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1
Guo, Hui, Youdi Zhang, Lie Chen, et al. "Correction: Non-halogenated-solvent-processed highly efficient organic solar cells with a record open circuit voltage enabled by noncovalently locked novel polymer donors." Journal of Materials Chemistry A 8, no. 5 (2020): 2851. http://dx.doi.org/10.1039/d0ta90012e.
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Correction for ‘Non-halogenated-solvent-processed highly efficient organic solar cells with a record open circuit voltage enabled by noncovalently locked novel polymer donors’ by Hui Guo et al., J. Mater. Chem. A, 2019, 7, 27394–27402.
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Pan, Guo-Hui, Huajun Wu, Shuai He, et al. "Correction: Dye-embedded YAG:Ce3+@SiO2 composite phosphors toward warm wLEDs through radiative energy transfer: preparation, characterization and luminescence properties." Nanoscale 10, no. 48 (2018): 23198. http://dx.doi.org/10.1039/c8nr90266f.
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Correction for ‘Dye-embedded YAG:Ce3+@SiO2 composite phosphors toward warm wLEDs through radiative energy transfer: preparation, characterization and luminescence properties’ by Guo-Hui Pan, Jiahua Zhang et al., Nanoscale, 2018, DOI: 10.1039/c8nr07360k.
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Abt, Oded. "Muslim Ancestor, Chinese Hero or Tutelary God." Asian Journal of Social Science 42, no. 6 (2014): 747–76. http://dx.doi.org/10.1163/15685314-04206004.
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This paper examines the dynamic boundaries of Chinese identities and the role of family narratives in their formation. It examines the interplay between history and memory, focusing on traditions regarding ancestors of the Fujian Guo lineage of Muslim descent in China, Taiwan and the Philippines, over six centuries. Existing scholarship approaches these traditions in ethnic terms, corresponding to the ethnic discourse prevalent in the P.R.C., focusing solely on mainland groups, but overlooking other variations found overseas. Hence, scholars portray the changing narratives as reflecting a linear process: from past sinicisation, to today’s more “historically authentic” Hui identity. The present analysis offers a broader socio-cultural overview, showing how the pan-Asian Guo lineage re-imagines familial history across time and space by highlighting the forced assimilation narrative in which their early Ming ancestors falsely adopted Guo Ziyi, a Han-Chinese national hero, as their ancestor. The paper follows the narrative’s continuous transformations, analysing different interpretations of assuming Chinese identity among Muslims’ descendants within different contexts of contemporary Asia.
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Boo-Chai, Khoo. "Li Guo-hui et al. Investigation and analysis of microbiological flora in blood and wounds in burned patients. (Chinese)." Plastic and Reconstructive Surgery 87, no. 3 (1991): 597. http://dx.doi.org/10.1097/00006534-199103000-00091.
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Williams, Richard. "Reviewer Acknowledgements." Journal of Agricultural Studies 3, no. 2 (2015): 274. http://dx.doi.org/10.5296/jas.v3i2.8217.
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Journal of Agricultural Studies would like to thank the following reviewers for reviewing manuscripts from March 1, 2015, to September 1, 2015. Their comments and suggestions were of great help to the authors in improving the quality of their papers. Many authors, regardless of whether JAS publishes their work, appreciate the helpful feedback provided by the reviewers. Macrothink Institute appreciates the following reviewers’ rigorous and conscientious efforts for this journal. Each of the reviewers listed below returned at least one review during this period. Ashit Kumar Paul,Eliana Mariela Werbin,Ewa Moliszewska,Ferdaous Mani, Gajanan T Behere,Gerardo Ojeda,Hui Guo,Mohamed EL Sayed Megahed,Mohammad Reza Alizadeh,Moses Olotu,Pramod Kumar Mishra,Richard UwieraSahar Bahmani,Sait Engindeniz,Syed Rizwan Abbas,Zakaria Fouad Abdallah, Richard WilliamsEditorJournal of Agricultural Studies-------------------------------------------Macrothink Institute5348 Vegas Dr.#825Las Vegas, Nevada 89108United StatesPhone: 1-702-953-1852 ext.521Fax: 1-702-420-2900Email: jas@macrothink.orgURL: http://jas.macrothink.org
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Zhu, Wenjuan, Wanling Li, Hui Yang, Linying Wang, Jun Guo, and Jinnan Gao. "Abstract P6-05-14: The association of sleep quality with anxiety, depression and social support in breast cancer patients with chemotherapy." Cancer Research 83, no. 5_Supplement (2023): P6–05–14—P6–05–14. http://dx.doi.org/10.1158/1538-7445.sabcs22-p6-05-14.
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Abstract Background:Chemotherapy has side effects on breast cancer patients, and sleep disturbance is one of the common psychological symptoms. Purpose: This study aimed to examine the incidence of sleep disorders and investigate the relationship between anxiety and depression, hope, social support and sleep disorders in breast cancer patients with chemotherapy in China.Results:Total 350 patients were administered questionnaires, and 329 patients completed the questionnaires. The recovery rate was 94%. The majority of participants reported clinically significant sleep disturbance prior to chemotherapy (67.8%), during chemotherapy (71.8%), and after chemotherapy (72.2%). Pearson correlation analysis showed that the higher the direct support, emotional support, social interaction support, informational support and total social support score, the lower the total PSQI score of breast cancer patients (r = -0.212, -0.292, -0.236, -0.271, and -0.195 p< 0.01, respectively). Multifactorial model analysis showed that direct support, anxiety and age were the three main factors that affected sleep quality in breast cancer patients. Conclusions:social support may provide a powerful tool to reduce anxiety and improve sleep quality in breast cancer patients with chemotherapy. Citation Format: Wenjuan Zhu, Wanling Li, Hui Yang, Linying Wang, Jun Guo, Jinnan Gao. The association of sleep quality with anxiety, depression and social support in breast cancer patients with chemotherapy [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 P6-05-14.
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Casals-Terré, Jasmina. "Ying Sing Fung, Qidan Chen, Fuying Du, Wenpeng Guo, Tongmei Ma, Zhou Nie, Hui Sun, Ruige Wu, Wenfeng Zhao (Eds.): Microfluidic chip-capillary electrophoresis devices." Analytical and Bioanalytical Chemistry 408, no. 8 (2016): 1989–91. http://dx.doi.org/10.1007/s00216-015-9291-0.
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Guo, Yongxin, Xinlei Guo, Yisen Wang, Tao Wang, Hui Fu, and Jiazhen Li. "Closure to “Flow condition identification and discharge calibration for submerged radial gates” by YONGXIN GUO, XINLEI GUO, YISEN WANG, TAO WANG, HUI FU and JIAZHEN LI, J. Hydraulic Res. 59(4), 2021, 683–690 https://doi.org.10.1080/00221686.2020.1818305." Journal of Hydraulic Research 60, no. 6 (2022): 1012–13. http://dx.doi.org/10.1080/00221686.2022.2106595.
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Mango, Frank D. "“Distinguishing gases derived from oil cracking and kerogen maturation: Insights from laboratory pyrolysis experiments.” Guo Liguo, Xiao Xianming, Tian Hui, Song Zhiguang, 2009, Organic Geochemistry 40, 1074–1084." Organic Geochemistry 41, no. 7 (2010): 719–20. http://dx.doi.org/10.1016/j.orggeochem.2010.02.012.
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Hostetler, Laura. "Huang yu sou lan: Meiguo guo hui tu shu guan suo cang ming qing yu tu = Reading Imperial Cartography: Ming Qing Historical Maps in the Library of Congress." Imago Mundi 67, no. 2 (2015): 243–44. http://dx.doi.org/10.1080/03085694.2015.1027572.
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Zhao, Hui, Meng Zhang, Zhengcheng Guo, Cong Zhang, Shuliang Li, and Guojin Wu. "Abstract 5300: Therapeutical antibody against TIGIT disrupts inhibitory signaling and restores antitumor immunity." Cancer Research 82, no. 12_Supplement (2022): 5300. http://dx.doi.org/10.1158/1538-7445.am2022-5300.
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Abstract T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed mainly on T cell and NK cells. And because of its central role in limiting antitumor immune response and few immune-related adverse events with defect TIGIT, it has been an attractive target in cancer immunotherapy recently. Here we describe a humanized antibody against TIGIT by blocking its function and mediating ADCC to deplete TIGIT positive Treg cells. The antibody was derived from hybridoma of mice immunized with TIGIT-mFc. Comparing to TIGIT antibody in clinical (Tiragolumab), this antibody had higher affinity to 293T cells overexpressing human TIGIT (EC50=0.45nM vs 1.3nM) or cyno TIGIT (EC50=2.6nM vs 13nM), and also had higher binding affinity to activated CD8 T cell from PBMC (EC50=0.65nM vs 1.47nM), with lower Kd (0.9nM vs 1.8nM). This antibody also more efficiently blocked TIGIT binding to its ligand CD155 overexpressed on 293T cells with FACS assay than Tiragolumab (IC50=1nM vs. 1.4nM). In the cell-based reporter assay, the antibody had a lower IC50 than Tiragolumab (5nM vs. 21nM). When the primary CD8 T cell was co-cultured with 293T cells overexpressing CD155 and anti-CD3 scFv (OKT3) on the surface, the antibody increased the secretion of INF-γ along with an increase of antibody concentration. At last, this antibody-mediated depletion of TIGIT positive Treg from PBMC cultured in vitro with higher efficiency than Tiragolumab. In sum, the antibody described here was a better candidate drug targeting TIGIT for cancer immunotherapy Citation Format: Hui Zhao, Meng Zhang, Zhengcheng Guo, Cong Zhang, Shuliang Li, Guojin Wu. Therapeutical antibody against TIGIT disrupts inhibitory signaling and restores antitumor immunity [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 5300.
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Shomali, Maysoun, Zhuyan Guo, Jane Cheng, et al. "Abstract P4-02-08: Amcenestrant in combination with CDK4/6 inhibitor palbociclib demonstrates synergistic anti-tumor activity in ER+ endocrine-resistant breast cancer xenograft models." Cancer Research 82, no. 4_Supplement (2022): P4–02–08—P4–02–08. http://dx.doi.org/10.1158/1538-7445.sabcs21-p4-02-08.
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Abstract Nearly 70% of newly diagnosed cases of breast cancer (BC) are estrogen receptor positive (ER+) where endocrine therapy is a primary treatment. Despite initial efficacy seen with endocrine therapies, approximately 40% of patients develop acquired resistance which ultimately limits the use of these agents even as most of these tumors continue to require ERα. The strategies to combat these cancers with resistance are not yet defined and represent the next major clinical challenge in ER+ breast cancer. Amcenestrant is an optimized oral SERD (selective estrogen receptor degrader) with potent antagonist and degradation activity irrespective of ESR1 mutational status, and is currently being evaluated as monotherapy and in combination with CDK4/6 inhibitors and other targeted therapies for ER+ breast cancer patients in clinical trials. Here, we report that in preclinical models, amcenestrant achieved significant anti-tumor efficacy/regression as a monotherapy and strong synergistic activity when administered together with the CDK4/6 inhibitor, palbociclib, in subcutaneously xenografted endocrine resistant ER+ BC mouse models: ESR1-Y537S mutant-driven MCF7 tumor and HCI-013 PDX (patient-derived xenograft). Transcriptional profile analysis of xenograft tumor biopsies revealed the modulation of different pathways by SERD and palbociclib and highlighted crosstalk of ER and CDK4 signaling pathways. Interestingly, CDK4/6 inhibition by palbociclib induces partial activation of ER pathways as potential mechanism of tumor escape which is completely abolished by the combination treatment of amcenestrant with palbociclib. Early clinical data also showed that amcenestrant in combination with palbociclib, exhibited a favorable safety profile and encouraging antitumor activity in patients with endocrine resistant, ER+/HER2-, advanced breast cancer, which supports its potential to become a new endocrine backbone therapy for ER+ HER2- breast cancer. In conclusion, amcenestrant is an oral SERD, which exhibits significant anti-tumor activity as a single agent and shows synergistic activity with CDK4/6 inhibitor palbociclib in ER+ BC xenografts preclinically and in early clinical development. Citation Format: Maysoun Shomali, Zhuyan Guo, Jane Cheng, Amy Sullivan, Youssef El-Ahmad, Fangxian Sun, Sukhvinder Sidhu, Joon Sang Lee, Hui Cai, Jack Pollard, Laurent Debussche, Chris Soria, Monsif Bouaboula. Amcenestrant in combination with CDK4/6 inhibitor palbociclib demonstrates synergistic anti-tumor activity in ER+ endocrine-resistant breast cancer xenograft models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-02-08.
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Wang, Long, Yilin Liu, Hui Shi, et al. "Abstract 6273: CTS3157, a novel MTA-cooperative PRMT5 inhibitor for targeting MTAP-deleted human tumors." Cancer Research 83, no. 7_Supplement (2023): 6273. http://dx.doi.org/10.1158/1538-7445.am2023-6273.
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Abstract MTAP deletion is common in about 15% of all human cancers and coincides with the deletion of tumor suppressor locus containing CDKN2A/B. Methylthioadenosine (MTA), the substrate of MTAP, accumulates as a result of MTAP deletion. Increased levels of MTA result in partial inhibition of the PRMT5 enzyme by competing with S-adenosylmethionine (SAM, the methyl donor for PRMT5 substrate) due to structural similarity. Cancer cell lines with MTAP-deletion exhibit profound sensitivity to PRMT5 inhibition, suggesting MTAPnull-selective PRMT5 inhibitors have the potential to treat patients with MTAP deficiency (Kryukov et al., 2016). We identified CTS3157 as an orally bioavailable small molecule MTA-cooperative PRMT5 inhibitor that binds to PRMT5-MTA complex and inhibits PRMT5 enzymatic activity. Cell-based assays revealed that CTS3157 demonstrated potent PRMT5 inhibition as evidenced by suppression of symmetric dimethylarginine (SDMA) and cell growth inhibitory activity for MTAP-deleted cell lines over isogenic MTAPWT cell lines. Moreover, CTS3157 series compounds exhibited strong cell growth inhibition in a diverse panel of MTAPnull human tumor cell lines across several lineages. In vivo, CTS3157 demonstrated potent antitumor response after once-daily oral administration in MTAP-deleted xenograft models. The anti-tumor activity is correlated with PRMT5 modulation as measured by reduced SDMA levels. At molecular level, PRMT5 inhibition by CTS3157 resulted in massive RNA splicing defects and differentially expressed genes involving key cellular activities in MTAPnull cells. In summary, MTAPnull-selective PRMT5 inhibitor CTS3157 showed strong and durable antitumor responses in vitro and in vivo in MTAP-deleted tumors across diverse lineages. CTS3157 is an effective and promising therapeutics against MTAP-deleted tumors. Citation Format: Long Wang, Yilin Liu, Hui Shi, Yuanyuan Liu, Qiugeng Ouyang, Jiannan Guo, Yiqin Wang, Youzhen Wang, Guoliang Xu, Yuan Mi, Haiping Wu. CTS3157, a novel MTA-cooperative PRMT5 inhibitor for targeting MTAP-deleted human tumors. [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 6273.
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Gao, Zhidong, Jing Zhou, Ying Xin, et al. "Abstract 5873: Distinct prevalence and spectrum of germline cancer susceptibility gene mutations between early-onset and late-onset colorectal caner." Cancer Research 82, no. 12_Supplement (2022): 5873. http://dx.doi.org/10.1158/1538-7445.am2022-5873.
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Abstract Background: In the past few decades, the incidence of early-onset CRC (<50 years of age) has increased globally. Previous studies with small sample sizes have shown that early-onset CRC appears to have a distinct clinical, pathologic, and molecular features compared to late-onset CRC (≥ 50 years of age). However, few studies in a large population have focused on the differences in germline gene mutation spectrums of these two groups of patients. Methods: Hybrid capture-based next-generation sequencing (NGS) were performed in 5080 colorectal patients in a CAP/CLIA-approved laboratory (3DMed). NGS testing for germline mutations and MSI was implemented. Results: Of 5080 colorectal patients, early-onset CRC was observed in 1305 (25.7%) patients. The incidence of germline mutation was higher in early-onset CRCs than late-onset CRCs (8.97% vs. 4.15%,OR=2.27, P<0.0001). Consistently, the frequency of MSI-H was higher in early-onset CRCs (13.0% vs. 5.7%, OR=2.48, P<0.0001). The most frequently mutated gene was MLH1 (3.07%) in early-onset CRCs, followed by MSH2 (1.69%), APC (1.0%), MSH6 (0.84%), PMS2 (0.38%), RAD50 (0.31%), CHEK2 (0.31%), MUTYH (0.23%), BRCA1 (0.23%), and BRCA2 (0.23%). The frequency of MMR gene mutations among early- and late-onset patients was 5.98% and 1.27%, respectively (OR=4.95, P<0.0001). MMR gene mutations accounted for 60% of germline mutations of early-onset patients, while this percentage was lower for late-onset CRC (30%). Higher frequencies of APC, RAD50 and CHEK2 gene mutations were associated with early-onset CRCs (all P<0.05). The mutation frequencies of other DDR genes, MUTYH, BRCA1, BRCA2, ATM, ATR, FANCD2, TP53, were not statistically different between the two groups. The late-onset CRC tended to harbor a wider spectrum of germline cancer gene mutations, including an additional 14 cancer-related gene that were not found in early-onset CRC. Conclusions: Our findings revealed different prevalence and spectrum of germline cancer gene mutations between early-onset and late-onset CRC, suggesting that young patients should be specially considered. Citation Format: Zhidong Gao, Jing Zhou, Ying Xin, Bin Liang, Kai Shen, Peng Guo, Kewei Jiang, Mujun Yin, Xiaodong Yang, Zhanlong Shen, Hui Zhang, Depei Huang, Yingjiang Ye. Distinct prevalence and spectrum of germline cancer susceptibility gene mutations between early-onset and late-onset colorectal caner [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 5873.
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Jia, Haiqun(John), Dorthy Fang, Molly Lobsinger, et al. "Abstract 2908: PT217, an anti-DLL3/anti-CD47 bispecific antibody, exhibits anti-tumor activity through novel mechanisms of action." Cancer Research 82, no. 12_Supplement (2022): 2908. http://dx.doi.org/10.1158/1538-7445.am2022-2908.
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Abstract Small cell lung cancer (SCLC) is the most lethal subtype of lung cancers with few patients surviving more than 5 years from diagnosis. While SCLC initially responds well to standard chemotherapy treatment, chemotherapy-resistant recurrence is characteristic and available treatment options for recurrent and refractory diseases are limited. Immunotherapy as an alternative or additional treatment has been very successful in treating many cancers, yet it has shown disappointingly limited benefits in SCLC and notable treatment related toxicities have been observed. Delta like 3 (DLL3) is an attractive target for SCLC immunotherapy, as its expression is highly restricted to SCLC and can therefore be used for targeting purposes. On the other hand, CD47 is also strongly expressed on the surface of SCLC cells, where it inhibits macrophage-mediated tumor cell killing. We have developed PT217, a DLL3/CD47 bispecific antibody with effector effect competent Fc to specifically target SCLC cells via two mechanisms. First, PT217 blocks the CD47-SIRPα interaction and stimulates phagocytosis of tumor cells by macrophage. Second, PT217 exhibits robust effector effect (ADCC by NK cells and ADPC by macrophage) mediated by the functional Fc of PT217. Interestingly, it appears that the tumor cells targeted by NK cells are subsequently engulfed by macrophage. Elevated phagocytosis of the tumor cells by macrophages and dendritic cells is expected to increase the presentation of tumor neoantigens that may eventually lead to T cell-mediated killing of tumor cells that do not expression DLL3. In vivo, PT217 demonstrated tumor suppression activity in xenograft mouse models. In addition to the strong tumor killing activity, PT217 also demonstrated good safety profile in NHP studies. Furthermore, PT217 exhibits regular mAb-like manufacturability in process development and CMC. We expect to initiate a phase 1 trial to target SCLC in the first half of 2022. Citation Format: Haiqun(John) Jia, Dorthy Fang, Molly Lobsinger, Yan Long, Kelan Chen, Albert Lam, Yangyang Guo, Kaisa Selesniemi, Ming Wang, Hui Zou. PT217, an anti-DLL3/anti-CD47 bispecific antibody, exhibits anti-tumor activity through novel mechanisms of action [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 2908.
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Lin, Yanan, Shengbang Zhang, Jie Ran, et al. "Abstract 5135: Standardized off-the-shelf engineered NK cell therapy with improved ADCC properties to treat malignancies." Cancer Research 83, no. 7_Supplement (2023): 5135. http://dx.doi.org/10.1158/1538-7445.am2023-5135.
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Abstract In the treatment of solid tumors, chimeric antigen receptor(CAR)-engineered NK (CAR-NK) cells have distinct advantages over CAR-T cells, such as a lack graft-versus-host disease in allogenic setting to make “off the shelf” medicine; much safer because they are less likely to cause cytokine storms; and NK cells have their own activated receptors that recognize tumor surface antigens and thus have a natural ability to kill a wide range of tumors. In addition, NK cells are the main performers of antibody-dependent cell-mediated cytotoxicity (ADCC), which binds to the Fc-terminus of antibodies through their surface Fc receptor CD16A, thereby killing antibody-targeted tumor cells. Enhancing the ADCC action of NK cells themselves enhances the therapeutic efficacy of monoclonal antibodies targeting tumor surface antigens and is therefore of great importance in the treatment of tumors, especially solid tumors. We screened two optimal structures among nine different Fc chimeric receptors, and NK cells overexpressing these two receptors killed K562 and Daudi six times more intensely than normal NK cells when combined with rituximab, while the killing ability was comparable to that of normal NK without rituximab, indicating that NK cells expressing chimeric Fc receptors have stronger ADCC effects. Moreover, these NK cells can kill target cells in multiple rounds. In vivo experiments in mice demonstrated that NK cells expressing chimeric Fc receptors in combination with EGFR monoclonal antibodies had a stronger inhibitory effect on tumor growth than monoclonal antibodies or NK cells alone. Here we provide a novel broad “off the shelf” NK cells that can significantly enhance the killing ability of hematological and solid tumors in combination with different monoclonal antibodies. Citation Format: Yanan Lin, Shengbang Zhang, Jie Ran, Can Song, Shengcang Zhu, Hui Shi, Ping Guo, Shengjiang Tan, Yuchun Gu, Lida Wu. Standardized off-the-shelf engineered NK cell therapy with improved ADCC properties to treat malignancies. [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 5135.
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Chen, Yunyun, Jiangmei Li, Yanan Guo, et al. "Abstract 1528: 6B5, an anti-human B7-H3 therapeutic antibody that enhances antibody-dependent cellular cytotoxicity and inhibits tumor growth in B7-H3-humanized mice." Cancer Research 83, no. 7_Supplement (2023): 1528. http://dx.doi.org/10.1158/1538-7445.am2023-1528.
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Abstract B7-H3 (CD276) is a type I transmembrane protein belonging to the B7 family of immune-regulatory ligands. Initially reported as a costimulatory signal of human T cells, increasing evidence suggests that it may also have coinhibitory function. TLT-2 has been identified as a potential cognate receptor for B7-H3, but others may exist. Overexpression of B7-H3 protein is found in a variety of human cancers, including lung adenocarcinomas, neuroblastomas, gliomas, and pancreatic tumors—and is associated with poor prognosis and survival. While B7-H3 can promote T cell activation and anti-tumor responses in the context of CD3 stimulation, its coinhibitory function inhibits T and NK cell activity in the tumor microenvironment. We generated 6B5, a fully human B7-H3 monoclonal antibody, from murine B7-H3 knock-out RenMab™ mice, which contain the full human immunoglobulin variable domain. 6B5 is cross-reactive with rodent and cynomolgus monkey B7-H3. It displays higher affinity for tumor cell lines than Enoblituzumab. 6B5 has no staining on normal human tissues. In vitro antibody-dependent cellular cytotoxicity (ADCC) against H520 squamous cell carcinoma cells was potentiated by 6B5 relative to Enoblituzumab and, critically, did not exhibit the hook effect at high dosage. In vivo efficacy of 6B5 in humanized B7-H3 mice bearing murine EL4 lymphomas was comparable to Enoblituzumab. ADCC enhancement in vivo was comparable to afucosylation or five-point mutations. Epitope mapping revealed non-overlapping B7-H3 binding epitopes of 6B5 and Enoblituzumab. Taken together, these data suggest that 6B5 is a promising therapeutic anti-human B7-H3 IgG monoclonal antibody that may find clinical application in a range of cancers, including current refractory types. Citation Format: Yunyun Chen, Jiangmei Li, Yanan Guo, Wenqi Hu, Ting Mao, Li Hui, W. Frank An, Yi Yang, Feng Li. 6B5, an anti-human B7-H3 therapeutic antibody that enhances antibody-dependent cellular cytotoxicity and inhibits tumor growth in B7-H3-humanized mice [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 1528.
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Niu, Zhenlan, Xuan Yu, Zhiyuan Shen, Jing Guo, Qingcong Lin, and Hui Xu. "Abstract 5345: Development and validation of humanized HLA mouse model platforms for preclinical evaluation of novel peptide vaccines." Cancer Research 84, no. 6_Supplement (2024): 5345. http://dx.doi.org/10.1158/1538-7445.am2024-5345.
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Abstract The human leukocyte antigen (HLA) class I major histocompatibility complex (MHC) plays an integral role in immune surveillance by presenting intracellular antigen peptides on the cell surface, enabling recognition by cytotoxic T cells and subsequent elimination. Harnessing this intrinsic process for cancer immunotherapy is a promising therapeutic strategy; thus, developing preclinical models to evaluate the efficacy of novel peptide vaccines in vivo and ex vivo is critical. Previously, we developed a humanized MHC I mouse model (B-HLA-A2.1 mice), in which we successfully demonstrated efficacy of peptide vaccines as assessed by splenocyte IFN-γ production measured via ELISpot. Here, we provide evidence that B-HLA-A2.1 mice can also mount immune responses to NY-ESO-1 and WT1-Db126 peptides using the same assay. Additionally, immunization with WT1-Db126 at 7, 14, and 21 days prior to tumor inoculation with WT1-expressing MC38 colon cancer cells significantly reduced tumor volume. Additionally, we have generated two new humanized HLA models: B-HLA-A11.1 mice and B-HLA-A24.2 mice. Flow cytometric data demonstrate successful expression of the human HLAs on the cell surface of splenocytes isolated from both strains. Compared to wild-type C57BL/6 mice, analysis of leukocyte and lymphocyte subpopulations in the humanized mice indicates that the CD4/CD8 ratio is altered in favor of CD4+ T cells in both strains, similar to what was observed in B-HLA-A2.1 humanized mice. Despite these observed alterations, B-HLA-A24.2 mice were able to mount an immune response to peptide SART2 93-101, which was measured by splenocyte IFN-γ production. In summary, our data indicate that humanized HLA-A mice provide a powerful preclinical model for in vivo/ex vivo evaluation of novel peptide vaccines. Citation Format: Zhenlan Niu, Xuan Yu, Zhiyuan Shen, Jing Guo, Qingcong Lin, Hui Xu. Development and validation of humanized HLA mouse model platforms for preclinical evaluation of novel peptide vaccines [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 5345.
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Xu, Jianming, Haiping Jiang, Yueyin Pan, et al. "Abstract CT078: First-line treatment with sintilimab (sin) vs placebo in combination with chemotherapy (chemo) in patients (pts) with unresectable gastric or gastroesophageal junction (G/GEJ) cancer: Final overall survival (OS) results from the randomized, phase III ORIENT-16 trial." Cancer Research 83, no. 8_Supplement (2023): CT078. http://dx.doi.org/10.1158/1538-7445.am2023-ct078.
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Abstract Background: The phase III ORIENT-16 trial evaluated sin (a PD-1 inhibitor) versus placebo plus chemo as first-line (1L) treatment in pts with advanced G/GEJ adenocarcinoma. Sin+chemo previously showed a significant improvement in OS vs chemo in pts with PD-L1 combined positive score (CPS) ≥5 (HR 0.660; 95% CI 0.505-0.864; P=0.0023) and in all pts (HR 0.766; 95% CI 0.626-0.936; P=0.0090), with a median follow-up of 18.8 months (m) at interim analysis (Xu, et al. Ann Oncol 2021). Here we report the results from the final analysis (NCT03745170). Methods: This double-blind, phase III trial enrolled 650 pts ≥18 years of age with untreated, unresectable, locally advanced, or metastatic G/GEJ adenocarcinoma, regardless of PD-L1 expression. Pts were randomized 1:1 to receive sin (3 mg/kg in pts weighing <60 kg or 200 mg in pts weighing ≥60 kg, IV Q3W) or placebo plus chemo (oxaliplatin 130 mg/m2 IV Q3W for up to 6 cycles, capecitabine 1000 mg/m2 PO Bid d1-14 Q3W) for 24 months. The primary endpoints were OS in pts with CPS ≥5 and all randomized pts. The data cutoff date for the final analysis was Sep 2, 2022. Results: With a median follow-up of 33.9 m, sin+chemo continued to show OS benefit over chemo in all pts (15.2 vs 12.3 m; HR 0.681 [95% CI: 0.571, 0.812]; P<0.0001); estimated OS rates at 24 and 36 m for sin+chemo vs chemo were 37.6% vs 20.6% and 26.0% vs 10.7%, respectively. OS benefits with sin+chemo vs chemo across subgroups were generally consistent with the previous report. The updated PFS was superior with sin+chemo vs chemo (HR 0.638, 95% CI 0.530-0.768; P<0.0001). The updated confirmed ORR per RECIST v1.1 was 58.2% vs 48.8% in all pts with measurable disease at baseline, with a median DoR of 9.9 vs 7.0 m, respectively; 47.8% of responders in sin+chemo group and 25.9% of responders in chemo group had DoR ≥12 m. In pts with CPS ≥5, significant OS benefit (median OS 19.2 vs 12.9 m; HR 0.587 [95% CI: 0.467, 0.738]; P<0.0001) and superior PFS (HR 0.621, 95% CI 0.490-0.787; P<0.0001) with sin+chemo over chemo remained. A delayed numerical OS improvement was observed for subgroup pts with CPS <5. No new or unexpected safety signals were identified. Conclusion: The previously reported significant OS benefit with sin+chemo vs chemo was more evident in CPS ≥5 pts and in all pts with 15 m of additional follow-up, further confirming sin+chemo as a standard of care for 1L treatment of G/GEJ adenocarcinoma. Citation Format: Jianming Xu, Haiping Jiang, Yueyin Pan, Kangsheng Gu, Shundong Cang, Lei Han, Yongqian Shu, Jiayi Li, Junhui Zhao, Hongming Pan, Suxia Luo, Yanru Qin, Qunyi Guo, Yuxian Bai, Yang Ling, Yingmei Guo, Yuling Chen, Yan Wang, Hui Zhou. First-line treatment with sintilimab (sin) vs placebo in combination with chemotherapy (chemo) in patients (pts) with unresectable gastric or gastroesophageal junction (G/GEJ) cancer: Final overall survival (OS) results from the randomized, phase III ORIENT-16 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT078.
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Mai, Hai-Qiang, Ya-Qian Han, Guo-Wu Wu, et al. "Abstract CT113: A dose-exploring, randomized, open-label, Phase I study for toripalimab subcutaneous injection in patients with advanced nasopharyngeal carcinoma." Cancer Research 84, no. 7_Supplement (2024): CT113. http://dx.doi.org/10.1158/1538-7445.am2024-ct113.
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Abstract Background Toripalimab, a humanized IgG4K monoclonal antibody specific for PD-1, in combination with gemcitabine and cisplatin (GP) has been approved as a first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) by the US FDA in October 2023. This is the first-in-human clinical trial (NCT05751486) to investigate the pharmacokinetics of toripalimab subcutaneous (SC) formulation in RM-NPC and determine the appropriate subcutaneous administration regimen for subsequent clinical trials. Methods Patients with histologically confirmed RM-NPC and without previously systemic therapy for RM disease were enrolled. Eligible patients were assigned to receive toripalimab SC 240 mg every 3 weeks (Q3W), 360 mg Q3W or 480 mg Q6W, in combination with GP for up to 6 cycles, followed by toripalimab SC monotherapy until disease progression, intolerable toxicity, or completion of 2 years of treatment. Tumor response was assessed per RECIST v1.1. The primary endpoint was pharmacokinetic (PK) profile. Secondary endpoints included safety, efficacy, and immunogenicity. Results From November 24, 2022 to November 20, 2023, a total of 38 patients (240 mg cohort, n=12; 360 mg cohort, n=13; 480 mg cohort, n=13) were enrolled, the median follow-up time was 6.8 months. The median age was 49 years, and 28 (73.7%) patients were males. PK analysis showed that in the first cycle, the exposure (AUC0-21days and Ctrough) of toripalimab 360 mg Q3W SC regimen was comparable to that of 240 mg Q3W intravenous (IV) regimen (table 1). Objective Response Rates (ORR) in 240 mg, 360 mg and 480 mg cohorts were 100%, 92.3% and 92.3%, respectively. By November 20, 2023, 71.1% (27/38) patients have ongoing responses. No new safety signal was identified. The incidence of Grade ≥3 adverse events (AEs) was 76.3% with no fatal AEs. The incidence of investigator-determined immune-related AEs was 36.8% with 1 (2.6%) Grade ≥3. Conclusions Toripalimab SC formulation showed similar safety and clinical efficacy with toripalimab IV formulation when combined with GP in patients with RM-NPC. The exposure of toripalimab 360 mg Q3W SC was comparable to that of 240 mg Q3W IV. Toripalimab SC formulation is planned for phase III clinical development. Table 1. PK parameters of each dose cohort. Parameters JS001sc Cohorts (N = 36) IV ref-model based 240 mg SC Q3W, n=12 480 mg SC Q6W, n=12 360 mg SC Q3W, n=12 240 mg IV Q3W, n=1014 Cycle 1 Ctrough, μg/mL GM (% CV) 10.2 (57.1) 8.4 (43.5) 18.6 (50.1) 10.2 (61.8) Cycle 1 AUC (0-Xd), μg•d/mL GM (% CV) 8376 (0-21 d) (39.3) 25316 (0-42 d) (35.4) 14229 (0-21 d) (58.2) 13386 (27.0) Bioavailability 62.6% (25.3%-100.0%) Citation Format: Hai-Qiang Mai, Ya-Qian Han, Guo-Wu Wu, Kun-Yu Yang, Chuan-Ben Chen, Mo Wang, Xian-Ming Luo, Shuang-Hui Wei, Xi Tan, Peng Xue, Rui-Hua Xu. A dose-exploring, randomized, open-label, Phase I study for toripalimab subcutaneous injection in patients with advanced nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT113.
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Gao, Feng, Bin Liu, Liandong Jing, et al. "Abstract 1145: PH020-803: an MTA-cooperative and brain-penetrable PRMT5 inhibitor that selectively targets MTAP-deleted tumors." Cancer Research 83, no. 7_Supplement (2023): 1145. http://dx.doi.org/10.1158/1538-7445.am2023-1145.
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Abstract Background: Methylthioadenosine phosphorylase (MTAP) gene deletion occurs in ~10% of human cancers and is enriched in non-small cell lung cancer, pancreatic cancer and brain cancer. Since MTAP is the only enzyme responsible for methylthioadenosine (MTA) degradation, homozygous deletion of MTAP gene leads to intracellular accumulation of MTA. MTA competes with S-adenosylmethionine (SAM, the methyl donor) and results in partial inhibition of protein arginine methyltransferase 5 (PRMT5) activity. Recent studies reported that tumor cells with MTAP loss are vulnerable to PRMT5 inhibition. Based on the synthetic lethality interaction, an MTA cooperative PRMT5 inhibitor has the potential to selectively target MTAP-deleted tumors and avoid hematologic toxicity of substrate-competitive (such as GSK3326595) or SAM-competitive (such as JNJ64619178) PRMT5 inhibitors. Methods: A pair of HCT116 isogenic cell lines (MTAP-/- and MTAP+/+) were used to determine the effects of PH020-803 on cell proliferation and intracellular symmetric dimethylarginine (SDMA) content. Human CD34+ hematopoietic stem cells (HSCs) were collected to evaluate hematological toxicity. Intravenous injection of PH020-803 in rats were performed to assess the brain-penetration capability. The in vivo efficacy was tested in cell derived xenograft (CDX) mouse models with tumor harboring MTAP gene deletion. The in vitro and in vivo pharmacokinetic and safety properties were assessed with corresponding assay methods. Results: PH020-803 dramatically decreased SDMA content and inhibited proliferation in HCT116 MTAP-/- cells (SDMA, IC50=1.04 nM; proliferation, IC50=19 nM), but had very weak effect on HCT116 MTAP+/+ cells (SDMA, IC50=535.5 nM; proliferation, IC50=1620 nM). In contrast, both GSK3326595 and JNJ64619178 had no obvious selectivity (proliferation: 595, IC50=8 nM and 35 nM in MTAP-/- cells and MTAP+/+ cells, respectively; 178, IC50=1 nM and 3 nM, respectively). PH020-803 mildly inhibited CD34+ HSC (IC50=900.2 nM), compared to potent cytotoxicity of GSK3326595 (IC50=15.8 nM). PH020-803 showed excellent brain penetration with a Kp value of 0.16. In two CDX models (HCT116 MTAP-/- and LU99), PH020-803 at a dose of 100 mg/kg QD potently inhibited tumor growth without hematologic toxicity observed. A 10-day repeated dosing study in mice (300 mg/kg QD) suggested that red blood cell and reticulocyte counts significantly decreased in GSK3326595 group, but not in PH020-803 group. Caco-2 and MDCK-MDR1 assays demonstrated excellent membrane permeability of PH020-803 without obvious efflux. Accordingly, PH020-803 possessed good pharmacokinetic profile in mice and rats with absolute bioavailability at 74% and 58%, respectively. Conclusion: The present data suggest that PH020-803 is an MTA-cooperative and brain-penetrable PRMT5 inhibitor that selectively targets MTAP-deleted tumors. Citation Format: Feng Gao, Bin Liu, Liandong Jing, Yongyong Wu, Pengzhi Zhang, Shuai Yuan, Hui Zhao, Yu Gao, Zhizhong Li, Xiaofan Wang, Yongqi Guo. PH020-803: an MTA-cooperative and brain-penetrable PRMT5 inhibitor that selectively targets MTAP-deleted tumors [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 1145.
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Gao, Feng, Bin Liu, YongYong Wu, et al. "Abstract 4005: PH009-1, a highly potent and selective fourth-generation EGFR-TKI overcoming EGFR common mutations and T790M/C797S-mediated resistance in NSCLC." Cancer Research 83, no. 7_Supplement (2023): 4005. http://dx.doi.org/10.1158/1538-7445.am2023-4005.
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Abstract Background: Epidermal growth factor receptor (EGFR) activating mutations have been reported in 10-50% of patients with non-small cell lung cancer (NSCLC). The common mutations, ex19del (D) and L858R (L) substitution, are sensitive to first- and second-generation EGFR-TKIs. However, acquired on-target resistance, especially T790M (T) mutation, comprises the anti-tumor effects of these inhibitors. Though the third-generation EGFR-TKI Osimertinib potently inhibits both EGFR common mutations and T790M mutation, 10-24% of patients acquire C797S (C) resistant mutation. Here, we report a highly potent and selective fourth-generation EGFR-TKI, PH009-1, designed to overcome both EGFR common mutations and T790M/C797S-mediated resistance in NSCLC. Methods: Kinase selectivity of Ph009-1 was assessed by KINOMEscan against 468 human kinases. A functional safety panel including 47 targets contributing to clinical adverse drug reactions was used to evaluate pharmacological profiling of PH009-1. Biochemical enzyme activities were detected with kinase assays and anti-proliferative activities were measured in various tumor and engineered Ba/F3 cell lines. The in vivo anti-tumor efficacy was tested in four cell derived xenograft (CDX) mouse cancer models with tumor harboring single, double or triple mutant EGFR. The in vitro and in vivo pharmacokinetic (microsome metabolic stability, hepatocyte metabolic stability, plasma protein binding, drug-drug interaction, oral absorption, et al) and safety properties (hERG potassium channel assay, Ames assay, repeated dosing study, et al) of PH009-1 were assessed in various species with corresponding assay methods. Results: High kinase selectivity and very low off-target effects were observed in KINOMEscan and safety panel assays, respectively. PH009-1 inhibited kinase activity of all tested EGFR mutants with IC50<4 nM. Furthermore, PH009-1 displayed potent anti-proliferation activity against Ba/F3 (EGFR L, D, LC, DC, DT, LTC, DTC) with IC50 of 3.6, 3.1, 1.6, 1.7, 0.3, 3.9, 3.1 nM, respectively. Excellent selectivity of PH009-1 was observed when compared the above values to IC50 against Ba/F3 (WT, 93.3 nM), A431 (WT, 2415 nM), LoVo (WT, 3700 nM) and NCI-H23 (WT, 2359 nM). In all four CDX cancer models including HCC827 (D), Ba/F3 (DC), Ba/F3 (LC) and Ba/F3 (DTC), PH009-1 at a dose of 40 mg/kg BID induced tumor regression or eradication without significant effect on mouse body weight. Favorable pharmacokinetic and safety profiles were suggested in in vitro and in vivo pharmacokinetic and safety evaluations. Conclusion: The present data suggest that PH009-1 is a promising and highly selective fourth-generation EGFR TKI with potent in vitro and in vivo activity against single, double and triple EGFR mutations including T790M and C797S. Citation Format: Feng Gao, Bin Liu, YongYong Wu, Liandong Jing, Pengzhi Zhang, Jing Wang, Shuai Yuan, Hui Zhao, Yu Gao, Zhizhong Li, Xiaofan Wang, Yongqi Guo. PH009-1, a highly potent and selective fourth-generation EGFR-TKI overcoming EGFR common mutations and T790M/C797S-mediated resistance in NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4005.
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Shi, Jing, Jiaqing Yan, Yaling Huang, et al. "Abstract 739: AMT-253, a first-in-class MUC18-targeting antibody-drug conjugate, for the treatment of MUC18-positive solid tumors." Cancer Research 84, no. 6_Supplement (2024): 739. http://dx.doi.org/10.1158/1538-7445.am2024-739.
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Abstract MUC18, also known as MCAM (melanoma cell adhesion molecule) or CD146, is a type I transmembrane glycoprotein originally identified as a cell adhesion molecule of melanoma that plays important roles in tumor growth and progression including tumor angiogenesis, epithelial-mesenchymal transition (EMT), and metastasis. MUC18 is overexpressed in a variety of solid tumors including (but not limited to) melanoma, osteosarcoma, head and neck, lung, esophagus, breast, ovarian, and cervical cancer and hepatocellular carcinoma, with restricted presence on normal healthy tissues, mainly on blood vessels and a minor subset of T helper cells. Limited expression in normal tissues and high expression in tumors makes MUC18 a promising target for the development of antibody drug conjugate (ADC). AMT-253 is a novel ADC targeting MUC18. It is composed of a humanized MUC18-targeting IgG1 antibody conjugated with Exatecan, a topoisomerase I inhibitor, attached to a proprietary self immolative T moiety linker through reduced interchain disulfide bonds with a drug-to-antibody ratio (DAR) of 8. AMT-253 was stable in vitro with less than 0.5% of payload releasing when incubated with human, monkey, mouse or rat plasma for 21 days at 37°C. AMT-253 selectively bound to cell surface MUC18 and was efficiently internalized into MUC18-positive cancer cells. AMT-253 exhibited antiproliferative activity against several MUC18-positive cancer cell lines and demonstrated potent bystander killing effect in vitro. Treatment with AMT-253 resulted in tumor growth inhibition or regression in a panel of MUC18 positive cell line derived xenograft (CDX) or patient derived xenograft (PDX) models. In addition, AMT-253 was well tolerated in a GLP compliant toxicity study in cynomolgus monkeys at dose levels ≤45 mg/kg. Taken together, our preclinical in vivo efficacy and toxicity studies demonstrated that AMT-253 has a wide therapeutic window and could potentially provide benefits for cancer patients with highly unmet medical needs. AMT-253 is currently being evaluated in a Phase I first-in-human clinical trial (NCT05906862). Citation Format: Jing Shi, Jiaqing Yan, Yaling Huang, Jun Guo, Yan Kong, Xun Meng, Shu-Hui Liu. AMT-253, a first-in-class MUC18-targeting antibody-drug conjugate, for the treatment of MUC18-positive solid tumors [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 739.
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Lee, Dong Jun, Sabine Rottmann, Anna Wang, et al. "Abstract 1909: Advancing a novel tubulin-inhibitor ADC technology: The Adcentrx auristatin platform offers enhanced efficacy and safety profiles compared to vedotin technology." Cancer Research 84, no. 6_Supplement (2024): 1909. http://dx.doi.org/10.1158/1538-7445.am2024-1909.
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Abstract Auristatins represent an important class of anti-mitotic antibody-drug conjugate (ADC) payloads with potent cytotoxic effects on rapidly dividing cancer cells. Most notably, monomethyl auristatin E (MMAE) stands as the most extensively validated compound, laying the foundation for the vcMMAE (vedotin) linker-payload technology that has contributed to the approval of several ADCs, including brentuximab vedotin, polatuzumab vedotin-piiq, tisotumab vedotin-tftv, and enfortumab vedotin-ejfv. However, while these first-generation ADCs have paved the way for a paradigm shift in cancer treatment away from traditional chemotherapy, there remains a discernible opportunity for improvement in both efficacy and safety. In this context, we introduce the Adcentrx auristatin platform, which substantially expands the therapeutic window of auristatin-ADCs beyond the vedotin technology. Through systematic exploration, we have synthesized >100 proprietary auristatin analogues with a range of distinctive properties. We identified optimized linker-payloads by strategically pairing lead payload candidates with our proprietary i-ConjugationTM, an irreversible, stable cysteine conjugation technology, and fine-tuned linkers. The resulting ADCs with a drug-to-antibody ratio (DAR) of 8 were extremely hydrophilic with excellent in vivo pharmacokinetics, and sustained DAR retention for a period of 21-days. Comparative assessments against vedotin-ADCs revealed that Adcentrx-ADCs demonstrated superior efficacy across multiple targets and indications in various mouse xenograft models. In Sprague-Dawley rats, Adcentrx-ADCs exhibited remarkable tolerability, albeit their high drug loading of 8. In summary, our preclinical studies underscore the significant enhancement in the therapeutic index achieved by the Adcentrx auristatin platform. Furthermore, this technology presents a promising alternative mode of action to camptothecins, exhibiting tolerance to targets expressed in non-proliferative normal tissues but without the burden of severe dose-limiting toxicities such as interstitial lung disease. Citation Format: Dong Jun Lee, Sabine Rottmann, Anna Wang, Peter P. Challita, Andrew M. Hau, Wes Sisson, Mario M. Kuo, Kris Zhang, Monica Leung, Alexis Mahloch, Erin Nye, Paul Datta, Sam Janssen, Felipe Acosta, Oscar Betancourt, Maria Shahmoradgoli, Alexander Chu-Kung, MaoJun Guo, Pia M. Challita-Eid, Hui Li. Advancing a novel tubulin-inhibitor ADC technology: The Adcentrx auristatin platform offers enhanced efficacy and safety profiles compared to vedotin technology [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 1909.
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Li, Wenyuan, and Hui Guo. "Abstract 1538: Impact of C-reactive protein on the efficacy of immune checkpoint inhibitors in non-small cell lung cancer." Cancer Research 84, no. 6_Supplement (2024): 1538. http://dx.doi.org/10.1158/1538-7445.am2024-1538.
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Abstract Background: Immune checkpoint inhibitors (ICIs) therapy has achieved remarkable success in the treatment of non-small cell lung cancer (NSCLC). Clinical studies have suggested a correlation between C-reactive protein (CRP) levels and treatment efficacy, but it remains unclear whether CRP can directly impact the efficacy. Therefore, we investigated the imapct of CRP on the efficacy of ICIs in NSCLC. Methods: The tumor growth model was established in CRP knockout and wildtype mice by injecting LLC cells to evaluate the effect of CRP on tumor proliferation. The frequencies and phenotypes of macrophages and T cells in mouse tumors were detected by flow cytometry. The impact of CRP on macrophage polarization was evaluated using flow cytometry and IF, while its impact on T cell chemokines CCL5, CXCL9, and CXCL10 was analyzed by ELISA and qRT-PCR. mCRP and α-PD-1 were implemented in C57/BL6 mice injected with LLC cells to evaluate the effect of mCRP on tumor immunotherapy. The frequencies of T cells in mouse tumors were detected by flow cytometry. Expression of mCRP and infiltration of immune cells in human NSCLC tissues were analyzed using IHC. Results: We found that tumor progression was enhanced and the proportion of tumor-infiltrated M1 macrophages was decreased in CRP knockout mice. Using human PBMC-derived macrophage and RAW264.7 cell lines, we demonstrated that the monomeric form of CRP, known as mCRP, induced M1 polarization of macrophages, leading to increased secretion of CCL5, CXCL9, and CXCL10. In tumor bearing mice, mCRP treatment enhanced anti-tumor immunity and suppressed tumor progression by increasing CD4+ and CD8+ T cell recruitment. Surprisingly, the combined treatment of mCRP and α-PD-1 induced more significant tumor regression than α-PD-1 treatment alone. Additionally, high level of mCRP in NSCLC tissues is correlated with a more inflamed tumor microenvironment phenotype. Conclusion: mCRP can enhance the efficacy of immune checkpoint inhibitors in NSCLC by activating anti-tumor immunity. Citation Format: Wenyuan Li, Hui Guo. Impact of C-reactive protein on the efficacy of immune checkpoint inhibitors in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1538.
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Shi, Hui, Meng Wang, Jiaxin Huang, et al. "Abstract 4021: CTS2016, a novel AXL/FLT3 inhibitor for targeting AML/MDS and solid tumors." Cancer Research 83, no. 7_Supplement (2023): 4021. http://dx.doi.org/10.1158/1538-7445.am2023-4021.
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Abstract We identified CTS2016 as a novel, selective, orally bioavailable small molecule inhibitor with single-digit nanomolar enzymatic activity to AXL and FLT3. Overexpression of AXL is associated with metastasis, drug resistance, and poor prognosis of various hematological and solid tumors, which are all broadly modulated with epigenetic regulation. In addition, inhibition of AXL phosphorylation may overcome drug resistance to current FLT3 inhibitors in FLT3-ITD+ Acute Myeloid Leukemia (AML) (Park et al., 2015). We tested CTS2016 as a single agent or in combination with either venetoclax, a Bcl-2 inhibitor, or azacitidine, a hypomethylating agent (HMA) and an epigenetic modulation drug, in a series of in vitro and in vivo studies using various AML models CTS2016 resulted in a potent growth inhibitory effect with strong induction of cell death in a spectrum of AML cell lines carrying FLT3 mutations (FLT3-ITD and/or FLT3-TKD) CTS2016 orally administered once daily, demonstrated potent and dose-dependent antitumor responses in a variety of AML xenograft mouse models. The anti-tumor activity was correlated with the inhibition of receptor tyrosine kinase signaling, as measured by decreased phosphorylation of key downstream signaling targets of FLT3. In a tail vein injection of mouse LLC-Luciferase model, CTS2016 treatment could significantly reduce tumor metastasis. A combination of CTS2016 with venetoclax or azacitidine provides a therapeutic benefit over monotherapy and supports a rationale for testing these combination therapies in patients with relapsed or refractory (R/R) AML and myelodysplastic syndromes (MDS). In addition, CTS2016 significantly reduced the tumor burden of a leukemia model harboring FLT3-ITD-F691L, a drug-resistant mutation of FLT3. Notably, the selectivity of CTS2016 over other kinases (such as c-KIT) mitigates the off-target toxicity effects on normal hematological differentiation which is common in clinics for other FLT3 inhibitors. These data demonstrate that CTS2016 could be a promising therapy for treating patients diagnosed with AML and MDS harboring FLT3 mutations and solid tumors such as NSCLC and TNBC with high-expression of AXL. More proof-of-concept data would come from the ongoing clinical trial. Citation Format: Hui Shi, Meng Wang, Jiaxin Huang, Qiugeng Ouyang, Jiannan Guo, Youzhen Wang, Yuan Mi, Haiping Wu. CTS2016, a novel AXL/FLT3 inhibitor for targeting AML/MDS and solid tumors. [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 4021.
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Xu, Chang, Kie Kyon Huang, Jia Hao Law, et al. "Abstract P28: Comprehensive Molecular Phenotyping of ARID1A-deficient Gastric Cancer Reveals Pervasive Epigenomic Reprogramming and Therapeutic Opportunities." Cancer Research 84, no. 8_Supplement (2024): P28. http://dx.doi.org/10.1158/1538-7445.fcs2023-p28.
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Abstract Objective Gastric cancer (GC) is a leading cause of cancer mortality, with ARID1A being the second most frequently mutated driver gene in GC. We sought to decipher ARID1A-specific GC regulatory networks and examine therapeutic vulnerabilities arising from ARID1A loss. Design Genomic profiling of GC patients including a Singapore cohort (>200 patients) was performed to derive mutational signatures of ARID1A inactivation across molecular subtypes. Single-cell transcriptomic profiles of ARID1A-mutated GCs were analyzed to examine tumor microenvironmental changes arising from ARID1A loss. Genome-wide ARID1A binding and chromatin profiles (H3K27ac, H3K4me3, H3K4me1, ATAC-seq) of gastric cell lines were generated to identify gastric-specific epigenetic landscapes regulated by ARID1A. Distinct cancer hallmarks of ARID1A-mutated GCs were converged at the genomic, single-cell, and epigenomic level, and targeted by pharmacological inhibition. Results We observed prevalent ARID1A inactivation across GC molecular subtypes, with distinct mutational signatures and linked to a NFKB-driven pro-inflammatory tumour microenvironment. ARID1A-depletion caused loss of H3K27ac activation signals at ARID1A-occupied distal enhancers, but unexpectedly gain of H3K27ac at ARID1A-occupied promoters in genes such as NFKB1 and NFKB2. Promoter activation in ARID1A-mutated GCs was associated with enhanced gene expression, increased BRD4 binding, and reduced HDAC1 and CTCF occupancy. Combined targeting of promoter activation and tumour inflammation via bromodomain and NFKB inhibitors confirmed therapeutic synergy specific to ARID1A-genomic status. Conclusion Our results suggest a therapeutic strategy for ARID1A-mutated GCs targeting both tumour-intrinsic (BRD4-assocatiated promoter activation) and extrinsic (NFKB immunomodulation) cancer phenotypes. Citation Format: Chang Xu, Kie Kyon Huang, Jia Hao Law, Joy Shijia Chua, Taotao Sheng, Natasha M. Flores, Melissa Pool Pizzi, Atsushi Okabe, Angie Lay Keng Tan, Feng Zhu, Vikrant Kumar, Xiaoyin Lu, Ana Morales Benitez, Benedict Shi Xiang Lian, Haoran Ma, Shamaine Wei Ting Ho, Kalpana Ramnarayanan, Chukwuemeka George Anene-Nzelu, Milad Razavi-Mohseni, Siti Aishah Binte Abdul Ghani, Su Ting Tay, Xuewen Ong, Ming Hui Lee, Yu Amanda Guo, Hassan Ashktorab, Duane Smoot, Shang Li, Anders Jacobsen Skanderup, Michael A. Beer, Roger Sik Yin Foo, Joel Shi Hao Wong, Kaushal Sanghvi, Wei Peng Yong, Raghav Sundar, Atsushi Kaneda, Shyam Prabhakar, Pawel Karol Mazur, Jaffer A. Ajani, Khay Guan Yeoh, Jimmy Bok-Yan So, Patrick Tan, Singapore Gastric Cancer Consortium. Comprehensive Molecular Phenotyping of ARID1A-deficient Gastric Cancer Reveals Pervasive Epigenomic Reprogramming and Therapeutic Opportunities [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P28.
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Sun, Ao, Mengshi Gao, Rong Guo, et al. "Abstract 2372: ATG-102, a novel LILRB4 x CD3 T cell engager, targeting two nonoverlapping epitopes of LILRB4, for the treatment of monocytic AML." Cancer Research 84, no. 6_Supplement (2024): 2372. http://dx.doi.org/10.1158/1538-7445.am2024-2372.
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Abstract Background: Acute myeloid leukemia (AML) is the most common acute leukemia in adults, and the treatment of AML, especially monocytic AML subtypes still has a poor outcome. T cell engagers (TCE) have been well used for the treatment of hematological malignancies, such as B cell leukemia and multiple myeloma. However, lack of ideal target antigens that only express on AML and leukemic stem cells (LSCs) but not on normal hematopoietic stem cells (HSCs) hampers the development of TCE therapy for AML. Leukocyte immunoglobulin-like receptor B4 (LILRB4), an inhibitory receptor belonging to the LILR family, is highly and restrictedly expressed on monocytic M4/M5 AML subtypes and LSCs, but not on normal HSCs which makes it an ideal target for TCE. Here we report a novel LILRB4 x CD3 bispecific T cell engager based on AnTenGagerTM platform, ATG-102. It targets two distinct epitopes of LILRB4, inducing potent T cell-dependent cellular cytotoxicity (TDCC) with low CRS, resulting in a potent anti-tumor efficacy in vitro and in vivo. Method: ATG-102 was constructed by introducing a high affinity anti-CD3 single chain fragment variable (scFv) to the hinge region of one of the heavy chains of a LILRB4 monoclonal antibody. A scFv targeting another epitope of LILRB4 was connected to the C terminal of the same heavy chain by GSSS linker, enabling a trivalent, dual epitope recognition of LILRB4. ATG-102 was evaluated in a series of preclinical studies for binding epitope and affinity, T cell activation, T cell dependent cytotoxicity (TDCC), and cytokine release. The in vivo antitumor efficacy of ATG-102 was evaluated in a humanized PBMCs and THP-1-luciferase cells engrafted NCG mice model. Results: ATG-102 binds to LILRB4 positive cells with a single-digit nM affinity. It binds to two distinct and nonoverlapping epitopes of LILRB4. ATG-102 showed limited binding capability to CD3+ cells before LILRB4 crosslinking. However, with the presence of LILRB4 positive THP-1 cell, ATG-102 strongly activated primary T cells, upregulating early and later markers of T cell activation, CD69 and CD25, respectively. ATG-102 induced strong TDCC against LILRB4-high expressing THP-1 cells, and it induced more potent TDCC against LILRB4-low expressing MOLM-13 cells than a benchmark antibody. While compared with benchmark, ATG-102 induced significantly lower release of IL-6, which is one of the major cytokines involved in cytokine release syndrome (CRS). In addition, ATG-102 demonstrated more potent in vivo anti-tumor efficacy compared with the benchmark antibody at 1 mg/kg and 0.1 mg/kg dose level in PBMC-humanized NCG mice bearing THP-1-luciferase cells. Conclusion: ATG-102 demonstrates trivalent, dual epitope recognition of LILRB4, conditionally redirects and activates T cells to recognize and kill monocytic AML cells. It demonstrates potent in vitro and in vivo anti-tumor efficacy with low risk of CRS. Citation Format: Ao Sun, Mengshi Gao, Rong Guo, Huiling Liu, Zaoshun Hu, Enlin Zheng, Hui Yuwen, Peng Chen, Jay Mei, Bo Shan, Bing Hou. ATG-102, a novel LILRB4 x CD3 T cell engager, targeting two nonoverlapping epitopes of LILRB4, for the treatment of monocytic AML [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 2372.
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Cai, Hui, Veronica Wendy Setiawan, Xingyi Guo, et al. "Abstract 468: Associations of circulating miRNAs with pancreatic cancer risk differ by years between blood collection & and cancer diagnosis." Cancer Research 84, no. 6_Supplement (2024): 468. http://dx.doi.org/10.1158/1538-7445.am2024-468.
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Abstract Pancreatic adenocarcinoma (PDAC) is one of the most fatal cancers and currently used biomarkers for PDAC diagnosis are not adequate for early detection. Therefore, new biomarkers for PDAC early detection are urgently needed. We conducted a large-scale study to prospectively evaluate the association of circulating miRNAs with PDAC risk. Specially, we aimed to examine whether the associations of miRNAs expression levels and changes of those levels from blood collection to cancer diagnosis (BCCD) with PDAC risk. We used pre-diagnostic plasma samples of 1307 PDAC cases from 5 cohort studies (290 from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, 395 from the Shanghai Women’s and Men’s Health Studies, 154 from the Southern Community Cohort Study, and 468 from the Multiethnic Cohort). Cancer free controls (n=1307) were selected and individually matched to index cases in each cohort. All miRNAs were measured by the NanoString nCounter Analysis System using the Human v3 miRNA Expression panel (798 miRNAs total). Data were pooled and quantile normalized prior to analysis. Associations of circulating miRNAs with PDAC risk were assessed by odds ratio per decile change in miRNA levels using conditional logistic regression. Fold-change of miRNA for cases versus controls by BCCD was analyzed via linear regression. Median time of BCCD was 7.13 years (range: 0.03-19.61 years). We first conducted the association analysis stratified by BCCD: < 5 years, 5-10 years, and >10 years. We found 20 miRNAs were significantly associated with PDAC risk in the <5 years after FDR correction. In the analysis of regressing fold-change of these 20 miRNAs on BCCD, we found the fold change of miR-155-5p was inversely associated with BCCD (β=-0.04, P<0.01), i.e., the case-control difference was larger when blood was drawn closer to PDAC diagnosis, suggesting its potential utility as disease biomarkers for early detection. Conversely, the fold-change of miR-93-5p (β=0.04, P=0.01), miR-223-3p (β=0.03, P=0.02), let-7i-5p (β=0.03, P<0.01), and miR-191-5p (β=0.05, P<0.01) were positively associated with BCCD, i.e., the case-control difference increased with an increasing the time interval of BCCD, indicating they are more likely biomarkers for PDAC risk. Ingenuity pathway analyses of these five significant miRNAs revealed that they were significantly enriched in ribonucleotide reductase signaling pathways at p<0.05. Notably, the silencing of ribonucleotide reductase M2 subunit suppresses tumorigenesis in pancreatic cancer by deactivating the PI3K/AKT/mTOR pathway, further supporting our findings. Findings of this large-scale multiethnic study suggest that changes in circulating levels of let-7i-5p, miR-155-5p, miR-93-5p, miR-191-5p, and miR-223-3p may help identify individuals at an elevated risk of developing PDAC, allowing for screening tests and close surveillance. Citation Format: Hui Cai, Veronica Wendy Setiawan, Xingyi Guo, Jie Wu, Rachael Z Stolzenberg-Solomon, Claire Zhu, Yu-Tang Gao, Jordan Berlin, Fei Ye, Qiuyin Cai, Wei Zheng, Xiao-ou Shu. Associations of circulating miRNAs with pancreatic cancer risk differ by years between blood collection & and cancer diagnosis [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 468.
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Guo, Yan, Judy Bai, Katherine Ma, et al. "Abstract 3505: Cancer disparities in race exposed through geospatial analysis of mutational signatures and environmental exposure." Cancer Research 83, no. 7_Supplement (2023): 3505. http://dx.doi.org/10.1158/1538-7445.am2023-3505.
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Abstract Background: Cancer has been disproportionally affecting minorities in the US due to socioeconomic, environmental, and genetic disparities. Cancer disparities are usually measured in incidence, mortality, survival, etc. Genomic-based cancer disparity analyses have been less common. In the past decade, mutational signatures were proposed as characteristic footprints of endogenous or exogenous carcinogens, which remarkably propelled the progress of genomic cancer research. The disparities caused by uneven exposure to environmental pollutants may be recorded in mutational signatures. Method: The Cancer Genome Altas is one of the richest genomic cancer datasets, empowering hundreds of secondary and tertiary cancer studies. One aspect of TCGA data that is seldomly utilized is geospatial information. Based on the contribution hospital location, we estimated the patients’ approximate location. Furthermore, utilizing data on 450 pollutants released by the Environmental Protection Agency from 2007-2017, we were able to establish associations between mutational signatures and certain pollutants. To remove the noise introduced by approximating the location and average pollution level, stringent statistical procedures were applied. Results: First, we showed that mutation frequencies varied substantially between different races. For example, TP53 was mutated in 46% of Black breast cancer patients, compared to 31% in Whites. Such differences in single genes translated to the level of mutational signatures. Liver cancer has aflatoxin as an affirmed carcinogen, and we compared the quantities of aflatoxin signature across races. It was found that aflatoxin contributed significantly higher (FDR = 0.002) to mutations in Asian than in Caucasians. In-depth analyses revealed that aflatoxin had a strong effect on hepatitis C virus infection in addition to the previously reported effect on hepatitis B virus infection. Similarly, as a known critical player in head and neck tumors, APOBEC signature was found at a significantly higher level (FDR = 0.01) in patients with positive infection of human papillomavirus. Furthermore, analyses from the geospatial perspective revealed several potential associations between pollutants and mutational signatures. For example, the pollutant carbofuran is positively associated with mutational signature SBS10a with the etiology of Polymerase epsilon exonuclease domain mutations (FDR = 0.02). Summary: We conducted a thorough mutational signature-based cancer disparity analysis. Our results reinforced previously known facts and expectations of oncogene mutations. The novel results demonstrated representative links between various forms of cancer disparity and genomic mutation footprints. Most importantly, such disparities can be interrogated at the mutational signature level and correlated to environmental pollutants. Citation Format: Yan Guo, Judy Bai, Katherine Ma, Shangyang Xia, Shuguang Leng, Hui Yu, Xi Gong. Cancer disparities in race exposed through geospatial analysis of mutational signatures and environmental exposure [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 3505.
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Liu, Yilin, Long Wang, Hui Shi, et al. "Abstract 4596: Targeting arginine methylome in 9p21/MTAP-deleted malignant cancers with a next generation PRMT5-specific inhibitor CTS3497." Cancer Research 84, no. 6_Supplement (2024): 4596. http://dx.doi.org/10.1158/1538-7445.am2024-4596.
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Abstract It remains largely challenging to treat cancer patients with chromosome 9p21-deletion which occurs in approximately 15% of human cancers. Recently, specific targeting of protein arginine methyltransferase 5 (PRMT5), a key member of the type-II PRMT family and a master epigenetic modulator of arginine methylome essential for cancer progression, has emerged as a promising therapy in various hematological and solid tumors with MTAP deletion serving as a precision biomarker. To optimize the potential of targeting PRMT5, we developed CTS3497, a potent, brain-penetrable, orally bioavailable MTA-cooperative PRMT5 inhibitor, using our EpigenPLUSTM platform. The overall excellent drug-like properties of CTS3497 support fast track IND application, and it is anticipated to enter Phase 1 trials in 2024. CTS3497 demonstrated potent PRMT5 inhibitory activity in cellular pharmacodynamics (PD) assays, evidenced by the suppression of symmetric dimethylarginine (SDMA). Additionally, it exhibited profound cell growth inhibition with a low single-digit nM IC50 and 171-fold high selectivity for MTAPnull over isogenic MTAPwt cell lines. Moreover, CTS3497 displayed strong inhibitory effects on cell growth across diverse panels of MTAPnull cancer cell lines and patient-derived xenograft organoids (PDXOs) spanning various lineages. In vivo, oral administration of CTS3497 resulted in significant tumor regression in multiple MTAP-deleted xenograft models, notably MTAPnull brain tumors. The observed anti-tumor activity correlated with PRMT5 modulation, as indicated by reduced SDMA levels. Impressively, sustained tumor growth inhibition led to the complete tumor regression, with no regrowth even after discontinuation of CTS3497 treatment. The brain penetration property of CTS3497 underscores its therapeutic potential for both primary brain tumors, and brain metastases arising from specific cancers like lung cancer. At the molecular level, PRMT5 inhibition by CTS3497 induced substantial and distinctive RNA splicing defects and differentially expressed gene signatures, impacting key cellular activities downstream of arginine and epigenetic reprogramming in MTAPnull cancer cells. Furthermore, a synergistic anti-tumor effect was observed in multiple MTAP-deleted tumors when combining PRMT5 inhibition with CTS2190, an investigational type-I PRMT inhibitor currently in phase I/II clinical trials. In summary, CTS3497, a PRMT5 inhibitor selectively targeting MTAPnull tumor cells, demonstrated robust and durable anti-tumor responses both in vitro and in vivo across diverse lineages of MTAP-deleted tumors. Its superior ADME properties and favorable safety profiles observed in preclinical studies mark a breakthrough in the next generation epigenetic therapy. CTS3497 emerges as a promising therapeutic option for patients with MTAP-deleted malignancies. Citation Format: Yilin Liu, Long Wang, Hui Shi, Yuanyuan Liu, Qiugeng Ouyang, Xingnian Fu, Meng Wang, Jiannan Guo, Yiqin Wang, Youzhen Wang, Guoliang Xu, Yuan Mi, Haiping Wu. Targeting arginine methylome in 9p21/MTAP-deleted malignant cancers with a next generation PRMT5-specific inhibitor CTS3497 [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 4596.
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Hau, Andrew M., Maria Shahmoradgoli, Dong Jun Lee, et al. "Abstract 1891: Preclinical characterization of ADRX-0706: A next-generation anti-Nectin-4 antibody-drug conjugate with improved therapeutic window." Cancer Research 84, no. 6_Supplement (2024): 1891. http://dx.doi.org/10.1158/1538-7445.am2024-1891.
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Abstract Nectin-4 is a well validated tumor target, which is highly expressed in several solid cancers such as urothelial, head-and-neck, breast, lung, pancreatic, ovarian, and cervical cancer, while expression in normal tissues is limited. A first-generation antibody-drug conjugate targeting Nectin-4, called enfortumab vedotin-ejfv (EV), was granted accelerated FDA approval in 2019 for urothelial cancers, and is currently approved for frontline therapy in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma, providing groundbreaking improvement in patient survival. However, clinical use of EV has also revealed safety-driven limitations, which result in reduced and/or interrupted drug exposures impacting efficacy. To overcome these limitations in therapeutic window and to maximize on the potential of Nectin-4 as a tumor target beyond urothelial cancers, Adcentrx has developed ADRX-0706, a Nectin-4-targeting next-generation ADC with a drug-antibody ratio of 8. ADRX-0706 is comprised of a novel fully human IgG1k monoclonal antibody linked to an optimized tubulin inhibitor payload AP052 through a proprietary cleavable linker. ADRX-0706 has strong binding affinity and selectively induces cytotoxicity in Nectin-4-expressing tumor cells. Importantly, ADRX-0706 is designed to have improved bystander effect, which allows tumor regression even in cases of heterogeneous Nectin-4 expression. This translates to superior in vivo efficacy of ADRX-0706 over EV in multiple mouse xenograft models of other indications beyond bladder cancer. In a mouse clinical trial of patient-derived cervical cancers with a range of Nectin-4 expression levels, ADRX-0706 reaches a 73% ORR. Since peripheral neuropathy is a main platform toxicity for this payload class, ADRX-0706 is assessed in an in vitro co-culture model to evaluate its neurotoxic potential. While EV displays a 75% decrease in neurite outgrowth, ADRX-0706 strikingly has no impact at concentrations up to 1mg/ml, suggesting a lower risk of peripheral neuropathy in humans for ADRX-0706. In preclinical repeat dose toxicology study, ADRX-0706 reaches an HNSTD of 18mg/kg in NHPs well above therapeutic exposures in mouse pharmacology studies, indicating a tremendous increase in the therapeutic index compared to EV. In summary, the highly selective and potent anti-tumor activity in multiple tumor types and wide preclinical therapeutic index of ADRX-0706 support clinical evaluation of this next generation anti-Nectin-4 ADC. ADRX-0706 is currently in a phase 1a/b study (NCT06036121). Citation Format: Andrew M. Hau, Maria Shahmoradgoli, Dong Jun Lee, Wes Sisson, Anna Wang, Peter P. Challita, Erin Nye, Mario M. Kuo, Alexis Mahloch, Monica Leung, Oscar Betancourt, Alexander Chu-Kung, Maojun Guo, Hui Li, Sabine Rottmann, Pia M. Challita-Eid. Preclinical characterization of ADRX-0706: A next-generation anti-Nectin-4 antibody-drug conjugate with improved therapeutic window [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 1891.
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Wang, Jianwei, Kun Wang, Tianling Qin, et al. "Analysis and prediction of LUCC change in Huang-Huai-Hai river basin." Open Geosciences 12, no. 1 (2020): 1406–20. http://dx.doi.org/10.1515/geo-2020-0112.
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AbstractLand use/cover change plays an important role in human development and environmental health and stability. Markov chain and a future land use simulation model were used to predict future change and simulate the spatial distribution of land use in the Huang-Huai-Hai river basin. The results show that cultivated land and grassland are the main land-use types in the basin, accounting for about 40% and 30%, respectively. The area of cultivated land decreased and artificial surfaces increased from 1980 to 2010. The degree of dynamic change of land use after the 1990s was greater than that before the 1990s. There is a high probability of exchange among cultivate land, forest and grassland. The area of forest decreased before 2000 and increased after 2000. Under the three emission scenarios (RCP2.6, RCP4.5, and RCP8.5) of IPSL-CM5A-LR climate model, the area of cultivated land will decrease and that of grassland will increase in the upstream area while it will decrease in the downstream area. The above methods and rules will be of great help to future land use planning.
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Yin, Zheng, and Kim Tae-Man. "≪Hai Guo Tu Zhi≫ and Weiyuan‘s Marine Awareness." Chinese Studies 67 (June 30, 2019): 323–36. http://dx.doi.org/10.14378/kacs.2019.67.67.18.
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Hou, Bing, Hui Xie, Shengyue Piao, Zhi Guo, Bo Shan, and Jay Mei. "Abstract 4032: Identification of Muc5B mutation as a positive predictive biomarker for mTORC1/2 inhibition by ATG-008 in lung cancer." Cancer Research 82, no. 12_Supplement (2022): 4032. http://dx.doi.org/10.1158/1538-7445.am2022-4032.
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Abstract Background: mTOR is a serine/threonine kinase that regulates cell growth, metabolism, proliferation, and survival. mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2) are critical mediators of the PI3K-AKT pathway. Signaling by the PI3K/AKT/mTOR pathway is frequently deregulated in solid tumors and hematological malignancies. Inhibition of mTOR by small molecule inhibitors has therefore attracted great attention as an anti-cancer therapy. However, due to relatively modest clinical efficacy, no mTOR inhibitor has been approved for the treatment of lung cancer. The research of potentially predictive biomarkers is a key aspect of all anti-tumor treatment strategies to improve the proportion of patients benefiting from therapy. Multiple genetic alternations have been reported to be correlated with better anti-tumor efficacy of mTOR inhibition in animal models or patients, such as NFE2L2 mutation, STK11 mutation, or RICTOR amplification. Here, we report Muc5B mutation as a positive predictive biomarker for mTORC1/2 inhibition by ATG-008 (Onatasertib), a dual mTORC1/2 kinase inhibitor, in preclinical lung cancer models. Methods: 31 different lung cancer cell lines were treated with ATG-008 in vitro to determine the dose-response curves and the Area Under Curve (AUC) values. According to the AUC, the cell lines were classified as a sensitive group, medium group, and insensitive group. Unbiased genomic analysis of the tested cell lines was used to correlate the gene mutation, amplification, and expression with the sensitivity to ATG-008. The potential positive predictive biomarker, MUC5B mutation, was further validated in lung cancer CDX mouse models. Mouse bearing lung cancer cell lines with or without MUC5B mutation were orally treated with ATG-008 to determine the in vivo tumor growth inhibition. Results: ATG-008 inhibits lung cancer cell growth in vitro, with IC50 values ranging from 0.36µM to >10µM. By genomic analysis, we identified 23 genes with a significant difference in AUC values between mutant and wild type cell lines, among which MUC5B mutation was found in 7/10 sensitive cell lines and only 2/10 in insensitive cell lines. Cell lines that carried MUC5B mutation had significantly lower AUC compared with MUC5B wild type cell lines (p=0.0084). Oral dosing of ATG-008, 10mg/kg, QD, induced potent tumor growth inhibition(TGI) in MUC5B mutant CDX models, with 53.2% TGI in NCI-H82 model and 81.9% TGI in SK-MES-1 model. However, in MUC5B wild type models, the TGI is only 20.5% in NCI-H209 model and 36% in NCI-H526. Conclusion: These results suggest that the presence of MUC5B mutation correlates with more potent anti-tumor efficacy of ATG-008, potentially serving as a positive predictive biomarker for patient enrichment that warrants further investigation in the clinic. Citation Format: Bing Hou, Hui Xie, Shengyue Piao, Zhi Guo, Bo Shan, Jay Mei. Identification of Muc5B mutation as a positive predictive biomarker for mTORC1/2 inhibition by ATG-008 in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4032.
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Huang, Yuanyuan, Hangbo Ye, Qingliang Yang, et al. "Abstract 5820: An antibody drug conjugate platform based on novel camptothecin payloads with branch hydrophilic linkers and site-specific conjugation." Cancer Research 84, no. 6_Supplement (2024): 5820. http://dx.doi.org/10.1158/1538-7445.am2024-5820.
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Abstract Antibody-drug conjugates (ADCs) have recently gained momentum as a therapeutic modality for the cell-specific delivery of small molecules beyond their originally-intended purpose of treating cancer. However, the selection of combinations of an optimum target, antibody, payload, linker as well conjugation, to achieve maximal therapeutic efficacy without excessive toxicity, still presents a significant challenge. Topoisomerase I (Topo I) inhibitors such as camptothecin (CPT) analogs represent the much success in ADC payload applications as two CPT analog-ADCs, trastuzumab deruxtecan (DS-8201a—Enhertu®) with Dxd payload and sacituzumab govitecan (TrodelvyTM) with SN38 payload have been approved and over 20 CPT analog-ADCs are in the clinical trials now. Topo I inhibitors trigger cell apoptosis through their specific binding at the DNA-topoisomerase interface, leading to the inhibition of DNA supercoiling and entanglement, resulting in DNA damage and cell death. This class of payloads in ADCs has demonstrated more wider therapeutic windows in clinical trials than regular antitubulin payloads, such as maytansine and MMAE, based ADCs. Here, we detail the discovery of CPT analogs, as payloads with a branch hydrophilic linker and site-specific conjugation for ADCs designed to have a widened therapeutic window compared with Dxd-GGFG linked ADCs. The CPT analogs based on the core structure of SN-38, wherein the hydrogen of C-11 was replaced with fluorine, and the hydroxyl group of C-10 was optionally replaced with an amino or a ether group. Many of the novel CPT analogs were at single to tens of pM of IC50 potency in vitro against several tested tumor cell lines, and some were more potent than Exatecan in the comparison tests. The ADCs constructed with branch hydrophilic linkers and the CrossConjuTM technology of chemically site-specific conjugation at Fab region of an antibody through C-10 position of the CPT payloads either with amide bond, either bond or carbamide bonds, or through C-20 position of the CPT payloads with carbamide or carbonate bonds, exhibited much better antitumor efficacy in vivo CDX tumor models, while having higher or similar MTDs in mice toxicity study in comparison with the ADC constructed with GGFG-Dxd, demonstrated wider therapeutic widows than that conjugated with GGFG-Dxd. Moreover, some of the constructed ADCs can overcomes in vitro- and in vivo-acquired resistance of commercial therapeutic drugs. Herein, we showcase our platform approach in CPT-ADC designs and constructions and can be thereby broadly applicable to construction of various CPT-ADCs for targeted treatment of cancers. Citation Format: Yuanyuan Huang, Hangbo Ye, Qingliang Yang, Lingli Zhang, Huihui Guo, Xiaolei Liu, Wenjun Li, Lu Bai, Junxiang Jia, Juan Wang, Xiangfei Kong, Jun Zheng, Yifang Xu, Gengxiang Zhao, Linyao Zhao, Xiang Cai, Ziyu Zhao, Hui Xia, Xia Zhou, You Zhou, Robert Y. Zhao. An antibody drug conjugate platform based on novel camptothecin payloads with branch hydrophilic linkers and site-specific conjugation [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 5820.
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Lee, Ming J. "Dr. Xian-Hua Gao." Clinical Anatomy 7, no. 3 (1994): 167–68. http://dx.doi.org/10.1002/ca.980070311.
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Mao, Lili, Jun Guo, Lingjun Zhu, et al. "Abstract CT519: FCN-159, a MEK1/2 inhibitor, in patients with advanced melanoma harboring NRAS mutations: A phase 1A dose-escalation study." Cancer Research 82, no. 12_Supplement (2022): CT519. http://dx.doi.org/10.1158/1538-7445.am2022-ct519.
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Abstract Purpose: No targeted therapy has been approved for NRAS-mutant melanoma. We evaluated the safety and tolerability and determined the recommended phase 2 dose (RP2D) of FCN-159, a selective MEK1/2 inhibitor, in patients with NRAS-mutant advanced melanoma. Methods: This single-arm, open-label, dose-escalation, phase 1A study in China (NCT03932253) enrolled patients with unresectable stage III/IV melanoma harboring NRAS mutations. Patients received FCN-159 in doses escalating from 0.2 mg until the maximum tolerated dose (MTD). Oral FCN-159 was given once in the single-dose period and once daily (QD) in 28-day cycles in the continuous-dose period. The primary endpoint was the incidence of dose-limiting toxicity (DLT). Results: As of September 16, 2021, 33 patients were enrolled and received 0.2-15 mg FCN-159. All patients had received systemic treatments. One DLT event (grade 3 folliculitis) occurred in the 15 mg group, and no DLT occurred at other dose levels; MTD was defined as 15 mg QD. Grade ≥3 treatment-emergent adverse events (TEAEs) deemed related to FCN-159 were reported in 5 (15.2%) patients across dose levels; stomatitis (2; 6.1%) was the most common. No FCN-159-related TEAEs were serious or led to treatment discontinuation. Among 21 patients assigned to doses ≥6 mg, 4 had investigator-confirmed objective responses (objective response rate, 19.0%; 95% confidence interval [CI], 5.4-41.9); all were partial responses (Table). Median DOR was 4.8 months (95% CI, 2.8-NE). Seven patients had SD (CBR, 52.4%; 95% CI, 29.8-74.3). Median progression-free survival was 3.8 months (95% CI, 1.8-5.6). FCN-159 12 mg QD was determined to be the RP2D per assessment of safety, antitumor activity, and pharmacokinetic data. Conclusion: FCN-159 was well tolerated and showed antitumor activity in patients with NRAS-mutant advanced melanoma. FCN-159 12 mg QD as a treatment for NRAS-mutant advanced melanoma warrants future investigation. Tumor response was assessed by the investigators according to Response Evaluation Criteria in Solid Tumors version 1.1.BOR, best overall response; CBR, clinical benefit rate; CR, complete response; DOR, duration of response; NA, not applicable; NE, not evaluable; NR, not reached; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease. Table. Confirmed best overall response 6 mg(n = 5) 8 mg(n = 4) 12 mg(n = 6) 15 mg(n = 6) Total(N = 21) Confirmed BOR, n (%) CR 0 0 0 0 0 PR 2 (40.0) 1 (25.0) 0 1 (16.7) 4 (19.0) SD 1 (20.0) 1 (25.0) 3 (50.0) 2 (33.3) 7 (33.3) PD 2 (40.0) 2 (50.0) 1 (16.7) 2 (33.3) 7 (33.3) NE 0 0 2 (33.3) 1 (16.7) 3 (14.3) ORR, n (%), 95% CI 2 (40.0), 5.3–85.3 1 (25.0), 0.6–80.6 0 1 (16.7), 0.4–64.1 4 (19.0), 5.4–41.9 CBR, n (%), 95% CI 3 (60.0), 14.7–94.7 2 (50.0), 6.8–93.2 3 (50.0), 11.8–88.2 3 (50.0), 11.8–88.2 11 (52.4), 29.8–74.3 Median DOR (95% CI), months 4.8 (2.8–NE) NR (NE–NE) NA NR (NE–NE) 4.8 (2.8–NE) Citation Format: Lili Mao, Jun Guo, Lingjun Zhu, Yu Jiang, Wangjun Yan, Jian Zhang, Ai-min Hui, Zhuli Wu, Yuchen Yang, Han Zhao, Yiqian Jiang, Lu Si. FCN-159, a MEK1/2 inhibitor, in patients with advanced melanoma harboring NRAS mutations: A phase 1A dose-escalation study [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 CT519.
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Li, Jun, Chengshan Niu, Zhongwei Guo, et al. "Abstract 4488: TY-4028: a novel, targeted therapy for non small-cell lung cancer with EGFR exon 20 or HER2 exon 20 insertion mutations." Cancer Research 83, no. 7_Supplement (2023): 4488. http://dx.doi.org/10.1158/1538-7445.am2023-4488.
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Abstract Epidermal growth factor receptor (EGFR) activating mutations represent major drivers to the development of non-small cell lung cancer (NSCLC). Among the oncogenic EGFR mutations, a significant cohort, counting for approximately 4-10% of the EGFR mutation spectrum, bear EGFR exon 20ins mutations. Meanwhile, approximately 2% of NSCLC patients bear hotspot mutations in HER2. Strikingly, over 90% of the HER2 mutations occurred in NSCLC are identified as exon 20ins mutations. Despite the successful launch of 1st, 2nd, and 3rd generation of EGFR inhibitory agents in the clinic that inactivate oncogenic EGFR signaling through targeting specific EGFR mutations, de novo or acquired, none of these standard-of-care therapies is specific to EGFR exon 20ins or HER2 exon 20ins. In addition, trastuzumab and EGFR-TKIs have limited effectiveness for NSCLC patients with HER2 exon 20ins mutation. TAK-788 (mobocertinib) and JNJ6372 (amivantamab-vmjw) are the FDA approvals for NSCLC driven by EGFR exon 20ins mutations. Only T-Dxd is used as a second-line treatment for NSCLC patients with HER2 mutation. Considering the large population of lung cancer and the fact that many patients are missed in diagnosis due to the heterogeneous characteristics of EGFR and Her2 exon 20ins, there are probably more than ten thousand lung cancer patients suffering the EGFR or Her2 exon 20ins mutations. There are urgent unmet medical needs to develop target therapeutics for EGFR and Her2 exon 20ins mutations. We discovered and developed TY-4028, which is a novel, potent, and orally available inhibitor targeting EGFR and Her2 exon 20ins mutations and is currently in the IND enabling stage. In EGFR-related tumor cells and genetically engineered Ba/F3 cell lines, TY-4028 showed similar or better antitumor effects than TAK-788, and better antitumor effects than DZD9008. The B/P ratio (brain tissue AUC0-last/plasma AUC0-last) of SD rats was 1.63 and 1.04 respectively after oral administration of TY-4028 in male and female SD rats, which suggested that TY-4028 had good potential to cross Blood Brain Barrier (BBB). Preclinical studies showed a good PK profile and manageable toxicity with TY-4028. TY-4028 has remarkable efficacy in mouse models of EGFR exon 20ins and HER2 exon 20ins. The data showed that all doses of TY-4028 had significant effects, and the tumors nearly demonstrated complete regression in the PDX LU0387 model and PC9 CDX model. At the same dose, the efficacy of TY-4028 was similar to that of TAK-788, while the tolerance of TY-4028 was better than that of TAK-788. At the same dose, the efficacy of TY-4028 was better than that of DZD9008. Taken together, the data demonstrated TY-4028 has great potential to meet the unmet medical needs for NSCLC patients with EGFR exon 20ins mutation or HER2 exon 20ins mutation. #Jun Li and Chengshan Niu contributed equally to this work. *They are the correspondent authors. Citation Format: Jun Li, Chengshan Niu, Zhongwei Guo, Huan Wang, Bailu Zheng, Yuge Dou, Apeng Liang, Kaige Ji, Shengli Dong, Meihua Li, Yanchao Zhao, Yazhen Zhang, Aishen Gong, Hao Liu, Xinmiao Hu, Hui Su, Mingyu Jiang, Shaoqing Chen, Xiugui Chen, Yusheng Wu. TY-4028: a novel, targeted therapy for non small-cell lung cancer with EGFR exon 20 or HER2 exon 20 insertion mutations. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4488.
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Qin, Shukui, Xiaoyan Lin, Zhiqaing Meng, et al. "Abstract CT150: Result of an open-label phase 2 trial of dual TORC1/TORC2 inhibitor onatasertib (ATG-008) in HBV+ advanced hepatocellular carcinoma (HCC) subjects who have received at least one prior line of systemic therapy (TORCH)." Cancer Research 83, no. 8_Supplement (2023): CT150. http://dx.doi.org/10.1158/1538-7445.am2023-ct150.
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Abstract Background: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase related to the lipid kinases of the phosphoinositide 3-kinase (PI3K) family, which has been confirmed to be closely related to the development of a variety of human cancers. Onatasertib (ATG-008) is a 2nd generation mTOR inhibitor which inactivates both mTORC1 and mTORC2. Our previous clinical investigation (NCT01177397) has demonstrated preliminary evidence of antitumor activity of onatasertib across multiple solid and hematologic malignancies, with encouraging signals of activity in subjects with hepatitis B virus (HBV)+ unresectable, refractory HCC. Methods: Asian patients with advanced HBV+ HCC who had experienced progressive disease after at least 1 line of systemic therapy were enrolled in this study. Onatasertib was administered orally once a day (QD) at 3 dose levels (15 mg, 30 mg and 45 mg) or 20 mg twice daily (BID). The primary endpoints were pharmacokinetics (PK), safety and efficacy (NCT03591965). Results: As of July 11, 2022, 73 patients were enrolled and evaluated. The median age was 52.0 years and the median follow up duration was 26.5 months. The mean number of prior lines was 1.8. 63 patients (86.3%) had at least one Grade 3-4 treatment emergent adverse event (TEAE), and 25 (34.2%) had at least one serious adverse event (SAE). Among the 73 subjects, 3 achieved confirmed partial response (PR), all in the 45 mg QD cohort. 18 pts were enrolled in the 45 mg QD cohort, in which 11 (61.1%) pts had received at least 2 prior lines of systemic therapy and 15 (83.3%) pts had been exposed to an anti-PD-1/PD-L1 antibody. The overall response rate (ORR) in the 45 mg QD cohort was 16.7%. The median progression-free survival (mPFS) was 3.0 months (95% CI 1.9, 4.6) in the intention to treat (ITT) population and was 5.3 months (95% CI 1.9, 7.6) in the 45mg QD cohort. Median overall survival time (mOS) was not evaluable in the 45 mg QD cohort and the mOS was 13.4 months (95% CI 7.4, 19.8) in the ITT population. Onatasertib demonstrated linear pharmacokinetics between 15 mg QD and 45 mg QD in this Asian population and there was no significant exposure accumulation after multiple dosing, as previously seen in the US population. Conclusion: Onatasertib (ATG-008) showed encouraging single agent antitumor activity in patients with HBV+ advanced HCC after at least 1 prior systemic therapy, notably in the 45 mg QD dose level, in which most patients had been previously exposed to anti-PD-L1/PD-1 therapy. The results indicates that onatasertib has potential efficacy in HBV+ HCC patients who failed prior CPI treatment. Further study may be warranted, particularly in HBV+ HCC patients who have failed prior anti-VEGFR and anti-PDL1/PD-1 therapy. Citation Format: Shukui Qin, Xiaoyan Lin, Zhiqaing Meng, Zhenggang Ren, Yuxian Bai, Shanzhi Gu, Li Zheng, Qiu Li, Sun-Yong Oh, Yabing Guo, Yoong-Koo Kang, Wei-Yu Kao, Wei Li, Jung-Hwan Yoon, Helong Zhang, Pei-Jer Chen, Tsai-Sheng Yang, Jeong Heo, Zhendong Zheng, Hui Xie, Zhinuan Yu. Result of an open-label phase 2 trial of dual TORC1/TORC2 inhibitor onatasertib (ATG-008) in HBV+ advanced hepatocellular carcinoma (HCC) subjects who have received at least one prior line of systemic therapy (TORCH) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT150.
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Xu, Shuai, Yaohua Yang, Tianying Zhao, et al. "Abstract LB146: Multi Omics analyses identified novel loci and genes for lung cancer risk among European Descendants." Cancer Research 84, no. 7_Supplement (2024): LB146. http://dx.doi.org/10.1158/1538-7445.am2024-lb146.
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Abstract Introduction Genome-wide association studies (GWAS) have identified >60 genomic loci for lung cancer risk. However, causal genes and the underlying biological mechanisms for most of these loci remain unknown. Therefore, we conducted a multi-omics study to identify lung cancer susceptibility genes. Method We first conducted a transcriptome-wide association study (TWAS) using S-PrediXcan framework. Whole transcriptome data from adjacent-normal lung tissue samples and genomic data from 304 European-ancestry lung cancer patients were used to build genetic prediction models for expression levels of protein-coding genes and lincRNAs. The prediction models were then applied to GWAS meta-analysis results for lung cancer with 39,363 cases and 621,480 controls of European descents from TRICL-ILCCO, the UK Biobank, and FinnGen. COJO was used to assess whether those significant genes were independent of proximal (±1.5 Mb) GWAS-identified risk variants. To replicate our TWAS-identified genes, we used data from GTEx version 8 normal lung tissue (N=444) to build imputation models and then run association analyses. We acquired gene (N=107) and protein expression data (N=111) from tumor and matched adjacent-normal lung tissues from European-ancestry participants in the Clinical Proteomic Tumor Analysis Consortium. Paired Wilcoxon rank sum tests were then conducted to assess whether identified genes and their corresponding proteins were expressed differentially. Results Out of 18,850 genes (read count >6 and TPM >0.1 in at least 20% samples), 6,754 protein-coding genes and 802 lincRNAs were predicted reliably using genetic variants (R>0.1 and P<0.05). Among them, genetically proxied expression levels of 24 genes located at 15 loci were significantly associated with lung cancer risk at a Bonferroni adjusted P <0.05. Four genes were located at four novel loci, including SERF1A at 5q13.2, SMIM33 at 5q31.2, MUC5B at 11p15.5, and RASSF10 at 11p15.2. Six putative candidate genes, namely H4C13, HCP5B, STN1, COPS2, SKIV2L, and LINC00243 resided in previously GWAS-identified lung cancer loci but have not been reported. Of these six genes, SKIV2L (Padjust=1.49e-5) and LINC00243 (Padjust=3.47e-5) were independently associated with lung cancer risk even after adjusting for GWAS-identified variants. Among 24 identified genes, 16 showed a consistent significant association with lung cancer risk (p<0.05) based on the prediction models built using GTEx data. Of ten unreported or novel genes, MUC5B, SMIM33, SERF1A, STN1, COPS2, and LINC00243 showed differential gene expression at P <0.05 and consistent association direction with TWAS results. Three proteins, STN1, COPS2, and SKIV2L, showed differential expression in tumor and adjacent-normal tissue at P<0.05, which is consistent with our TWAS direction. Conclusion Our findings offer novel insights into lung cancer carcinogenesis by uncovering new genes and loci. Citation Format: Shuai Xu, Yaohua Yang, Tianying Zhao, Jiajun Shi, Jie Ping, Wanqing Wen, Hui Cai, Xingyi Guo, Ran Tao, Xiao-Ou Shu, Wei Zheng, Jirong Long, Qiuyin Cai. Multi Omics analyses identified novel loci and genes for lung cancer risk among European Descendants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB146.
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ZAGORODNYUK, Pavlo, and Andriy ZAGORODNYUK. "FROM NADRA GROUP TO GEO HUB." Ukrainian Geologist, no. 1-2(44-45) (June 30, 2021): 6–33. http://dx.doi.org/10.53087/ug.2021.1-2(44-45).238797.
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NADRA Group was founded in 1991 by Ukrainian geologists. Over time, NADRA Group has transformed into an international group of affiliated service companies that provided high-tech services to production companies. NADRA Group has employed more than one and a half thousand employees, and then the International Hub for natural resources was established on its basis, which brought together hundreds of partner companies, which led to the transition from linear to network business and signifi cantly expanded the activities. Subsequently, the activity of NADRA Group has spread to all natural capital and overcoming environmental and social challenges of the XXI century. Signifi cant expansion of the company’s business has led to the transition to the platform business and re-branding of the company into GEO Hub. Throughout its 30 years of operation, the company has worked in the stressful conditions of the transition from a planned to a market economy, being able to mobilize in time and systematically demonstrate new opportunities, concentrating on the new and achieving what was previously considered impossible.
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Sato, M. "Bei Yi-hui de Ge-ming Qing-jie--Zai Zhong-ri Liang-guo Cong-shi Ge-ming de Li-cheng (Kita Ikki's Radical Complex: The Course of His Involvement in Chinese and Japanese Revolutions), by Huang Tzu-chin. Taipei: Academia Sinica, 2001, 350 pp., NT$350 (hardcover ISBN 957-671-755-8), 341 pp., NT$300 (paperback ISBN 957-671-756-6)." Social Science Japan Journal 8, no. 1 (2004): 131–33. http://dx.doi.org/10.1093/ssjj/jyh046.
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Aradpour, Saber, Roohollah Noori, Qiuhong Tang, et al. "Metal contamination assessment in water column and surface sediments of a warm monomictic man-made lake: Sabalan Dam Reservoir, Iran." Hydrology Research 51, no. 4 (2020): 799–814. http://dx.doi.org/10.2166/nh.2020.160.
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Abstract In this study, metal concentrations in the water column and surface sediment of the Sabalan Dam Reservoir (SDR) were determined. Moreover, heavy metal pollution index (HPI), contamination index (CI), heavy metal evaluation index (HEI), enrichment factor (EF), geo-accumulation index (Igeo), sediment quality guidelines (SQGs), consensus-based SQGs (C-BSQGs), and mean probable effect concentration quotients (mPECQs) were evaluated for water and sediments of SDR. It was observed that metal concentrations in river entry sediment were lower, but those in river entry water were higher than corresponding values in the vicinity of the dam structure. The HPI values of water samples taken from 10 m depth in the center of SDR exceeded the critical limit, due to high concentrations of arsenic. However, according to CI, the reservoir water was not contaminated. The HEI values indicated contamination of SDR water with metals at 10 m depth. A comparison of water quality indices revealed that HEI was the most reliable index in water quality assessment, while CI and HPI were not sufficiently accurate. For SQGs, As and Cu concentrations in sediments were high, but mPECQ, Igeo, and EF revealed some degree of sediment pollution in SDR. The calculated EF values suggested minor anthropogenic enrichment of sediment with Fe, Co, V, and Ni; moderate anthropogenic enrichment with As and Mn; and moderate to severe anthropogenic enrichment with Cu. A comparison of SQG values revealed that the threshold effect and probable effect levels were the most reliable metrics in the assessment of sediment toxicity. Statistical analysis indicated similarities between metal concentrations in the center of the reservoir and near to the dam structure, as a result of similar sediment deposition behavior at these points, while higher flow velocity at the river entry point limited deposition of fine particles and associated metals.
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Wang, Haihui, Fika Tri Anggraini, Xuequn Chen, and Donald J. DeGracia. "Embryonic lethal abnormal vision proteins and adenine and uridine-rich element mRNAs after global cerebral ischemia and reperfusion in the rat." Journal of Cerebral Blood Flow & Metabolism 37, no. 4 (2016): 1494–507. http://dx.doi.org/10.1177/0271678x16657572.
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Prolonged translation arrest correlates with delayed neuronal death of hippocampal CA1 neurons following global cerebral ischemia and reperfusion. Many previous studies investigated ribosome molecular biology, but mRNA regulatory mechanisms after brain ischemia have been less studied. Here we investigated the embryonic lethal abnormal vision/Hu isoforms HuR, HuB, HuC, and HuD, as well as expression of mRNAs containing adenine and rich uridine elements following global ischemia in rat brain. Proteomics of embryonic lethal abnormal vision immunoprecipitations or polysomes isolated from rat hippocampal CA1 and CA3 from controls or following 10 min ischemia plus 8 h of reperfusion showed distinct sets of mRNA-binding proteins, suggesting differential mRNA regulation in each condition. Notably, HuB, HuC, and HuD were undetectable in NIC CA1. At 8 h reperfusion, polysome-associated mRNAs contained 46.1% of ischemia-upregulated mRNAs containing adenine and rich uridine elements in CA3, but only 18.7% in CA1. Since mRNAs containing adenine and rich uridine elements regulation are important to several cellular stress responses, our results suggest CA1 is disadvantaged compared to CA3 in coping with ischemic stress, and this is expected to be an important contributing factor to CA1 selective vulnerability. (Data are available via ProteomeXchange identifier PXD004078 and GEO Series accession number GSE82146).
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Minglu, Gao, Madeline Eschenburg, Ellen Larson та Dong Li Hui. "The Round Table 02 圆桌: A Conversation with the No Name Painting Group". Contemporaneity: Historical Presence in Visual Culture 4 (3 серпня 2015): 177–89. http://dx.doi.org/10.5195/contemp.2015.155.
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The following is a transcript of a conversation between three members of the No Name Painting Group, as well as Gao Minglu, Madeline Eschenburg, Ellen Larson, and Dong Li Hui. This interview was originally conducted in Chinese and has been edited for clarity.
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Metri, Vishal, Sandhya Rai, and Nicholas J. Laycock. "An Electrocrystallization Approach for Modeling Protective Scale Formation in CO2 Corrosion of Carbon Steel." ECS Meeting Abstracts MA2023-02, no. 11 (2023): 1069. http://dx.doi.org/10.1149/ma2023-02111069mtgabs.
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The CO2 corrosion of carbon steel has been extensively studied and many models have been developed to estimate the corrosion rate in various industrially relevant conditions [1]. These models agree moderately well in non-scaling environments but can produce significantly different results under higher temperature and higher pH conditions where protective scales of iron carbonate may be formed [2,3]. The scaling effect is typically incorporated in empirical models using a ‘scaling factor’ [2,3]. Nesic and co-workers developed a model that attempts to calculate the corrosion rate in scaled conditions from first principles [4,5,6], later including a numerical model to describe the formation kinetics and growth morphology of the surface layer [7]. In this and other models, the driving force for scaling is the degree of supersaturation (S) of FeCO3 at the steel surface, and it is generally assumed that protective films are formed by precipitation from solution, at a rate dependent on S [7,8,9]. To investigate the formation and structure of these surface scales, Williams and colleagues [10-14] completed a series of experiments using in-situ synchrotron x-ray techniques. The majority of this work accelerated the corrosion process through the application of a small anodic potential step, and focused on solutions of moderate chloride content, saturated with CO2 at ~ 1 bar, pH adjusted to ~ 6 and at temperatures of ~ 80 °C. Small Angle X-Ray Scattering (SAXS) showed that the first stage in scaling was the formation of a precipitated layer of Amorphous Ferrous Carbonate (AFC) [13], while X-Ray Diffraction (XRD) revealed that the reduction of corrosion rate was associated with the slower formation of crystalline siderite (FeCO3) and sometimes chukanovite (Fe2(OH)2CO3) (see Figure 1). Hassan et al [14] then developed a model for this process in which the protective scale forms directly on the steel surface by an electrocrystallization mechanism, using an Avrami model to describe the crystal nucleation and growth. The relative volume of siderite as a function of time was fitted with an Avrami-like equation. The anodic current transients formed during potentiostatic experiments (see Figure 1) were then fitted with separate components due to iron dissolution and electrocrystallization, allowing various kinetic parameters to be extracted from the experimental data. In this paper, we extend these previous ideas on the importance of considering electrocrystallization as a fundamental step in the scale formation process. There exist several models of the potentiostatic current time transient in the electrocrystallization literature [15,16]. Taking the potentiostatic data from Hassan et al [14], we fit the current time transient to some models from literature [15,16]. This fitting provides rich information about the kinetics of nucleation. We speculate on some differences from the models in Luo et al [15] by current transient fitting. We also provide expressions for surface coverage of siderite under different applied potentials with the Avrami equation to account for the scale protection factor more rigorously. Improved estimates of the protection factor by our methods can lead to reduced overestimation of corrosion rates thereby improving pipeline integrity assessments in existing software packages. References Kermani, A. Morshed, Corrosion 59 (2003) 659–683. Nyborg, NACE 02233, Corrosion 2002, OnePetro 2002. Nyborg, NACE 10371, Corrosion 2010, OnePetro 2010. Nešić, M. Nordsveen, R. Nyborg, A. Stangeland, Corrosion 59 (2003) 489–497. Nordsveen, S. Nešić, R. Nyborg, A. Stangeland, Corrosion 59 (2003) 443–456. Nesic, K.-L.J. Lee, V. Ruzic, NACE 02237, Corrosion (2002). Sun, S. Nešić, Corrosion 64 (2008) 334-346. L. Johnson, M.B. Tomson, Paper No. 268, CORROSION/91, NACE International, 1991. Van Hunnik, Pots,Hendriksen NACE 96006, Corrosion(1996). Ingham, M. Ko, G. Kear, P. Kappen, N. Laycock, J. A. Kimpton, D. E. Williams, Corrosion Science, 52, 3052-3061 (2010). Ingham, M. Ko, N. Laycock, J. Burnell, P. Kappen, J. A. Kimpton,D. E. Williams, Corrosion Science, 56, 96-104 (2012). Ko, B. Ingham, N. Laycock,D.E. Williams, Corrosion Science, 90, 192-201 (2015). Ingham, M. Ko, N. Laycock, N. Kirby and D.E. Williams, Faraday Discussions, 180, 171-190 (2015). Hassan Sk, A.M. Abdullah, M. Ko, B. Ingham, N. Laycock, D.E. Williams, Corrosion Sci., 126, 26–36 (2017). Gong Luo, Yuan Yuan, De-Yu Li, Ning Li, Guo-Hui Yuan, Coatings 2022, 12(8), 1195. Bewick, H.R. Thirsk, M. Fleischmann, Trans. Faraday Soc. 58 (1962) (2200- &). Figure 1
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Mohammed Hameed, Hasan. "SOIL EROSION ASSESSMENT WITHIN THE ERBIL WATERSHED USING GEO-INFORMATICS TECHNOLOGY." Halabja University Journal 6, no. 1 (2016): 311–29. http://dx.doi.org/10.32410/huj-10375.
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Li, Nanxi, Peng Ren, Jingya Wang, et al. "Immune-Related Molecules CD3G and FERMT3: Novel Biomarkers Associated with Sepsis." International Journal of Molecular Sciences 25, no. 2 (2024): 749. http://dx.doi.org/10.3390/ijms25020749.
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Sepsis ranks among the most common health problems worldwide, characterized by organ dysfunction resulting from infection. Excessive inflammatory responses, cytokine storms, and immune-induced microthrombosis are pivotal factors influencing the progression of sepsis. Our objective was to identify novel immune-related hub genes for sepsis through bioinformatic analysis, subsequently validating their specificity and potential as diagnostic and prognostic biomarkers in an animal experiment involving a sepsis mice model. Gene expression profiles of healthy controls and patients with sepsis were obtained from the Gene Expression Omnibus (GEO) and analysis of differentially expressed genes (DEGs) was conducted. Subsequently, weighted gene co-expression network analysis (WGCNA) was used to analyze genes within crucial modules. The functional annotated DEGs which related to the immune signal pathways were used for constructing protein–protein interaction (PPI) analysis. Following this, two hub genes, FERMT3 and CD3G, were identified through correlation analyses associated with sequential organ failure assessment (SOFA) scores. These two hub genes were associated with cell adhesion, migration, thrombosis, and T-cell activation. Furthermore, immune infiltration analysis was conducted to investigate the inflammation microenvironment influenced by the hub genes. The efficacy and specificity of the two hub genes were validated through a mice sepsis model study. Concurrently, we observed a significant negative correlation between the expression of CD3G and IL-1β and GRO/KC. These findings suggest that these two genes probably play important roles in the pathogenesis and progression of sepsis, presenting the potential to serve as more stable biomarkers for sepsis diagnosis and prognosis, deserving further study.
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Mishraki-Berkowitz, T., P. Ben Ishai, A. Aserin, Yu Feldman, and N. Garti. "The dielectric study of insulin-loaded reverse hexagonal (HII) liquid crystals." Physical Chemistry Chemical Physics 17, no. 14 (2015): 9499–508. http://dx.doi.org/10.1039/c4cp03162h.
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This paper discusses the structural, dynamic, and kinetic aspects of the insulin-loaded HII mesophase (containing GMO–TAG–water–glycerol–insulin) and the two empty reference systems (GMO–TAG–water and GMO–TAG–water–glycerol). Schematic representation of an insulin-loaded water–glycerol-filled HII cylinder, at 290 K.