-analogous PD-1 blockade. Kaplan-Meier estimated overall survival (measured from day of intracranial tumor implantation) of GL261-luc2 mice treated with TIGIT (1G9), PD-1 (8H3), TIGIT + PD-1 mAbs, or IgG control; and compared to groups that additional had CD8+, CD4+, or NK1.1+ antibody-based depletion. The treatment and dosing characteristics were the same as Figure 3. The n per group and number at risk table is included underneath the graph, along with the corresponding Cox regression analysis. Treatment groups with significantly different OS from the combination TIGIT + PD-1 combination-treated reference group were highlighted in yellow. HR = hazard ratio, CI = confidence interval.ConclusionsOur results recapitulate published findings regarding the synergistic benefits of combining TIGIT 1G9 mAb with anti-PD-1 using the clinically-relevant 8H3 mAb in syngeneic mouse glioblastoma, and extend those findings to anti-TIGIT+anti-PDL1 combinations. TIGIT/CD226 was highly co-expressed by immuno-responsive GL261-luc2’s tumor-infiltrating lymphocytes (TILs); wheres CD155/PD-L1 expression predominated in tumor-infiltrating myeloid cells. Depletion of CD8+ or CD4+ TILs modestly reduced anti-TIGIT+anti-PD1’s efficacy—suggesting a mechanism that is at least partially independent of T (and NK) cells. Our preliminary results suggest a complex interplay between TIGIT/CD226/CD155 and PD-1/PD-L1/PD-L2 axes in tumors and their microenvironmental constituents that warrants further investigation; plus, careful consideration of antibody clones’ functionality is necessary for designing immunotherapy combinations.AcknowledgementsWe gratefully acknowledge the support of the The Jennifer Oppenheimer Cancer Research Initiative; The Ben and Catherine Ivy Foundation; Hope It’s A Beach Thing; and the Pan Mass Challenge (Erica’s Entourage and CRUS11TOUR), and the NCI (P01CA236749; K12CA090354).ReferencesDixon KO, Schorer M, Nevin J, Etminan Y, Amoozgar Z, Kondo T, Kurtulus S, Kassam N, Sobel RA, Fukumura D, Jain RK, Anderson AC, Kuchroo VK, Joller N. Functional anti-TIGIT antibodies regulate development of autoimmunity and antitumor immunity. J Immunol 2018 April 15;200(8):3000–3007.Hung AL, Maxwell R, Theodros D, Belcaid Z, Mathios D, Luksik AS, Kim E, Wu A, Xia Y, Garzon-Muvdi T, Jackson C, Ye X, Tyler B, Selby M, Korman A, Barnhart B, Park SM, Youn JI, Chowdhury T, Park CK, Brem H, Pardoll DM, Lim M. TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM. Oncoimmunology 2018 May 24;7(8):e1466769.Raphael I, Kumar R, McCarl LH, Shoger K, Wang L, Sandlesh P, Sneiderman CT, Allen J, Zhai S, Campagna ML, Foster A, Bruno TC, Agnihotri S, Hu B, Castro BA, Lieberman FS, Broniscer A, Diaz AA, Amankulor NM, Rajasundaram D, Pollack IF, Kohanbash G. TIGIT and PD-1 immune checkpoint pathways are associated with patient outcome and anti-tumor immunity in glioblastoma. Front Immunol 2021 May 7;12:637146.Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ, Ramkissoon SH, Jones KL, Conway AS, Liao X, Zhou J, Wen PY, Van Den Abbeele AD, Hodi FS, Qin L, Kohl NE, Sharpe AH, Dranoff G, Freeman GJ. Glioblastoma eradication following immune checkpoint blockade in an orthotopic, immunocompetent model. Cancer Immunol Res 2016 February;4(2):124–35. Iorgulescu JB, Gokhale PC, Speranza MC, Eschle BK, Poitras MJ, Wilkens MK, Soroko KM, Chhoeu C, Knott A, Gao Y, Lim-Fat MJ, Baker GJ, Bonal DM, Nguyen QD, Grant GRL, Ligon KL, Sorger PK, Chiocca EA, Anderson AC, Kirschmeier PT, Sharpe AH, Freeman GJ, Reardon DA. Concurrent dexamethasone limits the clinical benefit of immune checkpoint blockade in glioblastoma. Clin Cancer Res 2021 January 1;27(1):276–287.

The cover picture illustrates the design process of a new 5‐LO inhibitor through molecular hybridization. The highlighted portions in each chemical structure represent the regions where structural fusion is applied, and the sparks depict the process of fusion. The target compound acts on the 5‐LO protein in mouse, relieving the ear edema. The drugs indicated by the prohibition sign in the bottom right corner are steroid‐based drug and a 5‐LO target drug called Zeiluton, both have toxicity issues. More details are available in the article by Young‐Chang Kim, Aizhan Abdildinova, Ye Jin Shin, Dong Kyun Han, Jong Yeon Hwang, Hyae Gyeong Cheon, Young‐Dae Gong. image

This study aims to evaluate the antioxidant ability and α-glucosidase inhibitory activities of Codonopsisjavanica extract to elucidate its mechanism in the treatment of diabetes type 2. The roots of Codonopsisjavanica were extracted with ethanol solvents and fractionated with n-hexane, ethyl acetate and butanol solvents. The total extract and the fractions were evaluated for free radical scavenging by 2.2-diphenyl-1-picrylhydrazyl method and α-glucosidase inhibitory activity in vitro. The study results show that ethyl acetate fraction from Codonopsisjavanica roots had the strongest antioxidant activity with a value of IC50 of 80.6 ± 2.8 µg/mL and a strong α-glucosidase enzyme inhibitory activity with a value of IC50 of 80.4 ± 5 µg/mL. These data suggest that ethyl acetate fraction from Codonopsisjavanica roots may have potential for the prevention and treatment of diabetes type 2. Keywords Codonopsisjavanica, diabetes type 2, α-glucosidase, antioxidant ability, fraction. 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