Artigos de revistas sobre o tema "Xiu geng tang"

Traditional Chinese medicine (TCM) has been used for thousands of years. Most Chinese herbal formulae consist of several herbal components and have been used to treat various diseases. However, the mechanisms of most formulae and the relationship between formulae and their components remain to be elucidated. Here we analyzed the putative mechanism of San-Huang-Xie-Xin-Tang (SHXXT) and defined the relationship between SHXXT and its herbal components by microarray technique. HepG2 cells were treated with SHXXT or its components and the gene expression profiles were analyzed by DNA microarray. Gene set enrichment analysis indicated that SHXXT and its components displayed a unique anti-proliferation pattern via p53 signaling, p53 activated, and DNA damage signaling pathways in HepG2 cells. Network analysis showed that most genes were regulated by one molecule, p53. In addition, hierarchical clustering analysis showed that Rhizoma Coptis shared a similar gene expression profile with SHXXT. These findings may explain why Rhizoma Coptis is the principle herb that exerts the major effect in the herbal formula, SHXXT. Moreover, this is the first report to reveal the relationship between formulae and their herbal components in TCM by microarray and bioinformatics tools.

Coptis chinensisrhizomes (CR) are one important ingredient of traditional Chinese herbal formulas such as San-Huang-Xie-Xin-Tang which is used for treatment of cardiovascular and neurodegenerative diseases. Recent studies suggest that the extract of CR might be a potential therapeutic agent for amelioration of neurological disorders associated with oxidative stress. In the present study we aimed at revealing the main active compound(s) of the CR extract and at investigating the mechanism of action. Four main alkaloids of the CR extract (berberine, coptisine, jatrorrhizine, and palmatine) were selected for this study. Results showed that out of those alkaloids only pretreatment with coptisine significantly attenuated tert-butylhydroperoxide induced reduction of cell viability, increased rate of apoptosis, and declined mitochondrial membrane potential. Elisa assay and quantitative real-time PCR analyses revealed that thioredoxin-interacting protein (TXNIP) gene expression was downregulated by coptisine, which could explain the neuroprotective effect, hypothetically, by strengthening the thioredoxin defense system against oxidative stress and attenuation of apoptosis signal-regulating kinase (Ask1) mediated apoptotic signaling. A comparison between coptisine and CR extract identified coptisine as the main single component responsible for the neuroprotective effect. Based on the results the CR extract and coptisine are promising candidate agents for prevention or improvement of diabetic neuropathy and neurodegenerative disorders.

Abstract Introduction: Breast cancer is the most common malignancy worldwide in females, with more than 2.26 million new cases and 680 thousand of deaths in 2020. Advanced breast cancer is characterized by complicated genomic landscape and requires comprehensive genomic profiling. However, tissue biopsy is hard to get in patients with recurrent metastasis. Meanwhile, limited studies have been reported to use liquid biopsy and were not capable of reporting gene copy number loss. Here we reported a comprehensive genomic profiling study in advanced breast cancer patients using liquid biopsy. Methods: The prospective study is part of the Predicine’s Phoenix Program, a global molecular biomarkers screening program in multiple solid tumors. Currently, the study enrolled 220 advanced breast cancer patients from 8 centers in China, who were naïve to the 1st line treatment. 10ml of blood was collected from each patient and delivered to a central lab for ctDNA analysis. The study applied PredicineCARE, an NGS-based liquid biopsy assay, to profile somatic mutations, copy number variations, and gene fusions among these patients. Results: The study identified 793 somatic mutations and 283 copy number variants among blood samples from 220 patients. The most common altered genes were TP53(101/220, 46%), PIK3CA(77/220, 35%), BRCA2(37/352, 17%), PTEN(26/220, 12%), and ATM(24/220, 11%). Gene copy number gain incidents were identified on MYC(n=28), AKT3(n=23), FGFR1(n=18), and PIK3CA(n=16), etc. The study also reported gene copy number loss incidents through liquid biopsy, such as CDKN2A(n=17), BRCA1(n=12), TP53(n=11), RB1(n=11), BRCA2(n=10), PTEN(n=9), and ATM(n=8). Conclusions: This study revealed the comprehensive mutational landscape of advanced breast cancer patients through liquid biopsy, providing novel biomarkers for clinical diagnosis and targeted therapy mechanism studies. Citation Format: Haoran Tang, Feng Xie, Yue Zhang, Shidong Jia. Liquid biopsy-based comprehensive genomic profiling reveal mutational landscape in advanced breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1049.

Abstract Introduction: NSCLC accounts for more than 80% of all lung cancer, and has been shown for clinical benefits from targeted therapies, according to tests of multiple genes, such as EGFR, KRAS, ALK, ERBB2. Previous studies revealed molecular characteristics and responses of targeted therapies in NSCLC. However, most studies used tissue biopsies. There is increasing interest to characterize the molecular profile of NSCLC through liquid biopsy. Hence, here we report a comprehensive genomic profiling study in unresectable NSCLC patients using liquid biopsy. Methods: The prospective study is part of the Predicine’s Phoenix Program, a global molecular biomarkers screening program in multiple solid tumors. Currently, the study enrolled 352 unresectable advanced NSCLC patients from 24 centers in China, who were naïve to the 1st line treatment or recurrent after 1st line targeted therapies. 10ml of blood was collected from each patient and delivered to a central lab for ctDNA analysis. The study applied PredicineCARE, an NGS-based liquid biopsy assay, to profile somatic mutations, copy number variations, and gene fusions among these patients. Results: The study identified 1614 somatic mutations and 202 copy number variants among blood samples from 352 patients. The most common altered genes were TP53(176/352, 50%), EGFR(144/352, 41%), PIK3CA(35/352, 10%), CDNK2A(35/352, 10%), KRAS(28/352, 8%), and RB1(28/352, 8%). Gene copy number gain incidents were identified on MYC(n=22), PIK3CA(n=16), EGFR(n=15), and MET(n=7), etc. Notably, the study also reported gene copy number loss incidents through liquid biopsy, such as CDKN2A(n=16), PTEN(n=11), and RB1(n=10). The study identified 12 gene fusion incidents, including 7 EML4-ALK fusions, 2 RET fusions(KIF5B-RET and NCOA4-RET), 2 NTRK fusions(ETV6-NTRK3 and NOS1AP-NTRK1), and 1 rare CD74-NRG1 fusion. Conclusions: This study revealed the comprehensive mutational landscape of advanced NSCLC through liquid biopsy, providing novel biomarkers for clinical diagnosis and targeted therapy mechanism studies. Citation Format: Haoran Tang, Feng Xie, Yue Zhang, Shidong Jia. Liquid biopsy-based comprehensive genomic profiling reveal mutational landscape in real-world patients with unresectable NSCLC. [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 5582.

Abstract Mutated KRAS proteins are ideal cancer targets, as they are expressed frequently and specifically in certain solid tumors. A large proportion of human colorectal cancer and pancreatic ductal adenocarcinoma express the tumor driver KRAS gene mutations G12V/G12D, but drugs targeting G12V/G12D are not available, revealing a huge unmet clinical need. While small molecules often fail to target the KRAS mutation G12V/G12D, T cell receptor-mimic (TCR-mimic) antibodies can specifically recognize KRAS mutations presented by human leukocyte antigen (HLA), opening up possibilities for targeting such intracellular antigens. Here, we discovered novel antibodies highly specific to G12V/HLA and G12D/HLA complexes by immunizing our proprietary RenTCR-mimicTM mice and using high-throughput Beacon-based screening. These TCR-mimic antibodies have higher affinities compared to endogenous TCRs, which may effectively reduce the possibility of tumor escape. Germline distribution analysis indicated their high sequence diversity, which suggests diverse epitope targeting. Although pancreatic cancer is extremely difficult to treat and has an extremely low KRAS mutant peptide-HLA complex density on the cell surface, our TCR-mimic antibodies exhibited potent in vitro tumor lysis activity when assembled into CD3 T cell engagers. Furthermore, these antibodies demonstrated convincing off-target safety. Together, our results indicate promising therapeutic potential of these KRAS mutation-targeted TCR-mimic antibodies for the treatment of solid tumors. Citation Format: Jun Du, Wanbo Tang, Xin Jiao, Limin Zhao, Pengfei Du, Yuqi Zhang, Jian Bao, Han Chen, Chaoshe Guo, W. Frank An. Targeting mutant KRAS proteins with novel TCR-mimic fully human antibodies [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 6717.

Abstract Background: Non-Small Cell Lung Cancer (NSCLC), accounting for over 80% of all lung cancers, benefits from targeted therapies based on genetic tests like EGFR, KRAS, ALK, and ERBB2. While prior studies focused on molecular characteristics through tissue biopsies, limited research has explored NSCLC molecular profiles via liquid biopsy, especially across different human races. This study presents a comprehensive genomic profiling analysis of unresectable NSCLC patients in the U.S. and China, using a globally harmonized liquid biopsy assay. Methods: As part of Predicine's Phoenix Program, a global molecular biomarkers screening initiative, 61 patients in the U.S. and 352 patients in China with unresectable advanced NSCLC were enrolled. All were treatment-naïve or recurred after 1st-line targeted therapies. Blood samples (10ml) were tested using PredicineCARE, an NGS-based liquid biopsy assay, to profile somatic mutations, copy number variations, and gene fusions. Results: The assay, validated in both regions using the same reference materials, achieved a Limit of Detection (LOD) of 0.25% mutation allele frequency, with a positive predictive value exceeding 99%. Profiling NSCLC patients in the U.S. and China revealed common genes like TP53, CDKN2A, EGFR, KRAS, RB1, and PIK3CA. TP53 and PIK3CA variations showed equivalent prevalence. However, EGFR variations were significantly higher in China (p<0.05), while CDKN2A (p<0.001), KRAS (p<0.01), and RB1 (p<0.01) variations were notably higher in the U.S. Conclusions: This study unveils the mutational landscape of advanced NSCLC through liquid biopsy. Unique prevalence patterns between U.S. and China cohorts suggest novel biomarkers for clinical diagnosis and provide insights for targeted therapy mechanism studies. Citation Format: Haoran Tang, Cancan Jia, Feng Xie, Yue Zhang, Xiaoxi Dong, Yong Huang, Shading Jia. Comparative genomic profiling of unresectable NSCLC patients in the U.S. and China using a globally harmonized liquid biopsy assay platform [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 2410.

Abstract Background Osteosarcoma (OS) is a highly aggressive malignant tumor of mesenchymal origin and prone to early hematogenous metastases. The 5-year overall survival of metastatic OS is only approximately 20% to 30%. Therefore, it is still clinical dilemma in the treatment of OS. Thus,understanding the molecular features of metastatic osteosarcoma become increasingly important. Methods Formalin-fixed, paraffin-embedded or fresh tissues and matched blood samples were collected from OS patients for whole exome sequencing using next-generation sequencing at OrigiMed (Shanghai, China), a College of American Pathologists accredited and Clinical Laboratory Improvement Amendments certified laboratory. Genomic alterations including single nucleotide variations (SNVs), short and long insertions/deletions (INDELs), copy number variations (CNVs), and gene rearrangements were assessed. Tumor mutational burden (TMB) and the number of tumor neoantigens (NEO) were also measured. Results In total, 38 patients including 29 males and 9 females were recruited with a median age of 19.5 years. Among them, 12 patients had first metastases to bone (group B). The metastatic sites included femur, fibula, pelvis, ribs, sacrum, and spine. The median age of group B was 19.5 years. Twenty-six (26) patients had first metastases to lung (group L). The median age of group L was 14 years.The most frequently mutated genes in OS was TP53 (55.3%), followed by MYC (36.8%), MUC16 (26.3%), PTK2 (21.1%), RAD21 (21.1%), and CDK4 (18.4%). However, genetic features between Groups B and Group L patients were different. In group B patients, the median percentage of SNVs and short INDELs was 94.7% of the overall mutations, and the median percentage of CNVs was 4.3%. In contrast, the median percentage of SNVs and short INDELs in group L was 58.8%, and the median percentage of CNVs was 36.7%. The mutations patterns were clearly different between Group B and Group L with a predominant SNV & INDEL in Group B and a mixture feature of SNV & INDEL and CNV in Group L. Inaddition the median TMB in group B was significantly higher than that in group L (4.85 muts/Mb vs 2.4 muts/Mb, P<0.05). Also, the median number of tumor NEO in group B was nearly 6 times higher than that in group L (743 vs 128.5, P=0.0016). Conclusion Our study identified different molecular features of patients with OS firstly metastasizing to lung and to bone. OS with first bone metastases had a predominant SNV and short INDEL, high TMB level, and high NEO counts, while OS with first lung metastasis had an increased CNV, low TMB, and low NEO counts. Our results suggest that metastatic OS that firstly spread to bone and to lung may be two distinct subgroups and may adopt different treatment strategies. Citation Format: Lu Xie, Zhenyu Cai, Xiaodong Tang, Wei Guo, Fanfei Meng, Xin Zhang, Xiaoliang Shi, Fei Pang. Distinct genetic features between osteosarcomas firstly metastasizing to bone and to lung [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 5669.

Abstract Homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene occurs in approximately 15% of all cancers due to its proximity to the commonly deleted tumor suppressor gene CDKN2A. Elevated methylthioadenosine (MTA) levels, driven by loss of MTAP, compete with the methyl donor S-adenosylmethionine (SAM) for binding to protein arginine N-methyltransferase 5 (PRMT5), placing the methyltransferase in a hypomorphic state, and vulnerable to further PRMT5 inhibition. The screening of a DNA-encoded library, designed to identify small molecules that preferentially bind to PRMT5 in the presence of MTA, resulted in the identification of AM-9934 as a promising hit. Using structure-based drug design, potency and cooperativity were enhanced to deliver AM-9747, an MTA-cooperative PRMT5 inhibitor suitable for in vivo proof-of-concept studies. Further optimization led to AMG 193, an orally bioavailable and MTA-cooperative PRMT5 inhibitor with potent biochemical and cellular activity, and an improved pharmacokinetic profile. Insights into the binding mode of AMG 193 were elucidated by the crystal structure of AMG 193 bound to the MTA-PRMT5 complex. AMG 193 activity is enriched in MTAP-null cells in vitro, as illustrated in the HCT116 isogenic pair; AMG 193 is ~40X selective for MTAP-null cells (IC50 = 0.1 mM) over MTAP WT cells (IC50 > 4 mM) in viability assays and >100X selective in an assay evaluating symmetric dimethylarginine (SDMA) levels. AMG 193 was profiled in a panel of >850 cancer cell lines, and response demonstrated preferential sensitivity in MTAP-null cells compared to WT across multiple cancer lineages, including pancreatic, lung, biliary tract, and lymphoma. Response strongly correlated with both MTAP and CDKN2A copy number loss, and cell lines that were dependent on PRMT5, as shown by RNAi and CRISPR knockdown, were most sensitive to AMG 193 treatment. In vitro mechanism-of-action studies demonstrated that PRMT5 inhibition induced DNA damage, cell cycle arrest in G2/M, and an increase in alternative mRNA splicing in MTAP-null cells. In mice oral, once-daily administration of AMG 193 selectively inhibited SDMA in tumor versus normal tissue and was well tolerated with no hematologic perturbations. Importantly, AMG 193 demonstrated robust anti-tumor activity across a broad range of MTAP-null CDX and PDX tumor models derived from NSCLC, pancreatic, and esophageal cancers. In vitro synergy was observed with the combination of AMG 193 and several chemotherapeutic agents, including carboplatin and paclitaxel, or the KRASG12C inhibitor, sotorasib. In vivo, these combinations led to enhanced anti-tumor activity relative to single agent in MTAP-null NSCLC tumor models. In February 2022, AMG 193 became the first MTA-cooperative PRMT5 inhibitor to enter clinical development and is currently being evaluated in subjects with advanced MTAP-null solid tumors in the ongoing FIH study (NCT05094336). Citation Format: Brian Belmontes, Katherine Slemmons, Siyuan Liu, Antonia Policheni, Jodi Moriguchi, Hong Tan, Fang Xie, Famke Aeffner, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Mikkel Vestergaard, Sanne Cowland, Jan Andersson, Ian Sarvary, Patricia Lopez, Nuria Tamayo, Liping H Pettus, Susmith Mukund, Jennifer R Allen, Sanne Glad, Matthew P Bourbeau. The discovery and preclinical characterization of AMG 193, a first-in-class MTA-cooperative PRMT5 inhibitor with broad activity against MTAP-null cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B177.

Abstract Background: Colorectal cancer (CRC) is one of the most common causes of cancer-related death in the world. More comprehensive studies of key molecular alterations in CRC progression were urgent. DNA methylation promotes tumor progression. However, the mechanism of the ANKRD13 gene methylation that drives colorectal cancer evolution remains largely unknown. This was the first study focused on the role of ANKRD13 and the hypermethylated mechanisms in colorectal cancer. Methods: Chi-Square tests were utilized to the comparison of the baseline characteristics of patients with hypomethylation ANKRD13B and hypermethylated ANKRD13B. Kaplan-Meier analysis were used to estimate the difference of overall survival between the two groups patients. The methylation level of ANKRD13B was quantified by qMSP in colorectal cancer, normal colon epitheliums and colorectal adenoma tissues. CRISPR/dCas9-DNMT3A and CRISPR/dCas9-TET1-CD methylation editing tools were applied to enable targeted and specific CpG methylation at the CpG loci near stop codon of ANKRD13B. Transwell-migrated assay, wound scratch assay and colony formation assay were preformed to ascertain the abilities of viability, migration and invasion in the editing CRC cell lines. The methylated RNA immunoprecipitation (MeRIP) assays, chromatin immunoprecipitation (ChIP) assays and 5-AZA treatment assays were performed combined with qPCR to quantify the m6A levels of ANKRD13B mRNA following hypermethylated-editing. Results: Here, we identified a novel oncogenic gene, ANKRD13B, encoding ankyrin repeat domain 13B. This gene was frequently hypermethylated in CpG islands surrounding the stop codon region of colorectal cancer. This hypermethylation was associated with poor clinical outcomes in patients diagnosed with colorectal cancer. Compared with normal tissue (4.2%), this type of epigenetic alteration upregulated ANKRD13B expression in both adenoma (73.0%) and adenoma cancer tissues (83.3%) (P< 0.0001), and it also promoted colorectal cancer cell growth, invasion, and migration. Demethylation treatment can reduce the ANKRD13B expression and the growth, migration, and invasion of the cancer cell. Moreover, we found that the aberrant ANKRD13B methylated surrounding the stop codon, and it can promote RNA N6-methyladenosine methylation modification, suggesting that aberrant DNA 5mC methylation promotes ANKRD13B expression and tumor progression in an RNA m6A-dependent manner. Conclusions: In summary, our findings illustrated that ANKRD13B is an oncogenic gene of colorectal cancer that is commonly methylated and overexpressed in colorectal cancer whose function in the pathogenesis of colorectal cancer depends on RNA m6A-dependent manner. Aberrant DNA 5mC methylation promotes ANKRD13B expression and tumor progression in an RNA m6A-dependent Manner. Key words: ANKRD13B, DNA methylation, Epigenetic regulation, Colorectal cancer Citation Format: JingRong Weng, JinXin Lin, YuMo Xie, GuanNan Tang, LiangLiang Bai, JinHua Chen, ZengHong Huang, ZhuoKai Zhuang, ShaoYong Peng, Heng Wang, GaoPo Xu, Yu Zhang, XiaoXia Liu, MeiJin Huang, YanXin Luo, XiaoLin Wang, Huichuan Yu. RNA m6A methylation relay the oncogenic flow from DNA methylationto gene expression of ANKRD13B [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 6006.

Abstract Background: Breast cancer stands as the most prevalent malignancy affecting women’s health. The disease consists of three subtypes, including hormone receptor (HR) positive, HER2-positive, and triple-negative breast cancer (TNBC). In recent years, the advent of targeted therapies such as PI3K inhibitors has significantly improved the prognosis of breast cancer patients. However, the detection of relevant molecular markers, such as PIK3CA mutations, relies on tissue samples, which imposes limitations on the clinical application of these therapies. Consequently, this study presents a comprehensive analysis of genomic profiling that compares breast cancer patients across distinct pathological classifications, utilizing a liquid biopsy approach. Methods: In this retrospective study, 214 patients with advanced breast cancer were recruited. Plasma samples collected prior to first line treatment were analyzed using PredicineCARE, a targeted next-generation sequencing (NGS) liquid biopsy assay, to detect somatic alterations in ctDNA of blood, including single nucleotide variations (SNVs), gene fusions, and copy number variations (CNVs). Results: Based on the IHC classifications of tumor tissue, this cohort comprised 119 HR-positive, 61 HER2-positive, and 34 TNBC patients. The assay identified a total of 1456 mutations and 2357 gene copy number variants in plasma samples. Among these, the most frequently mutated genes and those with copy number variations (top 5) in HR-positive patients were TP53 (40%), PIK3CA (39%), ATM (22%), ERBB2 (19%), and FGFR1 (19%). In HER2-positive patients, they were TP53 (39%), PIK3CA (31%), ERBB2 (30%), NTRK1 (20%), and RAD50 (20%). For TNBC patients, the top genes were TP53 (59%), ERBB2 (44%), PIK3CA (35%), NTRK1 (35%), and BRCA2 (26%). Regarding the PIK3CA gene, the most prevalent mutation site was H1047, occurring in 12.61% of HR-positive patients, 14.75% of HER2-positive patients, and 11.76% of TNBC patients. Similarly, both E542 (4.20% in HR-positive, 3.28% in HER2-positive, and 2.94% in TNBC patients) and E545 (3.36% in HR-positive, 3.28% in HER2-positive, and 2.94% in TNBC patients) showed equivalent prevalence across the three classifications. These findings suggest the potential efficacy of PI3K inhibitors in various pathological types of breast cancer. Conclusions: This study offers insights into the genomic landscape of advanced breast cancer subtypes through liquid biopsy. The observed prevalence of PIK3CA mutations supports the potential efficacy of PI3K inhibitors across these diverse types of breast cancer, laying the groundwork for personalized therapeutic strategies and biomarker identification for prognosis and targeted therapies. Citation Format: Xiaoran Liu, Yaxin Liu, Cancan Jia, Yue Zhang, Feng Xie, Haoran Tang, Shidong Jia, Huiping Li. Comprehensive genomic profiling of advanced breast cancer subtypes: Insights from liquid biopsy analysis and implications for personalized therapies [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 1752.

Abstract The potential for synthetic lethality occurs when the same oncogenic events that promote carcinogenesis, also create vulnerabilities for cancer cells. Targeting cancers with these vulnerabilities, but not resident normal tissues, is the promise of synthetic lethal therapies. The compound LC30 is a potent and orally bioavailable compound that is synthetic lethal with deregulated MYC. No off-target liabilities have been demonstrated by kinome and safety profiling and long-term treatment is well tolerated by rodents and canines. LC30 is active against a wide spectrum of cell line xenografts derived from both liquid and solid cancers, including B and T cell malignancies, lung, colon, gastric, mammary and liver cancer cell lines, with efficacy that correlates with levels of MYC. Experiments aimed at unlocking the key to LC30’s synthetic lethality have revealed that LC30 is active in both resting cells and during cell division, so it is not simply an anti-mitotic compound. In resting cells, LC30 disrupts golgi structure, a phenotype that possibly relates to MYC control of centrosomal gene expression. Anti-angiogenic effects are observed in xenografts and have been confirmed using in vitro assays of endothelial cell migration and tubule formation. We speculate that the golgi phenotype and resulting faulty trafficking of secretory vesicles containing pro-angiogenic factors may underly the vascular phenotype. In dividing cells, LC30 potently deregulates the positioning of the chromosomal passenger protein complex (CPPC), a mitotic complex comprised of a catalytic subunit, Aurora B kinase (AURKB), the scaffolding protein inner centromere protein (INCENP) as well as survivin and borealin. The CPPC is dynamically relocated during mitotic progression so that AURKB activity can be localized to specific locations where activity is required. The phenotypic effects of LC30 treatment are consistent with this compound functioning as an inhibitor of the localization, but not catalytic activity of the CPPC. This includes the induction of multipolar spindles, micronuclei and polyploidy, leading to mitotic arrest and both mitotic and post-mitotic apoptosis. This unique mode-of-action, to disrupt CPPC passage in the mitotic cell, is a key component of the MYC synthetic lethality as cells without MYC overexpression do not develop multipolar spindles, lethal polyploidy and apoptose with treatment. LC30 represents a new class of anticancer compound that is a non-kinase, synthetic lethal inhibitor that unlocks MYC-induced vulnerabilities in cancer cells. Citation Format: Qiong Shi, Ting Zhang, Julia Kalashova, Jinhua Li, Chenglu Yang, Hongmei Li, Xiaohu Zhou, Yan Long, Yidan Xia Abuliezi, Gang Lv, Duo Yu, Shenqiu Zhang, Jing Zhang, Thaddeus D Allen, Hong Liu, Dun Yang. An orally available small molecule inhibitor for synthetic lethal targeting of MYC expressing tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C10.

Abstract Background: Cancers often overexpress multiple clinically relevant oncogenes. However, it is not known if multiple oncogenes within a cancer combineuniquely in specific cellular sub-populations to influence clinical outcome.We studied this phenomenon using the prognostically relevantoncogenes MYC, BCL2 and BCL6 in Diffuse Large B-Cell Lymphoma(DLBCL). Methods: Quantitative multispectral imaging simultaneously measured oncogene co-expression at single-cell resolution in reactive lymphoid tissue (n=12)and four independent cohorts (n=409) of DLBCL. Mathematically derived co-expression phenotypes were evaluated in DLBCLs with immunohistochemistry (n=316) and nine DLBCL cohorts with gene expression data (n=3974). Bulk and single-cell RNA sequencing was performed on patient-derived B-cells with induced co-expression of MYC,BCL2 and BCL6. Results: Unlike in non-malignant lymphoid tissue where the co-expression of MYC, BCL2 and BCL6 in a B-cell is limited, DLBCLs show multiple permutations of oncogenic co-expression in malignant B-cells. The percentage of cells with a unique combination MYC+BCL2+BCL6-(M+2+6-) consistently predicts survival in contrast to that of other combinations (including M+2+6+). An estimated percentage of M+2+6-cells can be derived from any quantitative measurement of the component individual oncogenes, and correlates with survival in immunohistochemistry and gene expression datasets. Comparative transcriptomic analysis of DLBCLs and transformed patient-derived B-cells identifies cyclin D2 (CCND2) as a potential BCL6-repressedregulator of proliferation in the M+2+6- population. Conclusions: Unique patterns of oncogene co-expression at single-cell resolution affect clinical outcomes in DLBCL. Similar analyses evaluating oncogenic combinations at the cellular level may impact diagnostics and target discovery in other cancers. Citation Format: Michal M. Hoppe, Patrick Jaynes, Shuangyi Fan, Yanfen Peng, Shruti Sridhar, Phuong Mai Hoang, Xin Liu, Sanjay de Mel, Limei Poon, Esther Chan, Joanne Lee, Choon Kiat Ong, Tiffany Tang, Soon Thye Lim, Chandramouli Nagarajan, Nicholas F. Grigoropoulos, Soo-Yong Tan, Susan Swee-Shan Hue, Sheng-Tsung Chang, Shih-Sung Chuang, Shaoying Li, Joseph D. Khoury, Hyungwon Choi, Pedro Farinha, Anja Mottok, David W. Scott, Carl Harris, Alessia Bottos, Gayatri Kumar, Kasthuri Kannan, Laura J. Gay, Hendrik F. Runge, Ilias Moutsopoulos, Irina Mohorianu, Daniel J. Hodson, Yen-Chee Lin, Wee-Joo Chng, Siok-Bian Ng, Claudio Tripodo, Anand D. Jeyasekharan. Patterns of oncogene co-expression at single cell resolution influence survival in diffuse large B-cell lymphoma. [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 5557.

Abstract A large fraction of tumors with BRCA1 or BRCA2 mutations only have weak responses to PARP inhibitor (PARPi) treatment, and often develop PARPi resistance. To address these challenges, we have developed SYX1097, a selective and potent oral Polθ inhibitor as a single agent or in combination with PARPi for treating tumors with BRCA mutations. Both Polθ and PARP1 play key roles in microhomology-mediated end joining for DNA double-strand repair and in single-strand DNA gap filling during DNA replication. Using in vitro cellular assays and in vivo animal models, we show that SYX1097 alone or combined with PARPi without obvious side effects. SYX1097 dramatically inhibited proliferation in BRCA -/- isogenic cells with IC50 <20 nM, while only had very weak effect on their parental cells (>10000nM). SYX1097 also enhanced tumor cell sensitivity to Olaparib 5 to 15 times. SYX1097 in vivo efficacious started at 50mg/kg mono-therapy, and generate >50% tumor regression at 5mg/kg when combined with Olaparib. In a 20-day repeated dosing study, SYX1097 200mg/kg BID was fully tolerated by mice. When considering additive hematological toxicity, comparing with “ATRi + PARPi”, “SYX1097 + PARPi” manifested deep and durable tumor regression without significant body weight loss or reticulocytes decrease. Moreover, SYX1097 is found synthetic lethal with defect of genes not involved in homologous recombination repair and able to suppress tumors with specific gene defect in vivo, which indicated SYX1097 can be used as single agent guided by specific biomarker.SYX1097 has a clean safety profile tested with Safety-Screen 44TM Panel, and is well tolerated in mice, rats and dogs. It possesses remarkable pharmacokinetic properties in various species, with no hematological toxicity observed during the preclinical toxicity studies. SYX1097 is advancing towards IND filing in 2024.Collectively, SYX1097 is a promising small molecule that may be utilized as a single agent or in combination with PARPi for cancer treatment not only limited by HR deficiency. Citation Format: Yilan Zhang, Kai Jiang, Xiaokang Xu, Liu Wu, Chongxun Ge, Yue Xie, Hu He, Song Liu, Xuzhen Tang, Song Shi. Clinic-ready Polθ inhibitor SYX1097 suppresses solid tumors in vivo [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 7119.

Abstract Background: Molecular characteristics play a pivotal role in cancer diagnosis, treatment selection, and disease monitoring across various tumor types. While previous research has elucidated the molecular classification of colorectal cancer using tissue NGS, limited investigation has explored the molecular profile of colorectal cancer through liquid biopsy, especially across diverse human races. This study presents a comprehensive genomic profiling analysis of colorectal cancer patients, using a globally harmonized liquid biopsy assay to compare patient cohorts from both the U.S. and China. Methods: The prospective study is part of Predicine’s Phoenix Program, a global molecular biomarker screening initiative across multiple solid tumors. At present, the study has enrolled 57 patients in the U.S. and 62 patients in China, all presenting with advanced colorectal cancer. A 10ml blood sample was collected from each patient and tested using PredicineCARE, an NGS-based liquid biopsy assay, to profile somatic mutations, copy number variations, and gene fusions among these patients. Results: The assay, validated in both the U.S. and China using the same reference materials, achieved a LOD of 0.25% mutation allele frequency, with a positive predictive value exceeding 99%. Subsequently, the assay was applied to profile molecular aberrations in colorectal patients in both the U.S. and China. Among U.S. patients, the most commonly altered genes were APC (60%), KRAS (56%), TP53 (54%), MYC (25%), PIK3CA (16%), and EGFR (14%). In Chinese patients, the predominant altered genes were TP53 (48%), APC (42%), KRAS (32%), GNAS (21%), EGFR (16%), and PIK3CA (11%). The prevalence of GNAS variations was significantly higher in China than in the U.S. (p < 0.05), while the prevalence of APC (p < 0.05), KRAS (p < 0.01), and MYC (p < 0.001) variations was significantly higher in the U.S. than in China. Conclusions: This study reveals the extensive mutational landscape in advanced colorectal cancer patients through liquid biopsy. Distinct prevalence patterns in certain genes between the U.S. and China cohorts offer novel biomarkers for clinical diagnosis and provide insights for targeted therapy mechanism studies. Citation Format: Haoran Tang, Cancan Jia, Feng Xie, Yue Zhang, Xiaoxi Dong, Yong Huang, Shidong Jia. Genomic profiling of colorectal cancer - insights from liquid biopsy comparisons between U.S. and China cohorts [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 5015.

Abstract Introduction: Molecular characteristics have significant clinical values in cancer distinguishing, treatment selection, and disease monitoring across large numbers of tumors. Previous studies have revealed the molecular classification of GI tract tumors through biomarkers such as gene alternations, MSI, EBV, and chromosomal instability (CIN). However, the clinical utility of these biomarkers remained limited. Here we reported a comprehensive genomic profiling study, comparing molecular characteristics between unresectable gastric and colon cancer patients. The study also investigated the potential use of molecular biomarkers for longitudinal disease monitoring. Methods: The prospective study planned to collect tissue and plasma samples from 200 unresectable GI tract cancer patients. Currently, 17 gastric cancer patients and 11 colon cancer patients were enrolled. Baseline tumor tissue samples were collected from 19 patients and baseline plasma samples were collected from 9 patients whose tissue biopsies were unavailable. Patients were then treated with targeted and chemo- therapies. Among the patients whose baseline plasma samples were collected, longitudinal plasma samples were collected from 7 patients every 2 weeks during treatment. Baseline tissue and plasma samples were tested using the 600-genes PredicineATLAS. The study also applied PredicineCNB, a low-pass whole-genome sequencing (LP-WGS) assay, using baseline and longitudinal plasma samples to monitor disease during treatment. Results: The PredicineATLAS assay identified 135 somatic gene mutations and 40 copy number variants among 28 patients. The median tumor mutation burden (TMB) was 4.15 Muts/Mb while the maximum TMB was 14.30 Muts/Mb. The genes with the most common alternations were TP53 (76% in gastric cancer and 64% in colon cancer), APC (24% in gastric cancer and 64% in colon cancer), and MYC (24% in gastric cancer and 64% in colon cancer). Meanwhile, the prevalence of PIK3CA and KRAS mutations was significantly higher in colon cancer than in gastric cancer (PIK3CA: colon 7/11 vs. gastric 2/17, p<0.05; KRAS: colon 8/11 vs. gastric 0/17, p<0.001). Among those 7 patients whose diseases were monitored by PredicineCNB during treatment, 5 patients were observed to have significant decrease in blood-based copy number burden (bCNB) score, after two weeks of treatment. Notably, one colon patient, who has been monitored for 5 timepoints by now, showed continually decreasing bCNB score and reached the criteria of healthy donor judging by an in-house database. Conclusions: This study compared the variation landscape between gastric and colon cancer patients, and demonstrated the technical feasibility of genome-wide copy number variations through liquid biopsy, revealing its potential clinical utility of longitudinal disease monitoring. Citation Format: Haoran Tang, Feng Xie, Yue Zhang, Shidong Jia. Comparative genomic profiling and disease monitoring in unresectable gastric and colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2197.

Background:Gout is a chronic autoinflammatory disease caused by monosodium urate (MSU) crystal deposition [1].Acute gout is characterized by an acute inflammatory reaction that resolves spontaneously within a few days[2], which is one of the distinguishing features of gout compared to other arthropathies or self-inflammatory diseases. Autophagy is a lysosomal degradation pathway that is essential for cellular growth, survival, differentiation, development and homeostasis [3]. Studies have demonstrated that autophagy might play a key role in the pathogenesis of primary gouty arthritis (GA) [4-7]. However, the roles of autophagy in the development of gout have not yet been elucidated.Objectives:The aim of our study was to investigate the changes in autophagy-related gene (ATG) mRNA and protein in patients and the clinical importance of these genes in primary gouty arthritis (GA) and to explore the roles of autophagy in the pathogenesis of GA.Methods:The mRNA and protein expression levels of ATGs (ATG3, ATG7, ATG10, ATG5, ATG12, ATG16L1, ATG4B and LC3-2) were measured in peripheral blood mononuclear cells (PBMCs) from 196 subjects, including 57 acute gout patients (AG group), 57 intercritical gout patients (IG group) and 82 healthy control subjects (HC group). The relationship between ATG expression levels and laboratory features was analyzed in GA patients.Results:The expression levels of ATG4B, ATG5, ATG12, ATG16L1, ATG10 and LC3-2 mRNA were much lower in the AG group than in the IG and HC groups (p<0.05), while the ATG7 mRNA level was much higher in the AG group than in the IG and HC groups (p<0.05). The protein expression levels of LC3-2, ATG3, ATG7 and ATG10 were much higher in the AG group than in the other groups, while those of ATG5, ATG12, ATG16L1 and ATG4B were far lower in the AG group than in the other groups (p<0.05). In GA patients, the levels of ATG mRNA and protein correlated with laboratory inflammatory and metabolic indexes.Conclusion:Altered ATG expression suggests that autophagy is involved in the pathogenesis of GA and participates in regulating inflammation and metabolism.References:[1]Dalbeth N, Choi HK, Joosten LAB, Khanna PP, Matsuo H, Perez-Ruiz F, et al. Gout. Nat Rev Dis Primers. 2019;5: 69.doi:10.1038/s41572-019-0115-y.[2]Schauer C, Janko C, Munoz LE, Zhao Y, Kienhöfer D, Frey B, et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat Med. 2014;20: 511-517.doi:10.1038/nm.3547.[3]Han Y, Zhang L, Xing Y, Zhang L, Chen X, Tang P, et al. Autophagy relieves the function inhibition and apoptosis-promoting effects on osteoblast induced by glucocorticoid. Int J Mol Med. 2018;41: 800-808. doi:10.3892/ijmm.2017.3270.[4]Yang QB, He YL, Zhong XW, Xie WG, Zhou JG. Resveratrol ameliorates gouty inflammation via upregulation of sirtuin 1 to promote autophagy in gout patients. Inflammopharmacology. 2019;27: 47-56.doi:10.1007/s10787-018-00555-4.[5]Mitroulis I, Kambas K, Chrysanthopoulou A, Skendros P, Apostolidou E, Kourtzelis I, et al. Neutrophil extracellular trap formation is associated with IL-1β and autophagy-related signaling in gout. PLoS One. 2011;6: e29318.doi: 10.1371/journal.pone.0029318.[6]Crişan TO, Cleophas MCP, Novakovic B, Erler K, van de Veerdonk FL, Stunnenberg HG, et al. Uric acid priming in human monocytes is driven by the AKT-PRAS40 autophagy pathway. Proc Natl Acad Sci U S A. 2017;114: 5485-5490.doi:10.1073/pnas.1620910114.[7]Lee SS, Lee SW, Oh DH, Kim HS, Chae SC, Kim SK. Genetic analysis for rs2241880(T > C) in ATG16L1 polymorphism for the susceptibility of Gout. J Clin Rheumatol. 2019;25: e113-e115.doi:10.1097/rhu.0000000000000685.Disclosure of Interests:Yu-Qin Huang: None declared, Quan-Bo Zhang Grant/research support from: National Natural Science Foundation of China(General Program) (no.81974250) and Science and Technology Plan Project of Sichuan Province (no.2018JY0257), Jian-Xiong Zheng: None declared, gui-lin jian: None declared, tao-hong liu: None declared, Xin He: None declared, fan-ni xiao: None declared, qin xiong: None declared, Yu-Feng Qing Grant/research support from: Science and Technology Project of Nanchong City (no.18SXHZ0522)

Abstract Cutaneous T cell lymphoma (CTCL) is an incurable skin homing T cell malignancy. We have previously reported p38 as therapeutic targets for CTCL.1 However, the mechanism underlying p38 signaling is not completely understood. To further investigate p38 and its downstream signaling components, we examined public database of gene expression and found that p38γ is overexpressed in CTCL as compared to normal T cells. In addition, p38γ has negligible expression in normal lymphoid tissues, with the exception of high level expressed in smooth and cardiac muscle cells. We have demonstrated that p38γ over-expression increases cell proliferation and knockdown of p38γ causes Hut78 cell death. p38γ plays an important role in inflammation-associated tumorigenesis3 and inhibition of its activity has emerged as a strategy to treat a spectrum of cancers.4 The transcription factor, NFATc4, downstream of p38γ, is also significantly up-regulated in CTCL cells by microarray analysis, and it is at non-detectable level in normal T cells.1We have demonstrated that shRNA-mediated knockdown of p38γ reduced NFATc4 mRNA levels in Hut78 cells, and that inhibition of NFATc4 by siRNA reduces the proliferation of CTCL cells. We also found that the cytokine IL17A functions downstream of p38γ and NFATc4, as knockdown of either p38γ or NFATc4 significantly reduced IL17A mRNA levels in Hut78 cells. This result suggests that IL17A is a target for transcriptionally activated NFATc4. Previously we have shown that IL17A rescues Hut78 cells from apoptosis induced by combined inhibition of NFAT and NFkB (treated with curcumin and Ly2228820). This implicates IL17A as a key mediator for CTCL survival. Therefore, we propose a novel p38γ - NFATc4 - IL17A signaling pathway in malignant T cells that promotes the survival of CTCL which provides potential therapeutic target against this disease. To further define the role of p38 and identify targets that increase the antitumor efficacy of p38 inhibition, we performed a synthetic lethal RNA interference (RNAi) screen in Hut78 cells treated with 10 µM of the p38 MAPK inhibitor Ly2228820. We transduced control and Ly2228820-treated Hut78 cells with a pooled retroviral RNAi library consisting of 4290 shRNAs that targeted more than 1000 genes involved in human cancers. If a shRNA from the library is not toxic to the control cells, but causes cell death in Ly2228820-treated cells, the gene targeted by this shRNA would be identified by the screen as synthetically lethal to p38 inhibition. Among many hits identified from the screen, we selected UCHL5 for further analysis. UCHL5encodes a deubiquitin enzyme that cleaves K48-linked polyubiquitin chains and plays an important role in the regulation of protein stability. Interestingly, combination of Ly2228820 and b-AP15, a small molecule inhibitor of UCHL5, significantly reduced the protein levels of NFATc4 isoform but not other NFAT isoforms. NFATc4 protein levels are known to be regulated by ubiquitin-proteasome pathway.2 Our finding thus suggests UCHL5 as a potential new regulator that stabilizes NFATc4 protein. Further studies are needed to confirm this prediction. More importantly, combination of Ly2228820 and b-AP15 enhanced apoptosis in CTCL cell lines (HH and Hut78) and primary Sézary cells, but was not toxic in normal PBMC cells. In summary, our findings suggest that the p38γ - NFATc4 - IL17A signaling pathway plays an important role in the survival of CTCL. In addition, improving the efficacy of targeting this pathway via p38 may also benefit from combined inhibition of UCHL5, a potentially important regulator of NFATc4 that needs further characterization. Reference: 1 Bliss-Moreau M, Coarfa C, Gunaratne PH, Guitart J, Krett NL, Rosen ST (2015). Identification of p38beta as a therapeutic target for the treatment of Sezary syndrome. The Journal of investigative dermatology135:599-608. 2 Fan Y, Xie P, Zhang T, Zhang H, Gu D, She M et al (2008). Regulation of the stability and transcriptional activity of NFATc4 by ubiquitination. FEBS letters582:4008-4014. 3 Qi X, Yin N, Ma S, Lepp A, Tang J, Jing W et al (2015). p38gamma MAPK Is a Therapeutic Target for Triple-Negative Breast Cancer by Stimulation of Cancer Stem-Like Cell Expansion. Stem cells33:2738-2747. 4 Yin N, Qi X, Tsai S, Lu Y, Basir Z, Oshima K et al (2015). p38gamma MAPK is required for inflammation-associated colon tumorigenesis. Oncogene. Disclosures Querfeld: Actelion: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Objective: Due to the shared pathogenesis of asthma and rheumatoid arthritis (RA), patients with asthma were found to have a higher risk of RA. While the benefits and safety of Chinese herbal medicine (CHM) for asthma have been reported, the scientific evidence regarding its effect on RA is limited. This longitudinal cohort study aimed to determine the relation between CHM use and RA risk in patients with asthma.Methods: Using the nationwide claims data, we enrolled 33,963 patients 20–80 years of age who were newly diagnosed with asthma and simultaneously free of RA between 2000 and 2007. From this sample, we utilized propensity score matching to create sets of participants as treatment and control groups, which comprised 13,440 CHM users and 13,440 non-CHM users. The incidence rate and hazard ratio (HR) for RA between the two groups were estimated at the end of 2013. A Cox proportional hazards model was constructed to examine the impact of the CHM use on the risk of RA.Results: The cumulative incidence of RA was substantially lower in the CHM user group. In the follow-up period, 214 patients in the CHM user group (1.92 per 1,000 person-years) and 359 patients in the non-CHM user group (2.92 per 1,000 person-years) developed RA (adjusted HR = 0.63, 95% confidence interval: 0.54–0.75). Of the commonly-prescribed formulae, nine CHM products were associated with a lower RA risk: Xiao-Qing-Long-Tang, Ma-Xing-Gan-Shi-Tang, Ding-Chuan-Tang, Xin-Yi-Qing-Fei-Tang, Bei Mu, Jie Geng, Xing Ren, Da Huang, and San Chi.Conclusion: This study found that patients with asthma who received CHM treatment, in addition to the conventional therapy, had a lower risk of RA. Use of CHM treatment may be integrated into conventional therapy to reduce subsequent RA risk among asthma patients.

Abstract Background Yang Xin Tang (YXT) is a traditional Chinese herbal preparation which has been reported to improve cognitive function and memory in patients with dementia. As the underlying mechanism of action of YXT has not been elucidated, we examined the effects of YXT and its major herbal components in regulating gene transcription and molecular targets related to Alzheimer’s disease (AD). Methods Aqueous and ethanol extracts of YXT and selected herbal components were prepared and validated by standard methods. A series of biochemical and cellular assays were employed to assess the ability of the herbal extracts to inhibit acetylcholinesterase, reduce β-amyloid aggregation, stimulate the differentiation of neural progenitor cells, suppress cyclooxygenase, and protect neurons against β-amyloid or N-methyl-D-aspartate-induced cytotoxicity. The effects of YXT on multiple molecular targets were further corroborated by a panel of nine reporter gene assays. Results Extracts of YXT and two of its constituent herbs, Poria cocos and Poria Sclerotium pararadicis, significantly inhibited β-amyloid aggregation and β-amyloid-induced cytotoxicity. A protective effect of the YXT extract was similarly observed against N-methyl-D-aspartate-induced cytotoxicity in primary neurons, and this activity was shared by extracts of Radix Astragali and Rhizoma Chuanxiong. Although the YXT extract was ineffective, extracts of Poria cocos, Poria Sclerotium pararadicis and Radix Polygalae inhibited acetylcholine esterase, with the latter also capable of upregulating choline acetyltransferase. YXT and its components significantly inhibited the activities of the pro-inflammatory cyclooxygenases. Additionally, extracts of YXT and several of its constituent herbs significantly stimulated the phosphorylation of extracellular signal-regulated kinases and cAMP-responsive element binding protein, two molecular targets involved in learning and memory, as well as in the regulation of neurogenesis. Conclusions Several constituents of YXT possess multiple regulatory effects on known therapeutic targets of AD that range from β-amyloid to acetylcholinesterase. The demonstrated neuroprotective and neurogenic actions of YXT lend credence to its use as an alternative medicine for treating AD.

Abstract Objective: Illumination of the integrative effects of herbs in a formula is a bottleneck that limits the development of traditional Chinese medicine (TCM). In the present study, we developed a transcriptome-based multi-scale network pharmacology model to explore the combined effects of different herbs. Materials and Methods: First, we curated gene signatures at different biological scales, from the molecular to higher tissue levels, including tissues, cells, pathological processes, biological processes, pathways, and targets. Second, using the Xiexin Tang (XXT) formula as an example, we collected transcriptomic data in response to the treatment of XXT or its three compositive herbs on Michigan cancer foundation7 cells. Third, we linked each herbal drug to different biological scales by calculating the correlation scores between herb-induced gene expression profiles and gene signatures. Finally, the combined mechanisms of the three constituent herbs in XXT were deciphered by comparing their multi-scale effects with those of the formula. Results: The results showed that although XXT or single herbs regulated a large number of signatures on each biological scale, the phenotypic effects of these herbal drugs are concentrated onto the “Blood” tissue, types of hemocytes, and hemorrhagic injury-related pathological processes. At the molecular level, these herbs consistently regulate processes such as the cell cycle and blood coagulation-related pathways, as well as protein targets related to the immunoinflammatory response and blood coagulation, such as proteinase-activated receptor 2, integrin beta-3, inhibitor of nuclear factor kappa-B kinase subunit beta, and coagulation factor XII. The analysis of the combinational modes demonstrated that different herbs can cooperate by acting on the same objects and/or regulating different objects in related functions, and cooperative behaviors change at different biological scales. Conclusions: Our model can dissect the combined effects of herbal formulae from a multi-scale perspective and should be beneficial for the development and exploitation of TCM.

Hereditary Hemolytic Anemias (HHAs) are a rare but heterogeneous group of erythrocytic diseases, characterized by intrinsic cellular defects due to inherited genetic mutations. We investigated the efficacy of Chinese herbal medicine (CHM) in reducing the overall, diabetes-related, and cardiovascular diseases (CVDs)-related mortalities among patients with HHAs using a nationwide population database. In total, we identified 33,278 patients with HHAs and included 9,222 non-CHM and 9,222 CHM matched pairs after matching. The Cox proportional hazards model was used to compare the risk of mortality between non-CHM and CHM users. The Kaplan-Meier method and log-rank test were used to compare the cumulative incidence mortality between non-CHM and CHM users. The CHM prescription patterns were presented by the association rules and network analyses, respectively. The CHM prescription patterns were presented by the association rules and network analyses, respectively. CHM users showed significant reduced risks for of overall (adjusted hazard ratio [aHR]: 0.67, 95% confidence interval [CI]: 0.61–0.73, p &lt; 0.001), diabetes-related (aHR: 0.57, 95% CI: 0.40–0.82, p &lt; 0.001), and CVDs-related (aHR: 0.59, 95% CI: 0.49–0.72, p &lt; 0.001) mortalities compared with non-CHM users. Two CHM clusters are frequently used to treat Taiwanese patients with HHAs. Cluster 1 is composed of six CHMs: Bei-Mu (BM; Fritillaria cirrhosa D.Don), Gan-Cao (GC; Glycyrrhiza uralensis Fisch.), Hai-Piao-Xiao (HPX; Endoconcha Sepiae), Jie-Geng (JG; Platycodon grandiflorus (Jacq.) A.DC.), Yu-Xing-Cao (YXC; Houttuynia cordata Thunb.), and Xin-Yi-Qing-Fei-Tang (XYQFT). Cluster 2 is composed of two CHMs, Dang-Gui (DG; Angelica sinensis (Oliv.) Diels) and Huang-Qi (HQi; Astragalus membranaceus (Fisch.) Bunge). Further randomized clinical trials are essential to evaluate the safety and effectiveness of above CHM products and to eliminate potential biases in the current retrospective study.

Introdução: O padrão ouro atual para detectar o RNA de SARS-CoV-2 é por reação em cadeia da polimerase em tempo real de transcrição reversa (RT-rtPCR) em swabs nasofaríngeos (NPS). Por esse motivo, a demanda pelos NPS aumentou e sua escassez se tornou uma realidade em muitos países. Com isso o uso da saliva se mostra uma alternativa promissora na triagem epidemiológica além de ser de fácil coleta e não invasiva. Objetivo: realizar uma revisão sistemática da literatura para avaliar o uso da saliva como um espécime alternativo para a detecção de SARS-CoV-2. Metodologia: A pesquisa sistemática foi realizada em sete bancos de dados (PubMed, Cochrane Library, Lilacs, Scielo, Web of Science, Scopus e Google Scholar) usando a variação dos termos de pesquisa (COVID-19 OR SARS-CoV-2 OR 2019-nCoV) AND "Saliva" no ano de 2020, recuperando 5480 publicações. Resultados: Após a leitura dos títulos e resumos, 411 textos foram conduzidos para leitura integral e 30 publicações foram consideradas para avaliação qualitativa do artigo. Conclusão: A saliva se apresenta um método alternativo eficaz para a detecção de SARS-CoV-2 e diagnóstico de COVID-19.Descritores: Infecções por Coronavírus; Betacoronavirus; Saliva; Diagnóstico.ReferênciasHuang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506.Wang L, Wang Y, Ye D, Liu Q. A review of the 2019 Novel Coronavirus (COVID-19) based on current evidence. J Antimicrob Agents 2020;105948.Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med 2020;382:727-733.Coronaviridae Study Group of the International Committee on Taxonomy of V. 2020. 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Olecranon honey peach (Prunus persica L.) is a popular fruit tree cultivated in Guangdong Province of China. Due to its excellent economic values and popularity, it has recently been widely adopted and planted in several other southern Provinces and Autonomous Region in China, including Yunnan, Hunan, Jiangxi, Guizhou, and Guangxi. In Lianping County of Guangdong Province alone, the annual peach fruit production was about 78,800 tonnes (Xie et al. 2017). In July 2021, peach fruits showing soft rot symptoms were collected from an olecranon honey peach plantation in Lechang, Guangdong, China. Symptoms included tissue disintegration with bacterial oozes and rotting smells. To isolate the causal agent of soft rot in the peach fruits, the bacterial oozes from various rotted fruits were streaked on the modified YEB agar plate (Huang et al. 2021), and 21 bacterial colonies were selected for PCR amplification using the primers targeting the conserved region of 16S rDNA gene (Wei et al. 2020). A blastN analysis of the DNA sequences of the obtained PCR fragments in NCBI website indicated that 17 isolates named as ZL strains were potential bacterial species of Pectobacterium with about 99% similarity (Genbank accession number of ZL1: OK189602) to Pectobacterium aroidearum SCRI 109T (Genbank accession number: NR_159926). Three of them (ZL1, ZL2 and ZL3) were selected for assay of pathogenicity. The bacterial suspensions (10 μl, 1×106 CFU/ml) of strains ZL1, ZL2 and ZL3 were injected into olecranon honey peach fruits by using a syringe. A portion of peach fruits were similarly injected with sterile distilled water as the negative control. After 18 h incubation at 25 °C, the typical symptom of soft rot, i.e., tissue decay, became visible on the peach fruits inoculated with the bacterial suspensions. After inoculation for 42 h, bacterial oozes were exuded from rotting tissues. Peach fruits without injuries were also sprayed with the bacterial suspensions under the same conditions, but decay symptoms were not observed, suggesting that the bacterial infection needs the wounding or injuries. To fulfill the Koch’s postulates, bacterial colonies were re-isolated from bacterial oozes, and their conserved region of 16S rDNA fragments were amplified and sequenced. Bioinformatics analysis of the DNA sequence data confirmed that all the isolated colonies were Pectobacterium strains. Using the Biolog Gen III system, the representative strain ZL1 was identified as Pectobacterium (SIM 0.56). Transmission electron microscopy analysis showed that the bacterial cells of strain ZL1 were rod-shaped with peripheral flagella. To further determine the species of ZL strains, eight housekeeping genes (acnA, gapA, icd, mdh, mtlD, pgi, proA and rpoS) were analyzed by the methods described previously (Nabhan et al. 2013). The amplified DNA sequences analyzed by the blastN program in NCBI showed that the sequences of eight housekeeping genes from strains ZL1, ZL2 and ZL3 were identical to each other (Genbank accession number: OK274248 to OK274255), and most of the gene sequences shared over 99% similarity to their counterparts in P. aroidearum L6 (Genbank accession number: NZ_CP065044) (Xu et al. 2021), except that the acnA and proA genes showed about 98% and 96% similarity respectively to the corresponding genes of P. aroidearum L6. In addition, the multi-locus sequence analysis (MLSA) using DNA sequences of above eight housekeeping genes showed that ZL strains were grouped with other P. aroidearum strains. Taken together, the results of molecular and biochemical assays confirmed that ZL strains isolated from olecranon honey peach fruits were P. aroidearum. To our knowledge, this is the first report of P. aroidearum causing soft rot disease in olecranon honey peach in China. P. aroidearum is a relatively newly described soft rot pathogen (Nabhan et al. 2013). More recently, the pathogen was found causing soft rot infections in lettuce, Chinese cabbage, pepper (Capsicum annuum) fruits, konjac, carrot and Syngonium podophyllum (Barroso et al. 2019; Moraes et al. 2020; Sun et al. 2019; Tang et al. 2020; Xu et al. 2021). The results of this study add a new plant species to the host range of P. aroidearum.

Sweet viburnum [Viburnum odoratissimum Ker-Gawl. var. awabuki (K. Koch) Zabel ex Rumpl.] belonging to the family Adoxaceae, is a medical and landscape plant, native to Korea (Jeju Island), Taiwan, and Japan (Edita 1988). In June and September 2019, leaf spots were observed on approximately 65% to 80% of sweet viburnum plants in a hedgerow located in Fenghe Xincheng District (28°41'52.9"N 115°52'14.3"E) in Nanchang, China. Initial symptoms of disease appeared as dark brown spots surrounded by red halos (Figure 1 A), which expanded irregularly. Finally, the center of the lesions desiccated and became light-brown, surrounded by a deep-red halos (Figure 1 B). Ten leaf samples with typical symptoms were collected and washed with tap water for about 15 min. The tissue between the healthy and necrotic area (ca. 4 mm × 4 mm) was cut with a sterile scalpel and surface sterilized with 70% alcohol for 45 s, 2% NaClO for 2 min, washed in sterile deionized water three times, dried on sterilized filter paper, then placed in Petri dishes and incubated at 25℃ in the dark. After 3 to 5 days, the hyphal tips from the edges of growing colonies were transferred to fresh PDA dishes. Eventually, 54 fungal isolates were obtained and, of these, 39 isolates were identical in their morphological characteristics. Morphological analysis was performed according with Ellis (1971). The isolate S18, chosen as representative, formed a gray to grayish brown colony with concentric circleson PDA, and a diameter of 8.5 to 9 cm after 7 days incubation at 25℃ (Figure 1 G). Conidia were hyaline, straight or slightly curved, needle shaped, truncate at the base, and acuminate at the tip, with 2 to 6 pseudosepta, 18.90 to 38.38 µm (avg. = 27.51 µm) × 1.64 to 4.50 µm (avg. = 2.60 µm) (n = 36) (Figure 1 H). The genes of fungal isolates (i.e., ITS, tub2 and ACT) were amplified with ITS4/ITS5 for ITS (White, Bruns et al. 1990), Bt2a/Bt2b for tub2 (Glass and Donaldson 1995) and ACT783R/ACT512F for ACT (Carbone and Kohn 1999) and sequenced. The sequences were deposited in GenBank (MW165772 for ITS, MW175900 for ACT and MW168659 for tub2), which showing greater than 99.1% similarity to multiple C. cassiicola accessions, respectively. Pathogenicity tests were performed on healthy leaves in field by inoculating surface-sterilized mature leaves with puncture wound (Figure C) and non-wounded young leaves with 20 µL of a conidial suspension (105 conidia ml-1) (Figure F and G) at 26℃. After 4 to 7 days, all inoculated leaves reproduced similar symptoms as observed initially in the field (Figure 1 C, E and F). To fulfill Koch’s postulates, the fungus was isolated on PDA from the margins of leaf spots on inoculated leaves and confirmed as C. cassiicola by morphological characters and ITS gene sequencing. Previously, C. cassiicola was reported as an endophyte on Viburnum spp. and Viburnum odoratissimum (Alfieri et al. 1994). More recently, C. cassiicola has been reported as a pathogen of many plant species in China, such as kiwifruit (Cui, Gong et al. 2015), American sweetgum (Mao, Zheng et al. 2021), castor bean (Tang, Liu et al. 2020), and holly mangrove (Xie, He et al. 2020). To our knowledge, this is the first report of leaf spot disease on sweet viburnum caused by C. cassiicola in China and the precise identification of the causal agent will be useful for its management.

This study identifies A10398G alteration of mitochondrial ND3 gene in plasma exosome of 29 non-small cell lung cancer (NSCLC) patients, 31 controls and 13 pairs of tumor tissue and adjacent tissue of NSCLC patients, thereby assessing the relationship between this alteration in plasma exosome and tissue as well as the pathological characteristics of NSCLC patients. Using the PCR-RFLP method, the homoplasmy and heteroplasmy of A10398G were initially identified in mitochondrial DNA from both exosomes and lung tissues. The rate of variant 10398G in plasma exosome was 62.1% in the NSCLC group and 61.3% in the control group. However, there was no statistically significant difference in A10398G between the patient and control groups. The alteration of A10398G in plasma exosome and in tissue correlated with each other (correlation coefficient 0.69; p = 0.009). However, this alteration was not related to age, gender, smoking, alcohol drinks status, tumor size, histological stage and TNM stage. Keywords A10398G alteration, mitochondrial DNA, plasma exosome, non-small cell lung cancer. References [1] Y. Zhang, Y. Liu, H. Liu, W.H. Tang, Exosomes: biogenesis, biologic function and clinical potential, Cell Biosci, 9 (2019) 19. https://doi.org/10.1186/s13578-019-0282-2.[2] H. Valadi, K. Ekström, A. Bossios, M. Sjöstrand, J.J. Lee, J.O. Lötvall, Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells, Nat Cell Biol, 9(6) (2007) 654–659. https://doi.org/10.1038/ncb1596.[3] A. Sharma & A. Johnson, Exosome DNA: Critical regulator of tumor immunity and a diagnostic biomarker, J Cell Physiol, 235(3) (2020) 1921–1932. https://doi.org/10.1002/jcp.29153.[4] Global Cancer Observatory, Cancer Today. https://gco.iarc.fr/today/online-analysis-pie. (accessed 05 November 2020).[5] A.A.M. Yusoff, F.N. Zulfakhar, S.Z.N.M. Khair, W.S.W. Abdullah, J.M. Abdullah, Z. 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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus , is causing a serious worldwide COVID-19 pandemic. The emergence of strains with rapid spread and unpredictable changes is the cause of the increase in morbidity and mortality rates. A number of drugs as well as vaccines are currently being used to relieve symptoms, prevent and treat the disease caused by this virus. However, the number of approved drugs is still very limited due to their effectiveness and side effects. In such a situation, medicinal plants and bioactive compounds are considered a highly valuable source in the development of new antiviral drugs against SARS-CoV-2. This review summarizes medicinal plants and bioactive compounds that have been shown to act on molecular targets involved in the infection and replication of SARS-CoV-2. Keywords: Medicinal plants, bioactive compounds, antivirus, SARS-CoV-2, COVID-19 References [1] R. Lu, X. Zhao, J. Li, P. Niu, B. Yang, H. 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Tencomnao, Anti-COVID-19 Drug Candidates: A Review on Potential Biological Activities of Natural Products in the Management of New Coronavirus Infection, Journal of Traditional and Complementary Medicine, Vol. 11, 2021, pp. 144-157, https://doi.org/10.1016/j.jtcme.2020.12.001.[6] R. E. Ferner, J. K. Aronson, Chloroquine and Hydroxychloroquine in Covid-19, BMJ, Vol. 369, 2020, https://doi.org/10.1136/bmj.m1432[7] J. Remali, W. M. Aizat, A Review on Plant Bioactive Compounds and Their Modes of Action Against Coronavirus Infection, Frontiers in Pharmacology, Vol. 11, 2021, https://doi.org/10.3389/fphar.2020.589044.[8] Y. Chen, Q. Liu, D. Guo, Emerging Coronaviruses: Genome Structure, Replication, and Pathogenesis, Medical Virology, Vol. 92, 2020, pp. 418‐423. https://doi.org/10.1002/jmv.25681.[9] B. Benarba, A. Pandiella, Medicinal Plants as Sources of Active Molecules Against COVID-19, Frontiers in Pharmacology, Vol. 11, 2020, https://doi.org/10.3389/fphar.2020.01189.[10] N. T. Chien, P. V. Trung, N. N. Hanh, Isolation Tribulosin, a Spirostanol Saponin from Tribulus terrestris L, Can Tho University Journal of Science, Vol. 10, 2008, pp. 67-71 (in Vietnamese).[11] V. Q. Thang Study on Extracting Active Ingredient Protodioscin from Tribulus terrestris L.: Doctoral dissertation, VNU University of Science, 2018 (in Vietnamese).[12] Y. H. Song, D. W. Kim, M. J. C. Long, H. J. Yuk, Y. Wang, N. Zhuang et al., Papain-Like Protease (Plpro) Inhibitory Effects of Cinnamic Amides from Tribulus terrestris Fruits, Biological and Pharmaceutical Bulletin, Vol. 37, No. 6, 2014, pp. 1021-1028, https://doi.org/10.1248/bpb.b14-00026.[13] D. Dermawan, B. A. Prabowo, C. A. Rakhmadina, In Silico Study of Medicinal Plants with Cyclodextrin Inclusion Complex as The Potential Inhibitors Against SARS-Cov-2 Main Protease (Mpro) and Spike (S) Receptor, Informatics in Medicine Unlocked, Vol. 25, 2021, pp. 1-18, https://doi.org/10.1016/j.imu.2021.100645.[14] R. Dang, S. Gezici, Immunomodulatory Effects of Medicinal Plants and Natural Phytochemicals in Combating Covid-19, The 6th International Mediterranean Symposium on Medicinal and Aromatic Plants (MESMAP-6), Izmir, Selcuk (Ephesus), Turkey, 2020, pp. 12-13.[15] G. Jiangning, W. Xinchu, W. Hou, L. Qinghua, B. Kaishun, Antioxidants from a Chinese Medicinal Herb–Psoralea corylifolia L., Food Chemistry, Vol. 9, No. 2, 2005, pp. 287-292, https://doi.org/10.1016/j.foodchem.2004.04.029.[16] B. Ruan, L. Y. Kong, Y. Takaya, M. Niwa, Studies on The Chemical Constituents of Psoralea corylifolia L., Journal of Asian Natural Products Research, Vol. 9, No. 1, 2007, pp. 41-44, https://doi.org/10.1080/10286020500289618.[17] D. T. Loi, Vietnamese Medicinal Plants and Herbs, Medical Publishing House, Hanoi, 2013 (in Vietnamese).[18] S. Mazraedoost, G. Behbudi, S. M. Mousavi, S. A. Hashemi, Covid-19 Treatment by Plant Compounds, Advances in Applied NanoBio-Technologies, Vol. 2, No. 1, 2021, pp. 23-33, https://doi.org/10.47277/AANBT/2(1)33.[19] B. A. Origbemisoye, S. O. Bamidele, Immunomodulatory Foods and Functional Plants for COVID-19 Prevention: A Review, Asian Journal of Medical Principles and Clinical Practice, 2020, pp. 15-26, https://journalajmpcp.com/index.php/AJMPCP/article/view/30124[20] A. Mandal, A. K. Jha, B. Hazra, Plant Products as Inhibitors of Coronavirus 3CL Protease, Frontiers in Pharmacology, Vol. 12, 2021, pp. 1-16, https://doi.org/10.3389/fphar.2021.583387[21] N. H. Tung, V. D. Loi, B. T. Tung, L.Q. Hung, H. B. Tien et al., Triterpenen Ursan Frame Isolated from the Roots of Salvia Miltiorrhiza Bunge Growing in Vietnam, VNU Journal of Science: Medical and Pharmaceutical Sciences, Vol. 32, No. 2, 2016, pp. 58-62, https://js.vnu.edu.vn/MPS/article/view/3583 (in Vietnamese).[22] J. Y. Park, J. H. Kim, Y. M. Kim, H. J. Jeong, D. W. Kim, K. H. 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