Jun Ma Research Articles

Research landscape of radiotherapy for nasopharyngeal carcinoma from 1959 to 2022: A bibliometric analysis

BackgroundRadiotherapy, as the main treatment method for nasopharyngeal carcinoma (NPC), has evolved over time, but there has been no bibliometric study on NPC radiotherapy to date. In our study, the scientific achievements of NPC radiotherapy around the world were evaluated by bibliometric analyses, and the previous research hotspots and future trends are described. MethodsOriginal articles related to NPC radiotherapy were obtained from the Web of Science Core Collection. To identify research hotspots and future trends, countries/regions, institutions, journals, references, authors, and keywords were evaluated and visualized by Excel, VOSviewer, and CiteSpace. ResultsFrom 1959 to 2022, 7139 original articles were collected. The annual publications showed an increasing trend, especially after 2011. China had the most publications (n = 3719, 52.09 %). Sun Yat-sen University has the most publications and citations among institutions. Jun Ma is most productive and SR Baker has the highest co-cited centrality. International Journal of Radiation Oncology-Biology-Physics is the core journal, with most publications, citations and co-citations. Analysis of keywords showed intensity-modulated radiotherapy and chemoradiotherapy were the main keywords, and multicenter showed the strongest burst. ConclusionNPC radiotherapy has attracted increasing attention, and precision and artificial intelligence may be the future trends in this field.

Novel prognostic biomarkers in nasopharyngeal carcinoma unveiled by mega-data bioinformatics analysis

Nasopharyngeal carcinoma (NPC) is commonly diagnosed at an advanced stage with a high incidence rate in Southeast Asia and Southeast China. However, the limited availability of NPC patient survival data in public databases has resulted in less rigorous studies examining the prediction of NPC survival through construction of Kaplan-Meier curves. These studies have primarily relied on small samples of NPC patients with progression-free survival (PFS) information or data from head and neck squamous cell carcinoma (HNSCC) studies almost without NPC patients. Thus, we coanalyzed RNA expression profiles in eleven datasets (46 normal (control) vs 160 tumor (NPC)) downloaded from the Gene Expression Omnibus (GEO) database and survival data provided by Jun Ma from Sun Yat-sen University. Then, differential analysis, gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and network analysis were performed using STRING database. After that, 2142 upregulated differentially expressed genes (DEGs) and 3857 downregulated DEGs were screened. Twenty-five of them were identified as hub genes, which were enriched in several pathways (cilium movement, extracellular matrix structural constituent, homologous recombination and cell cycle). Utilizing the comprehensive dataset we amassed from GEO database, we conducted a survival analysis of DEGs and subsequently constructed survival models. Seven DEGs (RASGRP2, MOCOS, TTC9, ARHGAP4, DPM3, CD37, and CD72) were identified and closely related to the survival prognosis of NPC. Finally, qRT-PCR, WB and IHC were performed to confirm the elevated expression of RASGRP2 and the decreased expression of TTC9, CD37, DPM3 and ARHGAP4, consistent with the DEG analysis. Conclusively, our findings provide insights into the novel prognostic biomarkers of NPC by mega-data bioinformatics analysis, which suggests that they may serve special targets in the treatment of NPC.

Abstract 4456: De novo pyrimidine synthesis is a druggable vulnerability for chemotherapy resistant nasopharyngeal carcinoma with wild type IDH1

Abstract Chemotherapy resistance is a major obstacle to treat nasopharyngeal carcinoma (NPC), and strategies to overcome this resistance are required. Using proteomic analysis, we found that NPC patients resistant to gemcitabine plus cisplatin (GP) induction chemotherapy were characterized by abundant metabolic pathways. NPC with high expression of wild-type isocitrate dehydrogenase 1 (wtIDH1) was hyperdependent on de novo pyrimidine nucleotide synthesis and resistant to GP. Knockdown of IDH1 augmented the inhibition of de novo pyrimidine nucleotide synthesis induced by gemcitabine and cisplatin but reversed the suppression of purine nucleotide synthesis, which leading to DNA damage caused by nucleotide pool imbalance. IDH1 facilitated transcription of dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme for de novo pyrimidine nucleotide synthesis, through promoting chromatin accessibility by ALKBH5 in an α-ketoglutaric acid dependent manner. DHODH inhibitor, BAY2402234 significantly sensitized NPC cells to gemcitabine plus cisplatin chemotherapy. Collectively, these results reveal that wtIDH1-induced increase in de novo pyrimidine nucleotide represents a metabolic vulnerability that can be exploited pharmacologically, highlighting BAY2402234 as a promising strategy to enhance the efficacy of chemotherapy against NPC. Citation Format: Yingqin Li, Yuheng Zhao, Wuqi Zhang, Chunxian Ou, Jiaxi Shen, Jun Ma. De novo pyrimidine synthesis is a druggable vulnerability for chemotherapy resistant nasopharyngeal carcinoma with wild type IDH1 [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 4456.

Abstract 1999: DCAF7 acts as a scaffold to recruit USP10 for G3BP1 deubiquitylation and facilitates chemoresistance and metastasis in nasopharyngeal carcinoma

Abstract Though docetaxel plus cisplatin and 5-fluorouracil (TPF) induction chemotherapy becomes the standard care for locoregionally advanced nasopharyngeal carcinoma (NPC), some patients could not benefit from this therapy. The underlying mechanisms remain unclear. We found that DCAF7 was highly expressed in TPF resistant NPC patients, and promoted the cisplatin resistance and metastasis of NPC cells. Mechanistically, DCAF7 facilitates the interaction between USP10 and G3BP1, resulting in the removal of K48-linked ubiquitylation of G3BP1 at Lys76 mediated by USP10, thus preventing the degradation of G3BP1 through ubiquitin-proteasome pathway, and facilitates the stress granule (SG)-like structures formation. Moreover, knockdown of G3BP1 successfully reversed the SG-like structures formation and oncogenic effects exerted by DCAF7. Importantly, NPC patients with elevated DCAF7 expression exhibited high risks of metastasis, and is associated with a poor prognosis. This study identifies DCAF7 as a pivotal cisplatin resistance gene, and sheds light on the underlying mechanism of TPF resistance in NPC patients. The DCAF7-USP10-G3BP1 axis provides potential therapeutic targets and biomarker for NPC treatment. Citation Format: Qing-Jie Li, Xue-Liang Fang, Ying-Qin Li, Jia-Yi Lin, Cheng-Long Huang, Shi-Wei He, Sheng-Yan Huang, Jun-Yan Li, Sha Gong, Kai-Lin Chen, Na Liu, Jun Ma, Yin Zhao, Ling-Long Tang. DCAF7 acts as a scaffold to recruit USP10 for G3BP1 deubiquitylation and facilitates chemoresistance and metastasis in nasopharyngeal carcinoma [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 1999.

Abstract 1113: USP18 impairs the sensitivity of radiotherapy for nasopharyngeal carcinoma by promoting the ubiquitination and nuclear translocation of TRIM29

Abstract Radiotherapy is the main and preferred treatment for nasopharyngeal carcinoma (NPC), owing to its high sensitivity to radiation. However, there are ~20% patients suffering from tumor recurrence. Accumulating evidences show that protein ubiquitination plays a vital role in radiation caused DNA damage response. Here, we identified that the deubiquitinase USP18 is highly expressed in NPC tissues, and inversely associated with radiosensitivity of NPC cells. USP18 interacts with TRIM29 and promotes its K27-linked ubiquitination independent of its deubiquitinase activity. Further investigation reveals that USP18 acts as a scaffold to recruit the E3 ubiquitin ligase TRIM21 to directly ubiquitinate TRIM29 at Lys307, thus promoting its oligomerization and nuclear translocation, and thereby facilitates the DNA damage repair of NPC cells after irradiation. Clinically, higher expression of USP18 indicates poor response to radiotherapy and worse prognosis in NPC patients. Our findings reveal the critical role of USP18 in regulating radiosensitivity, and targeting USP18-TRIM21-TRIM29 axis maybe a novel strategy to synergize with radiotherapy for NPC patients. Citation Format: Jia-Yi Lin, Wei-Wei Zhang, Qing-Jie Li, Xue-Liang Fang, Jun-Yan Li, Shi-Wei He, Ying-Qin Li, Jun Ma, Na Liu, Yin Zhao, Rui Guo. USP18 impairs the sensitivity of radiotherapy for nasopharyngeal carcinoma by promoting the ubiquitination and nuclear translocation of TRIM29 [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 1113.

Notice of Violation of IEEE Publication Principles: Sequential Convex Programming for Collaboration of Connected and Automated Vehicles

Notice of Violation of IEEE Publication Principles<BR><BR>"Sequential Convex Programming for Collaboration of Connected and Automated Vehicles," <BR>by Xiaoxue Zhang, Jun Ma, Zilong Cheng, Frank L. Lewis, and Tong Heng Lee, <BR>in IEEE Transactions on Intelligent Vehicles, Early Access <BR><BR>After careful and considered review of the content and authorship of this paper by a duly constituted expert committee, this paper has been found to be in violation of IEEE’s Publication Principles. <BR><BR>This paper contains significant portions of original text from the paper cited below. The original text was copied without attribution (including appropriate references to the original author(s) and/or paper title) and without permission. <BR><BR>"Networked Model Predictive Control for Vehicle Collision Avoidance" <BR> by Bassam Alrifaee, <BR>in RWTH Aachen University, Dissertation, 04 May 2017 <BR>BR>"Sequential convex programming MPC for dynamic vehicle collision avoidance" <BR>by Bassam Alrifaee, Janis Maczijewski, Dirk Abel, <BR>in the Proceedings of the IEEE Conference on Control Technology and Applications, 2017, pp. 2202-2207 <BR><BR> <br/> This paper investigates the collaboration of multiple connected and automated vehicles (CAVs) in different scenarios. In general, the collaboration of CAVs can be formulated as a nonlinear and nonconvex MPC problem. Most of the existing approaches available for utilization to solve such an optimization problem suffer from the drawback of considerable computational burden, which hinders the practical implementation in real time. This paper proposes the use of SCP, which is a powerful approach to solving the nonlinear and nonconvex MPC problem in real time. To appropriately deploy the methodology, as a first stage, SCP requires linearization and discretization when addressing the nonlinear dynamics of the system model adequately. Based on the linearization and discretization, the original MPC problem can be transformed into a QCQP problem. Besides, SCP also involves convexification to handle the associated nonconvex constraints. Thus, the nonconvex QCQP can be reduced to a quadratic programming (QP) problem that can be solved rather quickly. Therefore, the computational efficiency is suitably improved despite the existence of nonlinear and nonconvex characteristics, whereby the implementation is realized in real time. Furthermore, simulation results in three different scenarios of autonomous driving are presented to validate the effectiveness and efficiency of our proposed approach.

Abstract 3423: NX-2127: A first-in-class clinical stage degrader of BTK and IKZF1/3 for the treatment of patients with B cell malignancies

Abstract Chronic activation of Bruton’s Tyrosine Kinase (BTK) signaling is a hallmark of B cell malignancies. Over the last decade, covalent and reversible inhibitors of BTK have proven effective for the treatment of many of these including chronic lymphocytic leukemia, diffuse large B cell lymphoma, mantle cell lymphoma, marginal zone lymphoma and Waldenstrom macroglobulinemia. However, the long-term efficacy of BTK inhibitors has been limited by both tolerability and the emergence of acquired resistance mutations. Mutations at C481, for example, dramatically reduce the binding of covalent BTK inhibitors, whereas other clinically-observed mutations such as V416L, T474I, and L528W reduce or eliminate the activity of next-generation non-covalent inhibitors. Targeted protein degradation is emerging as a new modality of small molecule drug discovery that offers improved selectivity and the potential to overcome resistance mutations through its ability to efficiently remove therapeutically relevant proteins such as BTK from cells. This approach has the further benefit of eliminating the scaffolding function of proteins that are otherwise unaffected by enzymatic inhibitors. Here, we present the discovery, structure-activity relationships, and pre-clinical characterization of NX-2127, a targeted protein degrader of BTK with concomitant immunomodulatory activity (IKZF1/3 degradation). NX-2127 degrades BTK in multiple B cell lymphoma lines with DC50’s in the range of 1-13 nM. NX-2127 displays efficient cellular degradation yet binds to WT and mutant BTK with affinities that render covalent and noncovalent BTK inhibitors ineffective, illustrating the power of event-driven pharmacology. NX-2127 drives cellular ternary complex formation between BTK and CRBN by inducing positive cooperativity in both WT and acquired resistance mutant settings. Consequently, NX-2127 induces potent degradation of C481S, T474I, V416L, and L528W-mutant BTK and suppresses activation marker expression on cells harboring these mutations. Furthermore, NX-2127 demonstrates oral bioavailability across pre-clinical species and shows robust tumor growth inhibition in WT and mutant mouse models of lymphoma upon once daily PO dosing. In pre-clinical safety studies, NX-2127 demonstrates an acceptable safety profile. NX-2127 is currently in phase 1 clinical trials (NCT04830137) for hematological malignancies. Citation Format: Jeffrey T. Mihalic, Nivetha Brathaban, Brandon Bravo, Timothy Ingallinera, Daisuke Kato, Hao Lu, Jun Ma, Joel McIntosh, Austin Tenn-McClellan, Ratul Mukerji, Mark A. Noviski, Ge Peng, Luz Perez, Ryan Rountree, May Tan, Jeffrey Wu, Jordan Ye, Stephanie Yung. NX-2127: A first-in-class clinical stage degrader of BTK and IKZF1/3 for the treatment of patients with B cell 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 3423.

The 100 most cited papers in nasopharyngeal carcinoma between 2000 and 2019: a bibliometric study.

To identify the 100 most-cited papers that have contributed to the understanding and treatment of nasopharyngeal carcinoma (NPC). We searched the NPC-related papers between 2000 and 2019 using the Web of Science database on October 12, 2022. Papers were identified in descending order according to the number of citations. The top 100 papers were analyzed. These 100 most cited papers on NPC have been cited for a total of 35,273 times, with a median number of citations of 281 times. There were 84 research papers and 16 review papers. The Journal of Clinical Oncology (n=17), International Journal of Radiation Oncology Biology Physics (n=13), and Cancer Research (n=9) published the most papers. Cancer Epidemiology Biomarkers & Prevention, Lancet, Cancer Cell, Molecular Cancer, and the New England Journal of Medicine had the largest average citations per paper. China contributed the most papers (n=71), followed by USA (n=13), Singapore (n=4) and, France (n=4). There were 55 clinical research papers and 29 laboratory research papers. Intensity-modulated radiation therapy technology (n=13), concurrent chemoradiotherapy (n=9), and neoadjuvant chemoradiotherapy (n=5) were the top three research topics. Epstein-Barr virus-related genes (n=9) and noncoding RNA (n=8) were the research domains in laboratory research papers. The top three contributors were Jun Ma (n=9), Anthony T C Chan (n=8), and Anne Wing-Mui Lee (n=6). This study provides an overview of the major areas of interest in the field of NPC with bibliometric analyses. This analysis recognizes some important contributions in the field of NPC and stimulates future investigations in the scientific community.

Abstract P6-05-21: Quality of Life and Perspectives of Older Adults with Early &amp; Locally Advanced Breast Cancers Undergoing Pre-operative Therapy

Abstract Background: Breast cancer (BC) is the commonest diagnosed cancer in Singaporean women. Increasingly, non-metastatic BC are treated aggressively with neoadjuvant therapy (NAT). Early identification and addressing supportive care needs of NAT treated patients is important for effective cancer care whilst maintaining optimal physical, psychological and social function. This project aims to explore the longitudinal trends of quality of life (QOL) of BC patients enrolled in a NAT program. Methods: This was a prospective cohort study of females aged 21 diagnosed with non-metastatic BC, referred to the NAT program at the SingHealth network of acute hospitals. The Functional Assessment of Cancer Therapy-Breast (FACT-B) was used as a health related QOL measure prior to NAT, within 2 months post definitive breast surgery and at 1-year post diagnosis. In older adults (OA) ≥65 years, the Attitude scale, Now vs Later as well as Health Outcome tool were also performed at baseline. Here we report pre-NAT baseline FACT-B and questionnaire results of OA patients recruited into the NAT program between Jun 2020 and Jun 2021. Results: Pre-NAT median FACT-B scores was 117 (IQR 102-126) for the entire cohort (n=119) and 116 (IQR 104-126) for OA (n=22). OA had significantly lower median Social Wellbeing score at baseline compared to patients &amp;lt; 65 years (p=0.01), while Physical, Emotional, and Functional Wellbeing were not significantly different. More than 50% of OA favoured QOL over quantity of life on the Attitude Scale. 68% of patients would rather have QOL now than 1 year later with half expecting their QOL to reduce by 50% in this time period. When the time scale was extended to 5 years, 64% would rather have QOL 5-years from now instead of QOL now with close to 80% expecting their QOL to be lower in 5 years than presently. Of the 4 outcomes, maintaining independence scored the highest, followed by keeping alive, then reducing/eliminating pain and other symptoms. Conclusion: Our study suggests that OA with BC report similar QOL to younger patients at baseline prior to NAT. Majority of OA patients favoured QOL over quantity of life, and viewed the ability to maintain independence as more important than survival prolongation representing their unique attitude towards cancer treatment and outcomes. Citation Format: Jun Ma, Zewen Zhang, Jasmine Yun Ting Tan, Whee Sze Ong, Sulastri Kamis, Benita Kiat Tee Tan, Veronique Kiak Mien Tan, Ravindran Kanesvaran, Tira Jing Ying Tan. Quality of Life and Perspectives of Older Adults with Early &amp; Locally Advanced Breast Cancers Undergoing Pre-operative Therapy [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 P6-05-21.

Abstract P4-07-49: Neoadjuvant therapy in Asian breast cancer patients with early &amp; locally advanced breast cancers – A contemporary experience from a large tertiary hospital in Singapore

Abstract Background: Non-metastatic breast cancers (BC) are increasing treated with neoadjuvant therapy (NAT). Complete pathological response (pCR) is associated with improved survival. Early identification of care needs during NAT is crucial. We report our institution’s experience with NAT. Methods: A prospectively recruited cohort diagnosed with BC, referred to NAT program at SingHealth acute hospitals between June 2020 and June 2021. Demographics, clinical data, pCR (absence of invasive carcinoma in breast and axilla), and Functional Assessment of Cancer Therapy Breast (FACT-B) as quality of life (QOL) measure were collected. Definition of young BC (YBC) were ≤40 years, older adults (OA) ≥65 years. Results: Among 119 eligible patients, 7 (6%) were clinically stage 1, 71 (60%) stage 2, and 41 (35%) stage 3. Twenty-eight (24%) were triple negative (TNBC; defined as HER2- hormonal receptor 0-10% [HR-]), 26 (22%) HER2+ HR-, 45 (38%) HER2+ HR+, 20 (17%) HER2- HR+. Among 71 HER2+ BC, two-thirds received anthracycline (A) based chemotherapy, a quarter A-sparing and remaining 9% taxane only. Majority (89%) received dual HER2 blockade. Among TNBC, 28 (71%) received additional platinum and 2 (7%) immunotherapy. Majority (77%; n=92) completed NAT. Toxicity was main reason for incompletion. Three patients did not undergo surgery: 1 defaulted, 1 demised and the last patient’s surgery was not due at analysis. Of the 116 who underwent surgery, 23 (20%) had breast conservation and 93 (80%) mastectomy. Forty-nine (42%) achieved pCR - 12 (43%) TNBC, 17 (65%) HER2+ HR-, 20 (44%) HER2+ HR+ and 0 in HER2- HR+ (p &amp;lt; 0.001). The pCR rates were also lower by increasing age (Multivariable OR 0.93; 95% CI, 0.90-0.97). Baseline median FACT-B scores was 117 (IQR 102-126) for the cohort: 108 for YBC, 116 for OA and 120 for the rest (p=0.200). At baseline, median score was 28, 24, 18, 22 and 27 in physical, social, emotional, functional wellbeing and BC subscale, respectively, and YBC and OA patients had lower social wellbeing scores than the remaining cohort (22 vs 24, p=0.011). Conclusion: Highest pCR were observed with HER2+ followed by TNBC. Pre-operatively, FACT-B scores were comparable by demographics, staging and tumor subtypes. However, care must be paid to social wellbeing for women in age extremes undergoing NAT. Citation Format: Zewen Zhang, Jun Ma, Jasmine Yun Ting Tan, Whee Sze Ong, Sulastri Kamis, Grace Yang, Benita Kiat Tee Tan, Veronique Kiak Mien Tan, Tira J. Tan. Neoadjuvant therapy in Asian breast cancer patients with early &amp; locally advanced breast cancers – A contemporary experience from a large tertiary hospital in Singapore [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-49.

The model of descriptive, diagnostic, predictive, and prescriptive analytics on 100 top-cited articles of nasopharyngeal carcinoma from 2013 to 2022: Bibliometric analysis.

Nasopharyngeal carcinomas (NPCs) are prevalent in southeast Asia. There is a need to systematically review the current trend and status of NPC research. However, most bibliometric analyses have tended to focus on descriptive and diagnostic analytics rather than predictive and prescriptive analyses. Thus, it is necessary to use the model of the 4 (called the descriptive, diagnostic, predictive, and prescriptive analytics [DDPP]) to derive insights from the data. This study aimed to apply the DDPP model to classify article themes and illustrate the characteristics of NPCs; compare NPC researcher achievements across countries, institutes, departments, and authors; determine whether the mean citations of keywords can be used to predict article citations; and highlight articles that are worthy of reading. The Web of Science Core Collection was searched for 100 top-cited articles and reviews related to NPCs published between 2013 and 2022. As part of Microsoft Office Excel 2019, Visual Basic for Applications was used to illustrate the number of publications and scientific productivity of authors over time and to generate network/temporal heatmaps, chord/Sankey diagrams, radar/impact beam plots, and scatter/pyramid charts about collaborations among countries. The DDPP model identifies institutions, authors, and hotspots of NPC research. The category, journal, authorship, and L-index (CJAL) score was applied to evaluate individual research achievements. A total of 10,564 publications were extracted from Web of Science Core Collection and screened for 100 top-cited articles and reviews related to NPCs. Despite having the highest number of publications (36%), China lags slightly behind the US in CJAL scores. CJAL was higher at Sun Yat-Sen University, Radiat Oncol department, and author Jun Ma from China. The number of article citations was significantly correlated with the number of weighted keywords (F = 1791.17; P < .0001). Six articles with significantly increasing citations over the last 4 years were recommended. This bibliometric study utilizes the DDPP model to analyze the scientific progress of NPC over the past decade. The whole genome is a hot topic that may prove to be a promising research area in the future. A temporal heatmap may serve as a tool for providing readers with articles that are worth reading, which could lead to additional research in bibliometrics.

Retracted: Research on wavelet neural network PID control of maglev linear synchronous motor

AbstractRetraction: [Jun Mao, Jun Ma, Research on wavelet neural network PID control of maglev linear synchronous motor, IET Circuits, Devices &amp; Systems 2022 (https://doi.org/10.1049/cds2.12136)].The above article from IET Circuits, Devices &amp; Systems, published online on 8 December 2022 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the Editor‐in‐Chief, Harry E. Ruda, the Institution of Engineering and Technology (the IET) and John Wiley and Sons Ltd. This article was published as part of a Guest Edited special issue. Following an investigation, the IET and the journal have determined that the article was not reviewed in line with the journal’s peer review standards and there is evidence that the peer review process of the special issue underwent systematic manipulation. Accordingly, we cannot vouch for the integrity or reliability of the content. As such we have taken the decision to retract the article. The authors have been informed of the decision to retract.

Abstract 353: Establishment and characterization of neuregulin-1 (NRG1) fusion driven XPDX models

Abstract Background: Neuregulin-1 (NRG1) rearrangements drive cancers by binding to ERBB3/ERBB2 heterodimers and activating downstream signaling. NRG1 fusion proteins have recently been identified in several cancer types including lung and ovary. To better understand the role of NRG1 fusions in cancer we established three XenoSTART patient-derived xenograft (XPDX) models driven by NRG1 rearrangements including two CD74-NRG1 lung models designated ST2891 and ST3204 and one SARAF-NRG1 ovary model designated ST2476. These models were established in athymic nude mice and characterized for receptor expression, genomic alterations, and in vivo drug sensitivity. Methods: ST2891 was established from an excision biopsy collected from a 68-year-old male with NSCLC following treatment with carboplatin/paclitaxel and carboplatin/pemetrexed. ST3204 was established from a lymph node biopsy collected from a 63-year-old female with NSCLC following treatment with cisplatin/pemetrexed. ST2476 was established from primary tissue collected from a chemo naïve 61-year-old female with ovarian cancer. The resulting models were passaged and characterized using immunohistochemical and genomic analysis including WES and RNAseq. In vivo studies were performed testing various chemotherapy and targeted agents; study endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a %T/C of ≤ 20 versus control was considered sensitive. Tumor regression (%T/C&amp;lt;0) versus Day 0 tumor volume was also reported. Results: All models reported ERBB2 and ERBB3 staining in evaluated passages with similar histology compared with archival clinical samples. WES analysis of the three models did not identify any variants in EGFR/ERBB2-4/RAS/RAF genes. RNA sequencing revealed CD74-NRG1 or SARAF-NRG1 gene fusions independently confirmed using molecular studies. In vivo, both lung models were resistant to weekly cisplatin or T-DM1 and daily palbociclib (50 mg/kg) or daily afatinib up to 10 mg/kg. ST3204 was found sensitive to weekly pertuzumab (1 mg/kg). Both lung models were resistant to trastuzumab (1 mg/kg). The ST2476 ovary XPDX was found resistant to endocrine therapies and reported some sensitivity to weekly cisplatin. Conclusion: We have established and characterized a panel of three XPDX models driven by NRG1 rearrangements including two CD74-NRG1 lung models and one SARAF-NRG1 ovary model. These models are valuable tools for further developing therapies targeting NRG1-driven cancers. Citation Format: Alyssa Simonson, Johnnie Flores, Crystal Moreno, Justine Hruzek, Kyriakos Papadopoulos, Drew Rasco, Amita Patnaik, Ronald Drengler, Allan White, Jun Ma, Michael J. Wick. Establishment and characterization of neuregulin-1 (NRG1) fusion driven XPDX models [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 353.

Abstract 5128: Identification and characterization of nasopharyngeal carcinoma prognostic subtypes based on a circRNA classifier: Implications of stratified treatment

Abstract Accurate risk stratification for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is crucial for treatment decisions and prognosis. Here, we introduce a circRNA-based classifier that could improve the prognostic stratification of LA-NPC patients. The circRNAs are identified by microarray profiling, followed by qRT-PCR validation and selection using a machine learning method in the training cohort (n = 170). Based on the proposed classifier, two prognostic-distinctive NPC subtypes are identified, namely the high-risk subtype (subtype H) and low-risk subtype (subtype L), which have significantly different disease-free survival (HR 2.99, 95% CI 1.58-5.67, P &amp;lt; 0.001). Validation in the internal cohort (n = 170) and external cohort (n = 150) yield similar results and the circRNA-based classifier is an independent risk factor of posttreatment relapse. Meanwhile, multiple interdependent features of different subtypes are observed, including relatively higher immune cell infiltration and immune-related pathways activation in subtype L; and predominant stromal, immunosuppressive and tumor-promoting components with moderate immune activation in subtype H. With a less aggressive and more immune-active tumor microenvironment, patients of subtype L could benefit from the addition of induction chemotherapy. In contrast, patients of subtype H, who are vulnerable to chemoresistance, display a strong tendency to benefit from additional immunotherapy. Overall, we define two NPC prognostic subtypes based on a circRNA classifier across multiple cohorts, which exhibit distinct biological ecosystems and suggest opportunities for the personalization of therapeutic regimens. Citation Format: Yelin Liang, Yuheng Zhao, Qian Li, Wei Jiang, Jun Ma, Na Liu, Yingqin Li. Identification and characterization of nasopharyngeal carcinoma prognostic subtypes based on a circRNA classifier: Implications of stratified treatment [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 5128.

Abstract 1126: Concurrent degradation of BTK and IMiD neosubstrates by NX-2127 enhances multiple mechanisms of tumor killing

Abstract B-cell receptor (BCR) signaling is integral for the development, adhesion, growth, and survival of human B cells. Chronic activation of BTK-mediated BCR signaling is a hallmark of many B cell lymphoid malignancies, making BTK an attractive therapeutic target. While covalent inhibitors of BTK have proven effective, they have been associated with the occurrence of acquired resistance mutations. IMiDs (immunomodulatory imide drugs) exert direct anti-cancer effects in B cell malignancies as well as enhance the activity of T cells. Based on clinical data of BTK covalent inhibitors and IMiDs in B-cell malignancies, a strategy combining BTK and IMiD targeting in a single oral, small molecule may improve anti-tumor activity. Here we describe NX-2127, a bifunctional molecule that catalyzes the degradation of BTK and IMiD neosubstrates Aiolos and Ikaros. In primary human T cells, NX-2127 degrades Aiolos (DC50=25 nM) and Ikaros (DC50=54 nM) and enhances IL-2 secretion. NX-2127 promotes superior in vitro killing of a DLBCL cell line, TMD8, and a MCL cell line, REC-1, as compared to BTK inhibitors ibrutinib, acalabrutinib, and pirtobrutinib, or IMiDs pomalidomide and lenalidomide. BTK inhibitors promote partial death of TMD8 cells (Emax = 17-33% viable) and REC-1 cells (Emax = 46-52% viable). By contrast, the dual BTK and IMiD activity of NX-2127 promotes complete killing of TMD8 and REC-1 cells and does so more potently than IMiDs alone. In REC-1 cells, suppression of Ikaros protein levels by IMiDs, BTK inhibitors, and NX-2127 correlates closely with downstream viability reduction, independent of drug mechanism. In vivo, oral administration of NX-2127 demonstrates dose proportional degradation of BTK and Aiolos protein in a TMD8 xenograft model, closely correlating with the degree of tumor control. RNA-seq analysis performed on REC-1 cells demonstrates that NX-2127 exhibits distinct regulation of gene expression when compared to ibrutinib or pomalidomide. Gene set enrichment analysis (GSEA) of these uniquely modulated genes reveals that NX-2127 downregulates gene sets involved in cell cycle, DNA replication, DNA repair, and survival signaling pathways. Furthermore, a key mediator of T cell recognition is more strongly upregulated by NX-2127 than pomalidomide and ibrutinib at both the transcript and cell surface expression levels in REC-1 cells, implying a potential immune-mediated anti-neoplastic mechanism. The gene expression signature of NX-2127 exposure supports the hypothesis that its anti-tumor effects include both tumor cell-intrinsic and tumor cell-extrinsic mechanisms and suggests that the combination of BTK degradation and IMiD activity may be more efficacious in treating certain B-cell malignancies than either activity alone. A phase 1a/b trial of NX-2127 for patients with relapsed or refractory B-cell malignancies is ongoing. Citation Format: Mark A. Noviski, Jun Ma, Ernestine Lee, Nivetha Brathaban, May Tan, Luz Perez, Daniel W. Robbins, Austin Tenn-McClellan, Janine Powers, Gwenn Hansen, Cristiana Guiducci, Ryan Rountree. Concurrent degradation of BTK and IMiD neosubstrates by NX-2127 enhances multiple mechanisms of tumor killing [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 1126.

On 0012-avoiding inversion sequences and a conjecture of Lin and Ma

The study of pattern avoidance in inversion sequences recently attracts extensive research interests. In particular, Zhicong Lin and Jun Ma conjectured a formula that counts the number of inversion sequences avoiding the length-four pattern 0012. Our object of the paper is to confirm this conjecture.

Abstract P5-01-11: Nonclinical activity of fulvestrant in a panel of ER+ breast XPDX models representing clinically acquired and innate resistance to endocrine therapies

Abstract Background: Fulvestrant is a selective estrogen receptor modulator (SERM) approved as a single agent for estrogen receptor positive, HER2 negative breast cancer patients at various stages of disease and in combination with CDK4/6 inhibitors following endocrine therapy failure. Although this agent requires intramuscular injection, it has demonstrated superior activity and fewer side effects versus some oral endocrine treatments however, resistance to fulvestrant often develops. To better understand fulvestrant resistance and its utility in patients who have failed other endocrine therapies, we evaluated the agent in a panel of ER+ breast models established from patients at various stages of disease representing endocrine-sensitive and -resistant disease. Methods: Sixty-five previously developed ER+ breast XPDX models were evaluated in this study. Models were grown subcutaneously in female athymic nude mice supplemented with estradiol in drinking water when necessary. All models were characterized at early and late passages for estrogen receptor expression by immunohistochemistry and profiled using WES and RNAseq. For in vivo studies, fulvestrant was administered by subcutaneous injection at 2.5 or 5 mg per dose once weekly until study completion. In vivo study endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a %T/C of ≤ 20 versus control was considered sensitive. Tumor regression (%T/C&amp;lt;0) versus Day 0 tumor volume was also reported. Models were grouped by patient clinical treatment prior to sample collection and model establishment including chemo-naïve, endocrine therapies other than fulvestrant, non-endocrine therapies, and fulvestrant. Results: All models retained ER expression in evaluated passages with similar histology compared with archival clinical samples. DNA/RNA sequencing identified several model-specific variants including ESR1 point mutations and fusions. In this study, 22% of models represented chemo-naïve patients, 24% were from patients treated with non-endocrine therapies, 20% were from patients treated with fulvestrant and the remaining 34% from patients treated with endocrine therapies other than fulvestrant. In vivo, 40% of the chemo-naïve group reported sensitivity to fulvestrant including several models with tumor regressions. Activity of fulvestrant was reported in 25% of models in the non-endocrine therapies group and in 20% of models from patients treated with either fulvestrant or endocrine therapies other than fulvestrant. Several models resistant to fulvestrant from chemo-naïve or patients treated with non-endocrine therapies harbored driver mutations including ESR1, PIK3CA, and AKT1 variants or were HER2+. In models from patients pretreated with fulvestrant, those who had also received a CDK4/6 inhibitor were particularly resistant. Conclusion: We evaluated fulvestrant in a panel of ER+ breast XPDX models representing endocrine-sensitive and -resistant disease from both chemo-naïve and pretreated patients, and identified models responsive and resistant to fulvestrant therapy. This panel can be utilized as a valuable tool in better understanding fulvestrant and endocrine therapy resistance and in developing novel therapies for patients resistant to currently available hormonal therapies. Citation Format: April Cabang, Crystal Moreno, Johnnie R Flores, Jenna Boedeker, Alyssa Simonson, Jun Ma, Amy Lang, Gladys Rodriguez, Arthur Rosenthal, Kyriakos Papadopoulos, Amita Patnaik, Drew Rasco, Lon Smith, Murali Beeram, Ronald Drengler, Luis Rodriguez, Steven Abbate, Scott Ulmer, Michael J Wick. Nonclinical activity of fulvestrant in a panel of ER+ breast XPDX models representing clinically acquired and innate resistance to endocrine therapies [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 P5-01-11.

Abstract P5-01-09: Establishment and characterization of two simultaneously developed T-DM1-resistant, ER+/HER2+ XPDX models from the same patient with differential in vivo sensitivity to trastuzumab deruxtecan (DS-8201a)

Abstract Background: Trastuzumab deruxtecan (DS-8201a) is an antibody-drug conjugate (ADC) consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody linked to a topoisomerase I inhibitor payload using a cleavable tetrapeptide-based linker and was recently approved for unresectable or T-DM1-refractory HER2+ breast cancer. While some mechanisms for clinical T-DM1 resistance have been identified, less is known about acquired or innate resistance to DS-8201a. We established two XPDX models of ER+/HER2+ breast cancer from tissue and fluid samples collected simultaneously from the same patient. These models designated ST4480B and ST4480C were developed and characterized for receptor expression, genomic alterations, and in vivo drug sensitivities toward multiple chemotherapies and targeted agents including DS-8201a and T-DM1. Methods: ST4480B and ST4480C were established from a 70-year-old Caucasian female with ER+/HER2+ metastatic breast cancer pretreated with chemotherapy and targeted agents including T-DM1 for nine months followed by capecitabine/trastuzumab/tucatinib combination for one year prior to sample collections. ST4480B was established from a lymph node biopsy and ST4480C from a fluid sample collected the same day; both were grown subcutaneously in female athymic nude mice supplemented with estradiol. The resulting models were passaged and receptor expression confirmed immunohistochemically; genomic analysis, including WES and RNAseq, was performed to further characterize models. For in vivo studies, both models were evaluated with several chemotherapy and targeted agents alone and in combination including: trastuzumab, pertuzumab, T-DM1, DS-8201a, neratinib, tucatinib, alpelisib, everolimus, and irinotecan. In vivo study endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a %T/C of ≤ 20 versus control was considered sensitive. Tumor regression (%T/C=—&amp;lt;0) versus Day 0 tumor volume was also reported. Results: ST4480B and ST4480C retained comparable receptor expression (ER=2+/HER2=2+) over tested passages with similar histology compared with archival clinical samples. DNA/RNA sequencing identified several conserved variants including PIK3CAE545K and TP53Q192* mutations and an ESR1-CCDC170 fusion. However, two variants identified only in ST4480C sequences included PIK3CAG1007R and PTENS287L. In vivo, ST4480B and ST4480C were found resistant to T-DM1 up to 10 mg/kg weekly with an average %T/C of 46 and 100, respectively. However, DS-8201a treatment at 3 mg/kg weekly resulted in partial tumor regressions in ST4480B (%T/C=-68) while ST4480C was found resistant to the therapy up to 10 mg/kg weekly (%T/C=84%). Both models were found resistant to trastuzumab, pertuzumab, neratinib, tucatinib, and irinotecan but sensitive to both alpelisib and everolimus. Conclusion: We established two XPDX models representing T-DM1-resistant, ER+/HER2+ breast cancer from both tissue and fluid samples collected simultaneously from the same patient which were found differentially responsive to DS-8201a. These models can be utilized as a valuable tool in better understanding innate resistance to DS-8201a. Citation Format: Johnnie R Flores, Anna Stackpole, Abimael Garza, Alexandra Ulmer, Alyssa Simonson, Kyriakos Papadopoulos, April Cabang, Jun Ma, Amita Patnaik, Drew Rasco, Amy Lang, Gladys Rodriguez, Murali Beeram, Michael J Wick. Establishment and characterization of two simultaneously developed T-DM1-resistant, ER+/HER2+ XPDX models from the same patient with differential in vivo sensitivity to trastuzumab deruxtecan (DS-8201a) [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 P5-01-09.

Contour-enhanced attention CNN for CT-based COVID-19 segmentation

Accurate detection of COVID-19 is one of the challenging research topics in today's healthcare sector to control the coronavirus pandemic. Automatic data-powered insights for COVID-19 localization from medical imaging modality like chest CT scan tremendously augment clinical care assistance. In this research, a Contour-aware Attention Decoder CNN has been proposed to precisely segment COVID-19 infected tissues in a very effective way. It introduces a novel attention scheme to extract boundary, shape cues from CT contours and leverage these features in refining the infected areas. For every decoded pixel, the attention module harvests contextual information in its spatial neighborhood from the contour feature maps. As a result of incorporating such rich structural details into decoding via dense attention, the CNN is able to capture even intricate morphological details. The decoder is also augmented with a Cross Context Attention Fusion Upsampling to robustly reconstruct deep semantic features back to high-resolution segmentation map. It employs a novel pixel-precise attention model that draws relevant encoder features to aid in effective upsampling. The proposed CNN was evaluated on 3D scans from MosMedData and Jun Ma benchmarked datasets. It achieved state-of-the-art performance with a high dice similarity coefficient of 85.43% and a recall of 88.10%.

Further Discussion on Relevant rules and regulations for designing, constructing universities

The purpose of this study focuses on studying Relevant rules and regulations for designing, constructing universities, as well as the service quality of the lecture hall via a case of National Economics University Hanoi. Jun Ma (2015) pointed The construction and sharing of university teaching resources library plays positive effect in promoting the innovation of teaching mode, learning mode and the mode of talents training and promoting the reform of higher education. By using description, qualitative analysis including synthesis and inductive methods, This study finds out that TCVN 3981:1985 on Universities - Design standards requires: Design standards for university lecture halls- The lecture hall is a large room, performing the teaching and learning functions of universities and colleges. Therefore, when designing this space must be very careful.