Journal articles on the topic 'Tang feng lou'

Abstract USP21 belongs to the ubiquitin-specific protease (USP) subfamily of deubiquitinating enzymes (DUBs), which catalyze the removal of ubiquitin chain from targeted proteins. Numerous efforts over the last decade have identified a wide range of USP21 substrates and revealed the momentous and multifaceted role of USP21 in physiological and pathological states, especially in tumorigenesis, indicating that USP21 is an appealing target for the therapy of many correlative diseases. Nevertheless, progress in the development of potent USP21 inhibitors remains limited. Herein, we present the discovery of HSN003839, a highly potent and selective USP21 inhibitor with excellent anticancer activity and drug-like properties. Following screening tool compounds to identify hits and subsequent optimization, we discovered a series of compounds with strong enzymatic inhibition for USP21 with IC50 < 100 nM. Among them, HSN003839 displayed low nanomolar cancer cells proliferation inhibitions and excellent ADMET properties. The mouse oral bioavailability (F) is 76.5% at 10 mg/kg. In a preliminary mouse CDX model, monotherapy of HSN003839 showed 105% tumor growth inhibition (TGI) at 30 mg/kg with no obvious body weight reduction. Further biological characterization, efficacy and toxicity studies are ongoing. The structure of HSN003839 was not presented and will not be disclosed at the time of presentation at AACR meeting. Citation Format: Xiaohui Liu, Ying Wang, Dongliang Xia, Wei Zhang, Yan He, Shijie Tian, Xuerong Feng, Xia Yang, Qi Zhang, Fei Liu, Shiyi Jiang, Ran Hu, Ming Tang, Xuelin Tang, Yuqing Liu, Weijiao Yuan, Xuedan You. Discovery of HSN003839, a highly potent inhibitor of ubiquitin-specific protease USP21 for cancer therapy [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 1835.

Abstract Tongtong Liu, Feng He, Xuyang Duan, Shuliang Li, Chang Liu, Jingying Ning, Feng Hao* KYinno Biotechnology (Beijing) Co., Ltd. No.3 Building, Yizhuang Biomedical Park, Beijing, China. Correspondence: Feng.hao@kyinno.com Protein kinases have become very popular targets in the treatment of cancer and other diseases, and since 2001, the FDA has approved more than 70 kinase inhibitor drugs. However, due to innate or acquired resistance in tumors, most of these small molecule inhibitors only delay tumor progression. The development of next-generation kinase inhibitors with better specificity and lower resistance is still ongoing. Ba/F3 is a mouse pro-B cell line whose survival and proliferation depend on IL-3. After transduction with driver genes such as kinase genes or their mutants, Ba/F3 cells switch from IL-3 dependence to driver gene dependence, making Ba/F3 cells a powerful tool for discovering new kinase inhibitors. Our group has constructed over 700 Ba/F3 engineered cell lines stably transfected with kinase gene mutants. These Ba/F3 kinase cell lines have been fully validated by sequencing, western blotting, and inhibitor testing, covering many popular kinases including EGFR (>150 cell lines), RAS (80 cell lines), FGFR (55 cell lines), ERBB2 (49 cell lines), MET (41 cell lines), RET (39 cell lines), BCR-ABL (37 cell lines), EML4-ALK (33 cell lines), and FLT3 (26 cell lines), etc. Most of these transformed Ba/F3 cell lines can be used for xenograft models in immunodeficient mice. Based on these Ba/F3 kinase cell line-derived xenograft models, we have established an in vivo screening platform to evaluate the efficacy and toxicity of candidate drugs against specific kinase mutation types, as well as their comparison with previous generation drugs. Overall, our data suggest that xenograft models derived from Ba/F3 kinase cell lines are powerful models for discovering next-generation kinase inhibitors. Citation Format: Stephanie Wang. An in vivo screening platform based on Ba/F3 kinase-engineered cell lines for discovering next-generation kinase inhibitors [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 A008.

We demonstrate experimentally and simultaneously the impact of the Polyimide (PI) coating layer on the coupling and propagation losses of the fabricated SOI slot waveguides at 1550 nm operation wavelength and TE polarization. Full Text: PDF References P. Dong, Y.K. Chen, G.H. Duan, and D.T. Neilson, "Silicon photonic devices and integrated circuits," Nanophot, 3, 215 (2014). CrossRef Q. Xu, V.R. Almeida, R.R. Panepucci, M. Lipson, "Experimental demonstration of guiding and confining light in nanometer-size low-refractive-index material," Opt. Lett., 29, 1626 (2004). CrossRef V.R. Almeida, Q. Xu, C.A. Barrios, M. Lipson, "Guiding and confining light in void nanostructure," Opt. Lett., 29, 1209 (2004). CrossRef A. Mickelson, "Silicon photonic slot guides for nonlinear optics," 2013 Int. Conf. Microw. Photonics, ICMAP 2013, (2013). CrossRef A. Martínez et al., "Ultrafast all-optical switching in a silicon-nanocrystal-based silicon slot waveguide at telecom wavelengths," Nano Lett., 10, 1506 (2010). CrossRef C. Koos et al., "All-optical high-speed signal processing with silicon-organic hybrid slot waveguides," Nat. Photonics., 3, 216 (2009). CrossRef Y. Li, K. Cui, X. Feng, Y. Huang, F. Liu, and W. Zhang, "Ultralow propagation loss slot-waveguide in high absorption active material," IEEE Photonics J., 6, 3 (2014). CrossRef Z. Wang, N. Zhu, Y. Tang, L. Wosinski, D. Dai, S. He, "Ultracompact low-loss coupler between strip and slot waveguides," Opt. Lett., 34, 1498 (2009). CrossRef

Abstract The repair of DNA double strand break (DSB) is crucial for genome stability and cell survival. There are three main DSB repair pathways: homologous recombination (HR), non-homologous end joining (NHEJ) and microhomology-mediated end joining (MMEJ). HR is a high-fidelity, error-free DSB repair pathway, and the dysfunction of HR confers cell genome instability and leads to tumorigenesis. HR deficiency is especially prevalent in gynecologic tumors, sharing about 10% population of all the gynecologic tumor patients. In situation of HR deficiency, MMEJ, in which DNA polymerase theta (Polθ) plays an essential role, is up-regulated to serve as a backup pathway for DSB repair. Several studies have proved that the inhibition of Polθ causes synthetic lethality with HR deficiency. Hence, Polθ emerges as a potential DNA damage repair target for the treatment of HR deficient tumors. Here we report a novel small molecular Polθ inhibitor, SS008871, which inhibits Polθ activity with an IC50 of 22 nM, and strongly inhibits cellular MMEJ pathway with an IC50 of single-digital nanomolar level. SS008871 strongly inhibits proliferation of HR deficient BRCA2-/- DLD-1 cells, and shows a >125× selectivity folds over DLD-1 parent cells as well as non-malignant cells. Besides, SS008871 elicits synergetic anti-proliferation activities in combination of a PARP inhibitor, olaparib on BRCA2-/- DLD-1 and MDA-MB-436 cells. In the BRCA2-/- DLD-1 xenograft model, SS008871 shows tumor growth inhibition as a single agent, and the combination of SS008871 and olaparib further results in tumor regression. Accordingly, the level of γH2AX, a common DSB marker, correlates well to the anti-tumor efficacy. In a human hematopoietic stem cells based in vitro hematotoxicity assay, SS008871 shows no significant inhibition on lineage-specific (myeloid, erythroid and megakaryocytic) cell differentiation and survival, suggesting the low hematotoxicity risk. In comparison, olaparib significantly attenuated hematopoietic stem cells on both differentiation and survival in the parallel assay, which is consistent with the hematological toxicity observed in human. Furthermore, there is no clinical abnormalities observed after a high dose treatment of SS008871 in mice, demonstrating that SS008871 is well-tolerated. Taken together, SS008871 is proved to be an encouraging Polθ inhibitor with good safety. Citation Format: Feng Zhou, Lu Liu, Lei Jiang, Feng Tang, Zhen Li, Wenqing Yang, Liting Xue, L Chen, Renhong Tang. Identification of SS008871, a novel Polθ inhibitor that effectively inhibits tumors with homologous recombination deficiency in vitro and in vivo [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 512.

Abstract Background In patients with the HR+/HER2+ breast cancer (BC) subtype, it can be more challenging to achieve pathological complete response (pCR) after neoadjuvant therapy compared with the HR-/HER2+ subtype. The importance of neoadjuvant therapy and the association of pCR with long-term clinical benefits have been widely demonstrated in HER2+ BC. This network meta-analysis aimed to identify the optimal anti-HER2 regimen, the role of endocrine therapy, and the better chemotherapy choice for the neoadjuvant treatment of HR+/HER2+ BC patients. Methods Literature for neoadjuvant clinical trials in HR+/HER2+ breast cancer was searched in Medline, EMBASE, Cochrane Library, and Web of Science for publications released before June 2023. Single-arm trials, retrospective studies, and observational studies were excluded, as well as studies containing no neoadjuvant phase and/or no anti-HER2 drugs. A network meta-analysis with the fixed-effect model in a Bayesian framework was performed. Odds ratios (ORs) with 95% confidence intervals (CI) for pathological complete response (pCR) analysis and hazard ratios (HRs) with 95% CI for event-free survival (EFS) were calculated. A ranking of treatment patterns was performed using SUCRA. (Registered in PROSPERO: CRD42023385644 Results 2,844 records were identified by the literature search, 60 trials were included after the screening, and valid data were extracted. 19 trials and 2,883 patients were included in the primary analysis of pCR. Compared with trastuzumab + chemotherapy (CT), three treatment regimens showed significantly higher pCR rates, T-DM1 based treatment (T-DM1, OR: 2.83, 95% CI: 1.90, 4.27; which includes T-DM1 alone, T-DM1 + pertuzumab or T-DM1 + endocrine therapy), trastuzumab + pertuzumab + CT (PH, OR: 2.57, 95% CI: 1.70, 3.94), and trastuzumab + tyrosine kinase inhibitor (TKI)+ CT (H+TKI, OR: 1.60, 95% CI: 1.22, 2.09; TKI includes lapatinib, neratinib and pyrotinib). The SUCRA ranking of pCR showed that T-DM1 was ranked first (SUCRA: 0.94), followed by PH (SUCRA: 0.85) and H+TKI (SUCRA: 0.60). PH came first in the SUCRA ranking of EFS (SUCRA: 0.74) as well as cumulative SUCRA combining pCR and EFS (SUCRA: 0.79). For chemotherapy strategies, platinum-containing regimens showed no significant increase in pCR rate compared to no platinum regimens (OR: 1.27, 95% CI: 0.95, 1.69), regimens with anthracycline also had no statistical difference from those without anthracycline (OR: 0.74, 95% CI: 0.51, 1.07). When assessing the impact of endocrine therapy, no significant difference in pCR rate was observed with or without endocrine therapy (OR: 1.18, 95% CI: 0.80, 1.73). Conclusions The PH regimen remains the best neoadjuvant treatment choice for HR+/HER2+ early BC patients considering pCR and EFS outcomes simultaneously. H+TKI did not show significant benefits, so it is not recommended to be given priority in clinical practice. The platinum-containing regimen’s potential benefit compared to the non-platinum regimen is uncertain and needs more clinical investigation. The necessity of adding endocrine therapy is not proven due to limited data availability. Funding: This study was sponsored by Shanghai Roche Pharmaceuticals Ltd. Disclosure: Hao Tang, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Yajing Feng, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Xin Yu, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Citation Format: Hao Wang, Shiwei Liu, Miao Yu, Kun Mi, Exian Mou, Li Xia, Weimin Xie, Hao Tang, Yajing Feng, Xin Yu. The optimal neoadjuvant treatment regimen for HR+/HER2+ breast cancer: a network meta-analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-01-04.

Abstract Background- Ma recipe is an ancient Chinese medicine recipe used for venomous snake bites. Four Chinese herbal medicines, prunella, vitex seed, red grass and eucalyptus leaves, were deemed essential ingredients in the Ma recipe prescription. Since Ma recipe has a powerful analgesic effect, it has been used to treat serious cancer pain in our clinic for over decade. It has observed that patients with advanced lung cancer、advanced liver cancer and some of other solid tumor also survive significantly longer after the elimination of cancer pain. In this small number of retrospective case series, we report the efficacy of Ma recipe therapeutics and pathological changes of tumor lesion before and after treatment in patients with advanced esophageal cancer. Methods-Treatment was in the form of prescriptions written by traditional Chinese doctors. This behavior is consistent with the norms of traditional Chinese medicine, and does not deviate from the conventional clinical practice. Ma recipe should be taken orally every day at 10 grams. Benefits from Ma recipe therapeutics was assessed by comparing symptom improvement and pathological changes before and after treatment, as well as by survival analysis. Results- A total of 12 patients with advanced esophageal cancer were treated by Ma recipe therapeutics. Seven of 12 had severe obstructive symptoms of eating difficulty and weakness that it must be treated symptomatically. These symptoms were reduced or disappeared within 7 to 30 days of Ma recipe treatment and were sustained clinical recovery maintained thereafter. There were no events of death and disease progression occur in all the patients with Ma recipe intervention at the data cutoff point of the median duration of exposure to Ma recipe therapeutics was 48 months (range, 12-85 months). All the treated patients returned to normal life. Of the 12 cases, 9 had pathological examinations before and after administration of Ma recipe. Results all 9 patients were diagnosed esophageal cancer in the pathological biopsy tissue specimens obtained prior to administration of Ma recipe, but no cancer cells were found in all Pathological biopsy tissue specimens were obtained after Ma recipe treatment. Of the 9 cases undergoing pathological examination, 6 received radiotherapy after administration of Ma recipe. Ma recipetherapeutics has not been found to have serious side effects in years of clinical practice. Conclusions- The survival benefit of Ma recipe therapeutics for patients with advanced esophageal cancer is enormous. The ability of Ma recipe treatment to rapidly improve obstructive symptoms in advanced esophageal cancer is a highlight. The pathological changes before and after treatment support that Ma recipe therapeutics has a definite curative effect on esophageal cancer. However, this study is a post hoc secondary analysis and the limitation of the insufficient number must be treated with caution. This study can only give an indication that Ma recipe therapeutics has the potential to become an approach for patients with advanced esophageal cancer. Citation Format: Jiangnan Feng, Zhenghua Ma, Hua Wu, Meiying Gao, Chengsheng Yi, Xia LIU, Jiangnan Feng. The benefit of Ma recipe, A combination of Chinese herbal medicines for patients with advanced esophageal cancer: A retrospective case report series [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 C138.

Electrochemical water splitting to produce hydrogen has attracted great interest as an environmentally-friendly renewable fuel. While cathodic hydrogen evolution (HER) is a relatively fast process that produces a valuable chemical, the anodic oxygen evolution reaction (OER) is a slow process that adds little to no economic value to water splitting.1,2 Generating a high-performance oxidizer such as ozone instead of oxygen could make water splitting more economically feasible because of the added value of ozone. However, electrochemical ozone production (EOP) catalysts are typically hindered by low current efficiencies, poor selectivity, low stability, and high energy demands, which limit the industrial application of this reaction.3,4 Further improvements in catalyst performance could be achieved by better understanding the mechanism of ozone production. Nickel and antimony doped tin oxide (Ni/Sb-SnO2, NATO) is currently reported to have the highest EOP current efficiency at room temperature. However, the mechanism of EOP on NATO electrodes has not yet been established. A primary complication when studying the mechanism of EOP using NATO electrocatalysts in water is that oxygen atoms in the ozone molecule can originate from sources other than water, such as dissolved molecular oxygen or the electrocatalyst oxide lattice.1,5,6 In this work, lattice oxygen participation in EOP is investigated by replacing water with acetonitrile, a polar aprotic solvent without oxygen atoms. Our results show that ozone can be generated in acetonitrile in similar quantities as aqueous conditions.2 These quantities are inconsistent with a 6-electron process based on calculated current efficiencies. Furthermore, the addition of small quantities of water is shown to have a negative impact on ozone generation. The origin of this impact is thought to not be mechanistic in nature. Instead, we suggest that adding water to the mixture leads to the generation of hydroxide ions which act as ozone scavengers. To our knowledge, this is the first report of electrochemical ozone production in a non-aqueous solvent. Future work will more conclusively determine the origin of oxygen atoms using isotopic labeling. Furthermore, the ability of nonaqueous solvents to stabilize reactive oxygen species and impact selectivity will be investigated. Utilizing the knowledge gained by studying ozone generation in nonaqueous solvents, it might be possible to design a better EOP system which could enhance the applicability of this reaction. (1) Lees, C. M.; Lansing, J. L.; Morelly, S. L.; Lee, S. E.; Tang, M. H. Ni- and Sb-Doped SnO2 Electrocatalysts with High Current Efficiency for Ozone Production via Electrodeposited Nanostructures. J. Electrochem. Soc. 2018, 165 (16), E833. https://doi.org/10.1149/2.0051816jes. (2) James L. Lansinga±, Lingyan Zhaob, Tana Siboonruanga, N. Harsha Attanayakea, Angela B. Leob, Peter Fatourosb, So Min Parkc, Kenneth R. Grahamc, John A. Keithb, Maureen Tang*a. Gd-Ni-Sb-SnO2 Electrocatalysts for Active and Selective Ozone Production. (3) Christensen, P. A.; Attidekou, P. S.; Egdell, R. G.; Maneelok, S.; Manning, D. A. C.; Palgrave, R. Identification of the Mechanism of Electrocatalytic Ozone Generation on Ni/Sb-SnO 2. J. Phys. Chem. C 2017, 121 (2), 1188–1199. https://doi.org/10.1021/acs.jpcc.6b10521. (4) Wang, Y.-H.; Chen, Q.-Y. Anodic Materials for Electrocatalytic Ozone Generation. Int. J. Electrochem. 2013, 2013, 1–7. https://doi.org/10.1155/2013/128248. (5) Jiang, W.; Wang, S.; Liu, J.; Zheng, H.; Gu, Y.; Li, W.; Shi, H.; Li, S.; Zhong, X.; Wang, J. Lattice Oxygen of PbO 2 Induces Crystal Facet Dependent Electrochemical Ozone Production. J. Mater. Chem. A 2021, 9 (14), 9010–9017. https://doi.org/10.1039/D0TA12277G. (6) Feng, J.; Johnson, D. C.; Lowery, S. N.; Carey, J. J. Electrocatalysis of Anodic Oxygen‐Transfer Reactions: Evolution of Ozone. J. Electrochem. Soc. 1994, 141 (10), 2708–2711. https://doi.org/10.1149/1.2059184.

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 Neuroblastoma, especially those with aberrant MYCN activation, often harbor an immunosuppressive microenvironment to fuel malignant growth and trigger treatment resistance. Despite this knowledge, there are no effective strategies to tackle this problem. Here we combined analyses of human neuroblastoma with live tracking and functional studies of the tumor microenvironment (TME) in zebrafish. We identified a tumor-associated chemokine (TAC) as a key driver of MYCN-mediated immunosuppression and neuroblastoma aggression. Taking advantage of in vivo zebrafish models of MYCN-driven neuroblastoma that resemble human high-risk disease, we demonstrated that TAC overexpression in zebrafish neural crest cells induces an immunosuppressive TME while promoting rapid tumor onset and progression. We also demonstrated that as early as the premalignant stage, tumor cells secrete TAC to attract CCR4-expressing Cd4+ cells to induce immunosuppression and tumor aggression. In addition, genetically depleting Cd4+ T regulatory cells abolishes the immunorestrictive and pro-tumorigenic effects of TAC. We showed that human MYCN-activated neuroblastoma upregulates and secretes TAC, which is a reliable predictor of poor patient survival. Analysis of primary patient samples demonstrates a strong positive association between MYCN and TAC expression in neuroblastoma cells together with the enrichment of FOXP3+ T cells in the TME. Our work provides the first example that MYCN can activate TAC to allure CD4+ immune cells to the TME and incite immunosuppression, positioning TAC as a potential novel immunotherapeutic target for the treatment of MYCN-driven high-risk neuroblastoma. Citation Format: Xiaodan Qin, Andrew Lam, Xu Zhang, Satyaki Sengupta, J. Bryan Iorgulescu, Sanjukta Das, Zhenwei Zhou, Tao Zuo, Grace K. Meara, Madison Rager, Alexander E. Floru, Hongru Ni, Chinyere Kemet, Divya Veerapaneni, Daniel Kashy, Liang Lin, Kenneth Lloyd, Lauren Kwok, Kaylee S. Smith, Raghavendar T. Nagaraju, Rob Meijers, Craig Ceol, Ching-Ti Liu, Sanda Alexandrescu, Catherine J. Wu, Derin B. Keskin, Rani E. George, Hui Feng. A tumor-associated chemokine attracts CCR4-expressing CD4+ cells to foster immune repression and tumor aggressiveness in MYCN-driven neuroblastoma [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_C20.

Internal short circuit (ISC) is a critical failure mechanism for lithium-ion cells that can lead to disastrous thermal runaway. Therefore, great effort has been made to understand its mechanisms by purposefully triggering ISC through various methods1, 2, such as embedding a nickel particle3 or a wax covered copper pad4 inside lithium-ion cells. While these methods have been successful in triggering ISC, none of them allows measurement of ISC current, a critical parameter that influences heat generation and risk of thermal runaway. Alternatively, Feng et al.5 reported a method of placing a resistor between two parallel-connected cells and using the resistor to externally short circuit the cells. This method could allow measurement of short circuit current, but the resistor is placed between two cells rather than between electrode layers to create different types of ISC6. Inspired by this method5 and the established ISC methods3, 4, here we report a new method that not only triggers lithium-ion cell ISC but also monitors ISC current. As shown schematically in Figure 1, the method works by inserting a pair of small nickel pads inside a lithium-ion cell. One pad is between cathode and separator. The other is between anode and separator. Then the pads are connected electronically outside the cell through insulated metal wires, a switch and a current sensor. Once the switch is closed, the anode and cathode will be shorted at the pad region to form an Anode-Cathode type ISC. The ISC current is forced to flow through the external circuit to be measured by the current sensor. The resistance of the external circuit is much lower than the resistance between nickel pads and their corresponding electrode, so heat generation is focused inside the cell at the pad region as in an ISC scenario. By adjusting dimension of the nickel pads and/or the pressure applied to the pad region, the ISC resistance can be adjusted for investigation of its effects. Furthermore, by connecting one of the pads electronically to the opposite tab, the Anode-Aluminum type ISC and the Cathode-Copper type ISC, can be created. Alternatively, these types of ISC can be created by removing part of electrode coating and placing one of the Ni pads to be in direct contact with current collector. In addition, by embedding thermocouples inside the cell7, temperature distributions can be simultaneously measured for understanding of electrochemically-thermally coupled phenomena during ISC. Figure 2 shows preliminary results obtained from a prototype lithium-ion cell using this new method. The cell has a single unit of electrodes and a nominal capacity of 0.02 Ah. Three types of ISC were created, including Anode-Cathode, Anode-Aluminum and Cathode-Copper. As expected, the Anode-Cathode type ISC had the smallest current while the Anode-Aluminum type ISC had the highest current6, which can be attributed to the high resistance of cathode and the contact resistance between nickel pad and electrode. More results and analysis will be presented. References X. Lai, C. Jin, W. Yi, X. Han, X. Feng, Y. Zheng and M. Ouyang, Energy Storage Materials, 35, 470 (2021). G. Zhang, X. Wei, X. Tang, J. Zhu, S. Chen and H. Dai, Renewable and Sustainable Energy Reviews, 141, 110790 (2021). IEEE, IEEE Std 1625-2008 (Revision of IEEE Std 1625-2004), 1 (2008). E. Darcy and M. Keyser, On-Demand Cell Internal Short Circuit Device, in Power Sources Conference 2014; 9-12 Jun. 2014; , Orlando, FL; United States (2014). X. Feng, X. He, L. Lu and M. Ouyang, Journal of The Electrochemical Society, 165, A155 (2018). S. Santhanagopalan, P. Ramadass and J. Zhang, Journal of Power Sources, 194, 550 (2009). S. Huang, Z. Du, Q. Zhou, K. Snyder, S. Liu and G. Zhang, Journal of The Electrochemical Society, 168, 090510 (2021). Figure 1

There is rapidly growing interest in the electrochemical reduction of both nitrite and carbon dioxide to mitigate environmental concerns and produce fuels and commodity chemicals (1). Urea is an important target in this area since it is the most widely used nitrogen fertilizer, and can also be used as a fuel and source of hydrogen. It can be produced simultaneously by electrochemical coreduction of NO2 - and CO2 (2-7). Various TiO2 based catalysts such as Cu-doped TiO2 (7) and FeTiO3 (4) have been reported to be effective for co-reduction of CO2 and NO2 -. Metallophthalocyanine catalysts have also been found to be effective in a gas-diffusion electrode configuration under ambient conditions (3). The primary objective of this research is to develop fast and straightforward methodologies that can be routinely used to comprehensively evaluate and compare commercial and new catalysts for co-electrolysis of CO2 and NO2 - in an anion exchange membrane multi-cathode electrolysis cell under ambient conditions. The second objective is using this methodology to synthesize urea and develop reliable and consistent urea measurement methods using various techniques including spectrophotometric, 1H-NMR, mass spectrometry, and enzyme-based methods. It was found that NO2 - and the electrolyte can cause interference during urea measurement. In this research, commercial catalysts such as iron (II) phthalocyanine were used for co-electrolysis of CO2 and NO2 -. Acknowledgements This project is funded in part by the Government of Canada. / Ce projet est financé en partie par le gouvernement du Canada, and by Memorial University References C. Tang, Y. Zheng, M. Jaroniec and S. Z. Qiao, Angew. Chem. Int. Ed., 60, 19572 (2021). M. Shibata, K. Yoshida and N. Furuya, J. Electrochem. Soc., 145, 2348 (1998). M. Shibata and N. Furuya, Electrochim. Acta, 48, 3953 (2003). P. Siva, P. Prabu, M. Selvam, S. Karthik and V. Rajendran, Ionics, 23, 1871 (2017). Y. G. Feng, H. Yang, Y. Zhang, X. Q. Huang, L. G. Li, T. Cheng and Q. Shao, Nano Lett., 20, 8282 (2020). N. N. Meng, Y. M. Huang, Y. Liu, Y. F. Yu and B. Zhang, Cell Reports Physical Science, 2 (2021). N. Cao, Y. L. Quan, A. X. Guan, C. Yang, Y. L. Ji, L. J. Zhang and G. F. Zheng, J. Colloid Interface Sci., 577, 109 (2020).

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 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 Background: KRAS is the best-known oncogene but had long been considered ‘undruggable’ until the approval of the first KRAS G12C inhibitor sotorasib in 2021. However, most current clinical-stage KRAS inhibitors target the KRAS G12C mutation. Inhibitors of other KRAS mutants such as KRAS G12D, the most frequent KRAS mutation in human cancer, are needed for patients. We have developed GFH375 (VS-7375), an oral, selective KRAS G12D inhibitor targeting both “ON” (GTP-bound) and “OFF” (GDP-bound) states of KRAS proteins. The in vitro potency, selectivity, and in vivo efficacy of monotherapy and combination therapy with avutometinib, a unique RAF/MEK clamp, were evaluated in preclinical studies. Methods: Biochemical and cellular assays were used to investigate inhibition to KRAS cycling and signaling. CellTiter-Glo assay was performed to determine the effects on proliferation of tumor cell lines. Several KRAS G12D CDX tumor models were employed to study the in vivo pharmacodynamic and anti-tumor effects. Results: GFH375 inhibited both nucleotide exchange on GDP-bound KRAS G12D and interaction between GMPPNP-bound KRAS G12D with RAF1 with single-digit nanomolar IC50 values. GFH375 suppressed phosho-ERK1/2 (p-ERK) level with sub-nanomolar IC50 values and potently inhibited cell proliferation across a panel of KRAS G12D tumor cell lines. GFH375 showed high selectivity for KRAS G12D relative to non-G12D KRAS variants, KRAS wild type cells, and NRAS, HRAS, or BRAF mutated cells. Following a single oral dose, GFH375 produced deep and durable inhibition of p-ERK in KRAS G12D CDX tumors. GFH375 demonstrated dose-dependent anti-tumor activity with tumor regressions at 10 or 30 mg/kg given orally twice daily in multiple KRAS G12D PDAC and CRC CDX tumor models. GFH375 also showed strong anti-tumor efficacy in an intracranial KRAS G12D tumor model starting as low as 10 mg/kg orally twice daily. Strong synergy between GFH375 and avutometinib was observed in vitro and was validated in vivo as anti-tumor activity of GFH375 was further enhanced by avutometinib. Conclusions: GFH375 is a highly potent and selective orally active inhibitor of KRAS G12D (ON/OFF) and demonstrated promising anti-tumor activity in multiple KRAS G12D tumor models. GFH375 was also effective in an intracranial tumor model. GFH375 showed strong synergy with avutometinib in vitro and in vivo. GFH375 is currently in IND-enabling development in preparation for clinical studies of monotherapy and potentially in combination with other agents for patients with KRAS G12D mutant tumors. Citation Format: Feng Yan, Tao Jiang, Tao Liang, Lijian Cai, Leitao Zhang, Xiaoming Xu, Yanhui Zhao, Xiaoling Lan, Xiaohui Zhang, Meng Liu, Qiang Liu, Jinting Gao, Fubo Xie, Xueyan Gao, Li Wang, Jingyang Zhang, Hongcan Ren, Dong Liu, Siyuan Le, Lili Tang, Silvia Coma, Yaofeng Cheng, Nathan Sanburn, Jonathan A. Pachter, Fusheng Zhou, Jiong Lan, Qiang Lu. GFH375 (VS-7375): An oral, selective KRAS G12D (ON/OFF) inhibitor with potent anti-tumor efficacy [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 3318.

Abstract Purpose: The effective treatment of AML and solid tumors remains an unmet medical need. Mesothelin (MSLN) is a glycophosphatidylinositol-linked tumor antigen overexpressed in a variety of malignancies, including AML and solid tumors, such as mesothelioma, cholangiocarcinoma, ovarian, pancreatic, lung, esophageal, gastric, colorectal, endometrial and triple-negative breast cancer. Early signs of clinical efficacy with MSLN-targeting agents have validated MSLN as a promising target for therapeutic intervention, but therapies with improved efficacy are still needed. CD3-based T cell engagers are highly potent therapeutic molecules with T cell cytotoxicity activities in the picomolar range. But high CRS risk and T cell exhaustion has been observed for high affinity CD3-based T cell engagers in clinicals, so we used high affinity MSLN and low affinity CD3 to improve efficacy of T cell engager. Experimental Design: We designed SMTE-001, a 78-kDa, tetra-specific, T-cell-activating protein molecule, which binds to two epitopes (membrane proximal and membrane distal) of MSLN, CD3ε on T cells, and to serum albumin. Experiments were conducted to assess the potency, activity, and half-life of HPN536 in in vitro assays, rodent models, and in nonhuman primates (NHP). This molecule was tested in a cytotoxicity assay using human PBMCs co-cultured with OVCAR3, Hela and NCI-H292 cells, which express different levels of MSLN. Soluble MSLN and CA125 (ligand of MSLN) was added to determine effects on cytotoxicity. In vivo xenograft mouse studies were conducted using a PBMC model. Results: Here we report the design and the promising preclinical activity of SMTE-001 molecule in vitro and in vivo. We demonstrate that the bivalent MSLN T cell engager has increased in vitro potency in T cell activation and tumor cell killing, as compared to a monovalent counterpart on high MSLN expressing cells. We also demonstrate that T cell exhaustion is reduced for the low-affinity CD3, compared to the low-affinity CD3 molecule. Because soluble MSLN and CA125 is shed from cancer cells into cancer patient serum, we also demonstrate that soluble MSLN and CA125 does not interfere with the cytotoxic activity of SMTE-001. Importantly, we demonstrate in vivo that SMTE-001 significantly inhibits tumor growth in a dose-dependent manner, while high-affinity CD3 molecule’ efficacy reduces when higher dosing. In cynomolgus monkeys, SMTE-001 shows pharmacokinetics in support of weekly dosing in humans. Conclusions: Collectively, these data demonstrate strong anti-tumor efficacy by this novel multispecific bivalent T cell engager. These data indicate the therapeutic potential of this molecule to activate T cells and improve the clinical efficacy in AML and MSLN-expressing solid tumors. Citation Format: Cuiqing Yang, Xiaohui Shao, Feng Zhou, Lei Zhou, Qi Deng, Yun Zhang, Guangcun Cheng, Yingying Hu, Huaiyuan Ma, Yadan Wu, Shuai Wang, Jie Zang, Lei Liu, Wenqing Yang, Yang Liu, Chunlei Xia, Jianzhong Hu, Ande Luo, Yayuan Fu, Zhuoxiao Cao, Renhong Tang. A multispecific T cell engager binding to both membrane proximal and membrane distal epitopes of MSLN with low affinity CD3 for the treatment of AML and solid tumors [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 6343.

Abstract 58 Background: In 2011, an international panel of breast cancer experts developed the first Advanced Breast Cancer (ABC) Consensus Guidelines to provide standards and improved care for the multidisciplinary care of patients with this common disease. We sought to adapt the ABC guidelines for China, incorporating cultural standards and available Chinese resource, and identifying suitable formed guideline. Methods: We organized the Chinese Consensus Guidelines Conference for ABC (CABC) yearly from 2013 through 2015 in Beijing as a joint effort between the China Medical Women's Association, the Organization of Beijing Sunshine Great Wall Oncology Program, Peking University, The panel included 50 breast oncology and surgery experts from 20 provinces, as well as two external consultant oncologists from the U.S. and Singapore. Permission was obtained from the ABC Chair to use the guidelines as a basis for our discussion. All questions were presented and discussed in detail, including a review of current applicable data, and panel members voted on each question. Results: The main issues discussed included; 1. In China the patient treatment decision making generally by family members. 2. Use of sequential single agent chemotherapy for standard risk in China most experts still prefer combination therapy. 3. The trastuzumab are not covered by health insurance in China and/or pertuzumab is not yet available. 5. For hormone receptor positive ABC, some physicians in China prefer to start with chemotherapy . 7. Not well accepted by Chinese patients. Details of final voting and Chinese consensus will be presented. Conclusions: Standard guidelines are critical, but must be tailored to be used effectively in specific countries. The CABC has effectively discussed, modified and distributed guidelines for the treatment of ABC in China. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: Huiping Li No relationship to disclose Hope S. Rugo Honoraria: Genomic Health Speakers' Bureau: Genomic Health Research Funding: Plexxikon, Macrogenics, OBI Pharma, Eisai, Pfizer, Novartis, Eli Lilly, GlaxoSmithKline, Genentech, Celsion, Nektar, Merck, Amgen Travel, Accommodations, Expenses: Novartis, Nektar, Roche/Genentech, OBI Pharma, Mylan Jin Zhang No relationship to disclose Zhimin Shao No relationship to disclose Zhenzhou Shen No relationship to disclose Binhe Xu No relationship to disclose Jiong Wu No relationship to disclose Zefei Jiang No relationship to disclose Erwei Song No relationship to disclose Yinhua Liu No relationship to disclose Xichun Hu No relationship to disclose Cuizhi Geng No relationship to disclose Bo Li No relationship to disclose Jinhai Tang No relationship to disclose Jifeng Feng No relationship to disclose Pin Zhang No relationship to disclose Junlan Yang No relationship to disclose Qingyuan Zhang No relationship to disclose Jian Liu No relationship to disclose Yuee Teng No relationship to disclose Yongsheng Wang No relationship to disclose Zhongsheng Tong No relationship to disclose Guohong Song No relationship to disclose Peng Yuan No relationship to disclose Hongmei Zhao No relationship to disclose Wuyun Su No relationship to disclose Tao Sun No relationship to disclose Seng-Weng Wong Consulting or Advisory Role: MSD Oncology, Novartis, Roche, Pfizer Speakers' Bureau: MSD Oncology, Bayer, Novartis Travel, Accommodations, Expenses: Bayer, Roche, Merck Serono, Boehringer Ingelheim Yanshen Lu No relationship to disclose Yongchang Zhou No relationship to disclose

Abstract The E3 ubiquitin ligase Casitas B-lineage lymphoma b (Cbl-b) is a member of the highly conserved family of Cbl (casitas b-lineage lymphoma) proteins, which associates with multi-immune response regulations including Teff and NK activation, Treg differentiation. Cbl-b KO mice showed enhanced immune responses and resistance to tumor transplantation. Previously, we reported a novel Cbl-b inhibitor, ZM-8026, which robustly activated T cells and efficiently inhibited tumor growth as monotherapy or in combination with anti-PD-1. Here, we further demonstrated that Cbl-b inhibition restores the Teff cells' function in immune suppression conditions, such as in the presence of PGE2, A2AR agonist, and TGF-β. CD8+T proliferation and cytokines induction were maintained in the presence of MDSC. Furthermore, CD8+T function was reversed from an exhausting status induced by a continuous anti-CD3/CD28 activation for a long period. To investigate whether continuous target occupancy was necessary for sustained TCR activation, the dynamic impacts of Cbl-b inhibition on CD8+T cell activation were explored using a washout assay. The results showed that the high-level activated T cells lasted for 48 h after more than 4hs preincubation with 1 µM Cbl-b inhibitor followed by a washout, however, short and weak activation states were found with less than 4hs preincubation or low inhibitor concentration treatment (< 0.1 uM). This finding revealed sufficient inhibitor concentration and treatment time ensure high T-cell activation. Further, in vivo efficacy studies demonstrated less anti-tumor growth efficacy for intermittent dosing (Q2D, Q3D) compared with QD dosing. In vitro and in vivo pharmacokinetics studies exhibited favorable ADME profiles and bioavailability of our Cbl-b inhibitor for oral administration in mice, rats, and dogs. At least in two syngeneic models, our Cbl-b inhibitor exhibited efficient anti-tumor growth with more than 70% TGI (tumor growth inhibition). In a CT26 syngeneic model, complete tumor growth inhibition in 6 of 8 mice was found in the Cbl-b inhibitor combined with an anti-PD1 antibody. The complete regression mice were re-challenged with the same tumor cells, and no measurable tumors were found for up to 30 days, suggesting the treatment-induced immune memory. Tumor samples in mice were collected, RNAseq showed that activated functions of tumor-infiltrated T, NK, DC, and macrophage were dramatically increased in the Cbl-b inhibitor treatment group, and the T and NK activation signature genes such as Gzmb, Ifng were significantly upregulated by RT-PCR. In conclusion, our Cbl-b inhibitor exhibited a favorable PK profile in multi-preclinical animals. The sustained T cell activation in vitro was identified and robust anti-tumor growth in vivo was demonstrated with optimized dosing frequency. Citation Format: Feng Zhou, Guimei Yang, Yajing Liu, Liting Xue, Weijie Chen, Zhengtao Li, Xiaowu Liu, Jian Li, Renhong Tang. An oral Cbl-b inhibitor with sustained T cell activation demonstrated robust anti-tumor efficacy along with enhanced infiltration and activation of functional T cells [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 661.

Background:Gout is an arthritic disease caused by the deposition of monosodium urate crystal (MSU) in the joints, which can lead to acute inflammation and damage adjacent tissue [1].Over the past decade, noncoding RNAs (ncRNAs) have been shown to have crucial importance in health and disease[2,3]. However, studies evaluating the function of ncRNAs in gout are scarce, and current knowledge of the role of ncRNAs in gout is still limited.Objectives:To assess the contribution of noncoding RNAs to gout and the clinical importance of these genes in primary gouty arthritis (GA).Methods:The mRNA expression levels of noncoding RNAs (LINC00173, LINC00963, LINC01330 and miRNA-182-5p) were measured in peripheral blood mononuclear cells (PBMCs) from 60 gout patients(including 30 acute gout patients, 30 intercritical gout patients) and 40 healthy subjects. The relationship between noncoding RNA expression levels and laboratory features was analyzed in GA patients.Results:The expression levels of LINC00173, LINC00963 and miRNA-182-5p were much lower in the AG and IG group than in the HC groups (p<0.05), and no significant difference was detected between AG and IG groups(P>0.05). The expression levels of LINC01330 were much lower in the AG group than in the IG and HC groups (p<0.05), and no significant difference was detected between AG and IG groups(P>0.05). In GA patients, the levels of noncoding RNAs mRNA correlated with laboratory inflammatory and metabolic indexes.Conclusion:Altered noncoding RNAs expression suggests that noncoding RNAs is involved in the pathogenesis of GA and participates in regulating inflammation and metabolism.References:[1]Xu Yi-Ting,Leng Ying-Rong,Liu Ming-Ming et al. MicroRNA and long noncoding RNA involvement in gout and prospects for treatment.[J].Int Immunopharmacol, 2020, 87: 106842.doi:10.1016/j.intimp.2020.106842[2]Yu Yunfang,Zhang Wenda,Li Anlin et al. Association of Long Noncoding RNA Biomarkers With Clinical Immune Subtype and Prediction of Immunotherapy Response in Patients With Cancer.[J].JAMA Netw Open, 2020, 3: e202149.doi:10.1001/jamanetworkopen.2020.2149[3]Zou Yaoyao,Xu Siqi,Xiao Youjun et al. Long noncoding RNA LERFS negatively regulates rheumatoid synovial aggression and proliferation.[J].J Clin Invest, 2018, 128: 4510-4524.doi:10.1172/JCI97965Figure 1.Relative Expression of noncoding RNAs in the PBMCs of Patients.Disclosure of Interests:Quan-Bo Zhang Grant/research support from: the National Natural Science Foundation of China(General Program) (no.81974250) and Science and Technology Plan Project of Sichuan Province (no.2018JY0257), Yu-Qin Huang: None declared, Fan-Ni Xiao: None declared, gui-lin jian: None declared, Yi-Ping Tang: None declared, Fei Dai: None declared, Jian-Xiong Zheng: None declared, Yu-Feng Qing Grant/research support from: Science and Technology Project of Nanchong City (no.18SXHZ0522).

Abstract Cancer metabolism is highly heterogenous and flexible with the Warburg effect or oxidative phosphorylation (OXPHOS) prevailing in a cancer type- and context-dependent manner. Past studies have demonstrated that targeting OXPHOS robustly inhibits glycolysis-deficient cancer cell viability and tumorigenicity. However, the therapeutic potential of OXPHOS inhibition in metabolically flexible glycolysis-competent cancers is unclear. Furthermore, whether the depletion of OXPHOS-derived ATP or the abolition of OXPHOS-supported biosynthesis is the major determinant of cancer cell susceptibility remains obscure. To address these questions, we exposed a panel of metabolically flexible glycolysis-competent cancer cell lines to OXPHOS inhibitors and tested cell survival and proliferation. We monitored metabolic phenotypes and changes in metabolites using seahorse metabolic flux assays and targeted metabolomics, respectively. Stable isotope-tracing was carried out with uniformly labelled [15N]-/[13C]-aspartate. Patient-derived xenograft (PDX) models of colorectal cancer in NSG mice were used for in vivo validation. Here we provide evidence that OXPHOS inhibition potently diminishes metabolically flexible glycolysis-competent cancer cell proliferation and tumorigenicity without causing devastating energy stress. The inhibition of cell proliferation by OXPHOS inhibitors is associated with S-phase cell cycle arrest and the enrichment of the G2/M DNA-damage check point regulation pathway, suggestive of replication stress. Indeed, IACS treatment significantly reduces the purine/pyrimidine nucleotide pools, which is primarily caused by aspartate deficiency resulting from a shortage in the electron acceptor NAD+. The supplementation of exogenous nucleosides, aspartate, or pyruvate that can accept electron generating NAD+, into the culture medium rescues cells from IACS-induced cell cycle arrest. Instructively, inhibition of GOT1, which catalyzes cytosolic aspartate biosynthesis when mitochondrial aspartate production is dampened, renders cancer cells grown in two- and three-dimensional cultures more susceptible to OXPHOS inhibition. Collectively, these results indicate that 1) disruption of nucleotide homeostasis is a major determinant of cancer cell susceptibility to OXPHOS inhibition; 2) OXPHOS inhibition is a promising avenue for the treatment of cancers that are metabolic flexible and glycolysis competent; and 3) GOT1 targeting is potentially a useful approach to improve the therapeutic efficacy of OXPHOS inhibition for cancer treatment. Citation Format: Xiaohong Zhao, Yuan Yuan Zhang, Liang Xu, Ting La, Yu Chen Feng, Hai Jie Tang, Ran Xu, Vinod K. Narayana, David P. De Souza, Lake-Ee Quek, Jeff Holst, Rick F. Thorne, Mark Baker, Tao Liu, Lei Jin, Xu Dong Zhang. Disruption of nucleotide homeostasis confers cancer cell susceptibility to oxidative phosphorylation inhibition independently of energy depletion. [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 3687.

Temperature has a significant impact on the luminescence profile of photonic materials for biological applications. This paper presents the effect of temperature on the luminescence profile of three different photonic materials in the range of the second biological window. The effect of temperature on luminescence properties is shown on glass, glass-ceramics, and phosphors co-doped with Eu3+/Nd3+/Yb3+ under UV laser diode excitation. Each sample has been analyzed for temperature effects on optical parameters in biological window ranges. Moreover the effect of temperature on mechanisms of energy transfer Eu3+ → Nd3+ → Yb3+ in all fabricated photonic materials was analyzed. Full Text: PDF References J. Zhou, J.L. Leano Jr., Z. Liu, D. Jin, K.-L. Wong et al., "Impact of Lanthanide Nanomaterials on Photonic Devices and Smart Applications", Small 14, 1801882 (2018). CrossRef Z. Li, Y. Zhang, G. Han, "Lanthanide-Doped Upconversion Nanoparticles for Imaging-Guided Drug Delivery and Therapy", Springer Series in Biomaterials Science and Engineering 6, 139 (2016). CrossRef A. Zhang, Z. Sun, M.Jia, et al., "Simultaneous luminescence in Ⅰ, Ⅱ and III biological windows realized by using the energy transfer of Yb3+→Er3+/Ho3+→Cr3+", Chemical Engineering Journal 365, 400 (2019). CrossRef M.-F. Tsai, S.-H.G. Chang, F.-Y. Cheng, V. Shanmugam, Y. Cheng et al., "Au Nanorod Design as Light-Absorber in the First and Second Biological Near-Infrared Windows for in Vivo Photothermal Therapy", ACS Nano 7, 5330 (2013). CrossRef S. Ding, L. Lu, Y. Fan, F. Zhang, "Recent progress in NIR-II emitting lanthanide-based nanoparticles and their biological applications", J. Rare Earth. 38, 451 (2020). CrossRef U. Rocha, K.U. Kumar, C. Jacinto, I. Villa, F. Sanz-Rodriguez et al., "Neodymium-Doped LaF3 Nanoparticles for Fluorescence Bioimaging in the Second Biological Window", Small 10, 1141 (2014). CrossRef M. Jia, Z. Sun, H. Xu, X. Jin, Z. Lv et al. "An ultrasensitive luminescent nanothermometer in the first biological window based on phonon-assisted thermal enhancing and thermal quenching", J. Mater. Chem. C 8, 15603 (2020). CrossRef H. Lin, T. Hu, Y. Cheng, M. Chen, Y. Wang, "Glass Ceramic Phosphors: Towards Long-Lifetime High-Power White Light-Emitting-Diode Applications–A Review", Laser Photonic Rev. 12, 1700344 (2018). CrossRef H. Su, Y. Nie, H. Yang, D. Tang, K. Chen, T. Zhang, "Improving the thermal stability of phosphor in a white light-emitting diode (LED) by glass-ceramics: Effect of Al2O3 dopant", J. Eur. Ceram. Soc. 38, 2005 (2018). CrossRef Kenry, Y.Duan, B. Liu, "Recent Advances of Optical Imaging in the Second Near-Infrared Window", Adv. Mater. 30, 1802394 (2018). CrossRef M.L. Debasu, H. Oliveira, J. Rocha, L.D. Carlos, "Colloidal (Gd0.98Nd0.02)2O3 nanothermometers operating in a cell culture medium within the first and second biological windows", J. Rare Earth. 38, 483-491 (2020). CrossRef L. Pavasaryte, A. Katelnikovas, V. Klimavicius, V. Balevicius, A. Krajnc et al., "Eu3+-Doped Y3−xNdxAl3O12 garnet: synthesis and structural investigation", Phys. Chem. Chem. Phys. 19, 3729 (2017). CrossRef K. Sadowska, P. Awramiuk, I Zgłobicka, K Rećko, J. Żmojda, "Quantum efficiency of europium doped LaPO4 phosphors for UV sensing applications", Photonics Lett. Poland 14, 28 (2022). CrossRef P. Lei, J. Feng, H. Zhang, "Emerging biomaterials: Taking full advantage of the intrinsic properties of rare earth elements", Nano Today 35, 100952 (2020). CrossRef K. Sadowska, T. Ragiń, M. Kochanowicz, P. Miluski, J. Dorosz, et al., "Analysis of Excitation Energy Transfer in LaPO4 Nanophosphors Co-Doped with Eu3+/Nd3+ and Eu3+/Nd3+/Yb3+ Ions", Materials 16, 1588 (2023). CrossRef

Abstract Microsatellite instability-high status (MSI-H) is typically associated with endometrial and gastrointestinal cancers. These tumors harbor large numbers of frameshift and single-nucleotide variants and are characterized by a high tumor mutational burden (TMB). The clinical benefits of immune checkpoint inhibitor (ICI) therapy on MSI-H cancers were well-demonstrated, however, 50% of these cancers are intrinsically resistant to PD-1 therapies and resistance inevitably develops with prolonged treatment. Thus, a novel efficient therapeutic strategy for MSI-H cancer is still needed. Werner syndrome ATP-dependent helicase (WRN) is a member of the RecQ helicases family and has recently emerged as a promising synthetic-lethal target in the treatment of MSI-H tumors. In MSI-H tumors, microsatellite sequences consisting of repeated nucleotides are unstable, and replication slippage causes a unique secondary structure that hinders the progression of replication forks. With its helicase activity, WRN unwinds this secondary structure to restart DNA synthesis and sustain MSI-H tumor cell growth. WRN knockdown or helicase enzyme-dead effectively inhibits cell proliferation and tumor growth in multiple preclinical MSI-H models. Here we identified ZM-3329, a novel and highly potent WRN inhibitor. Helicase activities were efficiently inhibited by ZM-3329 with IC50 less than 30 nM, and equal potency was identified on HCT-116 cell proliferation inhibition. In a panel of 124 tumor cell lines, ZM-3329 only specifically inhibited the growth of MSI-H but had no significant effects on the MSS (Microsatellite stable) tumor cell lines, indicating high selectivity against MSS. Additionally, ZM-3329 strongly inhibited the growth of MSI-H patient-derived organoids. The intracellular mechanism of action study revealed that inhibition of WRN by ZM-3329 in MSI-H cells led to the accumulative DNA damage signatures which was demonstrated by the increase of γH2AX and P21 expression, and arrested cell cycle to G2/M. ZM-3329 demonstrated favorable pharmacokinetic profiles in pre-clinical species, supporting oral administration in humans. ZM-3329 showed robust anti-tumor activities in multiple MSI-H xenograft models with significant tumor regression observed. Meanwhile, mice were tolerant well in all tested doses, and no abnormality was observed. In conclusion, a novel WRN inhibitor was developed, and robust antitumor activities were demonstrated in xenograft tumors and PDOs with different tissue types. In terms of synthetic lethality between MSI-H and WRN as well as broad anti-tumor activities across different tumor types, ZM-3329 would be developed as a tissue-agnostic therapy for MSI-H patients. Citation Format: Feng Zhou, Guimei Yang, Yajing Liu, Liting Xue, Yao Guo, Zhengtao Li, Weikun Wang, Jian Li, Renhong Tang. Discovery of a novel WRN inhibitor, ZM-3329 that efficiently inhibits MSI-H tumor growth [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 7278.

Armored scale insects (Hemiptera: Coccomorpha: Diaspididae) are major economic pests and are among the world's most invasive species. Here we describe a system of specimen and identification management that establishes a basis for well-vouchered molecular identification. We also present an expanded Bayesian phylogenetic analysis based on concatenated fragments of 4 genetic loci: the large ribosomal subunit (28S), elongation factor-1 alpha (EF-1α), cytochrome oxidase I and II (COI‒II), and the small ribosomal subunit (16S) of the primary endosymbiont, Uzinura diaspidicola (Bacteroidetes: Flavobacteriales). Our sample includes 1,389 individuals, representing 11 outgroup species and at least 311 described and 61 undescribed diaspidid species. The results broadly support Takagi's 2002 classification but indicate that some revisions are needed. We propose a revised classification recognizing 4 subfamilies: Ancepaspidinae Borchsenius, new rank, Furcaspidinae Balachowsky, new rank, Diaspidinae Targioni Tozzetti, and Aspidiotinae Westwood. Within Aspidiotinae, in addition to the existing tribes Aspidiotini Westwood, Parlatoriini Leonardi, Odonaspidini Ferris, Leucaspidini Atkinson, and Smilacicolini Takagi, we recognize as tribes Gymnaspidini Balachowsky, new rank, and Aonidiini Balachowsky, new rank. Within Diaspidinae we recognize the 2 tribes Lepidosaphidini Shimer and Diaspidini Targioni Tozzetti, and within Diaspidini we recognize three subtribes: Diaspidina Targioni Tozzetti, Fioriniina Leonardi, and Chionaspidina Brues & Melander. We regard Kuwanaspidina Borchsenius as a junior synonym of Fioriniina, Thysanaspidini Takagi as a junior synonym of Leucaspidini, and Protodiaspidina Takagi and Ulucoccinae Takagi as junior synonyms of Chionaspidina. To clarify the composition of the higher taxa we describe 2 new genera for Australian species heretofore misplaced in the genus Ancepaspis Ferris: Brimblecombia Normark (Aonidiini) and Hendersonaspis Normark (Leucaspidini). We also propose many additional minor modifications to the taxonomy of Diaspididae, including the following new combinations, revived combinations, and replacement names: Aonidia edgerleyi (Mamet), new combination (from Bigymnaspis Balachowsky); Aonidomytilus espinosai Porter, revived combination (from Porterinaspis González); Aspidiotus badius (Brain), new combination (this and the next 5 Aspidiotus species all from Aonidia Targioni Tozzetti); Aspidiotus biafrae (Lindinger), new combination; Aspidiotus chaetachmeae (Brain), new combination; Aspidiotus laticornis (Balachowsky), new combination; Aspidiotus rhusae (Brain), new combination; Aspidiotus sclerosus (Munting), new combination; Brimblecombia asperata (Brimblecombe), new combination (this and the next 5 Brimblecombia species all from Ancepaspis); Brimblecombia longicauda (Brimblecombe), new combination; Brimblecombia magnicauda (Brimblecombe), new combination; Brimblecombia reticulata (Brimblecombe), new combination; Brimblecombia rotundicauda (Brimblecombe), new combination; Brimblecombia striata (Brimblecombe), new combination; Cooleyaspis pseudomorpha (Leonardi), new combination (from Dinaspis Leonardi); Cupidaspis wilkeyi (Howell & Tippins), new combination (from Paracupidaspis Howell & Tippins); Cupressaspis isfarensis Borchsenius, revived combination (this species, the next 2 species in Cupressaspis Borchsenius, revived genus, and the next 9 species in Diaspidiotus Cockerell all from Aonidia); Cupressaspis mediterranea (Lindinger), revived combination; Cupressaspis relicta (Balachowsky), new combination; Diaspidiotus atlanticus (Ferris), new combination; Diaspidiotus marginalis (Brain), new combination; Diaspidiotus maroccanus (Balachowsky), new combination; Diaspidiotus mesembryanthemae (Brain), new combination; Diaspidiotus opertus (De Lotto), new combination; Diaspidiotus shastae (Coleman), new combination; Diaspidiotus simplex (Leonardi), new combination; Diaspidiotus visci (Hall), new combination; Diaspidiotus yomae (Munting), new combination; Diaspis arundinariae (Tippins & Howell), new combination (from Geodiaspis Tippins & Howell); Duplachionaspis arecibo (Howell), new combination (this and the next 10 Duplachionaspis MacGillivray species all from Haliaspis Takagi); Duplachionaspis asymmetrica Ferris, revived combination; Duplachionaspis distichlii (Ferris), revived combination; Duplachionaspis litoralis Ferris, revived combination; Duplachionaspis mackenziei McDaniel, revived combination; Duplachionaspis milleri (Howell), new combination; Duplachionaspis nakaharai (Howell), new combination; Duplachionaspis peninsularis (Howell), new combination; Duplachionaspis spartinae (Comstock), revived combination; Duplachionaspis texana (Liu & Howell) new combination; Duplachionaspis uniolae (Takagi), new combination; Duplachionaspis mutica (Williams) (from Aloaspis Williams), new combination; Epidiaspis doumtsopi (Schneider), new combination (from Diaspis Costa); Fiorinia ficicola (Takahashi), new combination (from Ichthyaspis Takagi); Fiorinia macroprocta (Leonardi), revived combination (this and the next 2 species of Fiorinia Targioni Tozzetti all from Trullifiorinia Leonardi); Fiorinia rubrolineata Leonardi, revived combination; Fiorinia scrobicularum Green, revived combination; Genaparlatoria pseudaspidiotus (Lindinger), revived combination (from Parlatoria); Greeniella acaciae (Froggatt), new combination (this and the next 4 Greeniella Cockerell species all from Gymnaspis Newstead); Greeniella cassida (Hall & Williams), new combination; Greeniella grandis (Green), new combination; Greeniella perpusilla (Maskell), new combination; Greeniella serrata (Froggatt), new combination; Hendersonaspis anomala (Green), new combination (from Ancepaspis); Hulaspis bulba (Munting), new combination (this and the next Hulaspis Hall species both from Andaspis MacGillivray); Hulaspis formicarum (Ben-Dov), new combination; Lepidosaphes antidesmae (Rao in Rao & Ferris), new combination (this and the next 19 species all from Andaspis); Lepidosaphes arcana (Matile-Ferrero), new combination; Lepidosaphes betulae (Borchsenius), new combination; Lepidosaphes citricola (Young & Hu), new combination; Lepidosaphes conocarpi (Takagi), new combination; Lepidosaphes crawi (Cockerell), revived combination; Lepidosaphes erythrinae Rutherford, revived combination; Lepidosaphes incisor Green, revived combination; Lepidosaphes indica (Borchsenius), new combination; Lepidosaphes kashicola Takahashi, revived combination; Lepidosaphes kazimiae (Williams), new combination; Lepidosaphes laurentina (Almeida), new combination; Lepidosaphes maai (Williams & Watson), new combination; Lepidosaphes mackieana McKenzie, revived combination; Lepidosaphes micropori (Borchsenius), new combination; Lepidosaphes punicae Laing, revived combination; Lepidosaphes quercicola (Borchsenius), new combination; Lepidosaphes recurrens (Takagi & Kawai), new combination; Lepidosaphes viticis (Takagi), new combination; Lepidosaphes xishuanbannae (Young & Hu), new combination; Lepidosaphes giffardi (Adachi & Fullaway), new combination (from Carulaspis MacGillivray); Lepidosaphes garciniae (Young & Hu), new combination (this and the next 2 species all from Ductofrontaspis Young & Hu); Lepidosaphes huangyangensis (Young & Hu), new combination; Lepidosaphes jingdongensis (Young & Hu), new combination; Lepidosaphes recurvata (Froggatt), revived combination (from Metandaspis Williams); Lepidosaphes ficicola Takahashi, revived combination (this and the next 2 species all from Ungulaspis MacGillivray); Lepidosaphes pinicolous Chen, revived combination; Lepidosaphes ungulata Green, revived combination; Lepidosaphes serrulata (Ganguli), new combination (from Velataspis Ferris); Lepidosaphes huyoung Normark, replacement name for Andaspis ficicola Young & Hu; Lepidosaphes tangi Normark, replacement name for Andaspis schimae Tang; Lepidosaphes yuanfeng Normark, replacement name for Andaspis keteleeriae Yuan & Feng; Leucaspis ilicitana (Gómez-Menor), new combination (from Aonidia); Lopholeucaspis spinomarginata (Green), new combination (from Gymnaspis); Melanaspis campylanthi (Lindinger), new combination (from Aonidia); Mohelnaspis bidens (Green), new combination (from Fiorinia); Parlatoria affinis (Ramakrishna Ayyar), new combination (this and the next 4 Parlatoria species all from Gymnaspis); Parlatoria ficus (Ramakrishna Ayyar), new combination; Parlatoria mangiferae (Ramakrishna Ayyar), new combination; Parlatoria ramakrishnai (Green), new combination; Parlatoria sclerosa (Munting), new combination; Parlatoria bullata (Green), new combination (from Bigymnaspis); Parlatoria leucaspis (Lindinger), new combination (this and the next species both from Cryptoparlatorea Lindinger); Parlatoria pini (Takahashi), new combination; Parlatoria tangi Normark, replacement name for Parlatoria pini Tang; Pseudoparlatoria bennetti (Williams), new combination (from Parlagena McKenzie); Pseudoparlatoria chinchonae (McKenzie), new combination (from Protodiaspis Cockerell); Pseudoparlatoria larreae (Leonardi), revived combination (from Protargionia Leonardi); Quernaspis lepineyi (Balachowsky), new combination (from Chionaspis); Rhizaspidiotus nullispinus (Munting), new combination (from Aonidia); Rolaspis marginalis (Leonardi), new combination (from Lepidosaphes); Salicicola lepelleyi (De Lotto), new combination (from Anotaspis Ferris); Tecaspis giffardi (Leonardi), new combination (from Dinaspis); Trullifiorinia geijeriae (Froggatt), new combination (from Fiorinia); Trullifiorinia nigra (Lindinger), new combination (from Crypthemichionaspis Lindinger); and Voraspis olivina (Leonardi), new combination (from Lepidosaphes).

Solid oxide cells (SOCs) offer great promise for efficient energy generation and storage in a variety of applications. Symmetrical SOCs with identical anode and cathode materials configuration favoring an efficient reversible operation of the cells, allow both electricity production from traditional and renewable energy sources in fuel cell mode, and clean, efficient fuel production (in reverse/electrolysis mode). In addition, the symmetrical cell design is particularly advantageous, including: decreased number of cell components, simplification of fabrication process and alleviating the chemical stability issues related with materials, as well as the enhanced resistance to coking and sulphur poisoning, when cells are fuelled by alternative sources (non-H2) [1]. However, electrode material candidates with excellent redox stability and electrocatalytic activities in both oxidizing and reducing conditions for symmetrical SOCs are limited due to the strict criteria. The design of electrode materials with in situ exsolution of nanoparticles significantly benefits the performance of SOCs [2]. In the anode operation condition, metallic nanoparticles are in situ exsolved from the parent electrode materials decorating on the electrode surface, substantially improving the catalytic activity and electronic conductivity of anode, thus boosting the cell performance. The in situ exsolved nanoparticles can be socketed to the parent oxide, enhancing the stability and hydrocarbon coking tolerance, making the symmetrical SOCs fuelled by cheaper and readily available non-hydrogen alternatives. Moreover, the possible reversible exsolution/dissolution of nanoparticles can potentially resolve the particle agglomeration and coke formation during usage of non-hydrogen fuels [2, 3]. The electrospinning technique has been reported to obtain nanofiber-structured electrodes for SOCs, which efficiently contributes to the enhancement of the electrochemical performance of SOCs [4]. In this work, the A-site deficient (Ln, Ba/Sr)2-α(Fe,M)2-x(Ni,Co)xO6-δ (Ln = selected lanthanides; M = Mn, Ti, Cr, Mo, W) perovskites were successfully obtained and evaluated as novel electrode materials for SOCs. It has been found that the A-site nonstoichiometry favours the in situ exsolution of metallic nanocatalysts (NixCo) from the parent materials in reducing condition. The selection of A-site cations (lanthanides) significantly affects the crystal structure (simple or double perovskite structure), while the B-site cations determine the stability of materials in air and reducing atmospheres. The reversibility of exsolved nanoparticles is systematically investigated under reducing and oxidizing conditions with different annealing temperatures. The possibility of in situ exsolution of nanooxides on the cathode (NixCoOy-like nanooxides) is also investigated. Nanofiber-structured electrodes with the ability of in situ exsolution of nanocatalysts are fabricated using the electrospinning technique, which significantly boost the electrochemical properties of constructed SOCs. References: [1] Y. Yang, Y. Wu, H. Bao, W. Song, H. Ni, D. Tian, B. Lin, P. Feng, Y. Ling, Electrochim. Acta, 362, 137171, (2020). [2] C. Su, W. Wang, M. Liu, M. O. Tadé, Z. Shao, Adv. Energy Mater., 5(14), 1–19, (2015). [3] K. Kousi, C. Tang, I. S. Metcalfe, D. Neagu, Small, 17(21), 2006479, (2021). [4] S. T. Aruna, L. S. Balaji, S. S. Kumar, B. S. Prakash, Renew. Sustain. Energy Rev., 67, 673–682, (2017).

Abstract Mounting evidence supports synergistic roles for the gut microbiome in cancer progression. Yet, the interplay between the gut microbiome and immune responses in cancer is still poorly understood. We recently showed that gut microbiome changes are closely associated with development of Kras-mutant lung adenocarcinoma (KM-LUAD) in a human-relevant, tobacco-associated mouse model (Gprc5a-/-; G). Knockout of the antimicrobial protein Lcn2 in these mice (Gprc5a-/-/Lcn2-/-; GL) further reduced microbial diversity while enhancing inflammation and tumor development. We thus hypothesized that microbial dysbiosis in the gut, such as that incurred by loss of Lcn2, may exacerbate LUAD development. Here, we investigated the effects of gut microbiome modulation on LUAD pathogenesis using fecal microbiota transfer (FMT) in both syngeneic and tobacco carcinogenesis models. Syngeneic G mice (transplant of G LUAD cells) that received FMT from GL donors (G &lt; GL) exhibited significantly increased tumor growth relative to littermates with FMT from G mice (G &lt; G). These effects were recapitulated in an independent syngeneic model (KrasG12D LKR13 cells in wild type mice). Tobacco carcinogen-exposed G &lt; GL mice also exhibited increased lung tumor development compared with similarly exposed G &lt; G littermates. 16S rDNA-Seq analysis of fecal pellets revealed significant differences in gut beta diversity between syngeneic G &lt; G and G &lt; GL mice. G &lt; GL mice additionally displayed elevated relative abundance of tumor-promoting Alistipes, while Ruminoccocus and Akkermansia, taxa associated with favorable response to immunotherapy, were reduced. We next performed single-cell RNA-sequencing to comprehensively probe the tumor immune microenvironment (TIME) and the immune milieu near the gut of tumors and mesenteric lymph nodes (MLNs), respectively. The TIME in G &lt; GL mice displayed an overall enhanced immunosuppressive phenotype evidenced by prominently increased fractions of T regulatory and Cd4+ Izumo1r+ exhausted T cells and, conversely, reduced levels of activated Isg15+ Cd8a+ T cells. MLNs from G &lt; GL mice showed markedly increased fractions of memory B cells expressing the immunosuppressor Bank1 and reduced levels of follicular B cells and Cd8a+ Clec9a+ class 1 dendritic cells (cDC1). Flow cytometry further showed enhanced immunosuppression in G &lt; GL relative to G &lt; G mice, including increased fractions of myeloid-derived suppressor cells in the TIME of the former group. Our findings show that gut microbiome dysbiosis fosters lung cancer development by promoting immunosuppression, perhaps via a local and systemic gut microbiota-immune system crosstalk. Modulating the gut microbiome may be a promising strategy for interception or early treatment of lung cancer. Citation Format: Zahraa Rahal, Fuduan Peng, Yuejiang Liu, Matthew C. Ross, Ansam Sinjab, Ke Liang, Jiping Feng, Chidera O. Chukwuocha, Manvi Sharma, Elizabeth Tang, Camille Abaya, Joseph Petrosino, Junya Fujimoto, Seyed Javad Moghaddam, Linghua Wang, Kristi L. Hoffman, Humam Kadara. Gut microbiome dysbiosis promotes immune suppression and lung cancer development [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 2883.

Abstract The E3 ubiquitin ligase Casitas B-lineage lymphoma b (Cbl-b) is a member of the highly conserved family of Cbl (casitas b-lineage lymphoma) proteins. CBL-b is widely expressed in immune cells and plays as a “gate keeper” to negatively regulate the activation of immune cells. Engagement of TCR/BCR triggers the Cbl-b-mediated ubiquitination and degradation of the key components in TCR axis, such as Vav1 and PLCγ, and consequently attenuates TCR/BCR signal axis which finally results in T/B cells exhaustion. Besides, Cbl-b was reported to negatively regulate the activation of dendritic cells, NK, NKT, and mast cells. Cbl-b KO mice show resistance to tumor transplantation, and the anti-tumor activities depend on the T and NK cells. According to the above observation, Cbl-b emerges as a novel intracellular immune checkpoint target to prevent immune cells from exhaustion and improve the antitumor immunotherapy. Here we identified a series of highly potent Cbl-b inhibitors. The inhibition of Cbl-b protein was evaluated by an in vitro CBL-b/E2-ubiquitin assay. Results showed that our candidates strongly inhibited Cbl-b with IC50s at single-digital nanomolar level, and meanwhile, these compounds displayed over than 10-fold selectivity against c-CBL/E2-ubiquitin, a member of the Cbl family, which was reported to synergistically enhance toxicity caused by Cbl-b. Consistent with the Cbl-b inhibition, these compounds further enhanced activation of Jurkat T cells as well as human PBMCs with dramatical increase of IL-2 or IFNɣ secretion in presence of anti-CD3/CD28, and without any significant cytotoxicity even up to 10 µM concertation. Furthermore, these compounds exhibited the restoring function in exhausted T cells in presence with PEG2 or adenosine treatment. Favorable ADME and bioavailability supported the oral administration. In naïve mice, our inhibitors dose-dependently promoted the cytokine IL-2 and IFNɣ production in serum and spleens following the anti-CD3 challenge. In a syngeneic model, CT26, oral administration of our Cbl-b inhibitor effectively inhibited tumor growth, while completely inhibited tumor growth in combination with an anti-PD1 antibody. Further study demonstrated that the increased lymphocytes infiltration and cytokines release in tumor tissues were observed either in Cbl-b mono or in anti-PD1 combo groups, which correlated well with anti-tumor efficacy. In conclusion, our selective Cbl-b inhibitors demonstrated robust immune activation and anti-tumor activity in vitro and in vivo and showed synergistic activities with immune checkpoint inhibitors, such as anti-PD(L)1. Currently, one of our leading molecules is in IND enabling studies. Citation Format: Feng Zhou, Zhengtao Li, Yajing Liu, Guimei Yang, Wansun Mai, Wenqing Yang, Liting Xue, Ping Chen, Renhong Tang. Identification of the selective CBL-b inhibitors which effectively prevent T cells from exhaustion and demonstrate synergistic anti-tumor activity in combination with an anti-PD1 antibody [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 3474.

Abstract The genome DNA is consistently threatened by a variety of intrinsic and exogenous DNA damage factors. Cell cycle checkpoint is one important mechanism in response to DNA damage and maintaining genome stability. In tumor cells, gene alterations, such as CCNE1 amplification (encoding for Cyclin E1), result in G1/S checkpoint loss and replication stress, leading to high dependency on the G2/M checkpoint. PKMYT1 inhibits crucial checkpoint protein CDK1 activity by phosphorylating CDK1 at the residues of Thr-14 and Tyr-15 in the G2/M phase. In CCNE1 amplification cells, the inhibition of PKMYT1 leads to the reduction of pCDK1 and loss of G2/M checkpoint, consequently results in premature mitosis and the accumulation of DNA damage, then finally induces cell death. Here we identify a novel small molecular ZM-2322, which displays robust intracellular binding to PKMYT1 and inhibits the specific downstream phosphorylation of CDK1 Thr-14 with IC50 values of 14 nM and 29 nM, respectively. ZM-2322 strongly inhibits the proliferation of the HCC1569 cell line with CCNE1 high-level amplification and shows a &gt;400 × selectivity folds over a CCNE1 wildtype cell line SKOV3. ZM-2322 also shows significant inhibition of tumor growth in a dose-dependent manner in the HCC1569 xenograft model, and the efficacy correlates well with PK and target inhibition. There is evidence showing that loss-of-function mutations of FBXW7, a cyclin E E3 ligase, lead to cyclin E accumulation and are synthetic-lethal with PKMYT1 inhibition. Consistently, a potent anti-proliferation of ZM-2322 is observed in DLD-1 FBXW7 -/- cells, but not DLD-1 parental cells. These data suggest a high potency of ZM-2322 on PKMYT1 inhibition and a potential good kinase selectivity which is further confirmed by using a kinase panel biochemical assay. As expected, when compared head-to-head with another clinical PKMYT1 inhibitor RP-6306 which shows inhibitory effect on 27 of 217 human kinases with inhibition rates &gt;90% at 1 μM, ZM-2322 is found to be a much more PKMYT1-selective inhibitor and hits only several individual kinases under the same assay condition, suggesting a potentiality in better safety profile and higher dose tolerance. Furthermore, our data illustrates that in combination with gemcitabine, ZM-2322 elicits strong synergetic anti-proliferation activities on HCC1569 cells in vitro and results in tumor regression with a minor effect on body weight in vivo. Besides, a strong synergy effect is also observed in the combo of ZM-2322 and ATR inhibitor in HCC1569 in vitro. These data indicate that ZM-2322 has the potential of application expansion and good tolerance under continuous administration. Taken together, our data suggest that ZM-2322 is a potent and highly selective PKMYT1 inhibitor. Citation Format: Feng Zhou, Lu Liu, Lei Jiang, Baoying Cheng, Zhentao Li, Dongxing Zhu, Jianbin Xue, Liting Xue, Renhong Tang. Discovery of ZM-2322, a highly selective, potent inhibitor of membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase (PKMYT1) [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 591.

Abstract Background/Purpose: CD47 has been validated to be expressed on various tumor types including acute myeloid leukemia, myelodysplastic syndrome and other hematologic or solid tumors. As primary ‘don’t eat me’ signal, high expression of CD47 on tumor cells interacts with SIRPα negatively regulating the phagocytosis level. However, poor safety profile as well as insufficient combinatory effect remain to be the issues limiting the clinical outcomes of CD47-targeting molecules. Herein, we used rational design strategies to generate SCR9168 with potent affinity improvement, and maintained favorable safety profiles in different animal species, including cynomolgus monkeys. Procedures: Mutagenesis was introduced to the residues critical for CD47/SIRPα binding interface. Affinity was measured by SPR analysis. In vitro activities were determined by biochemical- or cell-based binding, blocking and antibody-dependent cellular phagocytosis (ADCP) assays. The efficacy in vivo was assessed with the OE19 xenograft model. Pharmacokinetics (PK) and safety were monitored in both mice and cynomolgus monkeys. Results: The affinity of SCR9168 achieves 178 pM for human CD47 which is nearly 50-fold increase in comparison with wild-type SIRPα. Enhanced affinity has also been confirmed in binding to OE19 or DLD1 cell lines, as well as in blocking human SIRPα binding to Raji cells. SCR9168 remains strong binding potency to monkey, mouse or rat CD47 which allows the PK and safety assessment using these animal species. The combined effects of SCR9168 and multiple therapeutic antibodies targeting tumor-associated antigens (TAAs) have been evaluated with ADCP assays using human monocyte-derived macrophages. SCR9168 markedly increases the ratio of phagocytic cells combining with antibodies, such as cetuximab. However, due to the inert function of Fc fragment, no phagocytosis of red blood cells or platelets was caused after the incubation in vitro. In addition, SCR9168 treatment in combination with trastuzumab leads to significantly improved suppression of tumor growth in a dose-dependent manner. Moreover, administration of two doses at day 1 and day 11 in cynomolgus monkeys results in no toxicity events related to SCR9168 based on the data from hematological analysis. Conclusion: SCR9168 demonstrates the best-in-class potential among SIRPα mutein molecules. It elicits improved and dose-dependent efficacy in phagocytosis or tumor suppression combining with therapeutic antibodies, such as trastuzumab or cetuximab. Favorable safety profile with no phagocytosis of RBC or platelets in vitro as well as no hematological toxicity observation in cynomolgus monkeys allows broader dose range exploration in early clinical phase. SCR9168 is currently in development stage and IND enabling will be expected in the end of 2023. Citation Format: Yingying Hu, Yayuan Fu, Lei Liu, Wenjing Li, Liting Xue, Zhiyong Yu, Yun Zhang, Meijuan Gao, Yixin Tan, Fudong Wang, Yadan Wu, Jie Li, Zhenzhen Li, Feng Zhou, Wenqing Yang, Zhuoxiao Cao, Renhong Tang. Generation of a mutant SIRPa fusion protein with highly-improved affinity and favorable safety profile [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 6357.

Abstract Homologous recombination (HR) is a high-fidelity DNA double-strand break (DSB) repair pathway, and its dysfunction leads to cell genome instability and can result in tumorigenesis. In the situation of HR deficiency, DNA polymerase theta (Polθ) mediated microhomology-mediated end joining (MMEJ) is up-regulated to serve as a backup pathway for DSB repair. Several studies have proved that the inhibition of Polθ causes synthetic lethality with HR deficiency, and Polθ emerges as a potential DNA damage repair (DDR) target for the treatment of HR deficient tumors. In addition, there is evidence showing that the depletion of Polθ improves the sensitivity of some other DDR-related targeted therapies, chemotherapy, and radiotherapy. Here we identify a novel small molecular Polθ inhibitor, ZM-2311, which inhibits Polθ activity with an IC50 of 24 nM, and strongly inhibits cellular MMEJ pathway with a single nanomolar IC50. ZM-2311 illustrates a robust potency against tumor growth in a MDA-MB-436 SHLD2-/- xenograft model, suggesting potential monotherapy application in BRCA1 mutation patients with TP53BP1/Shieldin complex deficiency. Besides monotherapy, ZM-2311 elicits strong synergetic anti-proliferation activities in combination with PARP inhibitors on BRCA2-/- DLD-1 and endogenous HR deficient tumor cells in vitro and in vivo. Tumor regression is observed even at a low dosage, indicating a high potency of ZM-2311. As reversion mutation of HR genes such as BRCA1/2 mediated by the MMEJ pathway is reported to be a mechanism of PARP inhibitor resistance, ZM-2311 is evaluated and demonstrates its potential to overcome the resistance to PARP inhibitors. Furthermore, the combination of ZM-2311 with other DDR agents, such as ATR inhibitors, induces fatal DNA damage to HR deficient cells. Considering a low risk of hematotoxicity of Polθ inhibition, ZM-2311 may provide a new combination option for DDR agents. Besides, ZM-2311 was assessed in combination with different therapies respectively which functionally induce DNA damage, such as radiotherapy and chemotherapy. ZM-2311 renders tumor cells more sensitive to radiotherapy in both HR deficient cells and proficient cells in vitro, accompanying with the upregulation of Polθ expression after radiotherapy and an enhanced phosphorylation level of H2AX in the combination treatment. Similarly, ZM-2311 also achieves a robust synergetic effect in combination with chemotherapy in cell lines with different HR statuses. These results indicate a potential application expansion of ZM-2311 to HR-proficient tumors, which is expected to bring better efficacy and reduced hematotoxicity. Taken together, ZM-2311 has proved to be a highly potent Polθ inhibitor and has promising combination potential with multiple therapy strategies. Citation Format: Feng Zhou, Lu Liu, Lei Jiang, Shuo Qian, Liting Xue, Mengying Li, Zhengtao Li, Zhen Li, Jian Li, Renhong Tang. ZM-2311 a novel and highly potent Polθ inhibitor demonstrates synergistically anti-tumor activities in combination with different therapeutics [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 4539.

Background:Risk of rheumatoid arthritis (RA) had been reported in overweight obese compared with normal weight people. More, obesity is associated with high prevalence of cardiovascular disease (CVD) risk factors in RA. No previous publications have examined the detailed body composition parameters among RA, or its relation to CVD in RA.Objectives:This study looked at the body composition and the body mass index and correlated it with the subclinical cardiovascular disease as manifested by carotid intima media thickness (cIMT).Methods:During 2019, a cross-sectional study was carried out to recruit cases that met the 2010 American College of Rheumatology/EULAR criteria for diagnosis of RA. All the patients were free of cardiovascular and or cerebrovascular disease. Patients with clinical diagnosis of hypertension, diabetes, renal disease, dyslipidemia, thyroid disorder and pregnant female were excluded. None of the participants is smoker or had history of smoking.cMIT ultrasound (US) measures were obtained using a real-time US scanner equipped with a 7.5 MHz linear probe by a single sonographer. Patients underwent a detailed body composition analysis within the same week of the cIMT measurement. The body composition analysis involved assessing the level of total body water, protein, minerals, body fat mass, intra- and extracellular water, basal metabolic rate, waist hip ratio, visceral fat level, obesity degree, bone mineral content, body cell mass, arm and arm muscle circumference, detailed muscle fat analysis, obesity analysis, segmental lean analysis, weight control parameters, and segmental fat analysis.Results:During 2019, 35 female RA patients were recruited that met the inclusion criteria. The mean (SD) of the age was 52 (10) with a minimum of 20 and maximum of 72 years old. The mean (SD) of cIMT was 0.59 (0.098) mm with a minimum of 0 .38 and maximum of 0.87. The mean (SD) of the BMI was 30.7 (7.0) with a minimum of 20 and maximum of 56.9 Kg/m2. Mean systolic blood pressure was 126 (19) with a minimum of 91 and maximum of 140 mmHg. Also, the mean diastolic blood pressure was mmHg 74 (11) with a minimum of 49 and maximum of 96.The correlation of cIMT with the parameters of the body composition in a linear regression analysis showed a positive linear relationship between cIMT and each of the Body fat mass (kg): P=0.045, CI 0.000-0.004), BMI (p=0.029, CI: 0.001, 0 .009), the target weight (p=0.040, CI: 0.000- 0.001), extracellular water (P=0.033, CI: 0.002, 0.034) and bone mineral content (p=0.031, CI: 0.009, 0.192).The Multiple linear regression analysis showed persistence of the relationship between the cIMT and the age of the participants (p=0.049, CI:0.001-0.007) and the BMI (p=0.031, CI: 0.002- 0.032), with R2of the model was 0.38.Conclusion:To the best of our knowledge, this is the first paper to examine the detailed body composition parameters among RA and found a good correlation with subclinical cardiovascular disease as manifested by cIMT. More research with larger study population is needed to look at the association between body mass index and CVD risk factor in RA.References:[1]Body mass index and the risk of rheumatoid arthritis: a systematic review and dose-response meta-analysis. Qin B, Yang M, Fu H, Ma N, Wei T, Tang Q, Hu Z, Liang Y, Yang Z, Zhong R. Arthritis Res Ther. 2015; 17(1): 86. doi: 10.1186/s13075-015-0601-x[2]Body Mass Index and the Risk of Rheumatoid Arthritis: An Updated Dose-Response Meta-Analysis. Feng X, Xu X, Shi Y, Liu X, Liu H, Hou H, Ji L, Li Y, Wang W, Wang Y, Li D. Biomed Res Int. 2019; 2019: 3579081. doi: 10.1155/2019/3579081Disclosure of Interests:None declared

Internal short circuit (ISC) can be a main cause of Li-ion cell thermal runaway in field failures, but its mechanisms still require better understanding1 , 2. Due to the highly localized and electrochemical-thermal coupled nature of ISC, it is important to use in situ/operando measurement of critical parameters for insightful understanding of the mechanisms. We recently reported a method for in situ measurement of dynamic ISC resistance and ISC current during nail penetration as schematically shown in Figure 1(a)3. When an ISC is formed inside the small test cell by nail penetration, external current will flow from the large power supply cell to the test cell. The test cell capacity is much smaller than the large power supply cell, so the measured current (A) can be assumed to be equal to the ISC current. The ISC voltage (V) is measured directly. Then the ISC resistance can be obtained through dividing the ISC voltage by the ISC current. The local temperature at the ISC spot is directly measured by a thermocouple embedded at the tip of the smart nail4. The previous method enabled insightful understanding of ISC3. It was observed that the ISC resistance changed by several orders of magnitude during nail penetration and dramatically influenced heat generation and local temperature rise. In some cases, the local ISC temperature increased more than 500 ℃, and even caused melting of Al foil in contact with the nail and rapid recovery of ISC resistance. But the previous method has a shortcoming. As noted in Figure 1(a), the small test cell with ISC is chemically and thermally disconnected from the large power supply cell. Such disconnection makes the thermal behaviors of the cells different from a real-world large Li-ion cell in which the ISC location is electrochemically and thermally connected to the entire cell. In particular, it does not allow investigation of thermal runaway propagation from the ISC location to the large cell. Built on our previous work while addressing its shortcoming, here we report an improved method. As shown schematically in Figure 1(b), a small cell and a large cell are fabricated inside the same pouch, sharing the same electrolyte and the same separator. They are not only electrically connected, but also chemically and thermally connected. The measurement of ISC current, resistance and temperature is similar to our previous work. When the smart nail penetrates the small cell, the ISC current flows from the large cell to the small cell through the external wire and can be measured by a current sensor (A). The ISC resistance is obtained from directly measured ISC current and ISC voltage. The local temperature can be measured not only by the thermocouple embedded at the tip of the smart nail, but also by thermocouples embedded at different locations inside the large cell5. This new method will enable insightful understanding of the highly localized and electrochemical-thermal coupled ISC phenomena under conditions closer to field failures. The experimental data can also be used for validation and improvement of numerical models of ISC. References X. Lai, C. Jin, W. Yi, X. Han, X. Feng, Y. Zheng and M. Ouyang, Energy Storage Materials, 35, 470 (2021). G. Zhang, X. Wei, X. Tang, J. Zhu, S. Chen and H. Dai, Renewable and Sustainable Energy Reviews, 141 (2021). S. Liu, S. Huang, Q. Zhou, K. Snyder, M. Long and G. Zhang, 241st ECS Meeting, May 29- June 2, 2022, Vancouver, BC, Canada (2022). S. Huang, X. Du, M. Richter, J. Ford, G. M. Cavalheiro, Z. Du, R. T. White and G. Zhang, Journal of The Electrochemical Society, 167 (2020). S. Huang, Z. Du, Q. Zhou, K. Snyder, S. Liu and G. Zhang, Journal of The Electrochemical Society, 168 (2021). Figure 1

BackgroundThe prevalence of salivary glands ultrasound (SGUS) abnormalities in Sjögren’s syndrom (SS) is well described(2). However, the prevalence is still unknown in rheumatic inflammatory conditions such as rheumatoid arthritis (RA).ObjectivesThe main objective of this study was to describe the prevalence of SGUS parenchymal structural abnormalites in patients with RA. Secondary objectives were: i) to study correlation between disease duration and the SGUS OMERACT score and ii) to study correlation between duration of sicca syndrome and the SGUS OMERACT score.Methods561 patients with RA satisfying ACR/EULAR 2010 classification criterias were included in 10 french centers in the prospective cohort BCD, comparing joint ultrasonography to clinical follow-up. Cross sectionnal SGUS examination (parotid and submandibular) was performed in a substudy of this cohort. The new OMERACT-SGUS scoring system(1) was used and clinical, biological, immunological and radiological data were collected.Results100 patients agreed to be included in this substudy of BCD cohort, and a total of 98 SGUS patients data were evaluated (lack of SGUS data for 2 patients). Most patients were women (81%), mean age 59 years, with time from RA diagnosis of 11 years on average. The mean CRP-DAS-28 at baseline was at 3.2 with a third of patients in remission at inclusion. Anti-CCP antibodies or RF was positive in 92 patients (92%). 27 patients (27%) complained of eye dryness and 20 (20%) of mouth dryness. 12 (12%) suffered from both. The levels of self-reported fatigue was higher than in the general group of RA included in the study. Two thirds of patients benefited from csDMARD, with a third treated with bDMARDS. 33 (33%) also benefited from a corticosteroid treatment. Among 98 patients, 22 (22.5%) had at least one salivary gland scored grade 1 or more, this number was reduced to 18 patients (18.4%) when considering only the parotid glands. 7 patients (7.1%) had at least one salivary gland scored grade 2 or more, with a number reduced to 4 patients (4.1%) when considering only the parotids. Only one patient (1%) had a parotid gland scored 3. In the 7 patients presenting significant abnormalities in SGUS (grade 2 or more), 5 patients had either dry eye or dry mouth symptoms (71,4%).ConclusionOur findings suggest that 7% of RA patients present significant SGUS abnormalities according to OMERACT scoring system, associated with clinical sicca syndrome in 71% of cases. There was no significant association between the duration of rheumatoid arthritis and the OMERACT score (Spearman coefficient for correlation -0,028, p = 0,99). There was also no significant association found between the duration of sicca symptoms and the OMERACT score (Spearman coefficient for correlation 0,025, p = 0,89). This study highlights the importance of SGUS assessment in RA sicca patients to improve monitoring and follow-up in routine clinical practice.References[1]Jousse-Joulin S, D’Agostino MA, Nicolas C, Naredo E, Ohrndorf S, Backhaus M, Tamborrini G, Chary-Valckenaere I, Terslev L, Iagnocco A, Collado P, Hernández-Díaz C, Gandjbakhch F, Schmidt WA, Filippou G, Dejaco C, Stradner MH, Mortada MA, Hočevar A, Chrysidis S, El Mardenly G, de Agustín JJ, Thiele R, MacCarter DK, Finzel S, Hanova P, Zabotti A, Glaser C, Alavi Z, Hammenfors DS, Gatineau F, Bruyn GA. Video clip assessment of a salivary gland ultrasound scoring system in Sjögren’s syndrome using consensual definitions: an OMERACT ultrasound working group reliability exercise. Ann Rheum Dis. 2019 Jul;78(7):967-973.[2]Zhang X, Feng R, Zhao J, Wang Y, He J, Liu L, Cheng Y, Yao H, Tang S, Chen J, Zhang S, Zhang Z, Wang Q, He J, Li Z. Salivary gland ultrasonography in primary Sjögren’s syndrome from diagnosis to clinical stratification: a multicentre study. Arthritis Res Ther. 2021 Dec 20;23(1):305.Disclosure of InterestsNone declared

Abstract Objective: Benign breast disease (BBD), especially benign proliferative breast disease (BPBD), is related to increased breast cancer risk. However, few studies have examined whether conventional breast cancer risk factors influence risk of breast cancer among women with BBD. The aim of this study was to evaluate the associations of lifestyle factors with risk of breast cancer among women biopsied for BBD within a multi-center, hospital-based, case-control study in China, in order to provide scientific basis of health guidance for BBD patients and lay the foundation for primary prevention of breast cancer. Methods: A multi-center, hospital-based, case-control study was conducted. Patients with BPBD (n=608) and patients with non-proliferative breast disease (NPBD) (n=366) were collected from 23 hospitals in 11 provinces during April 2012 to April 2013. A face-to-face survey, baseline data and fasting blood was collected with all study subjects. Serum adiponectin levels were assayed using ELISA. After 10 years, the cumulative incidence rate of breast cancer in the two groups was counted through follow-up. Logistic regression analysis was used to obtain the association between specific factors and risk of breast cancer. Results: After 10 years’ follow-up, 388 BPBD and 240 NPBD cases were included in the final analysis (Table 1), of which 16 (4.12%) and 3 (1.25%) developed breast cancer, respectively. The cumulative incidence of breast cancer between the two groups was significant difference (P=0.041). Compared with women in the NPBD group, BPBD group were more likely to be central obesity (with higher waist-to-hip ratio (WHR)) (OR 24.98, 95% CI 1.845-336.203, P=0.015) and less likely to have physical activity (OR 0.626, 95% CI 0.416-0.943, P=0.025) and less often to eat carrots (OR 0.616, 95% CI 0.398-0.953, P=0.030) (Table 2). Subgroup analyze indicated that, physical activity, eat carrots and ham sausage, body weight, BMI, waist circumference and WHR were statistical differences in premenopausal BPBD patients, while only physical activity (OR 0.423, 95% CI 0.269-0.665 P &lt; 0.001) was the independent risk factors. Meanwhile, among the factors of Tea consumption, Glycemia, Body weight, BMI, Waist circumference, WHR and HMW/total adiponectin ratio in postmenopausal group, only HMW/total adiponectin ratio (OR 0.041, 95% CI 0.002-0.820 P=0.037) was statistically significant factor. These stratified multivariate logistic regression analysis results are shown in Table 3. Conclusion: In patients with BBD, physical activity may be the protect factor for breast cancer carcinogenesis in premenopausal women while lower HMW/total adiponectin ratio is a risk factor for postmenopausal women, which can provide direction for primary prevention of breast cancer. Table 1. Pathological types of all subjects. Table 2. The results of multivariate Logistic regression analysis. Table 3. Stratified multivariate Logistic regression analysis by menopause status. Citation Format: Chao Zheng, Dandan Ma, Linfeng Zhao, Maolin Guo, Shude Cui, Fuguo Tian, Zhimin Fan, Cuizhi Geng, Xuchen Cao, Zhenlin Yang, Xiang Wang, Hong Liang, Shu Wang, Hongchuan Jiang, Xuening Duan, Haibo Wang, Guolou Li, Qitang Wang, Jianguo Zhang, Feng Jin, Jinhai Tang, Liang Li, Shi-Guang Zhu, Wenshu Zuo, Fei Wang, Lixiang Yu, Fei Zhou, Yujuan Xiang, Mingming Guo, Yongjiu Wang, Wenzhong Zhou, Shuya Huang, Zhaohui Li, Yajie Zhou, Lijuan Hou, Xinyi Yang, Xuan Zhang, Liyuan Liu, Zhigang Yu. Lifestyle factors are associated with breast cancer risk in women biopsied for benign breast diseases in China: 10-year results of a multi-center, hospital-based, case-control study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-31.

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)

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(2016). An Exploration of Consumers' Response to Online Service Recovery Initiatives. International Journal of Market Research, 59(1), 97-115. Park, J., & Ha, S. (2016). Co-creation of service recovery: Utilitarian and hedonic value and post-recovery responses. Journal of Retailing and Consumer Services, 28, 310-316. Rezaei, S., Shahijan, M.K., Amin, M., & Ismail, W.K.W. (2016). Determinants ofapp stores continuance behavior: A pls path modellingapproach. Journal of Internet Commerce, 15(4), 408-440. Sengupta, S.A., Balaji, M., & Krishnan, B.C. (2015). How customers cope with service failure? A study of brand reputation and customer satisfaction. Journal of Business Research, 68(3), 665-674. Sloan, S., Bodey, K., & Gyrd-Jones, R. (2015). Knowledge sharing in online brand communities. Qualitative Market Research: An International Journal, 18(3), 320-345. Tan, C., Benbasat, I. & Cenfetelli, R.T. (2016). An Exploratory Study of the Formation and Impact of Electronic Service Failures. 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Rapid urbanization rates impact significantly on the nature of Land Cover patterns of the environment, which has been evident in the depletion of vegetal reserves and in general modifying the human climatic systems (Henderson, et al., 2017; Kumar, Masago, Mishra, & Fukushi, 2018; Luo and Lau, 2017). This study explores remote sensing classification technique and other auxiliary data to determine LULCC for a period of 50 years (1967-2016). The LULCC types identified were quantitatively evaluated using the change detection approach from results of maximum likelihood classification algorithm in GIS. Accuracy assessment results were evaluated and found to be between 56 to 98 percent of the LULC classification. The change detection analysis revealed change in the LULC types in Minna from 1976 to 2016. Built-up area increases from 74.82ha in 1976 to 116.58ha in 2016. Farmlands increased from 2.23 ha to 46.45ha and bared surface increases from 120.00ha to 161.31ha between 1976 to 2016 resulting to decline in vegetation, water body, and wetlands. The Decade of rapid urbanization was found to coincide with the period of increased Public Private Partnership Agreement (PPPA). Increase in farmlands was due to the adoption of urban agriculture which has influence on food security and the environmental sustainability. The observed increase in built up areas, farmlands and bare surfaces has substantially led to reduction in vegetation and water bodies. The oscillatory nature of water bodies LULCC which was not particularly consistent with the rates of urbanization also suggests that beyond the urbanization process, other factors may influence the LULCC of water bodies in urban settlements. Keywords: Minna, Niger State, Remote Sensing, Land Surface Characteristics References Akinrinmade, A., Ibrahim, K., & Abdurrahman, A. (2012). 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В данной работе продемонстрирована возможность применения ИК-микроспектроскопии для многомерной визуализации и анализа интеграции с нативными твердыми тканями зуба человека нового поколения биомиметических материалов, воспроизводящих минералорганический комплекс эмали и дентина.На основе ИК-картирования интенсивности конкретной функциональной молекулярной группы с использованием синхротронного излучения найдены и визуализированы характеристические особенности биомиметического переходного слоя в межфазной области эмаль/стоматологический материал и определено расположение функциональных групп, отвечающих процессам интеграции биомиметического композита REFERENCES Rohr N., Fischer J. Tooth surface treatment strategies for adhesive cementation // The Journal of Advanced Prosthodontics, 2017, v. 9(2), pp. 85–92. https://doi.org/10.4047/jap.2017.9.2.85 Pereira C. N. de B., Daleprane B., Miranda G. L. P. de, Magalhães C. S. de, Moreira A. N. 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Early childhood emotional dysregulation is critical in recognizing and preventing psychological well-being disorders, laying the groundwork for developing healthy emotional behaviors early on. This study aims to determine the direct influence of smartphone addiction, executive function, and the mother-child relationship on emotional dysregulation in early childhood in West Sumatra. This research method is a quantitative survey. The data collection technique in this research uses a questionnaire design on 309 parents who were selected using a simple random sampling method. This data processing tool uses the SmartPLS software. The results of the study indicate that smartphone addiction has a significant impact on emotional dysregulation in early childhood, executive function has a positive and significant effect on emotional dysregulation in early childhood, and the mother-child relationship has a positive and significant influence on emotional dysregulation in early childhood. 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We consider the magnetohydrodynamic flow and heat transfer of a classical Newtonian fluid in a straight channel with fixed irregular cross section. A spatial fractional operator is introduced to modify the classical Fourier's law of thermal conduction, and we obtain the space fractional coupled model. With the help of the finite element method, the coupled model is solved numerically. Finally, a special numerical example is proposed to verify the stability and efficiency of the presented method. References S. Aman, Q. Al-Mdallal, and I. Khan. Heat transfer and second order slip effect on MHD flow of fractional Maxwell fluid in a porous medium. J. King Saud Uni. Sci. 32.1 (2020), pp. 450–458. doi: 10.1016/j.jksus.2018.07.007 W. Bu, Y. Tang, Y. Wu, and J. Yang. Finite difference/finite element method for two-dimensional space and time fractional Bloch–Torrey equations. J. Comput. Phys. 293 (2015), pp. 264–279. doi: 10.1016/j.jcp.2014.06.031 X. Chi and H. Zhang. Numerical study for the unsteady space fractional magnetohydrodynamic free convective flow and heat transfer with Hall effects. App. Math. Lett. 120, 107312 (2021). doi: 10.1016/j.aml.2021.107312 T. G. Cowling. Magnetohydrodynamics. New York: Interscience, 1957 W. Fan, F. Liu, X. Jiang, and I. Turner. A novel unstructured mesh finite element method for solving the time-space fractional wave equation on a two-dimensional irregular convex domain. Frac. Calc. Appl. Anal. 20.2 (2017), pp. 352–383. doi: 10.1515/fca-2017-0019 L. Feng, F Liu, I. Turner, Q. Yang, and P. Zhuang. Unstructured mesh finite difference/finite element method for the 2D time-space Riesz fractional diffusion equation on irregular convex domains. Appl. Math. Model. 59 (2018), pp. 441–463. doi: 10.1016/j.apm.2018.01.044 L. Feng, F. Liu, I. Turner, and L. Zheng. Novel numerical analysis of multi-term time fractional viscoelastic non-Newtonian fluid models for simulating unsteady MHD Couette flow of a generalized Oldroyd-B fluid. Frac. Calc. Appl. Anal. 21.4 (2018), pp. 1073–1103. doi: 10.1515/fca-2018-0058 C. Li and A. Chen. Numerical methods for fractional partial differential equations. Int. J. Comp. Math. 95.6–7 (2018), pp. 1048–1099. doi: 10.1080/00207160.2017.1343941 C. Li and F. Zeng. Finite difference methods for fractional differential equations. Int. J. Bifur. Chaos 22.4, 1230014 (2012). doi: 10.1142/S0218127412300145 Y. Liu, X. Chi, H. Xu, and X. Jiang. Fast method and convergence analysis for the magnetohydrodynamic flow and heat transfer of fractional Maxwell fluid. App. Math. Comput. 430, 127255 (2022). doi: 10.1016/j.amc.2022.127255 H. Zhang, F. Liu, and V. Anh. Galerkin finite element approximation of symmetric space-fractional partial differential equations. App. Math. Comput. 217.6 (2010), pp. 2534–2545. doi: 10.1016/j.amc.2010.07.066 H. Zhang, F. Zeng, X. Jiang, and G. E. Karniadakis. Convergence analysis of the time-stepping numerical methods for time-fractional nonlinear subdiffusion equations. Frac. Calc. Appl. Anal. 25.2 (2022), pp. 453–487. doi: 10.1007/s13540-022-00022-6 M. Zhang, M. Shen, F. Liu, and H. Zhang. A new time and spatial fractional heat conduction model for Maxwell nanofluid in porous medium. Comput. Math. Appl. 78.5 (2019), pp. 1621–1636. doi: 10.1016/j.camwa.2019.01.006 L. Zheng, Y. Liu, and X. Zhang. Slip effects on MHD flow of a generalized Oldroyd-B fluid with fractional derivative. Nonlin. Anal.: Real World Appl. 13.2 (2012), pp. 513–523. doi: 10.1016/j.nonrwa.2011.02.016

This paper proposes the concept of multisensory landscape construction, pointing out that people’s perception and appreciation of a landscape is a process of overall impression and judgment formed with a combination of visual, auditory, olfactory, tactile, and even thermal and humid sense. Examples can be found in many famous traditional Chinese gardens. Around the West Lake area, there are famous soundscape scenic spots, e.g., Liu Lang Wen Ying (Orioles Singing in the Willows), Nan Ping Evening Bell (Evening Bell Ringing at the Nanping Hill), Zhejiang Qiu Tao (Autumn Wave of Zhejiang), and Jiu Li Song Tao (Wave of Pine Trees Lasts Nine Miles) . There are also some famous lightscape scenic spots, e.g., San Tan Ying Yue (Moon and Candlelight Mirrored in the Lake) and Ping Hu Qiu Yue (Moon over the Peaceful Lake in Autumn) . In terms of smellscape, in addition to the famous scenic spot Qu Yuan Feng He (Curved Yard and Lotus Pool in Summer), the West Lake area is also widely planted with osmanthus and other fragrant plants, forming a smellscape in which "late autumn is fragrant with osmanthus flowers and lotus in bloom for miles and miles." At Humble Administrator Garden, there are soundscape scenic spots such as Wu Zhu You Ju (Secluded Residence among Bamboo Bushes) and Liu Ting Ge (Pavilion to Pause and Listen); there are smellscape scenic spots such as the Orchid Field, the Magnolia Courtyard, the Panicum Pavilion, etc.; lightscape scenic spots such as Liu Ying Ge (Hall of Reflecting Shadows) and Ta Ying Ting (Pavilion of Shadow of Tower) can also be found there. In Chengde Summer Resort, there are soundscape scenic spots such as Wan He Song Feng (Wind of Ten Thousand Ravines and Pines) and lightscape scenic spots such as Xi Ling Chen Xia (Morning Sunset on West Ridge), etc.; smellscape scenic spots such as Qu Shui Hua Xiang (Fragrance of Flowers in the Curved Water) and Yuan Xiang Tang (Hall of Fragrance of Far Away) can also be found.The above classic cases eloquently prove that the creation of multisensory landscape and the integration of them are the valuable experience in traditional Chinese gardens, which play an important role in the achievement of famous landscape.Therefore, the design of landscape must pay attention to the creation and integration of soundscape, smellscape and lightscape. Another key point of the theory of multisensory landscape construction is that it is necessary to pay attention to both spatial and temporal dimensions so that the constructed landscape can be enjoyed everywhere and at all time periods. In this regard, the creation of the three-scape (specifically refer to soundscape, smellscape and lightscape) can also highlight their regional and temporal characteristics. By analyzing some classic cases of traditional Chinese gardens, this paper proposes that the construction of multisensory landscape and the integration of soundscape, smellscape and lightscape are the valuable experience in traditional Chinese gardens, which are also important for the achievement of famous landscapes and are excellent traditions that we should vigorously inherit and carry forward.

With rapid advancements in technologies involving genetic testing, epigenomic and transcriptomic profiling, many landmark consortia have generated rich multimodal data for the human genome. Among those, the consortia focused on human pancreas and islet research have greatly enhanced our understanding of different forms of diabetes. Despite new insights provided at an unprecedented scale and depth, current islet and pancreas data are fragmented across different portals with lack of common metadata/ontology standards, varying maturity of quality control pipelines, and disconnected from clinical research communities. To overcome these challenges, we developed Genomic Knowledgebase (GenomicKB), a graph database that integrates human genomic data, allowing researchers to explore and investigate human genome, epigenome, transcriptome, and 4D nucleome. The database uses a knowledge graph to consolidate genomic datasets and annotations from over 30 consortia and portals, resulting in 347 million entities, 1.36 billion relations, and 3.9 billion properties, which covers extensive pancreas and diabetes-related data including GWAS, disease ontology, and eQTL. Compared with traditional tabular data stored in separate data portals, GenomicKB emphasizes the relations among genomic entities and intuitively connects isolated data entries. With GenomicKB, complicated analysis among multiple modalities is transformed into coding-free queries and facilitates data-driven discoveries. Our knowledge graph structure is machine learning-ready and can be coupled with evolving artificial intelligence algorithms. In the future, GenomicKB will include pancreas and islet imaging and physiology datasets to build a comprehensive resource, PanKGraph, that will accelerate progress towards understanding diabetes etiology and pathophysiology, contribute to new diagnostic tool development, and inform transformative changes in diabetes prevention and care. Disclosure F. Feng: None. F. Tang: None. Y. Gao: None. D. Zhu: None. T. Li: None. S. Yang: None. Y. Yao: None. Y. Huang: None. D.C. Saunders: None. S.C. Parker: Research Support; Pfizer Inc. J. Cartailler: None. M. Brissova: None. J. Liu: None.

Herbal extract, rich with natural compounds, has been used for medicinal purpose such as treating neurological disorders such as cognitive defection for a long period of time, often without significant adverse effects. We compared AChE and BuChE – inhibition effect of total extracts and fractions of Huperzia serrata (Thunb.) Trevis. with alcaloid-rich extract. Our samples were subjected under supersonic extraction with ethanol 50o as solvent and fractionally extracted with n-hexane, EtOAc and n-butanol, respectively; alcaloid-rich extract was collected simutaneously. Ellman’s method was used to assay AChE and BuChE inhibition activity. Results: Alcaloid-rich extraction proved to be the superior AChE inhibiting agent, its activity nearly 6 fold of the most active Huperzia serrata extraction with IC50 value of 7.93 (5.43-10.98) µg/ml. While the fractions as well as the total extract did not provide any BuChE inhibition activity, alcaloid-rich extract showed weak ability (IC50 at 76.67 (64.78 – 91.84) µg/ml). Overall, the superior enzyme inhibition effect of alcaloid-rich extract might open a new approach in preventing and treating neurological disorders such as alzheimer’s. Keywords Huperzia serrata (Thunb.) Trevis, alcaloid, Acetylcholinesrerase inhibitors (AChE); butyrylcholinesterase (BuChE), Alzheimer. References [1] Dos Santos Picanco, Leide C et al., Alzheimer's disease: A review from the pathophysiology to diagnosis, new perspectives for pharmacological treatment, Current medicinal chemistry 25(26) (2018) 3141 - 3159. https://doi.org/10.2174/0929867323666161213101126.[2] B.M. McGleenon, K.B. Dynan, A.P. 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Canadian Journal of Chemistry 64(4) (1986) 837-839. https://doi.org/10.1139/v86-137.[7] Takuya Ohba, Yuta Yoshino et al., Japanese Huperzia serrata extract and the constituent, huperzine A, ameliorate the scopolamine-induced cognitive impairment in mice, Bioscience biotechnology and biochemistry 79(11) (2015) 1838-1844. https://doi.org/10.1080/09168451.2015.1052773.[8] Ju-Yeon Park, Hyuck Kim et al., Ethanol Extract of Lycopodium serratum Thunb. Attenuates Lipopolysaccharide-Induced C6 Glioma Cells Migration via Matrix Metalloproteinase-9 Expression, Chinese Journal of Integrative Medicine 24(11) (2018) 860-866. https://doi.org/10.1007/s11655-017-2923-9.[9] M. Maridass, G. Raju, Investigation of phytochemical and antimicrobial activity of Huperzia species, Pharmacologyonline 3 (2009) 688-692.[10] George.L.Ellman, K.Diane Courtney, et al., A new and rapid colorimetric determination of acetylcholinesterase activity, Biochemical Pharmacology 7(2) (1961) 88-95. https://doi.org/10.1016/0006-2952(61)90145-9.[11] Paul T Francis, et al., The cholinergic hypothesis of Alzheimer’s disease: a review of progress. Journal of Neurology, Neurosurgery & Psychiatry, 66(2) (1999) 137-147. http://dx.doi.org/10.1136/jnnp.66.2.137.[12] Prerna Upadhyaya, Vikas Seth, Mushtaq Ahmad, Therapy of Alzheimer’s disease: An update, African Journal of Pharmacy and Pharmacology 4(6) (2010) 408-421.[13] Hachiro Sugimoto, Hiroo Ogura, et al., Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor, The Japanese journal of pharmacology 89(1) (2002) 7-20.[14] N.T.K. Thu, et al., Acetylcholinesterase and butyrylcholinesterase inhibition effect of fractions extract of Huperzia serrata (Thunb.) Trevis. The journal of Pharmeceutical 56(11) 49-53 (in Vietnamese).[15] Xiaoqiang Ma, Changheng Tan, et al, Is there a better source of huperzine A than Huperzia serrata? Huperzine A content of Huperziaceae species in China. J Agric Food Chem, 53(5) (2005)1393-8. https://doi.org/10.1021/jf048193n.[16] Ya-Bing Yang, Xue-Qiong Yang, et al., A New Flavone Glycoside from Huperzia serrata. Chinese Journal of Natural Medicines 6(6) (2008) 408-410.[17] G.T. Ha, R.K. Wong, Y. Zhang, Huperzine a as potential treatment of Alzheimer's disease: an assessment on chemistry, pharmacology, and clinical studies, Chemistry & biodiversity 8(7) (2011) 1189-1204. https://doi.org/10.1002/cbdv.201000269.[18] H.Y. Zhang, X.C. Tang, Neuroprotective effects of huperzine A: new therapeutic targets for neurodegenerative disease, Trends in pharmacological sciences 27(12) (2006) 619-625. https://doi.org/10.1016/j.tips.2006.10.004.[19] Y. Wang, X.C. Tang, H.Y. Zhang, Huperzine A alleviates synaptic deficits and modulates amyloidogenic and nonamyloidogenic pathways in APPswe/PS1dE9 transgenic mice, Journal of neuroscience research 90(2) (2012) 508-517. https://doi.org/10.1002/jnr.22775.[20] C.Y. Wang, et al., Huperzine A activates Wnt/β-catenin signaling and enhances the nonamyloidogenic pathway in an Alzheimer transgenic mouse model, Neuropsychopharmacology 36(5) (2011) 1073-1089. https://doi.org/10.1038/npp.2010.245.[21] R.K. Gordon, et al., The NMDA receptor ion channel: a site for binding of Huperzine A, Journal of applied toxicology 21(S1) (2001) S47-S51. https://doi.org/10.1002/jat.805.[22] M. Rafii, et al., A phase II trial of huperzine A in mild to moderate Alzheimer disease, Neurology 76(16) (2011) 1389-1394. https://doi.org/10.1212/WNL.0b013e318216eb7b.[23] N.H. Greig, et al., A new therapeutic target in Alzheimer's disease treatment: attention to butyrylcholinesterase, Current medical research and opinion 17(3) (2001)1 59-165.[24] A. Ferreira, et al., Huperzine A from Huperzia serrata: a review of its sources, chemistry, pharmacology and toxicology, Phytochemistry reviews 15(1) (2016) 51-85. https://doi.org/10.1007/s11101-014-9384-y.

Marijuana (Cannabis sativa L.) is legal in Canada for medical and recreational purposes and is currently a multi-million-dollar industry. The province of Quebec follows British Columbia and Ontario in production acreage (Government of Canada 2018). During the growing season 2020-2021, five greenhouse growers throughout Quebec reported the presence of signs and symptoms reminiscent of powdery mildew including the presence of white powdery patches on the adaxial sides of leaves of several C. sativa cultivars. From one commercial facility, infected leaves of three cannabis cultivars (Sour Diesel, Orange Krush, and Lemon Sour) were photographed and the fungal mycelium was collected for identification in the laboratory. Fungal mycelium on leaf tissue was white and amphigenous and displayed unbranched hyaline conidiophores ranging from 130 to 275 μm in height (n = 50). Conidiophores arose from the upper surface of hyphal mother cells ranging from 35–70 × 8–13 μm in diameter (n = 25) and formed catenescent conidia. Conidia were broad ellipsoid-ovoid and measured, 24 to 35 × 12 to 19 μm (n = 50), and hyphae ranged from 3-8 μm in diameter (n = 30). Based on previous description (Qiu et al. 2020), the fungus was placed within the Golovinomyces genus. The species identification was confirmed through multi-locus phylogenetic using internal transcribed spacer (ITS), 28S large ribosomal subunit, and chitin synthase I (CHS1) genes amplified as recommended (Qiu et al. 2020), and directly sequenced with amplification primers (Centre Hospitalier de l’Université Laval de Quebec, CA). The three marker sequences shared 100% similarity for all the samples analyzed and were deposited in Genbank under accession numbers: OM131434 (28S), OM131448 (ITS), and OM141118 (CHS1). The phylogenetic analysis of the multi-locus sequences amplified grouped all three Quebec marijuana isolates in the G. ambrosiae accessions, confirming their identification. Pathogenicity was confirmed by transferring conidia onto detached healthy leaves of hop plants (Humulus lupulus) cultivar Northern Brewer kept under greenhouse conditions (28C, 50-60% relative humidity, and 14 h light) via paint brush inoculation. Hop leaves were used as surrogate due to the restricted availability of marijuana leaves. Inoculated leaves were placed in the growth chamber set at 20C, 50-60% relative humidity, and long days conditions as previously suggested (Weldon et al. 2020). The leaves developed powdery mildew colonies after 21 days, and the fungus was confirmed to be G. ambrosiae following morphological characterization and amplification of CHS1. Powdery mildew caused by G. ambrosiae (previous Golovinomyces cichoracearum) has been reported affecting hemp (Cannabis sativa) in New York and Oregon, United Sates (Weldon et al. 2020; Wiseman et al. 2021), and in British Columbia, Canada (Pépin et al. 2018; Punja et al. 2021), and this is the first report of G. ambrosiae causing powdery mildew on marijuana in Quebec. REFERENCES Government of Canada 2018. Online, retrieved January 7, 2021 https://www150.statcan.gc.ca/n1/daily-quotidien/180430/dq180430b-eng.htm Pépin N, Punja ZK, Joly DL. 2018. First report of powdery mildew caused by Golovinomyces cichoracearum sensu lato on Cannabis satia in Canada. Plant Disease. 102(12):2644. Doi: https://doi.org/10.1094/PDIS-04-18-0586-PDN Punja, Z. P. (2021). First report of the powdery mildew pathogen of hops, Podosphaeria macularis, naturally infecting cannabis (Cannabis sativa L., marijuana) plants under field conditions, Canadian Journal of Plant Pathology, Doi: https://doi.org/10.1080/07060661.2021.1960424. Qiu, P.-L., Liu, S.-Y., Bradshaw, M., Rooney-Latham, S., Takamatsu, S., Bulgakov, T. S., Tang, S.-R., Feng, J., Jin, D.-N., Aroge, T., Li, Y., Wang, L.-L., and Braun, U. 2020. Multi-locus phylogeny and taxonomy of an unresolved, heterogeneous species complex within the genus Golovinomyces (Ascomycota, Erysiphales), including G. ambrosiae, G. circumfusus and G. spadiceus. BMC Microbiology. 20:51. Doi : https://doi.org/10.1186/s12866-020-01731-9. Weldon WA, Ullrich MR, Smart LB, Smart CD, Gadoury DM. 2020. Cross-infectivity of powdery mildew isolates originating from hemp (Cannabis sativa) and Japanese hop (Humulus japonicus) in New York. Plant Health Progress. 21(1):47–53. Doi: https://doi.org/10.1094/PHP-09-19-0067-RS Wiseman, M. S., Bates, T. A., Garfinkel, A. R., Ocamb, C. M., and Gent, D. H. 2021. First Report of Powdery Mildew Caused by Golovinomyces ambrosiae on Cannabis sativa in Oregon. Plant Disease 105(9):2733. Doi: https://doi.org/10.1094/PDIS-11-20-2455-PDN.

In his directorial debut, The Man with the Iron Fists (2012), RZA not only evokes the textual borrowing techniques he has utilised as a hip-hop producer, but also reflects the influence of filmmaker Quentin Tarantino, who has built a career upon acknowledging mainstream and cult film histories through mise-en-scene, editing, and deft characterisation. The Man with the Iron Fists was originally to coincide with Tarantino’s rebel slave narrative Django Unchained (2012), which Tarantino has discussed openly as commentary regarding race in contemporary America. In 2011, Variety reported that RZA had joined the cast of Tarantino’s anticipated Django Unchained, playing “Thaddeus, a violent slave working on a Mississippi plantation” (Sneider, “Rza Joins ‘Django Unchained’ Cast”). Django Unchained follows Tarantino’s pattern of generic and trope mixology, combining elements of the Western, blaxploitation, and buddy/road film. He famously stated: “[If] my work has anything it's that I'm taking this from this and that from that and mixing them together… I steal from everything. Great artists steal; they don't do homages” (“The Directors of Our Lifetime: In Their Own Words”). He sutures iconography from multiple films in numerous genres to form new texts that stand alone, albeit as amalgamations of references. In considering meanings attached particularly to exploitation films, this article addresses the significance of combining influences within The Man with the Iron Fists and Tarantino’s Django Unchained, and the ideological threads that emerge in fusing exploitation film aesthetics. Ultimately, these films provide a convergence not only of texts, but also of the collective identities associated with and built upon those texts, feats made possible through the filmmakers’ use of pastiche. Pastiche in Identity Formation as Subversive A reflection of the postmodern tendency towards appropriation and borrowing, pastiche is often considered less meaningful than its counterpart, parody. Fredric Jameson suggests that though pastiche and parody share commonalities (most notably the mimicry of style and mannerisms), they do so to different effects. Jameson asserts that parody mimics in an effort to mock the idiosyncrasies within a text, whereas pastiche is “neutral parody” of “dead styles” (114). In short, as Susan Hayward writes, “In its uninventiveness, pastiche is but a shadow of its former thing” (302). For Jameson, the most ubiquitous form of pastiche is the nostalgia film, which attempts to recapture the essence of the past. As examples, he points to the George Lucas films American Graffiti (1973), which is staged in the United States of the 1950s, and Star Wars (1977), which reflects the serials of the 1930s-1950s (114-115). Though scholars such as Jameson and Hayward are contemptuous of pastiche, a growing number see its potential for the subversion and critique that the aforementioned suggest it lacks. For instance, Sarah Smith reminds us that pastiche films engage in “complicitous critique”: the films maintain the trappings of original texts, yet do so in order to advance critique (209). For Smith and other scholars, such as Judith Butler and Richard Dyer, Jameson’s criticism of pastiche is dismissive, for while these scholars largely agree that pastiche is a form of mimicry in which the distance between original and copy is minimal, they recognise that a space still exists for it to be critical. Smith writes: “[W]hile there may be greater distance between the parody and its target text than there is between the pastiche and the text it imitates, a prescribed degree of distance is not a prerequisite for critical engagement with the ur-text” (210). In this regard, fidelity to the original texts is not only required but to be revered, for these likenesses to the original “act as a guarantee of the critique of those origins and provide an opportunity for the filmmaker to position [himself or herself] in relation to them” (Smith 211). Essentially, pastiche is a useful technique in which to construct hybrid identities. Keri E. Iyall Smith suggests that hybrid identities emerge from “a reflexive relationship between local and global” (3). According to popular music scholar Brett Lashua, hybrid identities “make and re-make culture through appropriating the cultural ‘raw materials’ of life in order to construct meaning in their own specific cultural localities. In a sense, they are ‘sampling’ from broader popular culture and reworking what they can take into their own specific local cultures” (“The Arts of the Remix: Ethnography and Rap”). As will be evidenced here, Tarantino utilises pastiche as an unabashed genre poacher; similarly, as a self-avowed Tarantino student and hip-hop producer known for his sampling acumen, RZA invokes pastiche to reflect mastery of his craft and a hybridised identity his multifaceted persona. Plagiarism, Poaching, and Pastiche: Tarantino Blurs Boundaries As a filmmaker, Tarantino is known for indulging in excess: violence, language, and aesthetics. Edward Gallafent characterised the director’s work as having a preoccupation with settings and journeys, violence (both emotional and physical), complicated chronological structures, and dissatisfying conclusions (3-4). Additionally, pieces of Tarantino’s cinematic fandom are inserted into his own films. Academic and popular critics continually note Tarantino’s rise as an obsessive video store clerk turned respected and eccentric auteur. Tarantino’s authorship lies mostly in his ability to borrow (or in his words, steal) narrative arcs, characterisations, and camera work from other filmmakers, and use them in ways that feel innovative and different from those past works. It is not that he borrows generally from movements, films, and filmmakers, but that he conscientiously lifts segments from works to incorporate into his text. In Postmodern Hollywood: What’s New in Film and Why It Makes Us Feel So Strange, Keith M. Booker contends that Tarantino’s work often straddles lines between simplistic reference for reference’s sake and meditations upon the roles of cinema (90). Booker dismisses claims for the latter, citing Tarantino’s unwillingness to contextualise the references in Pulp Fiction, such that the film is best described not an act of citation so much as a break with the historical. Tarantino’s lack of reverence provides him freedom to intermingle texts and tropes to fit his goals as a filmmaker, rather than working within the confines of generic narratives. Each film feels both apart and distinct from genre categories. Jackie Brown, for example, has many of the traits attached to blaxploitation, from its focus on drug culture, the casting of Pam Grier who gained status playing female leads in blaxploitation films, and extreme violence. Tarantino’s use of humour throughout, particular in his treatment of character types, plot twists, and self-aware musical cues distances the film from easy characterisation. It is, but isn’t. What is gained is a remediated conception of cinematic reality. The fictions created in films of the past are noted in Tarantino’s play with tropes. His mixes produce an extreme form of mediated reality – one that is full of excess, highly exaggerated, and completely composed of stolen frameworks. Tarantino continues his generic play in Django Unchained. While much of it does borrow heavily from 1960s and 1970s Western filmmakers like Leone, Corbucci, and Peckinpah (the significance of desolate landscapes, long takes, extreme violence), it also incorporates strands of buddy cop (partners with different backgrounds working together to correct wrongs), early blaxploitation (Broomhilda’s last name is von Shaft suggesting that she is an ancestor of blaxploitation icon John Shaft, the characterisation of Django as black antihero enacting revenge on white racists in power), and kung fu (revenge narrative, in addition to the extensive training moments between Dr. Schultz and Django). The familiar elements highlight the transgressions of genre adherence. The comfort of the western genre and its tropes eases the audience, only for Tarantino to incorporate those elements from outside the genre to spark interest, to shock, to remind audiences of the mediated reality onscreen. Tarantino has been criticised for his lack of depth and understanding regarding women and people of colour, despite his attempts to provide various leading and supporting roles for both. Django Unchained was particularly criticised for Tarantino’s use of the term nigger - over 100 instances in the film. Tarantino defended his decision by claiming historical accuracy, poetic license, and his desire to confront audiences with various levels of racism. Many, including Spike Lee, disagreed, arguing Tarantino had no claim to making a film about slavery. Lee stated through Twitter: “American Slavery Was Not A Sergio Leone Spaghetti Western. It Was A Holocaust. My Ancestors Are Slaves. Stolen From Africa. I Will Honor Them” (“Spike Lee on Django Unchained: Filmmaker Calls Movie ‘Disrespectful’”). Not only does Lee evoke the tragedy of the American slave trade and the significance of race within contemporary filmmaking, but he uses genre to underscore what he perceives is Tarantino’s lack of reverence to the issue of slavery and its aftermath in American culture. Django Unchained is both physically and emotionally brutal. The world created by Tarantino is culturally messy, as Italian composers rub elbows with black hip-hop artists, actors from films’ referenced in Django Unchained interact with new types of heroes. The amounts of references, people, and spectacles in his films have created a brand that is both hyperaware, but often critiqued as ambivalent. This is due in part to the perception of Tarantino as a filmmaker with no filter. His brand as a filmmaker is action ordered, excessive, and injected with his own fandom. He is an ultimate poacher of texts and it is this aesthetic, which has also made him a fan favourite amongst young cinephiles. Not only does he embrace the amount of play film offers, but he takes the familiar and makes it strange. The worlds he creates are hazier, darker, and unstable. Creating such a world in Django Unchained provides a lot of potential for reading race in film and American culture. He and his defenders have discussed this film as an “honest” portrayal of the effects of slavery and racial tension in the United States. This is also the world which acts as context for RZA’s The Man with the Iron Fists. Though a reference abandoned in Django Unchained, the connection between both films and both filmmakers pleasure in pastiche provide further insight to connections between film and race. Doing the Knowledge: RZA Pays Homage As a filmmaker, RZA utilises Tarantino’s filmmaking brand techniques to build his own homage and add to the body of kung-fu films. Doing so furnishes him the opportunity to rehash and reform narratives and tropes in ways that change familiar narrative structures and plot devices. In creating a film which relies on cinematic allusions to kung fu, RZA—as a fan, practitioner, and author—reconfigures kung fu from being an exploitative genre and reshapes its potential for representational empowerment. While Tarantino considers himself an unabashed thief of genre tropes, RZA envisions himself more as a student who pays homage to masters—among whom he includes Tarantino. Indeed, in an interview with MTV, RZA refers to Tarantino as his Sifu (a Chinese term for master or teacher) and credits him not only for teaching RZA about filmmaking, but also for providing him with his blessing to make his first feature length film (Downey, “RZA Recalls Learning from ‘The Master’ Quentin Tarantino”). RZA implies that mastery of one’s craft comes from incorporating influences while creating original work, not theft. For instance, he states that the Pink Blossom brothel—the locus for most of the action in the film—was inspired by the House of Blue Leaves restaurant, which functions in a similar capacity in Tarantino’s Kill Bill: Vol. 1 (“RZA Talks Sampling of Kung Fu Films for Movie & The Difference Between Biting vs. Influence”). Hip-hop is an art form in which its practitioners “partake of a discursive universe where skill at appropriating the fragments of a rapidly-changing world with verbal grace and dexterity is constituted as knowledge” (Potter 21). This knowledge draws upon not only the contemporary moment but also the larger body of recorded music and sound, both of which it “re-reads and Signifies upon through a complex set of strategies, including samplin’, cuttin’ (pastiche), and freestylin’ (improvisation)” (Potter 22). As an artist who came of age in hip-hop’s formative years and whose formal recording career began at the latter half of hip-hop’s Golden Age (often considered 1986-1993), RZA is a particularly adept cutter and sampler – indeed, as a sampler, RZA is often considered a master. While RZA’s samples run the gamut of the musical spectrum, he is especially known for sampling obscure, often indeterminable jazz and soul tracks. Imani Perry suggests that this measure of fidelity to the past is borne out of hip-hop’s ideological respect for ancestors and its inherent sense of nostalgia (54). Hallmarks of RZA’s sampling repertoire include dialog and sound effects from equally obscure kung fu films. RZA attributes his sampling of kung fu to an affinity for these films established in his youth after viewing noteworthy examples such as The 36th Chamber of Shaolin (1978) and Five Deadly Venoms (1978). These films have become a key aspect of his identity and everyday life (Gross, “RZA’s Edge: The RZA’s Guide to Kung Fu Films”). He speaks of his decision to make kung fu dialog an integral part of Wu-Tang Clan’s first album Enter the Wu-Tang (36 Chambers): “My fantasy was to make a one-hour movie that people were just going to listen to. They would hear my movie and see it in their minds. I’d read comic books like that, with sonic effects and kung fu voices in my head. That makes it more exciting so I try to create music in the same way” (Gross, ““RZA’s Edge: The RZA’s Guide to Kung Fu Films”). Much like Enter the Wu-Tang (36 Chambers) and his other musical endeavours, The Man with the Iron Fists serves as further evidence of RZA’s hybrid identity., which sociologist Keri E. Iyall Smith suggests emerges from “a reflexive relationship between local and global” (3). According to popular music scholar Brett Lashua, hybrid identities “make and re-make culture through appropriating the cultural ‘raw materials’ of life in order to construct meaning in their own specific cultural localities. In a sense, they are ‘sampling’ from broader popular culture and reworking what they can take into their own specific local cultures” (“The Arts of the Remix: Ethnography and Rap”). The most overt instance of RZA’s hybridity is in regards to names, many of which are derived from the Gordon Liu film Shaolin and Wu-Tang (1983), in which the competing martial arts schools come together to fight a common foe. The film is the basis not only for the name of RZA’s group (Wu-Tang Clan) but also for the names of individual members (for instance, Master Killer—after the series to which the film belongs) and the group’s home base of Staten Island, New York, which they frequently refer to as “Shaolin.” The Man with the Iron Fists is another extension of this hybrid identity. Kung fu has long had meaning for African Americans particularly because these films frequently “focus narratively on either the triumph of the ‘little guy’ or ‘underdog’ or the nobility of the struggle to recognise humanity and virtue in all people, or some combination of both” (Ongiri 35). As evidence, Amy Obugo Ongiri points to films such as The 36th Chamber of Shaolin, a film about a peasant who learns martial arts at the Shaolin temple in order to avenge his family’s murder by the Manchu rulers (Ongiri 35). RZA reifies this notion in a GQ interview, where he speaks about The 36th Chamber of Shaolin specifically, noting its theme of rebellion against government oppression having relevance to his life as an African American (Pappademus, “This Movie Is Rated Wu”). RZA appropriates the humble origins of the peasant San Te (Gordon Liu), the protagonist of The 36th Chamber of Shaolin, in Thaddeus (whom RZA plays in the film), whose journey to saviour of Jungle Village begins with his being a slave in America. Indeed, one might argue that RZA’s construction of and role as Thaddeus is the ultimate realisation of the hybrid identity he has developed since becoming a popular recording artist. Just as Tarantino’s acting in his own films often reflects his identity as genre splicer and convention breaker (particularly since they are often self-referential), RZA’s portrayal of Thaddeus—as an African American, as a martial artist, and as a “conscious” human being—reflects the narrative RZA has constructed about his own life. Conclusion The same amount of play Tarantino has with conventions, particularly in characterisations and notions of heroism, is present in RZA’s Man with the Iron Fists. Both filmmakers poach from their favourite films and genres in order to create interpretations that feel both familiar and new. RZA follows Tarantino’s aesthetic of borrowing scenes directly from other films. Both filmmakers poach from films for their own devices, but in those mash-ups open up avenues for genre critique and identity formation. Tarantino is right to say that they are not solely homages, as homages honour the films in which they borrow. Tarantino and RZA do more through their poaching to stretch the boundaries of genres and films’ abilities to communicate with audiences. References “The Directors of Our Lifetime: In Their Own Words.” Empire Online. N.d. 8 May 2013 ‹http://www.empireonline.com/magazine/250/directors-of-our-lifetime/5.asp›. Booker, Keith M. Postmodern Hollywood: What’s New in Film and Why It Makes Us Feel So Strange. Westport, CT: Praeger, 2007. Downey, Ryan J. “RZA Recalls Learning from ‘The Master’ Quentin Tarantino.” MTV. 30 August 2012. 14 July 2013 ‹http://www.mtv.com/news/articles/1692872/rza-man-with-the-iron-fists-quentin-tarantino.jhtml›. Gallefent, Edward. Quentin Tarantino. London: Longman. 2005. Gross, Jason. “RZA’s Edge: The RZA’s Guide to Kung Fu Films.” Film Comment. N.d. 5 June 2013 ‹http://www.filmcomment.com/article/rzas-edge-the-rzas-guide-to-kung-fu-films›. Iyall Smith, Keri E. “Hybrid Identities: Theoretical Examinations.” Hybrid Identities: Theoretical and Empirical Examinations. Ed. Keri E. Iyall Smith and Patricia Leavy. Leiden: Brill, 2008. 3-12. Jameson, Fredric. “Postmodernism and Consumer Society.” Postmodern Culture. Ed. Hal Foster. London: Pluto, 1985. 111-125. Lashua, Brett. “The Arts of the Remix: Ethnography and Rap.” Anthropology Matters 8.2 (2006). 6 June 2013 ‹http://www.anthropologymatters.com›. “The Man with the Iron Fists – Who in the Cast Can F-U Up?” IronFistsMovie 21 Sep. 2012. YouTube. 8 May 2013 ‹http://youtu.be/bhJOQZFJfqA›. Pappademus, Alex. “This Movie Is Rated Wu.” GQ Nov. 2012. 6 June 2013 ‹http://www.gq.com/entertainment/movies-and-tv/201211/the-rza-man-with-the-iron-fists-wu-tang-clan›. Perry, Imani. Prophets of the Hood: Politics and Poetics in Hip Hop. Durham, NC: Duke UP, 2004. Potter, Russell. Spectacular Vernaculars: Hip-Hop and the Politics of Postmodernism. Albany, NY: SUNY P, 1995. “RZA Talks Sampling of Kung Fu Films for Movie & The Difference between Biting vs. Influence.” The Well Versed. 2 Nov. 2012. 5 June 2013 ‹http://thewellversed.com/2012/11/02/video-rza-talks-sampling-of-kung-fu-films-for-movie-the-difference-between-biting-vs-influence/›. Smith, Sarah. “Lip and Love: Subversive Repetition in the Pastiche Films of Tracey Moffat.” Screen 49.2 (Summer 2008): 209-215. Snedier, Jeff. “Rza Joins 'Django Unchained' Cast.” Variety 2 Nov. 2011. 14 June 2013 ‹http://variety.com/2011/film/news/rza-joins-django-unchained-cast-1118045503/›. “Spike Lee on Django Unchained: Filmmaker Calls Movie ‘Disrespectful.’” Huffington Post 24 Dec. 2012. 14 June 2013 ‹http://www.huffingtonpost.com/2012/12/23/spike-lee-django-unchained-movie-disrespectful_n_2356729.html›. Wu-Tang Clan. Enter the Wu-Tang (36 Chambers). Loud, 1993. Filmography The 36th Chamber of Shaolin. Dir. Chia-Liang Lui. Perf. Chia Hui Lui, Lieh Lo, Chia Yung Lui. Shaw Brothers, 1978. Django Unchained. Dir. Quentin Tarantino. Perf. Jamie Foxx, Leonardo DiCaprio, Christoph Waltz. Miramax, 2012. Five Deadly Venoms. Dir. Cheh Chang. Perf. Sheng Chiang, Philip Kwok, Feng Lu. Shaw Brothers, 1978. Jackie Brown. Dir. Quentin Tarantino. Perf. Pam Grier, Samuel L. Jackson, Robert Forster. Miramax, 1997. Kill Bill: Vol. 1. Dir. Quentin Tarantino. Perf. Uma Thurman, David Carradine, Darryl Hannah. Miramax, 2003. The Man with the Iron Fists. Dir. RZA. Perf. RZA, Russell Crowe, Lucy Liu. Arcade Pictures, 2012. Pulp Fiction. Dir. Quentin Tarantino. Perf. John Travolta, Uma Thurman, Samuel L. Jackson. Miramax, 1994. Shaolin and Wu-Tang. Dir. Chiu Hui Liu. Perf. Chiu Hui Liu, Adam Cheng, Li Ching.

Geometries associated relative stabilities, averaged binding energy, fragmentation energy, second-order energy difference and energy gaps of V-doped germanium cationic clusters GenV+ (n = 9-13) have been investigated by using density functional theory with the BP86 exchange-correlation potential and effective core potential (ECP) LanL2DZ basis sets. Natural population analysis charge is also examined to understand the associated charge transfer in structures of clusters. When an electron is removed from neutral cluster GenV to form the cation cluster GenV+, geometric structure of the lowest energy isomers change. The endohedral cage structure of the cation clusters appears at n = 10 in the cluster Ge10V+. The lowest energy isomers of cation cluster are in triplet state or singlet state. The cluster Ge10V+ is found to be the most stable in terms of stability parameters in the all system GenV+ (n = 9 - 13). Keywords: BP86/LANL2DZ, binding energy, V-Ge clusters, structure of clusters. 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Одним из подходов к формированию функциональных наноразмерных плёнок на поверхности AIIIBV является хемостимулированное термооксидирование. Для получения требуемого результата необходимо обоснованно выбрать объект, который может выступать в роли хемостимулятора процесса или модификатора структуры и свойств формируемых в результате оксидирования плёнок. Использование сложных соединений, способных совмещать обе эти функции, представляется перспективным. Цель статьи – исследование воздействия наноразмерных слоев хемостимулятора-модификатора Mn3(P0.1V0.9O4)2 на процесс термического оксидирования GaAs, состав и морфологиюформируемых пленок.Объект исследования – арсенид галлия (100) с нанесёнными на его поверхность наноразмерными слоями ванадат-фосфата марганца Mn3(P0.1V0.9O4)2. С целью увеличения скорости процесса и обеспечения высокой химической гомогенности продукта предлагается микроволновая активация синтеза хемостимулятора-модификатора Mn3(P0.1V0.9O4)2 и дальнейшее его нанесение на поверхность полупроводника методом spin-coating. Сформированные гетероструктуры Mn3(P0.1V0.9O4)2/GaAs термически оксидировали в интервале температур 490–550 oС в течение 60 минут в потоке кислорода.Осуществляли контроль толщины растущих плёнок (методами лазерной и спектральной эллипсометрии), их состав (рентгенофазовый анализ, Оже-электронная спектроскопия) и морфологию поверхности (атомно-силовая микроскопия).Исследования кинетики термооксидирования гетероструктур Mn3(P0.1V0.9O4)2/GaAs показали, что определяющим процессом является твердофазная реакция, лимитируемая диффузией в твердой фазе, и реализуется транзитный характер действия хемостимулятора без каталитического эффекта. Выявлено, что ванадат-фосфат марганца способствует увеличению прироста формируемой пленки в среднем на 70–220% по сравнению с эталонным оксидированием GaAs, приводит к интенсификации вторичных взаимодействий оксидов компонентов подложки с продуктами термолиза Mn3(P0.1V0.9O4)2 и отсутствию сегрегации мышьяка в плёнке в неокисленном состоянии.При термооксидировании гетероструктур Mn3(P0.1V0.9O4)2/GaAs формируются наноразмерные (50-200 нм) плёнки с достаточно выраженным рельефом. Необходимо дальнейшее исследование электрофизических характеристик плёнок, т. к. данные о составе позволяют предположить их диэлектрический характер. Это может быть использовано на практике для формирования на поверхности AIIIBV плёнок функционального назначения с варьируемыми в широких пределах характеристиками. ЛИТЕРАТУРА Tang M., Park J.-S., Wang Z., Chen S., Jurczak P., Seeds A., Liu H. Integration of III-V lasers on Si for Si photonics. Progress in Quantum Electronics. 2019;66: 1–18. 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Alloys used in engines are subjected to challenging environments characterized by thermal and mechanical cyclic loadings during start-up and shut-down processes. These conditions can significantly increase the occurrence of fatigue failure mechanisms. Therefore, this study focuses on investigating the low cycle fatigue (LCF) behavior of directionally-solidified alloy at two distinct temperatures, namely 600 °C and 800 °C. Strain-controlled LCF tests were conducted at the specified temperatures, utilizing constant total strain amplitudes of 0.4%, 0.6%, 0.8%, and 1% under a totally reversed loading ratio (R = -1). The Coffin-Manson model, based on plastic deformation, along with a hysteresis energy-based criterion model, were employed to predict and evaluate fatigue life and LCF behavior. Notably, the hysteresis energy and Coffin-Manson models exhibited superior capability in predicting LCF life at 800 °C compared to 600 °C. REFERENCES Salehnasab, J. Marzbanrad, E. 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