bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3768: Optimization of digital pathology through laser capture microdissection with a 405 nm laser
Authors: Philipson Thomas , Howard Marissa , Johnson Kevin , Still Amanda , Yunusov Furkat , Petricoin Emanuel , Espina Virginia , Gonzalez Noel , Carpino Alan , Liotta Lance 
Published: March 2024

Abstract
Tumor cellular heterogeneity is a complex problem in cancer molecular diagnostics and personalized therapy. The tumor is a product of the different types and interactions of host and immune cells. Investigators have created a variety of methods to procure separate subpopulations of the tumor microenvironment for individual analysis. One of the most successful methods of this is laser capture microdissection (LCM). This method captures specific subpopulations of cells under direct microscopic visualization. This LCM technology has successfully been used for over 20 years, revealing a variety of insights into cancer pathogenesis and mechanisms of therapeutic response employed in numerous clinical trials. Nevertheless, there are two drawbacks to the current systems. For UV cutting (365 nm), the tissue is significantly damaged by the UV light energy. Infrared (808 nm) laser systems do not damage the tissue however, this method has low power and poor resolution. Our first hypothesis to be tested is that a new class of near UV 405 nm laser will have small capture areas approaching single cells while simultaneously preventing cellular damage. The second weakness of LCM is the requirement for an open-faced tissue section without a coverslip. Moreover, when visualizing the tissue of interest, the identification of regions of interest is obscured due to the refractive index mismatch between the laser microdissection cap and the tissue surface. We hypothesize that using a volatile organic compound with a refractive index similar to glass would elucidate the tissue region of interest to allow proper visualization. We successfully developed and tested a near 405 nm wavelength LCM system that utilizes a “liquid” coverslip to visualize the sample of interest with higher clarity, resolution, and contrast for immunohistochemistry, immuno-fluorescence, blood smear slides, and conventional hematoxylin-eosin tissue staining. Overall, these critical improvements LCM technology now allow for single-cell tissue capture, system automation, tissue visualization, and opens the door for artificial intelligence-assisted spatial profiling.
Citation Format: Thomas Philipson, Marissa Howard, Kevin Johnson, Amanda Still, Furkat Yunusov, Emanuel Petricoin, Virginia Espina, Noel Gonzalez, Alan Carpino, Lance Liotta. Optimization of digital pathology through laser capture microdissection with a 405 nm laser [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 3768.
Abstract 3782: IASLC grading system predict distant metastases for resected lung adenocarcinoma
Authors: Wang Yuezhu , Smith Margaret R. , Liu Yin , Green Mary E. , Hassan Omer A. , Balmaceda Alexandra M. , Sexton Tammy , Li Wencheng , Xing Fei 
Published: March 2024

Abstract
The International Association for the Study of Lung Cancer (IASLC) proposed a new histological grading system for invasive lung adenocarcinoma (LUAD). However, whether this new grading system is able to predict distant metastases in LUAD patients has not been evaluated. This study investigated the feasibility of using this grading system to predict the occurrence of brain and bone metastases in patients with resectable LUAD which identifies patients who have a high probability of developing distant metastases after surgery. We collected clinical information and pathological reports of 179 early stage LUAD patients who underwent resection during 2008 to 2015 from Wake Forest Comprehensive Cancer Center. All patients were followed up for 5 years and both bone and brain metastasis-free survival were calculated. Tumor grading of all samples was evaluated by both IASLC grading and predominant pattern-based grading systems. The ability of predicting distant metastases using IASLC grading and tumor stage were examined by receiver operating characteristic curves (ROC). 28 out of 179 patients developed distant metastases in five years with a median overall survival of 60 months for metastasis-free patients and 38.9 for patients with distant metastasis. Compared to predominant pattern-based grading system, IASLC grading system showed a stronger correlation with distant metastasis incidence. Complex gland pattern is enriched in patients who developed bone and brain metastases compared to metastasis-free patients. IASLC grading system also showed a superior prediction power of distant metastasis compared to tumor stage with area under curve (AUC) of 0.69 for brain metastasis and 0.71 for bone metastasis. IASLC grading system is capable of predicting the incidence of distant metastasis among early-stage invasive LUAD patients.
Citation Format: Yuezhu Wang, Margaret R. Smith, Yin Liu, Mary E. Green, Omer A. Hassan, Alexandra M. Balmaceda, Tammy Sexton, Wencheng Li, Fei Xing. IASLC grading system predict distant metastases for resected lung adenocarcinoma [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 3782.
Abstract 3826: Predictive and prognostic factors in NUT carcinoma: A systematic review and individual patient data meta-analysis
Authors: Abdulwali Sameeha K. , El-Sibai Abduljalil M. , Ali Saad S. , Alaklabi Abdulaziz M. , Abdalla Hytham M. , Sabbah Ahmad N. , Shafqat Areez , Fawzy Nader A. , Sabbah Belal N. , Badran Ahmed , Arabi Tarek Z. 
Published: March 2024

Abstract
Background: NUT carcinoma (NC) is a rare cancer affecting midline structures and involving the lung, bones, and lymph nodes. Data on NC are limited mostly to case reports and case series.
Methods: PubMed, Web of Science, and Scopus were systematically searched for original articles describing confirmed NC patients. A quantitative individual patient data meta-analysis (IPD-MA) analyzing overall survival and risk factors for progression was performed for all NC patients with a clear age at diagnosis. Relevant patient characteristics and clinical parameters were compared in a multivariate Cox regression model.
Findings: Out of 4,701 studies screened, 175 studies met the inclusion criteria for the systematic review. 117 (66.9%) were case reports. 284 patients were included in the IPD-MA. 139 (48.9%) patients were male, 145 (51.1%) underwent surgery, 156 (54.9%) received radiotherapy, and 173 (60.9%) developed metastasis. The mean age at diagnosis was 35.82±18.33 and the median OS was 9 months. 77 (27.1%) patients received platinum-based agents, 39 (13.7%) received taxanes, and 15 (5.3%) received BET inhibitors as part of their first-line regiment. Age at diagnosis, gender, and the aforementioned drugs did not significantly influence OS. Presence of metastasis was an independent predictor of poor survival, while radiotherapy and surgery were significantly associated with better survival (table 1).
Interpretation: NC is associated with poor survival. Surgery and radiotherapy appear to be more effective treatment strategies, while medical modalities may not play a major role in the treatment of NC.
Predictors of overall survival in NUT carcinoma patients. Parameter Hazard ratio 95% confidence interval P-value Age at diagnosis 0.99 0.99-1 0.35 BET inhibitors 0.61 0.28-1.15 0.16 Platinum-based agents 0.73 0.47-1.13 0.16 Taxanes 1.29 0.78-2.1 0.31 Surgery 0.41 0.29-0.58 &lt;0.0001 Female gender 1.12 0.83-1.51 0.45 Metastasis 1.76 1.26-2.49 0.0011 Radiotherapy 0.48 0.36-0.67 &lt;0.0001
Citation Format: Sameeha K. Abdulwali, Abduljalil M. El-Sibai, Saad S. Ali, Abdulaziz M. Alaklabi, Hytham M. Abdalla, Ahmad N. Sabbah, Areez Shafqat, Nader A. Fawzy, Belal N. Sabbah, Ahmed Badran, Tarek Z. Arabi. Predictive and prognostic factors in NUT carcinoma: A systematic review and individual patient data meta-analysis [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 3826.
Abstract 3859: HSP90 blockade activates antitumor immunity by suppressing tumor glycolytic flux in head and neck squamous cell carcinoma
Authors: Chen Fanghui , Tang Chris , Yang Fan , Ekpenyong Asari , Qin Richard , Saba Nabil F. , Teng Yong 
Published: March 2024

Abstract
Accumulating evidence suggests that failure of antitumor immunity may be due to dysregulation of energy metabolism. Head and neck squamous cell carcinoma (HNSCC) exhibits increased activity of two key enzymes, pyruvate kinase M2 (PKM2) and platelet phosphofructokinase (PFKP), which are central to the glycolytic pathway responsible for the conversion of glucose to ATP energy. HSP90 is a molecular chaperone that plays a critical role in the folding, stabilization, and regulation of a wide range of client proteins involved in various cellular processes, including metabolism. However, whether HSP90 signaling contributes to tumor metabolism rewiring and antitumor immune response remains unknown. Using ganetespib as a drug model for HSP90 inhibition and combining results from clinical trials and animal treatment, our study demonstrated that HSP90 inhibition causes an obstruction of glycolytic flux in HNSCC cells by simultaneously suppressing both PKM2 and PFKP at the transcriptional and post-translational levels. In addition, ganetespib enhances T cell-driven antitumor immune responses by promoting CD8+ T cell infiltration into the tumor. Mechanistically, ganetespib downregulates IL8 signaling by inhibiting PKM2 and PFKP-mediated glycolysis in HNSCC cells, which in turn contributes to ganetespib-mediated T cell tumor infiltration. These findings provide a novel molecular basis for the use of effective HSP90 inhibitors to improve the outcome of HNSCC patients.
Citation Format: Fanghui Chen, Chris Tang, Fan Yang, Asari Ekpenyong, Richard Qin, Nabil F. Saba, Yong Teng. HSP90 blockade activates antitumor immunity by suppressing tumor glycolytic flux in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3859.
Abstract 3866: Azvudine: An emerging immunomodulator in the treatment of cancer and viral infections
Authors: Li Pan , Jia Limin , Wang Zhaoyang , Du Jinfa 
Published: March 2024

Abstract
Azvudine (FNC) is a nucleoside analog that has secured approval from the CDE in China for the treatment of both AIDS and COVID-19. In these contexts, it has showed remarkable efficacy and safety when taken orally. Typically, nucleoside analog drugs function by integrating into DNA and impeding DNA synthesis, evident in drugs like 5-FU, Capecitabine, Ara-C, and Gemcitabine. Furthermore, FNC has been reported to exhibit robust anti-tumor properties, curbing cell proliferation, initiating G1 and S phase arrests, and advancing apoptosis across various human cancer cell lines. Grounded in this mode of action, we have ascertained that the anti-tumor effects of FNC intricately align with the expression of deoxycytidine kinase (dCK) both in vitro and in vivo. Remarkably, our studies delved into the effects and underlying mechanisms of FNC in enhancing the tumor microenvironment within solid tumors. Our findings, stemming from cell-based assays and in vivo animal experiments, elucidate the following: 1. FNC can trigger immunogenic cell death (ICD) in tumor cells. This is evidenced by the surface presentation and liberation of damage-associated molecular patterns (DAMPs) such as Calreticulin, HSP70, HSP90, Annexin A1, and HMGB1, which in turn stimulate both innate and adaptive immune responses. 2. FNC substantially reduces the population of monocytic-myeloid derived suppressor cells (M-MDSC) and Polymorphonuclear-myeloid derived suppressor cells (PMN-MDSC) in the tumor microenvironment. Concurrently, it boosts the infiltration and proliferation of CD8+T, CD4+T and NK cells. This instigates the transformation of the tumor microenvironment from a 'cold' state to a 'hot' one, enhancing the synergistic effects of PD-1 when used in tandem with FNC. This mechanism was substantiated through a high proportion of MDSCs observed in H22 and CT-26 syngeneic models, and contrastingly, a low proportion in MC38 and LL/2 in vivo syngeneic models. Notably, every animal subjected to combined FNC and PD-1 treatment in the H22 and CT-26 in vivo models witnessed complete tumor regression. Given these revelations, there's a compelling argument that FNC monotherapy possesses immense potential as an anti-tumor agent. The potent anticancer effects of FNC in vitro and in vivo warrants further investigation of its anticancer potential as immunomodulator.
Citation Format: Pan Li, Limin Jia, Zhaoyang Wang, Jinfa Du. Azvudine: An emerging immunomodulator in the treatment of cancer and viral infections [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 3866.
Abstract 391: Role of NRF2 in HIF-2α-mediated cancer stem cell phenotype
Authors: Kwak Mi-Kyoung , Hallis Steffanus P. 
Published: March 2024

Abstract
The acquisition of cancer stem cell (CSC) properties is influenced by the microenvironment, with tumor hypoxia playing a pivotal role. Elevated levels of nuclear factor erythroid 2-like 2 (NRF2), a redox balance-maintaining transcription factor, have been linked to enhanced tumor growth and therapy resistance. This study investigates the potential role of NRF2 in hypoxia-inducible factor-2α (HIF-2α) regulation in cancers. First, in a model of a 72-hour hypoxic incubation, chronic hypoxia led to CSC characteristics, including increased expression of KLF4 and OCT4, heightened cancer migration, and spheroid growth, which are associated with HIF-2α accumulation. NRF2 inhibition mitigated these effects, while NRF2 activation enhanced chronic hypoxia-induced CSC traits. Mechanistically, NRF2/miR181a-2 signaling emerged as a regulator of HIF-2α-mediated CSC phenotypes in chronic hypoxic conditions. Second, in clear cell renal cell carcinoma (ccRCC), characterized by pVHL gene mutation and constitutive HIF-2α elevation, the role of NRF2 in aggressive cancer phenotypes was explored. Silencing of NRF2 impaired aggressive phenotypes in multiple ccRCC cell lines with a reduction in HIF-2α expression. Promoter analysis elucidated that NRF2 directly upregulates HIF-2α expression through antioxidant response elements in the human HIF-2α gene. Collectively, our study suggests the involvement of NRF2/miR181a-2 signaling in the development of HIF-2α-mediated CSC phenotypes in sustained hypoxic environments and also proposes NRF2 as a promising target for mitigating HIF-2α-mediated CSC traits in ccRCC.
Citation Format: Mi-Kyoung Kwak, Steffanus P. Hallis. Role of NRF2 in HIF-2α-mediated cancer stem cell phenotype [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 391.
Abstract 3921: The aged tumor microenvironment limits CD8+ T cell control of cancer
Authors: Chen Alex C.Y. , Jaiswal Sneha , Martinez Daniela , Yerinde Cansu , Ji Keely , Miranda Velita , Fung Megan E. , Weiss Sarah A. , Zschummel Maria , Taguchi Kazuhiro , Garris Christopher S. , Mempel Thorsten R. , Sen Debattama R. 
Published: March 2024

Abstract
Aging is associated with progressive loss of immune function, which parallels the rise in cancer incidence. The etiology and impact of age-related CD8+ T cell dysfunction in cancer remain poorly understood. Here, we demonstrate that increased tumor growth in aged hosts is associated with reduced CD8+ T cell infiltration and function. The transfer of young antigen-specific CD8+ T cells fails to restore tumor control in aged hosts due to the rapid induction of CD8+ T cell dysfunction. The aged tumor microenvironment drives a novel age-associated dysfunctional state (TADys) that is functionally, transcriptionally, and epigenetically distinct from canonical CD8+ T cell exhaustion. Overall, this study focuses on understanding the cell-intrinsic and -extrinsic effects on CD8+ T cell immunity in aging and explores a proper strategy to improve CD8+ T cell control of cancer.
Citation Format: Alex C.Y. Chen, Sneha Jaiswal, Daniela Martinez, Cansu Yerinde, Keely Ji, Velita Miranda, Megan E. Fung, Sarah A. Weiss, Maria Zschummel, Kazuhiro Taguchi, Christopher S. Garris, Thorsten R. Mempel, Debattama R. Sen. The aged tumor microenvironment limits CD8+ T cell control of 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 3921.
Abstract 3930: The therapeutic implications of consensus genomic subtypes of gastric adenocarcinoma
Authors: Jeong Yun Seong , Eun Young-Gyu , Lee Sung Hwan , Kang Sang-Hee , Yim Sun Young , Kim Eui Hyun , Noh Joo Kyung , Sohn Bo Hwa , Lee Ju-Seog 
Published: March 2024

Abstract
Background: Gastric adenocarcinoma (GAC) is heterogeneous lethal disease in genomic and clinical level. Although the clinical relevance of genomic and molecular subtypes of GAC has been demonstrated, differences in classification methods have made it difficult to use these findings in clinical applications. We aim to examine a consensus of genomic subtypes and correlate them with clinical outcomes.
Method: We collected genomic data from 2527 GAC tumors and divided the data into discovery (n = 1427) and validation sets (n = 1100). A cluster of clusters approach (COCA) was used to find consensus subtypes of gastric tumors. We constructed the GAC predictor of the integrated consensus subtype with 120 genes (GPICS120) and applied it to the validation data set in order to validate the clinical significance of the new subtypes. By analyzing genomic and proteomic data we evaluated each subtype's potential response rate to standard and experimental treatments such radiation therapy, targeted therapy, and immunotherapy and further validated their functional significance in cell line models.
Results: We identified 6 clinically and molecularly distinct genomic consensus subtypes (CGSs) by integrating 8 previously established genomic subtypes. CGS1 is characterized by worst prognosis, remarkably high stem cell characteristics, high IGF1 expression, and low genomic alterations. CGS2 showed canonical epithelial gene expression patterns. CGS3 and CGS4 are characterized by high copy number alterations and low immune activity. CGS5 has highest mutation burden and moderately elevated immune activity that is characteristics of MSI-high tumors. The majority of CGS6 tumors have extremely high methylation, high immune activity, and are EBV-positive. The most intriguing finding is that CGS1 is the most responsive to immunotherapy whereas CGS3 is significantly associated with benefit of chemoradiation therapy due to high basal level of ferroptosis. Furthermore, we showed that ferroptosis inducer statin sensitized radiation-resistant GAC cells to ionizing radiation, suggesting that statin can be used to enhance the efficacy of chemoradiation in GAC and it would warrant further investigation in preclinical models.
Conclusion: Consensus subtype is robust classification system and can serve as the basis for future clinical trials as well as pre-clinical research into targeted subtype-based therapies.
Citation Format: Yun Seong Jeong, Young-Gyu Eun, Sung Hwan Lee, Sang-Hee Kang, Sun Young Yim, Eui Hyun Kim, Joo Kyung Noh, Bo Hwa Sohn, Ju-Seog Lee. The therapeutic implications of consensus genomic subtypes of gastric adenocarcinoma [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 3930.
Abstract 4014: Humanized mouse model to assess PBMC donor derived autologous CD19 CAR Ts for efficacy against Raji tumors and related cytokine release
Authors: Ramalingam Senthil , Cai Danying , Shopland Lindsay , Keck James G. 
Published: March 2024

Abstract
Immuno-oncology cell therapies engage the immune system to treat cancer. In recent years, adoptive T-cell therapy with CD19-specific chimeric antigen receptors (CARs) has shown promise for treatment of various malignancies, including acute lymphoblastic leukemia. However, CAR-T-cell therapies have been hampered by various adverse events, including cytokine release syndrome (CRS). To predict and minimize CRS effects from CAR-T therapies, a human immune preclinical murine model that combines efficacy and toxicity readouts is essential. Here, we describe the development of PBMC humanized mouse model based on the NSG-MHC I/II-DKO strain to study autologous CD19 CAR-T treatment related tumor growth inhibition and CRS in vivo. Three different PBMC donors were used to generate CAR-T (CD28-Cd3z) directed against a CD19 epitome. Our preliminary data demonstrate that CD19 CAR-T treatment stimulated dynamic and PBMC donor dependent cytokine release with IFN-g, IL-10, IL-4, IL-2, IL-6 and TNF. Our model showed elevation of shared proinflammatory cytokines (IFN-g, IL-10, IL-2 and TNF) observed in humans after CD19 CAR-T treatment. Currently, we are evaluating our PBMC based cytokine release model in CD19 CAR-T cells tumor control study. Our results to date indicate that PBMC-engrafted NSG-MHC I/II-DKO mouse models are vital platforms to screen adoptive T-cell therapy for potential CRS.
Citation Format: Senthil Ramalingam, Danying Cai, Lindsay Shopland, James G. Keck. Humanized mouse model to assess PBMC donor derived autologous CD19 CAR Ts for efficacy against Raji tumors and related cytokine release [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 4014.