bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6309: Anti-tumor efficacy of SI-B001, a novel EGFR × HER3 bispecific antibody, against EGFR-driven epithelial tumors alone or in combination with paclitaxel and carboplatin
Authors: Renshaw Blair , Khalili Jahan Salar , Xiao Sa , Zhu Yi 
Published: June 2023

Abstract
EGFR is a member of the human epidermal growth factor receptor (ErbB) family with tyrosine kinase activity. Evidence indicates that EGFR is involved in the pathogenesis and progression of human carcinoma of different types. HER3 is a unique pseudokinase receptor of the ErbB family and known to mediate resistance to EGFR-targeting therapies. Therefore, we created SI-B001, an EGFR × HER3 bispecific antibody, which can bind EGFR × EGFR homodimers and EGFR × HER3 heterodimer to block their downstream pathways. We performed non-clinical studies to investigate in vitro and in vivo anti-tumor effects.
In vitro, the inhibition of tumor cell growth by SI-B001 was stronger than cetuximab and duligotuzumab in FaDu (mRNA expression levels of EGFRhigh/HER3high/NRG1medium). Importantly, testing with the cell line Oka-c-1 (mRNA expression levels of EGFRhigh/HER3high/NRG1low), showed that NRG1 supplementation did not change the potency of cetuximab. However, SI-B001 showed much stronger potency than cetuximab and duligotuzumab under conditions of NRG1 supplementation. This result indicates that the functionality of the bi-specific SI-B001 is competitive against a HER3 natural ligand and capable to act against cancer with HER3 ligand mediated resistance to cetuximab.
In vivo, single agent SI-B001 exhibited superior anti-tumor activity to cetuximab in the FaDu xenograft model. Meanwhile, SI-B001 in combination with paclitaxel and carboplatin led to a significant synergistic antitumor effect, which was stronger than the combination of cetuximab + paclitaxel + carboplatin. Compared to chemotherapy alone in this model, which could result in weight loss and treatment related mortality, no serious weight loss or deaths occurred in the single agent SI-B001 and the combination of SI-B001 with chemotherapy.
These results suggest that SI-B001 alone and in combination with chemotherapy can exhibit favorable safety and robust anti-tumor activity. Currently, 6 phase II clinical trials of SI-B001, either alone or in combination with chemotherapy, have been conducted in different epithelial carcinomas. These studies have shown a potential break-through activity in NSCLC and HNSCC with a very good safety profile.
Citation Format: Blair Renshaw, Jahan Salar Khalili, Sa Xiao, Yi Zhu. Anti-tumor efficacy of SI-B001, a novel EGFR × HER3 bispecific antibody, against EGFR-driven epithelial tumors alone or in combination with paclitaxel and carboplatin. [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 6309.
Abstract 6332: A humanized anti-cd40 antibody with anti-tumor pharmacological activity and cynomolgus monkey safety
Authors: Li Zhenyu , Zhao Lili , Zhang Guimin , Li Bin , Liu Zhong , Li Guangyan , Zhu Zhongsong 
Published: June 2023

Abstract
LNF1901 is a humanized CD40 agonistic antibody. LNF1901 can bind to CD40 protein of human(EC50=23.6ng/mL) and monkey(EC50=23.5ng/mL), but cannot bind to CD40 protein of rat and mouse. LNF1901 had strong activation effect on DC cells(EC50=0.04ug/mL) and had strong ADCC and CDC effects. AT a dose of 20mg/kg, the TGITW of LNF1901 was 59.9% in Female NPG mice were inoculated with Raji/CIK/DC subcutaneous transplanted tumor model. Following intravenous infusion of LNF1901 at doses of 6, 30, or 150 mg/kg to cynomolgus monkeys weekly for 4 weeks, the highest non-severely toxic dose (HNSTD) was considered to be 150 mg/kg.LNF1901 had demonstrated manageable safety and promising antitumor activity in vivo and in vitro tests.
Citation Format: Zhenyu Li, Lili Zhao, Guimin Zhang, Bin Li, Zhong Liu, Guangyan Li, Zhongsong Zhu. A humanized anti-cd40 antibody with anti-tumor pharmacological activity and cynomolgus monkey safety [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 6332.
Abstract 6360: In vivo antitumor efficacy evaluation of ASC63, an oral small molecule PD-L1 inhibitor, in a humanized mouse tumor model
Authors: Wu Jinzi J. , He Handan 
Published: June 2023

Abstract
Background: ASC63 is an oral small molecule programmed cell death-ligand 1 (PD-L1) inhibitor. After oral dosing, ASC63 is rapidly absorbed and converted to its pharmacologically active metabolite ASC63-A in vivo. In vitro studies showed that ASC63-A could activate PD-L1 dimerization and internalization from cell membrane, thus interfere PD-1/PD-L1 interaction and enhance T-cell activation. Here we report the in vivo antitumor efficacy of ASC63 in a humanized mouse tumor model.
Methods: 0.5×106 human PD-L1 knock in CT26 cells (CT26-hPD−L1) were implanted subcutaneously into BALB/c mice for tumor development. When the average tumor volume reached approximately 100 mm3, mice were randomly assigned (post-grouping, PG) and treated with vehicle, reference drug (10 mg/kg Atezolizumab intravenous injection twice a week [BIW]), 50 or 100 mg/kg ASC63 oral dosing twice a day (BID) for 18 days. Body weights and tumor volumes were measured regularly, and tumor growth inhibitions (TGI) of different groups were compared. TGI was calculated using the formula: TGI (%) =[1-(TRTV-1)/(CRTV-1)] ×100, where TRTV= mean relative tumor volume (RTV) of treatment group; CRTV= mean of control group.
Results: At PG-D18, the tumor volume of vehicle group reached 1548 mm3, and Atezolizumab, 50 and 100 mg/kg AS63 groups showed TGI values of 35.17, 17.12 and 36.87%, respectively. Atezolizumab 10 mg/kg BIW and ASC63 100 mg/kg BID produced similar antitumor activities. One mouse in 100 mg/kg ASC63 group had body weight loss more than 10% at PG-D6, and was back to normal at PG-D9 after extra nutrition was provided, while the rest of mice showed a gradually increase in body weight during the study. No significant difference of body weight or body weight change was found among different groups of mice.
Conclusion: Results of this study show that ASC63 is in general well tolerated in CT26-hPD−L1 humanized mouse tumor model, and ASC63 has comparable antitumor efficacy as the FDA-approved PD-L1 antibody, Atezolizumab. ASC63 is an oral small molecule PD-L1 inhibitor, and thus will have better patient compliance than injective PD-1/PD-L1 antibody. Results of this study support the continued investigation of ASC63.
Citation Format: Jinzi J. Wu, Handan He. In vivo antitumor efficacy evaluation of ASC63, an oral small molecule PD-L1 inhibitor, in a humanized mouse tumor model [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 6360.
Abstract 6361: A preclinical model of acquired anti-PD-1 resistance is responsive to SEA-TGT, an effector-function enhanced anti-TIGIT monoclonal antibody
Authors: Gruber David R. , Zeng Weiping , Thurman Bob , O'Connor Brian P. , Gardai Shyra J. , Smith Alyson J. 
Published: June 2023

Abstract
Immune checkpoint inhibitors, including monoclonal antibodies targeting the PD-1/PD-L1 axis, induce robust antitumor immunity in a subset of patients with various cancers. Despite continued success of these therapies, some patients experience limited efficacy owing to clinically complex and unresolved mechanisms of primary and acquired immunotherapy resistance. To begin to understand the mechanisms of acquired resistance to anti-PD-1 blockade, we developed a syngeneic murine CT26 colorectal tumor model that is resistant to anti-PD-1 therapy. To achieve this, CT26 tumors were subjected to successive rounds of increasing levels of anti-PD-1 therapy. When tumors grew out, they were cultured in vitro and then re-implanted and re-treated for three rounds until PD-1 resistance was achieved. To characterize the underlying drivers of acquired resistance across the generation of the model, wild type and anti-PD-1 resistant tumors and cultured cell lines were evaluated by flow cytometric immunophenotyping and RNA-sequencing analysis. To assess how observed changes in the tumor microenvironment impact response to various therapeutics, the resistant tumors were treated with anti-PD-1 therapy or SEA-TGT, a nonfucosylated anti-TIGIT mAb with enhanced Fc-function that drives activity through multiple modes of action. As expected, treatment with anti-PD-1 monotherapy was ineffective, however, treatment with SEA-TGT demonstrated potent anti-tumor activity. These data are consistent with responsiveness to anti-TIGIT agents in other in vivo models of PD-1 resistance and/or PD-1 refractory response, indicating that the factors driving resistance to anti-PD-1 therapy can be different than those driving response to other known checkpoint molecules such as TIGIT. Thus, investigational agents such as SEA-TGT may have the potential to be efficacious in tumors that are primary or secondarily resistant to anti-PD-1 therapy. We have initiated a phase 1 study (NCT04254107) evaluating the safety, tolerability, and activity of SEA-TGT monotherapy and in combination with anti-PD-1 therapy in patients with advanced malignancies.
Citation Format: David R. Gruber, Weiping Zeng, Bob Thurman, Brian P. O'Connor, Shyra J. Gardai, Alyson J. Smith. A preclinical model of acquired anti-PD-1 resistance is responsive to SEA-TGT, an effector-function enhanced anti-TIGIT monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6361.
Abstract 6450: Fatty acid intake as potential risk factor of colorectal cancer: A multicenter case control study in Iran
Authors: Seyyedsalehi Monireh Sadat , Boffetta Paolo , Zendehdel Kazem 
Published: June 2023

Abstract
A higher risk of colorectal cancer (CRC) has been associated with high animal fat intake, but not vegetable fat. To date, limited data provides the quantification of the effect exerted by fatty acids (FAs) on CRC overall and by anatomical sub-sites. This study aims to look at associations between some FAs intakes [cholesterol, total fat, total saturated fatty acids (SFAs), total monounsaturated fatty acids (MUFAs), total polyunsaturated fatty acids (PUFAs), total trans fatty acids (TFAs), oleic acid, myristic acid, total ruminant (rTFAs) and industrial fatty acids (iTFAs), eliadic acid (EA), conjugated linoleic acid (CLA), and CRC risk in a large case-control study (IROPICAN) in Iran . We analyzed 865 CRC cases (434 in colon, 404 in rectum, and 27 with unknown subsite) and 3,206 controls from seven provinces of Iran. Detailed information was collected by trained interviewers using validated lifestyle and food frequency questionnaires (FFQ). The different types of total and individual FAs intake were categorized into quartiles of intake. The odds ratios (OR) and 95% confidence intervals (CI) for the association between CRC them were calculated using multivariate logistic regression models by adjusting for the potential confounders. Furthermore, analyses were stratified by age (under and over 50) and also, we repeated the analyses for CRC subsites. There was a statistically significant positive association between CRC and high intake (quartile 4) compared to the low intake (quartile) of dietary total fat (OR=1.77, 95% CI=1.32-2.38), cholesterol (OR=1.58, 95% CI=1.22-2.05), total TFAs (OR=1.31, 95% CI=1.02-1.68), TFAs (OR=1.73, 95% CI=1.12-2.68), EA(OR=2.69, 95% CI=1.46-4.93), and SM (OR=1.45, 95% CI=1.00-2.09), as well as an inverse association with high intake of dietary rTFAs (OR=0.60, 95% CI=0.39-0.93), CLAs (OR=0.34, 95% CI=0.19- 0.60). Stratified analyses by age indicated that there was a statistically significant association between CRC and total fat intake [OR =1.30, 95% CI =1.16-1.46, p=0.006 for the interaction], cholesterol intake [OR =1.22, 95% CI=1.11-1.35, p=0.019 for the interaction], and iTFA intake [OR =1.31, 95% CI=1.06-1.62, p=0.02 for the interaction] after 50 years old. The results of our study indicate that decreasing fat consumption, particularly from industrial and animal sources, may reduce the risk of CRC.
Citation Format: Monireh Sadat Seyyedsalehi, Paolo Boffetta, Kazem Zendehdel. Fatty acid intake as potential risk factor of colorectal cancer: A multicenter case control study in Iran [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 6450.
Abstract 6633: T regulatory cell subsets in colorectal cancer: friends or foes
Authors: Elkord Eyad 
Published: June 2023

Abstract
T cells in the tumor microenvironment (TME) have diverse roles in anti-tumor immunity. Different T cell subsets may have opposing roles in tumor progression, especially in inflammatory cancers such as colorectal cancer (CRC). In different series of studies, we performed extensive characterization and critical analyses of T regulatory cell (Treg)-related markers and key inhibitory immune checkpoints (ICs) in CD4+ and CD8+ T cell subsets in the TME and periphery of CRC patients. We found a significant increase in levels of CD4+FoxP3+Helios+ T cells, which represent potentially highly immunosuppressive Tregs, in the TME. Additionally, tumor-infiltrating CD4+ T cells upregulated PD-1, CTLA-4, TIM-3 and LAG-3 immune checkpoints. CTLA-4, TIM-3, and LAG-3 were mainly co-expressed on FoxP3+Helios+ Tregs in the TME. Additionally, we found that FoxP3 expression and ICs including PD-1, CTLA-4, TIM-3, and LAG-3 were significantly upregulated in tumor-infiltrating CD8+ T cells. We then investigated associations between different tumor-infiltrating CD4+ and CD8+ T cell subpopulations and disease-free survival (DFS). Interestingly, a high frequency of circulating CD4+FoxP3+ Tregs was associated with poorer DFS, while higher frequency of these cells in the TME was associated with better DFS. Additionally, high frequencies of circulating CD4+FoxP3+Helios+ Tregs and tumor-infiltrating CD4+FoxP3-Helios- T cells were associated with poorer DFS. Moreover, a high frequency of CD4+FoxP3+Helios-PD-1+ Tregs in circulation was associated with worse DFS. In contrast, high frequencies of CD4+TIM-3+ T cells, FoxP3+Helios+TIM-3+ Tregs, and FoxP3-Helios+TIM-3+ CD4+ T cells in circulation were associated with longer DFS. Additionally, we found that high levels of certain circulating CD8+ T cell subsets (TIM-3+, FoxP3-Helios-TIM-3+ and FoxP3-Helios+TIM-3+ cells) were associated with longer DFS. In the TME, elevated levels of CD25+ and TIM-3+ CD8+ T cells, and FoxP3+Helios-TIM-3+ CD8+ Tregs were associated with better DFS. These data show that circulating and tumor-infiltrating immune checkpoint-expressing CD4+ and CD8+ Treg/T cell subsets play different roles in disease prognoses, and certain subsets could serve as independent predictive biomarkers in CRC patients.
Citation Format: Eyad Elkord. T regulatory cell subsets in colorectal cancer: friends or foes [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 6633.
Abstract 6634: Digital and spacial characterization of PD-L1 expression and IVD assay performance in the immune landscape of head and neck squamous cell carcinoma: A multimodal approach
Authors: Troccoli Clara , Matelski Lauren , Beharry Adam , Ly Vanessa , Wambaugh Morgan , Amen Melanie , Paces Will , Metcalf Geoffrey , Gianani Roberto , Turi Tom 
Published: June 2023

Abstract
The anti-PD-L1 antibody (22C3) is used as a companion diagnostic for successful checkpoint inhibitor therapy in head and neck squamous cell carcinoma. The positive predictive value of this assay, however, is less than ideal as a high PD-L1 score does not necessarily associate with a good response, and a good response may be seen with a low or negative PD-L1 score. In principle, this could be due to lack of accuracy and/or precision of the assay, as well as biological factors, such as variable expression across tumor cells and interacting immune cells. In this study, we describe a digital image analysis algorithm to address assay-related problems and improve both accuracy and precision, as well as improve identification of PD-L1 expression in differing cell populations of the tumor microenvironment. In addition, we propose a panel of assays that in aggregate might reveal inherent heterogeneity among cases with similar PD-L1 score and thus provide vital context underlying the efficacy of checkpoint inhibitors in the clinic. Here we show that applying novel machine-learning based digital image analysis to multiplex assays together with digital scoring of PD-L1 provides an accurate and precise assessment of the real-world tumor milieu that we hypothesize will help establish the immunophenotypes that inform therapeutic efficacy of checkpoint inhibitors. We have additionally interrogated whether expression of PD-L1 in these groups are consistent with known molecular patterns assayed using novel methodologies, such as high-plex digital spatial transcriptomics through the nanoString GeoMx Digital Spatial Profiler (DSP) platform and assessed the ability of the different digital platforms to provide concordant data relating to real-world expression patterns of PD-L1 and associated biomarkers. Thus, our results point to the importance of robust methodologies, used in combination, to evaluate complex tumor immune landscapes and the advantages of digital analyses to provide accurate and precise clinical contexts for better patient outcomes.
Citation Format: Clara Troccoli, Lauren Matelski, Adam Beharry, Vanessa Ly, Morgan Wambaugh, Melanie Amen, Will Paces, Geoffrey Metcalf, Roberto Gianani, Tom Turi. Digital and spacial characterization of PD-L1 expression and IVD assay performance in the immune landscape of head and neck squamous cell carcinoma: A multimodal approach [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 6634.
The Effect of Early College High Schools on STEM Bachelor's Degree Attainment: Evidence from North Carolina
Authors: Swiderski Tom 
Published: June 2023

Abstract
With growing demand for workers in science, technology, engineering, mathematics (STEM) and health care, it is important to assess not only whether education interventions impact educational attainment, but also students’ majors. This study examines the impact of Early College High Schools (ECHSs) on bachelor's degree attainment by field of study using data on four hundred thousand students from North Carolina (7,300 in an ECHS). Using propensity score weighting, I find that ECHSs increase bachelor's degree attainment within ten years of high school entry by 4.7 percentage points (19 percent over baseline), with STEM degree attainment increasing by 1.3 to 2.4 points (18 to 34 percent). However, within STEM and STEM-related fields, ECHSs increase degrees in the natural sciences (1.3 points or 45 percent), math/computer science (0.6 points or 60 percent), and psychology (1.2 points or 57 percent), but have null and directionally negative effects on engineering (−0.1 points or −7 percent) and health care (−0.3 points or −17 percent). Patterns are generally similar across student subgroups, though male students drive increases in computer science/mathematics, whereas female and White students drive decreases in health care. Thus, ECHSs increase STEM degree attainment overall, but more research is needed to examine whether intensive dual-enrollment experiences like the ECHS may create barriers or disincentives to pursuing certain STEM fields.
In the Shadow of Peace
Authors: Comstock Audrey L. 
Published: June 2023

Abstract
Despite decades of success, abuse has pervaded UN peacekeeping. This article argues that there has been a combination of incremental, conditional, and tenuous accountability for UN peacekeeping personnel accused of perpetrating sexual exploitation and abuse against civilians. This article argues that the relationship with accountability has been shaped by the reliance on troop-contributing countries to supply peacekeepers. This has limited the ability and desire of the UN to institute full accountability for peacekeeper actions. Looking at examples and trends of abuse and punishment, the article demonstrates that there has been a push-pull relationship of accountability between the media and nongovernmental organization reporting on one side and UN reliance on troop-contributing countries and institutional reluctance on the other side.
Sexual Violence and Peacekeeping
Authors: Johansson Karin , Kreft Anne-Kathrin 
Published: June 2023

Abstract
In the 1990s, conflict-related sexual violence (CRSV) started to transform into a matter of international security. Today, this is reflected in the Women, Peace and Security framework, which has left an impression also on UN peacekeeping mandates and operations, as well as on global protection imperatives. Simultaneously, academic attention to CRSV has skyrocketed in the past two decades. This article reviews what this growing body of research tells us about how peacekeeping authorities handle CRSV. In brief, scholars have identified encouraging trends in peacekeeping responsiveness to this violence, and prior research on its effectiveness in protecting civilians also gives cause for cautious optimism. Nonetheless, notable gaps in our knowledge remain, in particular when it comes to more local, fine-grained data and analysis. By way of conclusion, the article therefore outlines where the authors see the most promising avenues for future research on CRSV and peacekeeping.
African-Led Peace Support Operations in a declining period of new UN Peacekeeping Operations
Authors: Tchie Andrew E. Yaw 
Published: June 2023

Abstract
The United Nations is known to be the preeminent body to authorize and oversee international peacekeeping missions; however, new forms of African-led Peace Support Operations (PSO s) are increasingly common, innovative, and context-specific. This paper examines the evolution of African-led PSO s and argues that African-led PSO s are filling a vacuum and taking on responsibilities once assumed by the United Nations Peacekeeping Operations (UN PKO). The paper posits that the rise of African-led PSO s is due to the growing need for security and respond to the changing nature of conflict, the spread of insecurity and terrorism, and cross-border violence. Finally, the paper explores the implications of these operations for future missions in Africa, arguing that the future of African-led PSO s may be the preferred choice, with Regional Economic Communities and Ad-hoc Security Initiatives leading the way.