bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3517: A deep learning-based virtual staining system with multimodal-attention for precision medicine
Authors: Zhou Zixia , Jiang Yuming , Li Ruijiang , Xing Lei 
Published: March 2024

Abstract
Purpose: This study introduces a novel multimodal-attention-based virtual mIF staining (MAS) system designed for efficient, reliable virtual mIF staining from label-free fluorescence images. Our goal was to overcome the performance bottleneck and time-cost limitations associated with traditional mIF techniques and thereby enhance their clinical utility.
Method and Materials: Our approach involved developing a cutting-edge MAS model. This model is built upon a sophisticated end-to-end generative convolutional neural network (CNN) architecture. It ingeniously leverages autofluorescence and 4',6-diamidino-2-phenylindole (DAPI) slides as inputs to generate mIF images. To achieve this, we equipped the model with feature extractors enhanced by pretrained masked auto-encoders (MAEs) and a self-attention combination strategy. These components worked harmoniously to extract antigen-label-related features and precisely locate specific cells within the images.
Results: In our comprehensive study, we engaged 94 gastric cancer patients, utilizing the MAS system for automated virtual mIF staining of seven biomarkers, namely CD3, CD20, FOXP3, PD1, CD8, CD163, and PDL1, in both cancerous and non-cancerous tissues. Importantly, the MAS-produced virtual mIF stains matched the quality of traditional manual stains. Furthermore, we validated the prognostic accuracy for gastric cancer using these virtual mIF images, demonstrating their ability to provide clinical information that is as reliable and valuable as that obtained from manually stained mIF images.
Conclusions: Our study identifies the MAS system as an important advancement in mIF staining, enhancing personalized medicine with its efficiency and quality. This tool holds significant potential to enable personalized medicine efficiently and cost-effectively, streamlining the process of diagnosing diseases, making prognoses, and developing treatment plans.
Quantitative Comparison of Ablation Experiments for MAS system in predicting multiple biomarkers Biomarkers Index U-Net (Avg±Std) ReU-Net (Avg±Std) Att-ReU-Net (Avg±Std) MAS (Avg±Std) CD3 PSNR 27.053±4.10 27.419±4.15 28.073±4.00 28.546±4.40 CD3 SSIM 0.733±0.07 0.724±0.07 0.728±0.05 0.742±0.07 CD20 PSNR 28.835±4.66 29.244±4.76 28.672±4.52 29.243±4.99 CD20 SSIM 0.921±0.058 0.921±0.057 0.915±0.051 0.923±0.051 FOXP3 PSNR 31.769±3.29 31.838±3.10 31.098±3.20 31.862±3.11 FOXP3 SSIM 0.613±0.11 0.618±0.11 0.617±0.112 0.617±0.12 PD1 PSNR 27.908±4.47 27.950±4.43 30.283±4.37 31.717±4.17 PD1 SSIM 0.654±0.13 0.659±0.13 0.694±0.12 0.726±0.11
Citation Format: Zixia Zhou, Yuming Jiang, Ruijiang Li, Lei Xing. A deep learning-based virtual staining system with multimodal-attention for precision medicine [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 3517.
Abstract 3640: RAB26 accelerates endometrial cancer cell progression by regulating the Hedgehog signaling pathway
Authors: Gao Chao , Liu Yanyan , Han Yanyan , Xue Fengxia , Wang Yingmei 
Published: March 2024

Abstract
As one of the most common gynecological malignant tumors, endometrial cancer (EC) is continuously being studied since its etiology is still not clear. RAB26, a member of the RAB family, has been shown to influence cell proliferation, metastasis and other malignant phenotypes in several cancers. However, whether and how RAB26 plays roles in EC remain unknown. Our previous study showed that RAB26 was related to the cell cycle-associated protein IK, which has been shown to contribute to carcinogenesis. Herein, we further explored the clinical significance and biological function of RAB26 in EC. Immunohistochemical staining of 615 endometrial tissue samples was conducted to explore whether RAB26 expression was related to the clinicopathological characteristics of EC. In vitro and in vivo experiments were used to evaluate the role of RAB26 in EC and investigate the underlying mechanism. RAB26 expression was higher in EC than in normal endometrium (NE), hyperplastic endometrium (HE) and atypical hyperplastic endometrium (AHE). High RAB26 expression was positively correlated with tumor histological grade (P=0.010), FIGO stage (P=0.042) and tumor size (P=0.003) in EC. RAB26 attenuation inhibited cell proliferation and metastasis but promoted cell apoptosis and caused G0/G1 arrest. After RAB26 attenuation, RNA sequencing data showed that the Hedgehog signaling (SHH) pathway was enriched. Further western blot results confirmed that the levels of SHH pathway proteins (SHH, PTCH1, smo and Gli1) decreased as RAB26 expression was attenuated. Moreover, an agonist of the SHH pathway, purmorphamine, blocked the inhibitory effect of RAB26 attenuation on EC progression. The results of an in vivo study also showed that RAB26 attenuation exerted a significant antitumor effect. Accordingly, RAB26 may act as an oncogenic protein to promote EC progression through the SHH pathway. RAB26 may be a potential target for the treatment of EC patients.
Citation Format: Chao Gao, Yanyan Liu, Yanyan Han, Fengxia Xue, Yingmei Wang. RAB26 accelerates endometrial cancer cell progression by regulating the Hedgehog signaling pathway [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 3640.
Abstract 3667: Nucleic acid quantification in uveal melanoma aqueous humor
Authors: Chang Christina , Pike Sarah , Reid Mark , Peng Chen-Ching , Xu Benjamin , Berry Jesse , Xu Liya 
Published: March 2024

Abstract
Introduction: Uveal melanoma (UM) is the most common primary adult intraocular cancer. Though radiation brachytherapy is often employed for UM treatment, half of UM patients develop systemic metastases. In large tumors with macular involvement, the disease and its treatment can lead to blindness. Clinically, UM prognosis is estimated by tumor size, location, American Joint Cancer Commission (AJCC) staging, and histologic findings. Prognostic UM biomarkers have been established but lesions &lt;2 mm in height, particularly near the fovea, are difficult to biopsy, and thus physicians often do not perform biopsies on such tumors. Therefore, the use of aqueous humor (AH) as a liquid biopsy is a promising methodology. The purpose of the study was to quantify analytes in AH samples collected at diagnosis and post-brachytherapy from UM eyes with varying tumor sizes and AJCC Stages to analyze correlations between analyte (dsDNA, microDNA, and protein) concentrations and tumor features.
Methods: This case series study included 119 UM AH samples from 66 UM eyes and 16 control AH samples collected from age-matched non-UM glaucoma (GLC) eyes analyzed for unprocessed analytes using Qubit fluorescence assays.
Results: Most UM AH samples contained quantifiable analyte concentrations (dsDNA: 94.1%, miRNA: 88.0%, protein: 95.2%) and at higher concentrations than GLC controls (dsDNA, P=0.008; miRNA, P&lt;0.0001; protein, P=0.007). In samples taken at diagnosis, concentrations were higher at more advanced AJCC stages; comparing most advanced Stage III (n=8) to least advanced Stage I (n=24), median dsDNA was 4 times greater (P&lt;0.0001), protein was 3 times greater (P&lt;0.0001), and miRNA was 2 times greater (P=0.001). Analytes were quantifiable in &gt;70% of pre-brachytherapy samples from eyes with tumors &lt;2 mm tall (n=17). Height was positively associated with analyte concentrations at diagnosis (dsDNA: R=0.43, P=0.0007; miRNA: R=0.35, P=0.01; protein: R=0.39, P=0.005). In paired samples (n=53), all analyte concentrations were significantly higher post-therapy compared to diagnosis pre-therapy (Ps&lt;0.01).
Conclusions: Although AH analytes were also quantifiable in smaller, less advanced tumors, AH samples from eyes with larger, more advanced tumors had higher analyte concentrations. The detection of prognostic biomarkers in AH may allow for early UM recognition and guide personalized treatment.
Citation Format: Christina Chang, Sarah Pike, Mark Reid, Chen-Ching Peng, Benjamin Xu, Jesse Berry, Liya Xu. Nucleic acid quantification in uveal melanoma aqueous humor [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 3667.
Abstract 3669: Clinical application of urinary DNA methylation biomarkers for identifying patients with non-muscle invasive bladder cancer
Authors: Bonora Giancarlo , Zhu Ziqi , Gould Billie , Xiang Binggang , Zhou Kemin , Jia Shidong , Li Roger , Du Pan 
Published: March 2024

Abstract
Introduction
Differences in DNA methylation along cell-free DNA (cfDNA) fragments are known to exist between cancer patients and healthy individuals. Profiling these aberrant methylation patterns in urinary cfDNA (ucfNDA) holds great promise for the non-invasive detection and monitoring of bladder tumors, including non-muscle invasive bladder cancer (NMIBC). Here, we analyzed fragment-level DNA methylation patterns in urine samples obtained prior to repeat transurethral resection of a bladder tumor (reTURBT) from a cohort of NMIBC patients. The results were compared to traditional clinical disease assessment and mutation-based tumor fractions. We found a strong concordance between DNA methylation abnormality and clinical diagnosis, as well as tumor fractions, highlighting the potential of epigenetic alterations as a non-invasive indicator of bladder cancer status.
Methods
Patients with high-risk NMIBC (n = 30) were prospectively enrolled prior to reTURBT. The PredicineEPIC™ genome-wide methylation analysis and PredicineBEACON™ MRD profiling was performed on pre-repeat TURBT urine samples. Abnormally methylated genomic fragments were detected against a background model built from a panel of plasma samples from healthy donors.
Results
DNA methylation abnormality was significantly higher (p = 4.8 × 10−6) in samples classified as NIMBC positive by a clinical pathologist (n = 19) compared to negative samples (n = 11), as well as compared to hold-out healthy donor samples (n=24; p = 7.0 × 10−9). Classifying the samples based on a DNA methylation score cut-off derived from healthy donor samples, 24/30 samples showed concordant disease status. Furthermore, DNA methylation abnormality scores correlated positively with mutation-based tumor fractions (r = 0.62), with higher grade samples showing a stronger correlation (r = 0.81; n = 13) than lower grade samples (r = 0.54; n = 17).
Conclusion
We demonstrate the utility of methylation patterns extracted ucfDNA samples obtained prior to reTURBT to detect and monitor NMIBC. Urinary DNA methylation patterns were highly concordant with clinical pathology status and as well as tumor fractions determined from mutation analysis.
Citation Format: Giancarlo Bonora, Ziqi Zhu, Billie Gould, Binggang Xiang, Kemin Zhou, Shidong Jia, Roger Li, Pan Du. Clinical application of urinary DNA methylation biomarkers for identifying patients with non-muscle invasive 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 3669.
Abstract 3733: Gut microbiota-dependent bile acidtaurodeoxycholic acid, TDCAfacilitates anti-tumor immune responses by modulating cytotoxic CD8 T cell immunity
Authors: li Wenng , Wang Hesuiyuan , Coughlin Laura , Poulides Nicole , Valle Priscilla Del , Lichterman Jake , Zhan Xiaowei , Liao Chen , Palmer Suzette N. , Li Xin , Koh Andrew Y. 
Published: March 2024

Abstract
Gut microbiota are critical for effective immune checkpoint blockade therapy (ICT) for cancer. However, the underlying mechanisms by which gut microbiota and/or microbiota-derived metabolites augment antitumor response are largely unknown. Here, we utilized a preclinical melanoma (B16-F10) model and treated groups of mice (Jackson, C57BL/6J, female, 6-8 wks, n=14-26 per group) with seven distinct antibiotic treatments to induce unique gut microbiomes and metabolomes. Mice were then treated with ICT (anti-PD-1 and anti-CTLA-4), resulting in markedly heterogeneous tumor phenotypes (tumor volume and weight) as dictated by the specific antibiotic treatment. Using machine learning (e.g. random forest classifier), we identified metabolite candidates most strongly associated with ICT response (i.e. tumor volume and weight).One metabolite candidate, the bile acid taurodeoxycholic acid, TDCA, had previously been identified by my group as associated with anti-PD-1/anti-CTLA-4 response in human melanoma patients (PMID 28923537). Administration of TDCA alone is sufficient to overcome antibiotic-induced ICT hyporesponsiveness in mice. Utilizing both in vitro/ex vivo immune cell assays and in vivo preclinical models, we have validated that TDCA treatment directly boosted the antitumor cytotoxic CD8+ T cell responses (i.e. IFN-gamma production, anti-tumor cytotoxicity, tumor growth, etc.) without affecting innate immune responses. Bulk RNAseq of CD8 T cell analysis indicated that TDCA modulate CD8 T cell function through IFN pathway. Together, our findings suggest that the gut microbial metabolite TDCA could promote immunotherapy efficacy through regulation of CD8+ T cell immunity and has the potential to be utilized as a novel therapeutic agent to enhance ICT efficacy.
Citation Format: Wenng li, Hesuiyuan Wang, Laura Coughlin, Nicole Poulides, Priscilla Del Valle, Jake Lichterman, Xiaowei Zhan, Chen Liao, Suzette N. Palmer, Xin Li, Andrew Y. Koh. Gut microbiota-dependent bile acidtaurodeoxycholic acid, TDCAfacilitates anti-tumor immune responses by modulating cytotoxic CD8 T cell immunity [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 3733.
Abstract 3735: Combinatorial targeting of tumor-microenvironment together with antigen vaccination using innovative nano-immuno-gel for enhanced cancer-immunotherapy
Authors: Sunilkumar Anjali Kozhissery , Salvi Margaux , Mohammed Saira Nujoom , Zakkariya Zahara Thaivalappil , Cadena Alejandra Gomez , Chappan Shalin , Radhakrishnan Sreedevi Panachithanathu , Manohar Maneesh , Keechilat Pavithran , Nair Shantikumar , Romero Pedro , Jandus Camilla , Koyakutty Manzoor 
Published: March 2024

Abstract
Successful cancer-immunotherapy need to address three critical factors: a) Relieving the immuno-suppressive tumor microenvironment (TME) b) expanding antigen specific, functionally avid effector T cells, c) triggering systemic immunity with a balanced innate-adaptive response for continued effector cell-feeder supply-chain and memory generation. Combinatorial engagement of such multi-elemental components demands smart, engineered immunotherapy systems compared to conventional vaccines. Here, we report an injectable Nano-Immuno-Gel (NIG) that can neutralize immunosuppressive components (e.g., myeloid derived suppressor cells (MDSCs), M2 macrophages (Mϕ) in TME, together with generating strong effector T cells by nano-vaccination, and sustained release of cytokines to enhance systemic immunity against tumor. In a proof-of-concept study, we show that sustained-release of myeloid-suppressive drug from NIG depot efficiently inhibited MDSCs and M2 Mϕ, not only in TME, but also in the circulation and in peripheral systems, thus creating a conducive, hot TME infiltrated with CD8 effector cells. Follow-up antigen vaccination with novel nano-adjuvant enhanced DC-T cell engagement and sustained IL15 release from NIG provided systemic NK/T cell activation, rendering significant control of the tumor growth. Our data demonstrate the potential of rationally engineered multi-functional nano-immuno-gels (NIG) to combine sequential neutralization of the suppressive TME, antigen vaccination, and concurrent systemic immune activation for highly effective combinatorial cancer immunotherapy.
Citation Format: Anjali Kozhissery Sunilkumar, Margaux Salvi, Saira Nujoom Mohammed, Zahara Thaivalappil Zakkariya, Alejandra Gomez Cadena, Shalin Chappan, Sreedevi Panachithanathu Radhakrishnan, Maneesh Manohar, Pavithran Keechilat, Shantikumar Nair, Pedro Romero, Camilla Jandus, Manzoor Koyakutty. Combinatorial targeting of tumor-microenvironment together with antigen vaccination using innovative nano-immuno-gel for enhanced cancer-immunotherapy [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 3735.
Abstract 3916: TNG260, a small molecule CoREST inhibitor, sensitizes STK11-mutant NSCLC to anti-PD1 immunotherapy
Authors: Patel Ayushi , Sahu Soumyadip , Geng Ke , Punekar Salman , Stephens Janaye , Deng Jiehui , Chen Ting , Ahronian Leanne , Zhang Minjie , Andersen Jannik , Haines Brian , Wong Kwok-Kin 
Published: March 2024

Abstract
Loss of function (LOF) of the serine-threonine kinase STK11/LKB1, which has been reported in ~15% of non-small cell lung cancer (NSCLC), drives resistance to immune checkpoint therapies such as PD1. In vivo CRISPR screens in tumor-bearing immune competent mice identified the Corepressor of Repressor Element 1 Silencing Transcription (CoREST) complex as a synthetic lethal immune evasion target for STK11- mutant tumors. Here, we demonstrate that TNG260, a small molecule drug specifically targeting the CoREST complex, can sensitize STK11 mutant lung cancers to anti-PD1 immunotherapy. Combination treatment with TNG260 and anti-PD1 arrested KRAS/STK11 mutant NSCLC tumor growth with no major toxicity observed, as confirmed in both allograft and genetically engineered mouse models (GEMMs) of STK11 mutant NSCLC. Further transcriptional analysis via bulk RNA-seq revealed that treatment of KRAS/STK11 mutant lung tumors with TNG260 promotes genes related to inflammatory responses and suppresses genes related to cell cycle and mitotic checkpoint(s). This phenotype was not observed in STK11 wildtype KRAS/P53 mutant lung tumors. Furthermore, combinational treatment of TNG260 with PD1 antibody showed increased macrophages, neutrophils and dendritic cells signatures in vivo. Our data suggests that epigenetic reprogramming via TNG260 sensitizes STK11 mutant NSCLC tumors to anti- PD1 treatment via targeting of the CoREST complex. This work identifies new vulnerabilities in STK11 LOF cancers that can be exploited therapeutically. TNG260 is currently being investigated in combination with pembrolizumab for the treatment of STK11-mutant cancer (NCT05887492), including NSCLC.
Citation Format: Ayushi Patel, Soumyadip Sahu, Ke Geng, Salman Punekar, Janaye Stephens, Jiehui Deng, Ting Chen, Leanne Ahronian, Minjie Zhang, Jannik Andersen, Brian Haines, Kwok-Kin Wong. TNG260, a small molecule CoREST inhibitor, sensitizes STK11-mutant NSCLC to anti-PD1 immunotherapy [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 3916.
Abstract 393: RAS and PI3K activation promote glioblastoma progression and ischemia-associated tumor cell death
Authors: Kim Soo Yeon , Tang Miaolu , Chih Stephen , Thorpe Jessica , Lu Tong , Wang Hong-Gang , Li Wei 
Published: March 2024

Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor in adults. Despite the association of tumor necrosis and a poor prognosis in GBM, the mechanisms underlying tumor necrosis formation remain unclear, likely due to the lack of appropriate experimental models to examine the development of tumor necrosis. In our study, we developed mouse models with tumor necrosis by intracranially injecting human GBM cells expressing KRAS or PI3K active mutants into immunodeficient mice. Surprisingly, despite all tumors displayed similar sizes, the control tumors expressing an empty vector (EV) did not exhibit tumor necrosis. This intriguing observation led us to explore the potential role of KRAS and PI3K in promoting cell death within the tumor microenvironment. Ischemia, which is characterized by insufficient nutrients and hypoxia, is often found in GBM. Under an in vitro ischemia mimetic condition, we found that the KRAS or PI3K activated GBM cells showed more cell death compared to EV cells. Mechanistically, ischemia activates the p38 MAPK-MK2 pathway to induce cell death, a process further enhanced by KRAS or PI3K. Notably, we observed elevated expression of p-MK2 in the peri-necrotic areas of GBMs harboring KRAS or PI3K mutants compared to the cellular tumor zones. Moreover, we revealed that ischemia induces the unfolded protein response (UPR) pathway. Among UPR-related molecules, KRAS and PI3K upregulate ERN1, which encodes the transmembrane protein kinase IRE1, in ischemic conditions. Inhibition of ERN1 not only prevented ischemia-induced cell death but also inhibited the p38 MAPK-MK2 pathway. Furthermore, we observed an increase in the expression of pro-inflammatory cytokine IL-8 under ischemic conditions, a response that was prevented by inhibitors of p38 MAPK or MK2. Lastly, we found that ischemia induces ATP release and calreticulin exposure, indicating the cell death possessing certain immunogenic cell death features. In summary, our findings revealed a pivotal role of KRAS and PI3K in inducing cell death in the ischemic GBM tumor microenvironment through activating the IRE1-p38 MAPK-MK2 pathway. The cell death under this circumstance displays pro-inflammatory and immunogenic properties. Therefore, the IRE1-p38 MAPK-MK2 pathway may be exploited for the treatment of GBM in which RAS or PI3K is activated.
Citation Format: Soo Yeon Kim, Miaolu Tang, Stephen Chih, Jessica Thorpe, Tong Lu, Hong-Gang Wang, Wei Li. RAS and PI3K activation promote glioblastoma progression and ischemia-associated tumor cell death [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 393.