bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6683: Genetic alterations of circulating tumor DNA in advanced pancreatic cancer patients receiving 5-fluorouracil based chemotherapy
Authors: Heo SooBeen , Park Sunhwa , Chun Jung Won , Kim Yun-Hee , Kang Jun-Kyu , Kim Hwang-Phill , Woo Sang Myung , Kong Sun-Young 
Published: April 2023

Abstract
Background: Pancreatic cancer remains one of the most devastating malignancies due to lack of target therapeutic options for advanced disease. Liquid biopsy which analyzes tumor-related biomarkers in blood, has emerged as an innovative technology. The aim of this study was to identify circulating tumor DNA (ctDNA) mutations in pancreatic adenocarcinoma(PDAC) patients using multi-gene panels.
Methods: Total of 45 patients (27 male, median age 63 years) blood samples were obtained at baseline then follow-up after 2 months samples were acquired in 16 patients at National Cancer Center, Korea from November 2021 to April 2022. CtDNA were analyzed by next-generation-sequencing (NGS) panel of 118 genes and the varient allele frequency (VAF) of detected genes were analyzed. Then the association between outcomes of 5FU treated response and survival (overall survival and progression-free survival; OS and PFS) and VAF reduction at follow-up were analyzed.
Results: Total of 35 genes with 114 genetic alterations were detected and frequent mutations were as follows: KRAS (29.9%), TP53 (14.9%), GNAS(4.4%), SMAD4(4.4%), AR(3.5%), RNF434(3.5%), ATM(3.5%), BRCA2(2.6%) and PIK3CA(2.6%). The mean VAF level considering all pathogenic variants of 45 patients was 8.9%(range, 0 - 87.2) including 8 patients who were not detected ctDNA mutations in baseline, and the mean VAF was 4.2% (0 - 50.0) at follow-up in 16 patients. With association of clinical response, patients with partial response (PR) and stable disease (SD) were decreased VAF from 11% at baseline to 10% after 2 months, and three (60%) of patients showed clearance of ctDNA. Progressive disease (PD) patients were also decreased VAF 67% after 2 months, however, clearance of ctDNA was only observed in one patient (12.5%). Reduction of ctDNA more than 50% were associated with longer survival as PFS (&gt; 50% reduction groups vs. no reduction group; 5 vs. 3 months, p value=0.903, OS (undefined vs. 6 months, p value =0.180).
Conclusions: This study showed most common mutation was KRAS with several other mutations of ctDNA in PDAC, and outcomes represented association with ctDNA.
Citation Format: SooBeen Heo, Sunhwa Park, Jung Won Chun, Yun-Hee Kim, Jun-Kyu Kang, Hwang-Phill Kim, Sang Myung Woo, Sun-Young Kong. Genetic alterations of circulating tumor DNA in advanced pancreatic cancer patients receiving 5-fluorouracil based chemotherapy [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 6683.
Abstract 6693: Stability of urinary cell-free DNA and detection of T790M variant
Authors: Münch Carolin , Shamkeeva Saikal , Heinemann Mitja , Isermann Berend , Kasimir-Bauer Sabine , Aktas Bahriye , Nel Ivonne 
Published: April 2023

Abstract
Background: The so-called “liquid biopsy” has become a powerful tool for cancer research in the recent years, with circulating cell-free DNA (cfDNA) that originates from tumors as one of the most promising analytes. In contrast to plasma derived cfDNA, only a few studies were performed investigating urinary cfDNA. One reason might be quick degradation and hence relatively low concentrations of urinary cfDNA. This study focused on examining the stability of cfDNA in urine using different ways of preservation under various storage conditions.
Methodology: To mimic patient samples, a pool of healthy male and female urine donors was spiked with a synthetic cfDNA reference standard (fragment size 170 bp) containing the T790M mutation in the EGFR gene and preserved with three different buffers and no buffer over four different storage periods (0; 4; 12; 24 h) at room temperature vs. fridge. Preservatives used were the Urinary Analyte Stabilizer (UAS, Novosanis), the Urine Conditioning Buffer (UCB, Zymo) and a self-prepared buffer called “AlloU”. The cfDNA was extracted with the QIAamp MinElute ccfDNA Mini Kit (Qiagen) and the concentration measured with the Qubit™ 4 fluorometer (Thermo Fisher Scientific). Droplet digital PCR (ddPCR) was used for detection and quantification of the T790M mutation (Bio-Rad)
Results: From the model samples with no preservation buffer, almost no spiked cfDNA could be recovered and the T790M variant could not be detected using ddPCR, indicating that without preservation cfDNA was degraded below the detection limit by the nucleases present in urine. The most effective stabilizing buffer over all storage periods and at room as well as fridge temperature was the UAS, resulting in accurate detection of the T790M variant using ddPCR.
Conclusion: From a technical point of view, urinary cfDNA might be useful for non-invasive disease monitoring when the samples are stabilized and stored adequately during clinical routine.
Citation Format: Carolin Münch, Saikal Shamkeeva, Mitja Heinemann, Berend Isermann, Sabine Kasimir-Bauer, Bahriye Aktas, Ivonne Nel. Stability of urinary cell-free DNA and detection of T790M variant. [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 6693.
Abstract 6697: Deep learning algorithm for cancer detection using multimodal characteristics of whole methylome sequencing of cf-DNA
Authors: Park Juntae , Kim Minjung , Park Sook Ryun , Song Ki-Byung , Jun Eunsung , Oh Dongryul , Lee Jeong-Won , Park Young Sik , Song Ki-Won , Byeon Jeong-Sik , Kim Bo Hyun , Ki Chang-Seok , Cho Eunhae 
Published: April 2023

Abstract
Background Various cell-free DNA (cfDNA) features including methylation and genomic profiles have been investigated for their potential use in early cancer detection. We developed deep learning models based the data generated by the enzymatic conversion based whole methylome sequencing of cfDNA.
Methods Cell-free whole genome Enzymatic Methyl sequencing(cfWEMseq) data were generated from 198 cancer patients (stage I: 11%, II: 17%, III: 22%, IV: 20%, unknown: 31%) and 69 healthy controls. The cancer types were consisted of breast (n=31), liver (n=24), esophageal (n=38), pancreatic (n=30), colon (n=34), ovarian (n=18), and lung (n=23). Sequence data was produced on average of 200 million reads using Novaseq 6000 (Illumina). For model training and evaluation, data partitioning was stratified by cancer type, and 5-fold cross validation was used. Coverage and methylation beta values ​​were calculated by binning at fixed size of 100K, 1M, and 5M base and variable size from Topologically Associated Domains (TAD). Genome Coverage (GC), Genome Methylation Beta values ​​(GMB), and Mutation Signature (MS) features were trained using a one-dimensional convolutional neural network (1D-CNN). The performance of the model was evaluated by measuring the average value of the results measured in each test set of 5 fold.
Results We tested the cancer detection performance of various feature combinations using all data from cfWEMseq (n=267). Regardless of the bin size, the GMB single model achieved higher performance than the GC single model. The best-performing model is the ensemble model of GMB (100k bin) and MS. The cancer detection performance of this ensemble model reached an accuracy 96% (CI: 93.6% to 98.1%), AUC 0.99 (CI: 0.97 to 1.0) and sensitivity 98.0% (CI: 92.4% to 99.5%) with a specificity of 90%.
Conclusions These results provide an opportunity for higher accuracies by integrating methylation information and genomic data using cfWEMseq. This research was supported through the National Research Foundation (NRF) funded by the Ministry of Science and ICT (2020M2D9A3094213).
Citation Format: Juntae Park, Minjung Kim, Sook Ryun Park, Ki-Byung Song, Eunsung Jun, Dongryul Oh, Jeong-Won Lee, Young Sik Park, Ki-Won Song, Jeong-Sik Byeon, Bo Hyun Kim, Chang-Seok Ki, Eunhae Cho. Deep learning algorithm for cancer detection using multimodal characteristics of whole methylome sequencing of cf-DNA. [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 6697.
Abstract 670: Sex differences in the innate immune response to lung cancer
Authors: May Lauren A. , Landry Joseph W. , Martin Rebecca , Li Howard Y. , Koblinski Jennifer , Bos Paula D. 
Published: April 2023

Abstract
Lung cancer is the second most diagnosed cancer. Lung cancer exhibits a sex difference, though the exact mechanisms behind this difference are not well understood. Men have a higher lifetime risk of developing lung cancer and often have more severe disease than women. There are thought to be multiple factors that contribute to this difference, including the environment, lifestyle, sex hormones, and differing immune responses. Mouse tumor models of lung, breast, colon, melanoma and kidney were used in immune competent or immune compromised mouse models treated with the chemotherapy ABT-263. The study of the immune response to lung tumors utilized ex vivo killing assays, multicolor flow cytometry, and clonogenic survival, as well as humanized mice and patient-derived xenografts. We observe a sex difference in two models of lung cancer in immunocompetent mice, but not in models of breast, colon, kidney, or melanoma. This difference is dependent on the innate immune system, specifically through natural killer cells and macrophages. This sex difference is lost in ovariectomized mice. Multicolor flow cytometry shows differences in innate immune cell populations in tumors and spleens in males and females. Preliminary data suggests the pro-apoptotic ligand TRAIL secreted from innate immune cells is more effective on cells exposed to female compared to ovariectomized female mouse serum. Reduced tumor growth in female mice can be further enhanced with ABT-263, and this effect requires NK cells. Patient-derived xenografts transplanted into female humanized mice grow more slowly than those transplanted into non-humanized mice, confirming the role of the immune system in modulating tumor growth. This research opens the potential for immune stimulating therapies, combined with ABT-263, as a novel treatment approach.
Citation Format: Lauren A. May, Joseph W. Landry, Rebecca Martin, Howard Y. Li, Jennifer Koblinski, Paula D. Bos. Sex differences in the innate immune response to 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 670.
Abstract 792: SARS-CoV-2 spike S1 mediated lung tumor regression in a mouse model
Authors: Sheinin Monica , Pahan Kalipada , Paidi Ramesh K. 
Published: April 2023

Abstract
Lung cancer is the leading cause of cancer related deaths worldwide, with a relatively low 5-year survival rate. Although there are some therapies against lung cancer, new effective treatment options are urgently required. Recently during the COVID-19 pandemic, we have seen that SARS-CoV-2 binds to its receptor angiotensin-converting enzyme 2 (ACE2) via spike S1 to enter the cells. This study underlines the importance of SARS-CoV-2 spike S1 in inducing death in human lung cancer cells. Interestingly, we have seen that recombinant spike S1 treatment at very low doses led to death of human A549 lung cancer cells. On the other hand, boiled recombinant SARS-CoV-2 spike S1 remained unable to induce death, suggesting that the induction of cell death in A549 cells was due to native SARS-CoV-2 spike S1 protein. SARS-CoV-2 spike S1-induced A549 cell death was also inhibited by neutralizing antibodies against spike S1 and ACE2. Moreover, our newly designed wild type ACE2-interacting domain of SARS-CoV-2 (wtAIDS), but not mAIDS, peptide also attenuated SARS-CoV-2 spike S1-induced cell death, suggesting that SARS-CoV-2 spike S1-induced death in lung cancer cells depends on its interaction with ACE2 receptor. Similarly, recombinant spike S1 treatment also led to death of H1299 and H358 human lung cancer cells. Finally, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) intoxication led to the formation tumors in lungs of A/J mice and alternate day intranasal treatment with low dose of recombinant SARS-CoV-2 spike S1 from 22-weeks of NNK insult (late stage) led to induced apoptosis and tumor regression in the lungs. These studies indicate that recombinant SARS-CoV-2 Spike S1 protein may have implications in the treatment of lung cancer.
Citation Format: Monica Sheinin, Kalipada Pahan, Ramesh K. Paidi. SARS-CoV-2 spike S1 mediated lung tumor regression in a mouse 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 792.
Abstract 821: Targeting metastatic prostate cancer using planetary ball-milled (PBM) nanoparticles
Authors: Singh Santosh K. , Lillard James W. , Singh Rajesh 
Published: April 2023

Abstract
Men are most likely to develop prostate cancer (PCa), which has a high morbidity and fatality rate. Chemotherapy, the most recommended therapeutic strategy to combat PCa, has shown adverse effects on patients and develops drug-resistant PCa resulting in overall restricted survival of the patients. Many studies have demonstrated that natural compound-mediated therapy can be an effective option for treating PCa. Among the natural compounds, Thymoquinone (TQ), a derivative of Nigella sativa, has shown anti-proliferative, antioxidant, and anti-cancer effects. However, issues remain regarding its bioavailability, safety, and effective delivery system to cancer cells in vivo. In this study, we developed TQ nanoparticles (NPs) alone or in combination with DTX-encapsulated planetary ball-milled nanoparticles (PBM-NPs), formulated with starch (natural polysaccharides) inner core and biodegradable co-polymers poly (ε-caprolactone)/poly (ethylene glycol), functionalized with a prostate-specific membrane antigen (PSMA) aptamer (A10) to target the metastatic niche in PCa metastasis pre-clinical (patient-derived xenograft (PDX) and intra-tibial metastatic (LNCaP, PC-3 cells were injected directly into the tibia of SCID mice.) models. To determine the minimum effective dose (MED), efficacy, and safety of PBM-NPs, mice were treated intravenously with dose levels of vehicle control (empty-PBM-NPs), DTX alone (5 mg/kg, weekly), TQ alone (10 mg/kg, weekly), and a combination of TQ and DTX (25-fold less than maximum tolerance dose) using PBM-NPs, respectively for five weeks. Blood serum chemistry for toxicity and immunohistochemistry were performed to characterize these metastatic models. Our results showed TQ+DTX PBM NPs suppressed p-EGFR, ERK1/2, ABCB1, and Caspase3-expression, which are regulated by the EGFR-dependent pathway. We detected OPG, RANKL, PTHrP, and ET-1 immunoreactivity in all xenografts in the bone. In conclusion, sustained-release of combination PBM NPs demonstrated more significant anti-tumor activity following their conjugation to a prostate cancer cell-specific ligand, the toxicity of the drug can be reduced, and effective concentrations of the drug can be maintained locally for prolonged periods and prevention of PCa bone metastasis.
Citation Format: Santosh K. Singh, James W. Lillard, Rajesh Singh. Targeting metastatic prostate cancer using planetary ball-milled (PBM) nanoparticles [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 821.
Abstract 854: A pharmaco-pheno-multiomic integration analysis of pancreatic cancer: A highly predictive biomarker model of biomarkers of Gemcitabine/Abraxane sensitivity and resistance
Authors: Silberberg Gilad , Killick-Cole Clare , Mosesson Yaron , Khoury Haia , Ren Xuan , Gilardi Mara , Ciznadija Daniel , Schiavini Paolo , Zipeto Marianna , Ritchie Michael 
Published: April 2023

Abstract
The overall survival of patients diagnosed with Pancreatic Cancer remains low. Initial responses to current therapeutic interventions are below 50%, leading to a high mortality rate shortly after diagnosis. To date, only a companion diagnostic, non-specific for pancreatic cancer, has been approved for this indication. A better understanding of the tumor cell biology and resistance mechanisms may shed light onto novel therapeutic targets that improve long-term outcome and improved patient stratification. In this study, we performed an exhaustive analysis to identify predictive biomarkers for gemcitabine/abraxane sensitivity using multiomics datasets. These datasets were integrated in a pharmaco-phenotypic-multiomic (PPMO) model predictive of therapeutic sensitivity or resistance, using sparse partial least squares (sPLS). Our results reveal major cellular discriminants in genomic variants, transcriptomics, and most pronouncedly in proteomics data. Tumors exhibiting Gemcitabine/Abraxane resistance associate with increased TPRV6 RNA expression, MUC13 protein expression, and USP42 mutation among others. Prospective application of the PPMO integration model was able to accurately predict Gemcitabine/Abraxane response profiles for 4/5 additional Pancreatic samples, therefore suggesting a potential application as a predictive diagnostic tool.
Citation Format: Gilad Silberberg, Clare Killick-Cole, Yaron Mosesson, Haia Khoury, Xuan Ren, Mara Gilardi, Daniel Ciznadija, Paolo Schiavini, Marianna Zipeto, Michael Ritchie. A pharmaco-pheno-multiomic integration analysis of pancreatic cancer: A highly predictive biomarker model of biomarkers of Gemcitabine/Abraxane sensitivity and resistance [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 854.
Abstract 869: Molecular genetic positioning of small intestine and papilla of Vater carcinomas including clinicopathological classification
Authors: Okamura Yukiyasu , Nakamura Masanori 
Published: April 2023

Abstract
Purpose: Small intestine carcinoma (SIC) cases in Japan have recently been treated with chemotherapy according to colorectal carcinoma classification, while papilla of Vater carcinoma (PVC) cases according to cholangiocarcinoma (CHC) classification. However, few research reports support the molecular genetic validity of these therapeutic choices. Here, we investigated the clinicopathological and molecular genetic factors of SIC and PVC.
Patients and Methods: We used the data from the Japanese version of The Cancer Genome Atlas (JCGA). Additionally, molecular genetic data on gastric adenocarcinoma (GAD), colorectal adenocarcinoma (CRAD), pancreatic ductal adenocarcinoma (PDAC), and CHC were also referred to.
Results: This study consisted of tumor specimens from 12 cases of SIC and three cases of PVC treated from January 2014 to March 2019. Among them, six cases had pancreatic invasion. t-Distributed Stochastic Neighbor Embedding analysis showed that the gene expression pattern of SIC was similar not only to those of GAD and CRAD, but also to that of PDAC in the pancreatic invasion cases. In addition, PVC resembled the GAD, CRAD, and PDAC, rather than the CHC. The molecular genetic characteristics of the six patients with pancreatic invasion were: one had high microsatellite instability (MSI-High), two had a TP53 driver mutation, and three had tumor mutation burden values &lt; 1 mutation/Mb with no driver mutation.
Conclusions: The molecular genetics of SIC and PVC suggested that they may be similar to GAD, CRAD, and PDAC. In addition, the data demonstrate that pancreatic invasive cases may be classified into several subtypes using molecular genetic factors.
Citation Format: Yukiyasu Okamura, Masanori Nakamura. Molecular genetic positioning of small intestine and papilla of Vater carcinomas including clinicopathological classification [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 869.
Abstract 899: Deciphering the benefits of variable delivery routes and molecular armoring to enhance efficacy of MUC1-CAR T-cells in targeting triple-negative breast cancer
Authors: Erler Piril , Cho Hana , Skinner Jordan , Poirot Laurent , Aranda-Orgilles Beatriz 
Published: April 2023

Abstract
As immune-therapies continue to develop for solid tumors, the tumor microenviroment (TME) poses many challenges that CAR T-cells need to overcome for efficient tumor cell clearance. Tumor immune evasion mechanisms, presence of immunosuppressive factors and cellular resistance to tumor infiltration are key mechanisms that the TME uses to reduce efficacy of T-cells against the tumor. Therapeutic options for triple negative breast cancer (TNBC) remain limited to date despite it being the most aggressive subtype of breast cancers and carrying the poorest prognosis. Tumor-associated MUC1 antigen is overexpressed in a large number of TNBC patients offering an effective discriminatory target for CAR T-cell therapy. Here, we present innovative strategies exploring alternative delivery routes and purposeful armoring of CAR T-cells to boost efficiency while preserving safety. To maintain anti-tumor CAR T-cell cytotoxic and proliferation in the hostile TME of solid tumors, we developed state-of-the-art multiplexed gene editing using high precision TALEN® technology. With that aim, we armored allogeneic CAR T-cells with specific attributes to release immune inflammatory cytokines and protect from inhibitory effects of the TGFB1 and PD1 pathways. A combination of strategies using allogeneic CAR T-cells with diverse attributes were evaluated against TNBC tumors in various in vivo pre-clinical models. Local CAR T-delivery resulted in effective control of tumor growth and robust antigen specific recognition. Furthermore, we assessed how the delivery route contributes to CAR-T cell distribution. CAR T-cell activity could also be increased systemically upon tumor-specific release of immunostimulatory cytokines without compromising safety. Our results demonstrate not only superior activity of armored MUC1-CAR T-cells resulting in tumor clearance but also in the recovery of normal glands. Thus, innovative strategies can be used to allow CAR T-cell efficiency in the hostile tumor microenvironment while preserving safety. Overall, our pre-clinical results underline the capability of armored allogenic MUC1-CAR T-cells to excel in the immune suppressive tumor micro-environment, suggesting that allogenic MUC1-CAR T-cell therapy could be an effective option in treating relapsed/refractory TNBC patients with limited therapeutic options.
Citation Format: Piril Erler, Hana Cho, Jordan Skinner, Laurent Poirot, Beatriz Aranda-Orgilles. Deciphering the benefits of variable delivery routes and molecular armoring to enhance efficacy of MUC1-CAR T-cells in targeting triple-negative breast 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 899.