bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2089: Vanishing deviance problem in high-dimensional penalized Cox regression
Authors: Yao Sijie , Li Tingyi , Cao Biwei , Wang Xuefeng 
Published: June 2023

Abstract
Penalized regression models, such as LASSO and elastic net, have been well-established for high-dimensional variable sections. For the analysis of censored survival outcomes, the penalized Cox regression model has been widely used. The parameter tuning in the penalized regression is often implemented based on the cross-validation (CV) via the “one standard error rule” (1se rule), resulting in a more parsimonious model. However, in a high-dimensional Cox regression model, a common observation is that the CV plot for tuning parameters against partial-likelihood deviance is often not U-shaped but L-shaped. In this case, the model selection will fail with either the “1se” or the“min” rule. We observed that this phenomenon is quite universal in the setting of high-dimensional prognostic biomarker selection, in which the standard CV steps often result in no or very few features included in the final model. We refer to this phenomenon as the “vanishing deviance” (VD) problem. In this study, we investigated this problem in more depth and demonstrated the issue and potential solution using real data from pan-cancer analysis of prognostic lncRNA biomarkers. To discover the cause behind the VD problem, we conducted an extensive set of simulations by varying sample sizes, feature dimensions, censoring rates, number of true biomarkers, and significance levels of true signals.Our results indicated that the main cause of the VD problem can be related to the limited sample size in the cancer omics dataset and a large number of true (or highly associated) biomarkers or signals underlying. To this end, we propose computational solutions that can alleviate the problem and we implemented them in the R package called CoxHive. We verified the performance of our solution based on both simulation studies and the analyses of the pan-cancer gene expression data. This software tool will greatly facilitate biomarker selection (including genomic and imaging biomarkers) in the high-dimensional setting.
Citation Format: Sijie Yao, Tingyi Li, Biwei Cao, Xuefeng Wang. Vanishing deviance problem in high-dimensional penalized Cox regression [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 2089.
Abstract 2100: Genomic profiles and immune cell infiltration landscapes for lymph node metastasis in T1 lung adenocarcinoma
Authors: Wu Fang , Pan Yue , Hu Chunhong , Chen Chen , Liu Wenliang , Fan Songqing , Shu Long , Zhao Lishu , Fu Yucheng , Zhang Sujuan , Liu Junqi , Zeng Yue , Peng Yurong , Zang Hongjing , Deng Chao , Qiu Zhenhua , Ma Fang , Yu Fenglei , Liu Xianling , Liu Lijuan , Yang Lingling , Shao Yang 
Published: June 2023

Abstract
Background: Comprehensive genomic and tumor immune microenvironment (TIME) analysis of T1 lung adenocarcinoma (LAD) may provide new insights into the biology of lymph node metastasis (LNM), thereby guiding surgical procedures and perioperative treatment.
Methods: A total of 212 cases of T1 LAD were included, of which 174 cases underwent whole exome sequencing to assess gene mutation and tumor mutation burden (TMB). Tumor mutation score (TMS) was constructed from LNM identified by LASSO regression. Immunohistochemical staining was performed to assess PD-L1 levels, tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) densities. Validation and supplementation were performed by RNA sequencing data from the TCGA database.
Results: A total of 25 genes were associated with the risk of LNM, of which STK11, NOTCH2, RHBDF2, EGFR, and CYP2D6 could be validated by RNA sequencing. The model predicted LNM (AUC = 0.904) and 2-year recurrence and metastasis (AUC = 0.700). Besides, TILs were negatively correlated with LNM of T1 LAD, while TAMs were positively (p&lt;0.05). Moreover, the TMS was correlated with the TIME, particularly TAMs(r=0.331, p&lt;0.001).
Conclusions: Tumor gene mutation promotes lymph node metastasis by changing the TIME, especially TAMs. Predictive models can identify high-risk patients and provide evidence for future studies of perioperative management.
Citation Format: Fang Wu, Yue Pan, Chunhong Hu, Chen Chen, Wenliang Liu, Songqing Fan, Long Shu, Lishu Zhao, Yucheng Fu, Sujuan Zhang, Junqi Liu, Yue Zeng, Yurong Peng, Hongjing Zang, Chao Deng, Zhenhua Qiu, Fang Ma, Fenglei Yu, Xianling Liu, Lijuan Liu, Lingling Yang, Yang Shao. Genomic profiles and immune cell infiltration landscapes for lymph node metastasis in T1 lung adenocarcinoma [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 2100.
Abstract 2101: Cancer-associated fibroblast activation predicts progression, metastasis, and prognosis of cutaneous squamous cell carcinoma
Authors: Knuutila Jaakko S. , Riihilä Pilvi , Nissinen Liisa , Kallionpää Roosa , Pellinen Teijo , Kähäri Veli-Matti 
Published: June 2023

Abstract
Purpose: Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer and the metastatic disease is associated with poor prognosis. At present, no established biomarkers are available for predicting the metastasis risk and prognosis of patients with cSCC. Cancer-associated fibroblasts (CAFs) promote the progression of cancer, but their role in cSCC is largely unknown. Here, we have examined the potential of CAF markers in the assessment of metastasis risk and prognosis of primary cSCC.
Experimental Design: We utilized multiplexed fluorescence immunohistochemistry for profiling of CAF landscape in metastatic and non-metastatic primary human cSCCs, the actual metastases, and in premalignant and benign epidermal lesions. Quantitative high-resolution image analysis was performed with two separate panels of antibodies for CAF markers and the results were correlated with clinical and histopathological parameters including disease-specific mortality.
Results: Increased stromal expression of fibroblast activation protein (FAP), α-smooth muscle actin, and secreted protein acidic and rich in cysteine (SPARC) were associated with progression of premalignant epidermal lesions to invasive cSCC. Furthermore, elevation of FAP and platelet-derived growth factor receptor-β (PDGFRβ) expression was associated with the risk of metastasis of primary cSCCs. High expression of PDGFRβ and periostin correlated with poor prognosis. Furthermore, a multi-marker defined CAF subset, PDGFRα-/PDGFRβ+/FAP+, was associated with invasion and metastasis and independently predicted poor disease-specific survival.
Conclusions: These results show, that fibroblast activation evolves during the progression of cSCC. High PDGFRβ expression alone and multimarker combination PDGFRα-/PDGFRβ+/FAP+ are potential biomarkers for the progression of primary cSCC to metastatic stage, and for poor prognosis.
Citation Format: Jaakko S. Knuutila, Pilvi Riihilä, Liisa Nissinen, Roosa Kallionpää, Teijo Pellinen, Veli-Matti Kähäri. Cancer-associated fibroblast activation predicts progression, metastasis, and prognosis of cutaneous squamous cell carcinoma [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 2101.
Abstract 2215: Periostin plays a crucial role in the recurrence of head and neck squamous cell carcinoma
Authors: Park Jung Je , Seo Ji Hyun , Won Seongjun , Ryu Somi , Baek Seung-Kuk , Koh Yoon Woo 
Published: June 2023

Abstract
Periostin (POSTN) is associated with many human tumors, such as colon, lung, breast, ovarian, prostate, and head and neck cancers. In this study, we focused on POSTN in Head and neck squamous cell carcinoma(HNSCC) because little is known about its possible role in carcinogenesis. This study aims to investigate the role of POSTN in the recurrence and prognosis of tongue cancer. A total of 97 patients diagnosed with tongue cancer in Gyeongsang National University Hospital between Jan 2012 and Dec 2017 were included. A retrospective review of medical records was performed, and the immunohistochemical staining with the POSTN antibody was done. Statistical analysis between cancer progression and POSTN expression was done. Referring to the clinical results that POSTN was related to the recurrence of tongue cancer, the effects of POSTN on HNSCC cell lines were investigated. Overexpression and depletion of POSTN were established in the HNSCC cell line. The results of POSTN in the HNSCC cell line were evaluated by colony-forming, migration, invasion, wound healing, and flow cytometry in vitro and in vivo. We also investigated the effects of POSTN overexpression and depletion on invasion, migration, and cell apoptosis. High expression of POSTN in HNSCC was related to cancer recurrence. In multivariate analyses, High expression of POSTN was a statistically significant risk factor for tongue cancer recurrence (HR, 16.8; p=0.040). Also, POSTN inhibits colony-forming, migration, invasion, and wound healing. This study showed that POSTN in HNSCC is a positive correlation with recurrence. And we also confirmed that POSTN promoted tumor progression in vitro and in vivo. POSTN plays an essential role in the growth and metastasis of tongue cancer and may be positioned as a therapeutic target for head and neck cancer.
Citation Format: Jung Je Park, Ji Hyun Seo, Seongjun Won, Somi Ryu, Seung-Kuk Baek, Yoon Woo Koh. Periostin plays a crucial role in the recurrence of head and neck squamous cell carcinoma [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 2215.
Abstract 2288: Longitudinal measurement of HPV copy number in cell-free DNA predicts progression-free survival in HPV-positive oropharyngeal cancer patients
Authors: Adamowicz Martyna Joanna , Carey Lara M. , Robert Christelle , Esnal-Zufiaurre Arantza , Warlow Sophie J. , Wescott Robert , Cuschieri Kate , Conn Brendan , Hay Ashley , Nixon Iain J. , Aitman Timothy J. 
Published: June 2023

Abstract
Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in global prevalence and is divided into two types dependent on association with human papillomavirus (HPV), with a more favorable prognosis in HPV+ve tumors. Assay of HPV copy number in plasma cell-free DNA (cfDNA) provides a minimally invasive method for detecting and monitoring tumor-derived HPV, with potential for enhancing clinical care. We have evaluated the utility of cfDNA droplet digital PCR (ddPCR) as a method for characterization and longitudinal monitoring of patients with OPSCC in a prospectively recruited cohort of 163 HPV+ve OPSCC patients. ddPCR assay of cfDNA for five HPV types showed overall 96.4% concordance with both p16 immunohistochemistry (IHC) and broad spectrum PCR analysis of solid tumor tissue. Longitudinal sampling in 105 HPV+ve patients, with median follow-up of 29 months, strongly predicted patient outcomes. Progression-free survival, stratified respectively by the presence or absence of detectable HPV cfDNA at a median of 13 weeks post-treatment, was 50% and 88% (p=0.001, hazard ratio 10.0 (95% CI 2.1-47.1)). In three patients sequential HPV measurement indicated cancer recurrence before the presence of clinical symptoms or detection on imaging. In two patients, greater reliance on sequential HPV measurement would have avoided surgical intervention which ultimately did not confirm disease presence. The high concordance of pre-treatment plasma cfDNA-HPV analysis with p16 IHC and HPV-PCR of solid tissue, together with the predictive value and utility of sequentially measured post-treatment cfDNA-HPV copy number, provide a compelling case for the routine use of cfDNA-HPV ddPCR in diagnostic classification and longitudinal monitoring of OPSCC.
Citation Format: Martyna Joanna Adamowicz, Lara M. Carey, Christelle Robert, Arantza Esnal-Zufiaurre, Sophie J. Warlow, Robert Wescott, Kate Cuschieri, Brendan Conn, Ashley Hay, Iain J. Nixon, Timothy J. Aitman. Longitudinal measurement of HPV copy number in cell-free DNA predicts progression-free survival in HPV-positive oropharyngeal cancer patients [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 2288.
Abstract 2856: Age-induced chronic accumulation of cortisol drives chemotherapy resistance in lung cancer
Authors: Raizada Devesh , Drapela Stanislav , Tejero Joanne , Sarigul Nadir , Ilter Didem , Gomes Ana 
Published: June 2023

Abstract
Lung cancer accounts for the largest number of cancer-associated deaths in the United States. While great strides have been made due to the introduction of immunotherapies and targeted therapies against oncogenic drivers, chemotherapies remain the standard of care for the majority of lung cancer patients. However, many patients do not respond to these treatments or relapse following an initial response. We postulate that part of the problem is the lack of consideration in preclinical research and clinical trials of the main driver of lung tumorigenesis, the aging process. Here, we show that the organismal reprogramming that occurs with aging makes lung tumors in an aged host more conducive to withstand chemotherapies. We traced this to an age-induced chronic accumulation of the stress hormone cortisol in circulation. Mechanistically our data show that chronic accumulation of cortisol drives the upregulation of metallothioneins—small, highly conserved, cysteine-rich metal-binding proteins—through activation of the glucocorticoid receptor in lung cancer cells, which in turn rewire these cells to be refractory to chemotherapies. Together, our work demonstrates a role for age-induced cortisol levels in promoting resistance to standard of care chemotherapies in lung cancer and offers a rationale for using therapeutic agents that block the glucocorticoid receptor to sensitize the average and most vulnerable lung cancer patients, the elderly, to chemotherapy.
Citation Format: Devesh Raizada, Stanislav Drapela, Joanne Tejero, Nadir Sarigul, Didem Ilter, Ana Gomes. Age-induced chronic accumulation of cortisol drives chemotherapy resistance in lung cancer [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 2856.
Abstract 2923: JAB-X1800: A potent immunostimulatory antibody-drug conjugate (iADC) targeting CD73
Authors: Ye Yang , Yang Guiqun , Wang Hongling , Sun Xin , Wang Yanping , Yan Fashun , Wang Lei , Long Wei 
Published: June 2023

Abstract
Background: STING emerges as a key immune sensor and activated STING pathway plays a key role in innate and adaptive immune response. STING agonist has shown promising potency to stimulate anti-tumor immunity. Considering immune-related toxicity due to systemic administration, as well as difficulty in intra-tumor administration, targeted delivery of STING agonist by iADC is warranted. We developed CD73-STING iADC JAB-X1800, which uses anti-CD73 mAb for targeted delivery of payload JAB-27670, a highly potent non-cyclic dinucleotide STING agonist.
Method: Binding assay and HEK293-STING-luciferase reporter assay were performed to test affinity of JAB-27670. Tumor cells with CD73 expression and THP-1 cells were co-cultured in the presences of iADC JAB-X1800 to assess the IFN-β production. The cell killing activity of iADC JAB-X1800 was evaluated when cancer cells co-cultured with human PBMCs. Furthermore, human and mouse plasma stability of iADC JAB-X1800 was assessed. Finally, the anti-tumor effects of iADC JAB-X1800 alone or in combination with anti-PD-1 were evaluated in animal models.
Results: JAB-27670 is a highly potent STING agonist with sub-nanomolar EC50 in binding and luciferase reporter assays. In CD73-expressing cancer cells and THP-1 co-culture experiments, iADC JAB-X1800 induced IFN-β production with significant improvement compared with the free payload. JAB-X1800 also induced potent killing in vitro. JAB-X1800 is stable in human and mouse plasma. A single dose of JAB-X1800 induced tumor regression in MDA-MB-231 xenograft model and hCD73-MC38 syngeneic model. JAB-X1800 conferred immunologic memory when tumor free mice were re-challenged. JAB-X1800 showed synergistic anti-tumor activity with anti-PD-1 in hCD73-MC38 syngeneic model.
Conclusions: The CD73-targeted STING agonist iADC JAB-X1800 demonstrated high stability in plasma, robust activity, and good tolerability in animal models, supporting clinical development of JAB-X1800 alone and in combination with anti-PD-1 for patients with CD73-expressing tumors.
Citation Format: Yang Ye, Guiqun Yang, Hongling Wang, Xin Sun, Yanping Wang, Fashun Yan, Lei Wang, Wei Long. JAB-X1800: A potent immunostimulatory antibody-drug conjugate (iADC) targeting CD73 [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 2923.
Abstract 3093: Synthesis and bioevaluation of LAT-1 efflux agonists for the treatment of pancreatic cancers
Authors: Moots Holly , Ikhlef Houssine , Sekhar Vandana , Phanstiel Otto 
Published: June 2023

Abstract
The purpose of this report is to describe the discovery and development of the world’s first L-type amino acid transporter 1 (LAT-1) efflux agonist. LAT-1 is used for the import of amino acid substrates (leucine, phenylalanine, and methionine) and LAT-1 expression has been showed to be increased in pancreatic ductal adenocarcinoma (PDAC) cells. LAT-1 is a promising target for the treatment of rapidly growing cancers, such as PDAC, in part, due to its key role in methionine import. Methionine is required for various cellular processes, including the generation of S-adenosylmethionine (SAM) and the maintenance of intracellular polyamine pools, which are essential for PDAC growth. Indeed, the biosynthesis of the higher polyamines (spermidine and spermine) requires the transfer of an aminopropyl group from decarboxylated S-adenosylmethionine (dc-SAM), illustrating the molecular connection between methionine and polyamine pools.
LAT-1 inhibition, such as with the known LAT-1 inhibitor JPH203, has shown efficacy in suppressing tumor growth in pancreatic cancer cell lines. While the early pre-clinical data is promising, competitive inhibitors of LAT-1 may have limited potency in the presence of high extracellular levels of LAT-1 substrates.
In contrast, LAT-1 efflux agonists are insensitive to extracellular LAT-1 substrates. These novel compounds reverse the flow of substrates through LAT-1, effectively depleting cells of key intracellular amino acids, rather than blocking the import of extracellular substrates like methionine.
The chiral piperazine (1), our lead efflux agonist, was discovered by a high throughput screen and was shown to deplete intracellular methionine, leucine and phenylalanine pools by LC-MS as well as decrease the synthesis of the higher polyamines (spermidine and spermine), a process which is reliant upon methionine as a precursor. A structure activity relationship (SAR) analysis of the four possible diastereomers of 1 was performed. The performance of these diastereomers and other derivatives were evaluated by LC-MS, HPLC, and Western blot. These molecules were shown to increase 3H-leucine efflux, decrease intracellular polyamine, SAM, and S-adenosylhomocysteine (SAH) levels, decrease phosphatidylethanolamine levels and induce the autophagic marker LC3-II. In summary, this novel method of methionine restriction allows one to alter intracellular methionine levels in a dose-dependent manner and provides a novel way to control pancreatic cancer cell growth.
Citation Format: Holly Moots, Houssine Ikhlef, Vandana Sekhar, Otto Phanstiel. Synthesis and bioevaluation of LAT-1 efflux agonists for the treatment of pancreatic cancers [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 3093.
Abstract 3111: The Sygnature CHARMD platform - combinatorial high-throughput assembly and review of molecular degraders
Authors: Hjerpe Roland , Birch Louise , Brien Alex , Cusin Lola , Duffy Lorna , Gourdet Benoit , Lawrence Rachel , MacFaul Philip , Mortlock Hannah , Neal Hannah , Pearce Christopher , Pitti Erica , Robles Gonzalo , Rodrigues Edith , Scott Catriona , Singh Rajesh , Thomson Stuart , Zhang Yujia , Jordan Allan 
Published: June 2023

Abstract
Recent interest the ability to degrade oncogenic proteins has grown exponentially, and the advent of Protein-Targeting Chimeras (PROTACs) has allowed many previously undruggable targets to be specifically targeted. However, the successful development of these bioavailable heterobifunctional degraders relies on the identification of a combination of ligase recruiter, linker and exit vector that allow formation of a competent ternary complex and target degradation. To this end, conventional single-compound synthesis is time-consuming and poses challenges for selection of degrader components with predictive SAR and ADME properties of the assembled bifunctional compound.
Here, we demonstrate a high-throughput integrated platform for generation and assessment of bifunctional degraders, incorporating combinatorial chemistry using both commercial and bespoke linkers, cell-based activity assays, and assessment of in vitro DMPK properties (lipophilicity, metabolic stability and experimental polar surface area). Alongside this, we have in place computational methods for ternary complex modelling, linker design and PROTAC prioritisation.
Altogether, our approach facilitates rapid screening and identification of bifunctional lead compounds for challenging oncology targets with the potential to deliver significant patient benefit. Our platform approach has been exemplified through application to oncology targets of significant current interests and our results in this area will be highlighted.
Citation Format: Roland Hjerpe, Louise Birch, Alex Brien, Lola Cusin, Lorna Duffy, Benoit Gourdet, Rachel Lawrence, Philip MacFaul, Hannah Mortlock, Hannah Neal, Christopher Pearce, Erica Pitti, Gonzalo Robles, Edith Rodrigues, Catriona Scott, Rajesh Singh, Stuart Thomson, Yujia Zhang, Allan Jordan. The Sygnature CHARMD platform - combinatorial high-throughput assembly and review of molecular degraders [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 3111.