bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3161: Novel gene signature for predicting aggressive type of bladder cancer and the associated therapeutic strategies
Authors: Sheu Jim Jinn-Chyuan , Chang Chung , Lin Bo-Chen , Hwang Tritium 
Published: June 2023

Abstract
We have previously developed a unique HD-MAC (high-dimensional analysis of molecular alterations in cancer) platform that enables us to define independent tumor biomarkers from a group of clinically-significant genes. Using this platform, 26 genes were identified as independent prognosis biomarkers whose overexpression determine shorter overall survivals in patients with bladder cancer. Through clinical association study (including tumor stage, lymph node invasion, angiogenesis, and metastasis), a gene signature containing 6 biomarkers was established which can be validated by two independent cohorts. Gene knock down effects on cancer cell survival further revealed PPT2 and PRPF19 as potential targets for target-based therapy. Correlation study between genetic dependencies and drug sensitivities across cell lines suggested several potent lead compounds which are likely to function through similar mechanisms of gene effect actions. Our study therefore provides newly defined prognostic biomarkers as well as the associated therapeutic strategies for possible clinical applications in patients with bladder cancer.
Citation Format: Jim Jinn-Chyuan Sheu, Chung Chang, Bo-Chen Lin, Tritium Hwang. Novel gene signature for predicting aggressive type of bladder cancer and the associated therapeutic strategies [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 3161.
Abstract 3162: Genome-scale metabolic modeling suggests novel molecular targets in ER-positive breast cancer
Authors: Mudge Zachary B. , Kovacs Kristof , Kemp Melissa L. , Badve Sunil S. , Gokmen-Polar Yesim 
Published: June 2023

Abstract
High expression of the epithelial splicing regulatory protein 1 (ESRP1) is correlated with poor prognosis in estrogen receptor positive (ER+) breast cancer and acquired resistance to tamoxifen/endocrine therapies. Our previous study revealed a novel functionality of ESRP1 in metabolic dysregulation by affecting lipid metabolism and oxidoreductase processes. To further understand how metabolic programming is affected by ESRP1 expression and identify novel therapeutic targets, we developed systems biology models to explore ER+ breast cancer metabolism. Flux balance analysis (FBA) is a computational approach to predict steady-state fluxes through metabolic reactions by posing cellular “objectives” such as maximization of biomass, ATP, or minimization of reactive oxygen species that reflect selective pressures posed by the tumor microenvironment or therapeutic insults. Our custom FBA pipeline leverages transcriptomic data, mutation information, and thermodynamic constraints to generate personalized genome-scale metabolic models. In this study, 100 ESRP1-high and 100 ESRP1-low tumors from the TCGA Breast Cancer Invasive Carcinoma dataset were simulated and compared; in a secondary analysis, we simulated metabolic rerouting of tamoxifen-resistant LCC2 cells and fulvestrant-resistant LCC9 cells upon ESRP1 knockdown. The intersection of statistically significant (p &lt; 0.05) reactions that were altered in both the TCGA and cell line contexts suggested that changes in eicosanoid metabolism and androgen and estrogen synthesis pathways are highly involved in ESRP1's role in breast cancer prognosis and resistance to endocrine therapies. Eicosanoid-utilizing enzymes are consistently altered between the ESRP1-low and high conditions; Hematopoietic prostaglandin D synthase (HPGDS), prostaglandin I2 synthase (PTDIS), and thromboxane A synthase 1 (TBXAS1) are druggable. Furthermore, reactions associated with cytosolic and lysosomal 4-hydroxy-17beta-estradiol production, catalyzed by the enzymes myeloperoxidase, lactoperoxidase, and peroxiredoxin 6, also emerged as consistently altered across the groups. The findings from this methodology have suggested novel metabolic targets to overcome tamoxifen/endocrine therapy resistance in ER+ breast cancer. Experimental validation of these targets is currently underway.
Citation Format: Zachary B. Mudge, Kristof Kovacs, Melissa L. Kemp, Sunil S. Badve, Yesim Gokmen-Polar. Genome-scale metabolic modeling suggests novel molecular targets in ER-positive 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 3162.
Abstract 321: Metformin enhances the efficacy of enzalutamide treatment in castration-resistant prostate cancer
Authors: Simpson Kendall Elizabeth , Zhang ZhuangZhuang , Zhang Qiongsi , Liu Xiaoqi 
Published: June 2023

Abstract
Prostate cancer remains to be the most commonly diagnosed cancer among men in the United states with approximately 268,500 new cases a year. One of the first treatment options for men with prostate cancer is androgen deprivation therapy (ADT), however, recurrence and metastases after ADT remain an issue and are categorized as castration-resistant prostate cancer (CRPC). Enzalutamide, an FDA approved drug currently prescribed to patients with CRPC, inhibits androgen receptor (AR) nuclear translocation preventing the transcriptional activity of AR. This therapy typically only extends the survival of patients with CRPC and can lead to Enzalutamide-resistance over time accenting the importance of new therapy targets. Metformin, a commonly used FDA approved therapy for type 2 diabetes, has been recently investigated as potentially having anti-tumor effects in many cancer types. In this study, we use Enzalutamide and Metformin in combination to explore possible re-sensitization of Enzalutamide-resistant CRPC to Enzalutamide. Recently, we have tested the effects of this combination treatment on cell viability, drug synergy, and cell proliferation in Enzalutamide-resistant CRPC. After treatment, we see a decrease in cell proliferation and viability as well as a synergistic effect of both Enzalutamide and Metformin in Enzalutamide-resistant CRPC. Following these results, we sought to explore how this combination treatment effected key signaling markers for EMT, WNT signaling, and TGFβ signaling as well as key signaling markers for prostate cancer such as AR and prostate specific antigen (PSA). Since Metformin inhibits Complex I of oxidative phosphorylation, we also tested this combinational treatment using seahorse analysis to determine the mitochondrial respiration. After initial testing, we will continue to move forward in testing the effects of this combination treatment in Enzalutamide-resistant CRPC as well as further elucidate the underlying mechanisms contributing to this phenotype.
Citation Format: Kendall Elizabeth Simpson, ZhuangZhuang Zhang, Qiongsi Zhang, Xiaoqi Liu. Metformin enhances the efficacy of enzalutamide treatment in castration-resistant prostate 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 321.
Abstract 3264: Sotorasib, a selective G12C K-RAS inhibitor, modulates the tumor microenvironment to promote TNFα and IFNγ signaling and augment immunotherapy response
Authors: Ibrahim Mohammed L. , Foresman Dana , Zheng Hong , Haura Eric B. , Abate-Daga Daniel , Yu Xiaoqing , Beg Amer A. 
Published: June 2023

Abstract
KRAS-G12C mutation represents a highly prevalent mutation in lung and colon carcinoma with unfavorable clinical outcome. Recently, new compounds were developed that selectively bind to K-RAS with G12C mutation. While recent clinical results demonstrate activity of these compounds, their underlying mechanisms of action and impact on the antitumor immune response are not well understood. Here, we tested G12C-Kras inhibitor (Sotorasib/AMG-510) using multiple approaches. We found that Sotorasib significantly promoted the tumor regression and the expansion of tumor infiltrating lymphocytes (TILs) in both CT26-G12C heterotopic colon cancer, and KP-G12C autochthonous GEMM lung cancer mouse models, with more profound impact when combined with anti-PD1 ICB immunotherapy. In addition, it generated a “hot” tumor microenvironment with strikingly augmented T cell effector phenotype, endorsed by enrichment of MHC-II high macrophage and reduction of suppressive myeloid cells. Interestingly, Single cell RNA sequencing of CT26-G12C tumors shows an enrichment of tumor clusters with TNFα and IFNγ as top upregulated pathways in Sotorasib-treated tumors, generating a more immune active TME. These immune active tumor clusters were conserved or further expanded upon cotreatment with anti-PD1 ICI. Conversely, immune-deficient, or Sotorasib-resistant tumors exhibited a remarkable contraction of the immune active clusters, substantiating that the immune-modulatory impact of Sotorasib relies on tumor cells adaptation and their cross talk with the tumor infiltrated lymphocytes. In vitro, Single cell RNA sequencing of CT26-G12C cells also revealed that Sotorasib and TNFα/IFNγ cytokines are affecting different tumor clusters. Moreover, further in vitro testing demonstrated that Sotorasib dramatically enhances KRAS-G12C mutant cancer cell killing by PSCA-specific CART cells. These findings provide insight into the molecular basis of G12C-Kras inhibitor-mediated immune modulation in the TME and provide insight for combinatorial regimens with checkpoint inhibitor and adoptive T cell immunotherapy to achieve optimum anti-tumor activity.
Citation Format: Mohammed L. Ibrahim, Dana Foresman, Hong Zheng, Eric B. Haura, Daniel Abate-Daga, Xiaoqing Yu, Amer A. Beg. Sotorasib, a selective G12C K-RAS inhibitor, modulates the tumor microenvironment to promote TNFα and IFNγ signaling and augment immunotherapy response [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 3264.
Abstract 3338: Targeted serum metabolomics for noninvasive detection of colorectal neoplasia
Authors: Fitzgerald Liam W. , Orton Dennis J. , Kopciuk Karen A. , Vogel Hans J. , Hilsden Robert J. , Bathe Oliver F. 
Published: June 2023

Abstract
Background: Using a shotgun metabolomics approach, we have previously reported distinct features in the circulating metabolome of patients with colorectal cancer (CRC) and adenoma. A clinically useful metabolomic assay requires a targeted approach that detects CRC with high sensitivity, and which also detects pre-malignant precursor lesions. Our objective was to identify a metabolomic signature for CRC, adenomatous polyps (AP), and sessile serrated adenomas (SSA), using a targeted approach.
Methods: Serum from patients with all stages of CRC (N=86), AP (N=48), SSA (N=46), as well as age- and sex-matched disease-free controls (DFC; N=120) were analyzed using a targeted metabolomic assay (Biocrates MxP® Quant 500). The assay was performed on liquid chromatography-tandem mass spectrometry (LC-MS/MS), quantifying 630 metabolites across 26 biochemical classes. Orthogonal partial least squares-discriminant analysis (OPLS-DA) was used to identify metabolite patterns distinguishing each neoplastic condition relative to DFCs. A small validation cohort (N=78) was additionally analyzed to test our meta-biomarkers.
Results: In comparisons with DFCs, statistically significant OPLS-DA models were constructed for all three neoplastic conditions. The OPLS-DA models for CRC, AP, and SSA consisted of 39, 14, and 22 metabolites, respectively, with the most frequently represented biochemical classes being triglycerides, phosphatidylcholines, bile acids, and acylcarnitines. Based on 7-fold internal cross validation, receiver operating characteristic (ROC) analysis demonstrated an area under the curve (AUC) of 0.85, 0.89, and 0.82 for CRC, AP, and SSA, respectively. When applied to the independent validation cohort, the sensitivity and specificity of each model were: 87.0% and 87.0% for CRC; 53.3% and 93.3% for AP; and 78.6% and 57.1% for SSA.
Conclusion: Metabolomic meta-biomarkers for CRC and its precursors demonstrated excellent performance based on internal validation. Importantly, these lesions were each detected with superior sensitivity compared to readily available stool-tests. A large external validation study in progress will be used to confirm these findings.
Citation Format: Liam W. Fitzgerald, Dennis J. Orton, Karen A. Kopciuk, Hans J. Vogel, Robert J. Hilsden, Oliver F. Bathe. Targeted serum metabolomics for noninvasive detection of colorectal neoplasia [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 3338.
Abstract 3339: Circulating long non-coding RNA HULC as an early indicator of hepatocellular carcinoma irrespective of etiology
Authors: George Joseph , Tsuchishima Mutsumi , Tsutsumi Mikihiro 
Published: June 2023

Abstract
Background: Hepatocellular carcinoma (HCC) is the 6th most common cancer worldwide and is highly prevalent in Asian countries. Long noncoding RNAs (lncRNAs) are non-coding transcripts with a size of more than 200 bases in length. Several studies reported that lncRNAs are highly deregulated in HCC and could be used as biomarkers for early diagnosis and prognostic purposes. In the present study, we measured the circulating lncRNA HULC as an early diagnostic marker for HCC with different etiology.
Methods: Serum samples were collected from healthy controls, liver cirrhosis (LC), and HCC patients with different etiology and stored at -80°C until assay. Total RNA was extracted using Qiagen RNeasy kit and tested for RNA quantity and purity using NanoDrop spectrophotometer. The RNA extract that contains lncRNA HULC was transcribed into cDNA using a reverse transcription kit. Employing target specific primers for the lncRNA HULC, qRT-PCR was performed with the synthesized cDNA using Qiagen QuantiFast SYBR Green PCR kit on a Rotor-Gene qRT-PCR system.
Results: Quantification of lncRNA HULC using qRT-PCR in the serum samples demonstrated significant increase in LC cases and in all HCC cases irrespective of etiology compared to the normal healthy controls. The highest concentration was observed in serum samples from HCC patients with hepatitis B virus (HBV) infection, which was about 8 fold higher compared to healthy controls. There was no significant difference between the mean HULC lncRNA levels in HCC patients with different etiology such as alcoholic cirrhosis, LC due to other reasons, hepatitis B and hepatitis C virus (HCV) infections, and HCC developed from other unknown causes. However, serum HULC lncRNA levels in LC cases without HCC was significantly lower compared to all HCC samples.
Conclusions: The results of the present study demonstrated that there is a significant increase in HULC lncRNA levels in the serum samples of all HCC patients irrespective of etiology. Therefore, the circulating lncRNA HULC could be used as an early diagnostic biomarker for HCC before appearing other clinical symptoms.
Citation Format: Joseph George, Mutsumi Tsuchishima, Mikihiro Tsutsumi. Circulating long non-coding RNA HULC as an early indicator of hepatocellular carcinoma irrespective of etiology [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 3339.
Abstract 3344: Early detection biomarkers of LncRNA H19 genotypes for determining childhood leukemia susceptibility
Authors: Tsai Chia-Wen , Chang Wen-Shin , Chen Chao-Chun , Hsu Pei-Chen , Wang Yun-Chi , Pei Jen-Sheng , Bau Da-Tian 
Published: June 2023

Abstract
The purpose of our study was to investigate whether genetic variations in lncRNA H19 were associated with susceptibility to childhood leukemia. 266 childhood leukemia patients and 266 healthy controls were enrolled in Taiwan, and two single nucleotide polymorphisms (SNPs), rs2839698 and rs217727, in H19 were genotyped and analyzed. There was a significant difference in the genotypic distribution of rs2839698 between patients and healthy controls (p=0.0277). Compared to the wild-type CC genotype, the heterozygous variant CT and homozygous variant TT genotypes were associated with significantly increased risks of childhood leukemia with an adjusted odds ratio (OR) of 1.46 (95% confidence interval [CI], 1.08-2.14, p=0.0429) and 1.94 (95%CI, 1.15-3.31, p=0.0169), respectively (p for tread=0.0277). The difference in allelic frequencies between childhood leukemia patients and controls was also significant (T versus C,
adjusted OR = 1.53, 95%CI, 1.13-1.79, p=0.0077). There were no significant differences in the genotypic and allelic distributions of rs217727 between cases and controls. Our results indicated that H19 SNP rs2839698, but not rs217727, may serve as a novel susceptibility marker for childhood leukemia.
Citation Format: Chia-Wen Tsai, Wen-Shin Chang, Chao-Chun Chen, Pei-Chen Hsu, Yun-Chi Wang, Jen-Sheng Pei, Da-Tian Bau. Early detection biomarkers of LncRNA H19 genotypes for determining childhood leukemia susceptibility [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 3344.
Abstract 3589: The use of a novel orthotopic xenograft model of fusion negative rhabdomyosarcoma to study the effect of ASAP1 on tumor progression and metastasis
Authors: Hammoudeh Sarah M. , Ng Yeap , Yadav Mukesh P. , Weigert Roberto , Randazzo Paul A. 
Published: June 2023

Abstract
ASAP1 is a multidomain ADP-ribosylation factor (Arf) GTPase-activating protein (GAP) involved in the regulation of the actin cytoskeleton, focal adhesions dynamics and receptor tyrosine kinases trafficking. ASAP1 expression levels correlate with progression of solid tumors (e.g. breast, colorectal, pancreatic, ovarian, gastric, and prostate cancer). The first evidence for a role of ASAP1 in cancer progression was the discovery that the amplification of ASAP1 gene on chromosome 8 correlates with poor prognosis in uveal melanoma. A similar amplification of chromosome 8 has been reported in ~72% of fusion negative rhabdomyosarcoma (FN-RMS) tumors, suggesting a potential role for ASAP1 signaling in the progression of FN-RMS. To determine the function of ASAP1 in tumor growth, invasion and metastasis, we used a tongue orthotopic xenograft of FN-RMS which recapitulates physiologically relevant tumor progression and metastasis to lymph nodes and lungs, two of the common metastatic sites in patients. Using intravital microscopy, we observed that injected FN-RMS cells formed elongated structures and exhibited dynamic branching, which might represent local invasion. H&E stained of fixed tissue revealed invasion into the tongue and local metastasis. Metastases to the regional lymph nodes, lower mandible and lungs were also observed. Using this system, we are now able to determine effect of knocking down and knocking out ASAP1 on the progression of the xenografts, including invasion in real time and metastasis.
Citation Format: Sarah M. Hammoudeh, Yeap Ng, Mukesh P. Yadav, Roberto Weigert, Paul A. Randazzo. The use of a novel orthotopic xenograft model of fusion negative rhabdomyosarcoma to study the effect of ASAP1 on tumor progression and metastasis. [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 3589.
Abstract 3622: Characterizing the metastatic potential and clonal dynamics of invasive subpopulations in TNBC cells in response to chemotherapy
Authors: De Santiago Carolina , Brock Amy 
Published: June 2023

Abstract
Triple negative breast cancer (TNBC) is one of the deadliest forms of breast cancer and is characterized by its high rates of metastasis, significant intra-tumor heterogeneity and lack of hormonal treatments. Through utilization of a novel genetic cell tracking technology, ClonMapper, we identify and characterize the origins of invasive subpopulations.
Genetic barcodes are stably integrated into HCC1806 cells to generate starting parental populations of ~1000 unique barcoded cells. Invasive barcoded subpopulations were selected by migration through transwell assays for 24 hours and then collected for expansion. Clonal abundance sequencing across all replicates showed a &gt;8-fold decrease in the number of unique barcodes. Similarity was quantified using the Bray-Curtis and Cosine similarity indexes. 5 out of 8 replicates shared the same lineages, where more than 50% of the replicates were composed of the same 9 unique barcodes thus indicating the pre-existence of invasive clones. Following cell subpopulation isolation, we observed that isolated subpopulations display faster growth rates than parental populations. A scratch assay verified that the 5 similar invasive subpopulations displayed elevated migration rates in this 2D migration format (invasive populations vs parental population, n= 6). Separate transwell assays also confirmed the 3-dimensional migration rates of isolated subpopulations.
Parental HCC1806 and invasive subpopulations were treated with doxorubicin, cisplatin, paclitaxel and 5-flourouracil (5-FU) at their respective LD50 for 48 hours then allowed to recover to confluency before assessment by scratch assay. We observed that paclitaxel significantly decreased the migration rate, but that both doxorubicin and 5-FU resistant cells had a significantly higher migration rate (chemoresistant populations vs parental population, n=5) indicating that these drugs select for more migratory populations. Future studies will elucidate whether invasive clones are pre-existing or de novo and determine the effect of chemotherapeutics on these populations.
Citation Format: Carolina De Santiago, Amy Brock. Characterizing the metastatic potential and clonal dynamics of invasive subpopulations in TNBC cells in response to 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 3622.