bluuebunny/crossref_metadata_2025_split huggingface dataset:
Upfront Neck Dissection for Treatment Selection and Improvement in Quality of Life as a Novel Treatment Paradigm for Deintensification in HPV+ OPSCC
Authors: Swiecicki Paul L. , Bellile Emily , Dragovic Aleksandar F. , McHugh Jonathan , Udager Aaron , Mierzwa Michelle Lynn , Shah Jennifer , Heft-Neal Molly , Rosko Andrew , Malloy Kelly M. , Casper Keith , Chinn Steven Bennett , Shuman Andrew G. , Stucken Chaz , Chepeha Douglas B. , Wolf Gregory T. , Bradford Carol Rossier , Eisbruch Avraham , Prince Mark E. , Worden Francis P. , Spector Matthew E. 
Published: March 2024

Abstract

Purpose:
Locoregionally advanced HPV+ oropharyngeal squamous cell carcinoma (OPSCC) has excellent cure rates, although current treatment regimens are accompanied by acute and long-term toxicities. We designed a phase II deescalation trial for patients with HPV+ OPSCC to evaluate the feasibility of an upfront neck dissection to individualize definitive treatment selection to improve the quality of life without compromising survival.

Patients and Methods:
Patients with T1–3, N0–2 HPV+ OPSCC underwent an upfront neck dissection with primary tumor biopsy. Arm A included patients with a single lymph node less than six centimeters, with no extracapsular spread (ECS) and no primary site adverse features underwent transoral surgery. Arm B included patients who had two or more positive lymph nodes with no ECS, or those with primary site adverse features were treated with radiation alone. Arm C included patients who had ECS in any lymph node and were treated with chemoradiation. The primary endpoint was quality of life at 1 year compared with a matched historical control.

Results:
Thirty-four patients were enrolled and underwent selective neck dissection. On the basis of pathologic characteristics, 14 patients were assigned to arm A, 10 patients to arm B, and 9 to arm C. A significant improvement was observed in Head and Neck Quality of Life (HNQOL) compared with historical controls (−2.6 vs. −11.9, P = 0.034). With a median follow-up of 37 months, the 3-year overall survival was 100% and estimated 3-year estimated progression-free survival was 96% [95% confidence interval (CI), 76%–99%].

Conclusions:
A neck dissection–driven treatment paradigm warrants further research as a deintensification strategy.
Abstract 1043: Identification of the novel immune synapse-localized proteome for immuno-oncology using Microscoop-induced targeted photo-biotinylation
Authors: Chong Weng-Man , Li Cecile , Huang Chun-Kai , Cheung Chantal Hoi Yin , Chang Hsiao-Jen , Chung Chia-Wen , Liao Jung-Chi 
Published: March 2024

Abstract
Although tens of immune synapse (IS) protein species are known, there remain many unknown IS-localized protein species. Understanding the proteome of the IS between a target cell and a lymphocyte is crucial for advancing immuno-oncology. The low abundance of ISs and the lack of a definitive enrichment marker have limited efficient proteomic profiling. Here, we used Microscoop™, an innovative system that integrates microscopy, machine learning, and targeted photo-biotinylation to enable precise and spatially specific enrichment of IS proteins, thereby facilitating proteomic discovery of the IS. We utilized Raji B cells as antigen-presenting cells (APCs) and induced IS formation with Jurkat T cells. The system first employed immunofluorescence imaging of CD3, a common IS marker in Jurkat T cells, and used a convolutional neural network-based deep learning algorithm to train the recognition of ISs from CMTPX-stained Raji B cells. Our automated system then successfully achieved spatially-targeted biotin-tagging of proteins at ISs through thousands of fields of view of imaging, deep learning-driven pattern generation, and photochemical labeling. Subsequent streptavidin pull-down and mass spectrometry analysis enabled the identification of IS-specific proteins. Remarkably, our spatial proteomic approach led to the isolation and identification of hundreds of different species at the IS interface, including proteins associated with key components of T-cell receptor (TCR) signaling pathways such as the TCR/CD3 complex, Src and Tec family tyrosine kinases, and pivotal NF-kB signaling proteins. Beyond these, we also identified a significant enrichment of proteins not previously associated with the IS. Our study not only illuminates previously unknown aspects of immune regulation at the IS interface, but also shedded light on proteins potentially important for immuno-oncology. These insights have significant implications for cancer research, particularly in understanding and manipulating immune responses for therapeutic purposes.
Citation Format: Weng-Man Chong, Cecile Li, Chun-Kai Huang, Chantal Hoi Yin Cheung, Hsiao-Jen Chang, Chia-Wen Chung, Jung-Chi Liao. Identification of the novel immune synapse-localized proteome for immuno-oncology using Microscoop-induced targeted photo-biotinylation [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 1043.
Abstract 1110: Estrogen receptor β signaling induced radio-resistance in bladder cancer
Authors: Ide Hiroki , Murakami Tetsushi , Kashiwagi Eiji , Kitaoka Sotaro , Komatsuda Akari , Nishimura Chugo , Funakoshi Shinsuke , Oya Mototsugu , Miyamoto Hiroshi 
Published: March 2024

Abstract
Introduction and Objective: Although radiotherapy (RT) combined with chemotherapy shows comparable outcomes to surgery, women tend to have higher mortality from bladder cancer (BC) compared to men. Emerging evidence indicated the involvement of estrogen receptorβ (ERβ) signaling in BC progression and the association of ER signaling with DNA repair pathways which are involved in radio-resistance. Therefore, we evaluated the association between ERβ signaling and the sensitivity to BC cells.
Methods: We compared the inhibitory effect of RT on BC cell viability between ERβ positive [5637 and T24 expressing control short-heparin RNA (shRNA)] and ERβ negative (5637 and T24 expressing ERβ-shRNA) cells. Moreover, we compared DNA double-strand breaks (DSB) via γ-H2AX foci formation, as well as the expression levels of DNA repair genes, in these cells after RT. Finally, in a mouse xenograft model, we evaluated it on the growth of ERβ positive tumor treated with radiation combined with mock or tamoxifen treatment.
Results: In vitro experiment showed that ionizing radiation reduced the numbers of viable cells in ERβ negative cells more significantly than those in ERβ positive cells. Moreover, tamoxifen treatment reduced the numbers of viable cells more than mock treatment in ERβ positive cells, while tamoxifen didn’t show significant effects in ERβ negative cells. The down-regulation of ERβ resulted in a delay in DSB repair 4-24 hours after RT. We then established radio-resistant cells and confirmed considerable elevation of the expression of ERβ as well as DNA repair genes including RAD51 and RAD54. Estradiol treatment induced the expression of these genes and tamoxifen abolished these effects. Finally, in vivo experiment showed that tamoxifen enhanced the cytotoxic effects of RT in xenograft bearing mice.
Conclusions: These results indicated that ERβ signaling inversely correlated with sensitivity to RT in BC. Thus, ERβ inhibition have a potential of enhancing the cytotoxic effects of radiation, especially in ERβ positive BC cells.
Citation Format: Hiroki Ide, Tetsushi Murakami, Eiji Kashiwagi, Sotaro Kitaoka, Akari Komatsuda, Chugo Nishimura, Shinsuke Funakoshi, Mototsugu Oya, Hiroshi Miyamoto. Estrogen receptor β signaling induced radio-resistance in bladder 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 1110.
Abstract 1125: TNIK induced chemoradiation resistance in small cell lung cancer
Authors: Chowdhury Dipanwita Dutta , Imada Eddie , Connis Nick , Nguyen Triet , Chang Jinhee , Council Danielle , Lafargue Audrey , Rezaee Mohammad , Tran Phuoc T. , Marchionni Luigi , Hann Christine L. 
Published: March 2024

Abstract
Chemoradiation (CRT) is the standard first-line therapy for limited stage small cell lung cancer (LS-SCLC), which is characterized by early metastasis, intrinsic-acquired CRT resistance and tumor recurrence. CRT confers a 20-25% 5-year overall survival in patients with LS-SCLC. In this study, we utilized patient-derived xenograft (PDX) models to demonstrate CRT resistance of SCLC and identified CRT resistance candidate genes from various SCLC PDX that represent the majority of molecular subtypes (n=4 that include SCLC-A and SCLC-N subtypes). RNA-seq data identified TNIK (Traf2- and Nck-interacting kinase) as one such gene that is consistently upregulated in SCLC PDXs exposed to CRT compared to single modality treatments. Copy number gains of TNIK were also present in human SCLC samples. Overcoming this CRT resistance is crucial in improving treatment outcomes and patient survival. Genetic depletion or pharmacological inhibition of TNIK reduced the in vitro clonogenic survival of TNIKhigh SCLC cells, NCI-H446 and makes them increasingly sensitive to CRT. In vivo, pharmacological inhibition of TNIK with the inhibitor NCB-0846, enhances the CRT sensitivity of NCI-H446 cell line-derived xenografts (CDX) in NOD SCID immunodeficient mice. Furthermore, pharmacological inhibition of TNIK in vivo demonstrated sensitivity to CRT in LX33 PDX. In conclusion, our results indicate that TNIK plays a role in conferring resistance to CRT in vitro in SCLC cell lines and in vivo in SCLC CDX and PDX models and therefore, can be a potential therapeutic target in limited stage SCLC.
Citation Format: Dipanwita Dutta Chowdhury, Eddie Imada, Nick Connis, Triet Nguyen, Jinhee Chang, Danielle Council, Audrey Lafargue, Mohammad Rezaee, Phuoc T. Tran, Luigi Marchionni, Christine L. Hann. TNIK induced chemoradiation resistance in 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 1125.
Abstract 1179: A single-cell atlas of human gastric malignancy reveals CD8+ T cell rejuvenation as a mediator of immunotherapeutic response
Authors: Liang Han , Chen Jian , Luo Yikai , Kang Muxing , Liu Wei , Wang Lie 
Published: March 2024

Abstract
Immune checkpoint inhibition (ICI) has emerged as a mainstream treatment for patients with advanced stage gastric cancer (GC). Cellular heterogeneity in the tumor microenvironment (TME) has a profound impact on the therapeutic responses to ICI. Here we characterize the kinetics of tumor-infiltrating immune populations in GC patients treated with anti-PD-1 using single-cell RNA and TCR sequencing (scRNA/TCR-seq), including primary tumors and metastases. Integrated with public GC scRNA-seq datasets, we construct the largest multi-omic atlas of GC cell states to date that captures the full trajectory of GC malignancy and comprises &gt;320,000 cells derived from 73 samples. We demonstrate the rejuvenation of exhausted CD8+ T cells into a proliferative state marked by the loss of LAYN expression as a major mediator of ICI response in the TME. In parallel, we observe enhanced immunogenicity of cancer cells in post-ICI tumors, thus highlighting the coordination between tumor-intrinsic and microenvironmental factors elicited by ICI. Our study provides a valuable resource of investigating the tumor response to anti-PD-1 treatment and suggests novel strategies for combination therapy and patient stratification.
Citation Format: Han Liang, Jian Chen, Yikai Luo, Muxing Kang, Wei Liu, Lie Wang. A single-cell atlas of human gastric malignancy reveals CD8+ T cell rejuvenation as a mediator of immunotherapeutic response [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 1179.
Abstract 1180: Asparagine deprivations enhance CD8+ T cell antitumor activity and ICB immunotherapy via ROS-mediated NFAT nuclear localization
Authors: Chang Hsuan Chia , Lin Kwang-Huei , Yang Huang Yu 
Published: March 2024

Abstract
Metabolic reprogramming plays a crucial role in the differentiation and activation of T cells. Both oxidative phosphorylation (OXPHOS) and glycolysis are upregulated to meet the high energy demands. However, the impact of amino acid metabolism on T cell activation remains unclear. Our study demonstrates that asparagine deprivation enhances the antitumor activity of CD8+ cytotoxic T lymphocytes (CTLs) and increases the flux of glycolysis and the tricarboxylic acid (TCA) cycle. Mechanistically, asparagine deprivation induces the production of reactive oxygen species (ROS) through mitochondrial complex I deficiency and leads to nuclear localization of NFAT, subsequently affecting cytokine production and T cell activation. In the animal model, we found that the clinical drug leunase exhibits antitumor activity that relies on the immune response of T cells. Leunase treatment promotes the activation of tumor-infiltrating lymphocytes (TILs) in vivo. Furthermore, the combination therapy of leunase and anti-PD1 demonstrates a synergistic effect. In patients with nasopharyngeal carcinoma (NPC), leunase therapy enhances the cytokines production and activation of CD8+ T cell. In summary, our findings offer valuable insights into how T cells adapt to changes in their nutritional environment.
Citation Format: Hsuan Chia Chang, Kwang-Huei Lin, Huang Yu Yang. Asparagine deprivations enhance CD8+ T cell antitumor activity and ICB immunotherapy via ROS-mediated NFAT nuclear localization [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 1180.
Abstract 1222: Mechanisms of succinate-mediated drug resistance in ER+ breast cancer
Authors: Hogstrom Jenny , Petrova Boryana , Perea Camila , Ward Madelyn , Wulf Gerburg , Collins Laura , Kanarek Naama , Muranen Taru 
Published: March 2024

Abstract
Breast cancer is the most prevalent cancer among women worldwide with estrogen receptor-positive (ER+) cancer constituting 70% of all breast cancers. Although ER+ breast cancers initially respond well to ER-targeted therapies and CDK4/6 inhibitors, approximately 30% patients acquire resistance to targeted therapies. In addition to intrinsic resistance that tumors develop, cancer-associated fibroblasts (CAFs) residing in the tumor microenvironment, also contribute to treatment-resistance and poor survival. The role of secreted metabolites by CAFs has been poorly studied in the context of targeted drug resistance. Therefore, to investigate the mechanism of stroma-mediated resistance to CDK4/6-inhibitors, we propagated patient-derived organoids (PDOs) and CAFs from treatment-naïve and treatment-resistant ER+ breast tumors. Our data show that the CAF conditioned media containing the polar metabolite fraction stimulates resistance to CDK4/6 inhibitors. Therefore, to identify metabolites that drive resistance, we performed an untargeted metabolomics on CAF conditioned media. We observed that the CAF conditioned media was enriched for TCA cycle intermediates, including succinate. Succinate is an oncometabolite that has an essential function in energy metabolism. Aside from causing metabolic reprogramming, succinate can be transported out of the mitochondria to perform other biological processes, such as epigenetic modifications and pseudohypoxia. Furthermore, succinate in the extracellular space binds to the succinate receptor SUCNR1 and induces G-protein coupled receptor-mediated signaling in cells expressing SUCNR1. To assess mechanism of resistance that these metabolites might induce, we treated breast cancer cells with the most enriched metabolites we had identified in our metabolomics assay. These experiments identified succinate as driver of CDK4/6 inhibitor resistance in ER+ breast cancer cells. Furthermore, treating tumor cells with SUCNR1 antagonist increased their sensitivity to CDK4/6-inhibitors, showing that succinate mediated resistance is conveyed via SUCNR1. This suggests that CAF secreted succinate plays a role in supporting a pro-tumor environment by promoting drug resistance towards CDK4/6 inhibitors. Defining this mechanism of resistance will elucidate potential therapeutic targets to augment patient response to therapy.
Citation Format: Jenny Hogstrom, Boryana Petrova, Camila Perea, Madelyn Ward, Gerburg Wulf, Laura Collins, Naama Kanarek, Taru Muranen. Mechanisms of succinate-mediated drug resistance in ER+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1222.
Abstract 123: Establishment of humanized CD3EDG/4-1BB mice for testing novel T cell engagers
Authors: Shang Chengzhang , Li Chong , Zhao Lei , Xu Qingqing , Jin James , Ren Menglian 
Published: March 2024

Abstract
Agonism of the 4-1BB receptor is an attractive therapeutic strategy for tumor cell therapy, due to the ability of this receptor to stimulate activity of T and NK cells for tumor cell killing. Many classes of biologics targeting 4-1BB have been generated to date, including bispecific or multispecific engagers designed to stimulate 4-1BB and CD3 activity on the T cell surface. To provide a preclinical platform to test such therapies, Biocytogen generated a humanized B-hCD3EDG/h4-1BB mouse model. This was achieved by crossing humanized mice expressing chimeric CD3E, CD3D and CD3G with mice expressing the human extracellular region of 4-1BB. Previously, we showed that these humanized CD3EDG mice and humanized 4-1BB mice can be used for validating efficacy of anti-human CD3 and 4-1BB antibody-based therapies, respectively. Here, we confirmed expression of human CD3 and 4-1BB on splenocytes in homozygous humanized B-hCD3EDG/h4-1BB mice by flow cytometry, which also demonstrated lack of murine CD3 and 4-1BB expression. Assessment of leukocyte subpopulations in the spleen and peripheral blood confirmed that humanization of the mice did not significantly alter the development or frequency of blood cell populations. Further evaluation of lymphocyte frequency was also performed, which demonstrates no significant alterations in the CD4/CD8 T cell ratio in spleen, lymph node, or peripheral blood of the animals. Presence of Treg and NK cells was also confirmed. Taken together, these data indicate that the humanized B-hCD3EDG/h4-1BB model is a novel, robust tool for testing novel T cell engagers.
Citation Format: Chengzhang Shang, Chong Li, Lei Zhao, Qingqing Xu, James Jin, Menglian Ren. Establishment of humanized CD3EDG/4-1BB mice for testing novel T cell engagers [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 123.
Abstract 1291: ASPIRE: Advocates and Scientists Partner in Research Education
Authors: Betts Laurie , Potter Jennifer , Carlisle Veronica , Spears Patricia A. 
Published: March 2024

Abstract
UNC Lineberger Comprehensive Cancer Center (LCCC) has a robust and growing cancer patient advocacy community. UNC Lineberger is the flagship publicly funded comprehensive cancer center in North Carolina. We are constantly looking for ways to educate patient and community advocates on recent advances in cancer biology research and clinical trials. Our advocates are also valuable partners for our basic and clinical researchers that may be early in their career. We developed and implemented an inaugural research education program for new advocates. We model this program partly on the highly successful and popular AACR Scientist Survivor Program that recently celebrated it’s 25th anniversary. Some of the UNC LCCC advocates participate in the SSP and were motivated to develop our own local program.
We will showcase our pilot 2024 ASPIRE education program that brings together cancer patient and community advocates and cancer researchers to learn from each other. The basic itinerary of the ASPIRE program is:
1.Three separate one-hour online presentations by UNC Lineberger researchers with a patient advocate moderator. The topics covered are:
Cancer 101 : cancer biology, diagnosis, staging, treatment.
Clinical Trials 101: clinical trials, phases, patient protection, progress with for example accrual of representative populations.
Research 101: bench research, bioinformatic, AI, how research works and how it may lead to new treatments. To showcase a tissue donation program being developed by UNC Patient Advocates that will benefit researchers.
2.The lecture series is followed by a breakfast roundtable discussion for all the participants to discuss their experiences. There will be short presentations and discussions in small groups of researchers and cancer patient advocates.
We will summarize our ASPIRE pilot experience, how our participation in the SSP program motivated this local program, and how we plan to incorporate feedback from participants to inform future programs. We hope this will lead to more informed patient advocates that can then be even more powerful in research advocacy.
Citation Format: Laurie Betts, Jennifer Potter, Veronica Carlisle, Patricia A. Spears. ASPIRE: Advocates and Scientists Partner in Research Education [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 1291.