bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1414: Assessment of the Cancer Testis antigen AKAP4, via tumor expression analysis and IHC, as a potential vaccine and immunotherapy target for colorectal cancer
Authors: Herath Mudiyanselage Chandana S. K. , Mitra Neil , Caballero Otavia L. , Gamage Dasuni N. , Yan Xiaohong , Cekic Vesna , Martz Joseph , Whelan Richard L. 
Published: June 2022

Abstract
Introduction: Cancer-Testis antigens (CTA’s) are normally expressed in germline tissue, however, aberrant expression occurs in some cancers. Restricted CTA expression in normal tissues make CTA’s potential vaccine targets. CTA’s have been associated with tumor cell proliferation and invasion. The CTA A-kinase anchor proteins 4 (AKAP 4) plays a role in cancer development and progression. The expression pattern of AKAP4 gene in CRC is not well characterized. This study’s aim was to assess AKAP4 expression in CRC and to assess this CTA’s potential as a vaccine target.
Methods: CRC patients (pts) undergoing surgery who donated tissue to an IRB approved tissue/data bank comprise the study group. Demographic and pathologic data were assessed. Tissues were OCT embedded and stored at -800C. Total purified RNA was isolated from tissue samples and cDNA synthesized. AKAP4 expression was analyzed by quantitative PCR (QPCR) using EXPRESS qPCR universal Supermix and Taqman assay. Comparative quantitative analysis was performed based on the delta-delta Ct method with GAPDH as internal control. Tumor and testis AKAP4 expression levels were determined; tumors with levels 0.1% or more than the testis was considered positive. Immunohistochemistry (IHC) was performed on a subset of tumor and normal tissue. The impact of tumor location and cancer stage on AKAP4 expression was determined and assessed (Wilcoxon signed rank test).
Results: 70 paired CRC and normal tissue specimens (35 M/36 F, age 67.8±14) were studied (86% colon,14% rectal; cancer stage: 1, 24%; 2,37%; 3, 31.%;stg 4, 7%). The percent of pts with a relative Malignant to Normal tissue AKAP4 expression ratio (MN) over 1 was 17%; the percent with both MN ratio over 1 and expression levels above 0.1% of testis levels was 16%. IHC demonstrated AKAP4 in a subset of CRC tumor samples. No significant difference was noted between colon vs rectal, or cancer stage groups. No expression was found in 21 normal samples.
Discussion: In a tumor subset the relative expression of AKAP4 was above that of normal colon and more than 0.1% of testis expression. IHC study demonstrated the antigen in CRC tumors. A larger study is needed determine if AKAP4 expression correlates with T, N, or final tumor stage. AKAP4 holds some promise as a vaccine target.
Citation Format: Chandana S. K. Herath Mudiyanselage, Neil Mitra, Otavia L. Caballero, Dasuni N. Gamage, Xiaohong Yan, Vesna Cekic, Joseph Martz, Richard L. Whelan. Assessment of the Cancer Testis antigen AKAP4, via tumor expression analysis and IHC, as a potential vaccine and immunotherapy target for colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1414.
Abstract 1429: DDT induces intergenerational epigenetic inheritance of cancer predisposition in a mouse model
Authors: Da Cruz Raquel Santana , Dominguez Odalys , Nasir Apsra , Gonsiewski Alexandra K. , Cruz Maria Idalia , Jin Lu , McCoy Matthew , de Assis Sonia 
Published: June 2022

Abstract
DNA sequence accounts for the majority of disease heritability, including cancer. Yet, not all familial cancer cases can be explained by genetic factors. There is mounting evidence that environmentally-induced epigenetic inheritance occurs and that the progeny’s traits can be shaped by parental environmental experiences. In humans, epidemiologic studies have implicated endocrine disruptors and environmental toxicants such as the pesticide DDT in intergenerational cancer development, including breast and childhood tumors. Using a mouse model, we investigated whether paternal DDT exposure may result in an intergenerational increase in breast cancer development. We also investigated the effects of DDT on the paternal germline and the mechanisms underlying intergenerational transmission. Male mice (c57bl/6) were exposed to DDT or to a control-vehicle (CO) solution and used for sperm collection or mating with unexposed females to produce the DDT or CO daughters. In another experiment, normal mouse embryos (zygote stage) were injected with RNA purified from sperm of DDT or CO males or miRNA mimic. Resulting zygotes were implanted into surrogate mothers to produce offspring. DDT daughters or RNA injected females were used to study breast cancer development (carcinogen-induced or orthotopic models). We found that the female progeny of males exposed to DDT in the pre-conception period have higher susceptibility of developing aggressive tumors in two different mouse models of breast cancer. Sperm of DDT-exposed males exhibited distinct patterns of small non-coding RNAs, with an increase in miRNAs and a specific surge in miRNA-10b levels. Remarkably, embryonic injection of the entire sperm RNA load of DDT-exposed males or synthetic miRNA-10b recapitulated the tumor phenotypes observed in DDT daughters. We also found that E3.5 embryos injected with miR-10b have altered transcriptional profile compared to controls. Our findings reveal a causal role for sperm RNAs in the inheritance of cancer predisposition and could explain some of the “missing heritability” of breast and other malignancies, if confirmed in humans.
Citation Format: Raquel Santana Da Cruz, Odalys Dominguez, Apsra Nasir, Alexandra K. Gonsiewski, Maria Idalia Cruz, Lu Jin, Matthew McCoy, Sonia de Assis. DDT induces intergenerational epigenetic inheritance of cancer predisposition in a mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1429.
Abstract 1474: Genome edited colorectal cancer organoid models reveal distinct microRNA activity patterns across different mutation profiles
Authors: Villanueva Jonathan W. , Kwong Lawrence , Han Teng , Martinez Salvador Alonso , Pan Fong Cheng , Shanahan Michael T. , Kanke Matt , Chen Shuibing , Dow Lukas E. , Danko Charles G. , Sethupathy Praveen 
Published: June 2022

Abstract
Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related deaths worldwide. DNA mutations drive colon tumor formation by disrupting gene regulatory mechanisms that facilitate cell survival and growth. Distinct combinations of mutations can result in unique changes to these gene regulatory mechanisms leading to variability in responses to available therapeutics. MicroRNAs (miRNAs) are important regulators of gene expression in CRC and it is known that their expression can be altered by oncogenic mutations. However, it is unknown how distinct combinations of CRC-risk mutations differentially affect the regulation and expression of miRNAs. We hypothesize that some miRNAs will exhibit strong genotype-dependent changes in CRC whereas others will be altered irrespective of genotype. Utilizing sequencing data from The Cancer Genome Atlas (TCGA) and cutting-edge intestinal organoid (enteroid) models with different combinations of oncogenic mutations that commonly occur in CRC, we identified several distinct patterns of genotype-dependent miRNA expression. We also found a suite of miRNAs that are up-regulated in a mutation-independent manner. Among these, we demonstrated that miR-24-3p is a candidate master regulator of genes that are down-regulated in all mutational-contexts. RT-qPCR for miR-24-3p in genetically modified human colonoids with different combinations of oncogenic mutations further supports that miR-24-3p is elevated across various mutational contexts. Functional studies in the HCT116 cell line revealed that miR-24-3p controls the number of metabolically active, viable cells by regulating apoptosis but not proliferation. Moreover, follow-up ex vivo studies in mouse enteroids confirmed that miR-24 controls intestinal cell survival. To identify candidate gene targets that mediate the function of miR-24-3p, I performed an RNA-sequencing (RNA-seq) analysis and identified HMOX1 and PRSS8 as top candidate miR-24-3p targets. These findings suggest that miR-24-3p is a genotype-independent regulator of tumor cell apoptosis in CRC and merits further investigation. Overall, our findings provide a novel perspective on approaches for precision medicine in CRC.
Citation Format: Jonathan W. Villanueva, Lawrence Kwong, Teng Han, Salvador Alonso Martinez, Fong Cheng Pan, Michael T. Shanahan, Matt Kanke, Shuibing Chen, Lukas E. Dow, Charles G. Danko, Praveen Sethupathy. Genome edited colorectal cancer organoid models reveal distinct microRNA activity patterns across different mutation profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1474.
Abstract 1484: Emerging microRNAs as biomarkers for colorectal cancer diagnosis: A meta-analysis
Authors: Fathi Sofia , Guessous Fadila , Karkouri Mehdi 
Published: June 2022

Abstract
Background: Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide. The current method of clinical screening is mainly based on colonoscopy. However, many CRC patients are unwilling to undergo colonoscopy because of the high procedure cost and the discomfort during examination. Therefore, it appears necessary to find novel and non-invasive biomarkers that would improve CRC early detection. MicroRNAs (miRNAs) are a class of non-coding RNAs with critical regulatory roles in fundamental cellular processes, such as proliferation, migration, and apoptosis. They can act as potential oncogenes or tumor suppressors in cancer development. Numerous studies have shown significant differences in miRNAs expression in serum or plasma of CRC patients and healthy subjects. Thus, the potential use of circulating miRNAs as diagnostic biomarkers in CRC seems to be a fast and relevant alternative to traditional and invasive methods. Here, we reviewed selected studies which identified dysregulated circulating miRNAs in CRC and evaluated their diagnostic value.
Methods: This meta-analysis study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The articles were searched in online databases such as PubMed, Google Scholar to identify all eligible studies that evaluated the diagnostic value of miRNAs for CRC. Then we explored the diagnostic accuracy of each miRNA using the random-effects model to estimate the pooled sensitivity (Se), specificity (Sp), Positive likelihood ratio (PLR) and Negative likelihood ratio (NLR) and the area under the curve (AUC), along with their corresponding 95% confidence intervals (CIs). The statistical analyses were performed using the Review Manager (Revman) 5.4 software and the Meta Disc software.
Results: Thirteen studies involving five microRNAs were included in our analysis. Our results suggested that serum miR-29a levels showed great potential as a high diagnostic biomarker for CRC. The overall pooled sensitivity, specificity, area under the curve (AUC), PLR and NLR of circulating miR-29a were 69.75%, 88.25%, 0.8351, 5.93 and 0.342 respectively.
Conclusion: miRNAs have become increasingly recognized molecular tools in CRC diagnosis. According to our results, circulating miR-29a level has potential value for early detection and might be used as a novel diagnostic biomarker for CRC in combination with other biomarkers.
Citation Format: Sofia Fathi, Fadila Guessous, Mehdi Karkouri. Emerging microRNAs as biomarkers for colorectal cancer diagnosis: A meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1484.
Abstract 1486: MicroRNA (miR)199a-5p targets JUN-B to decrease cell proliferation in esophageal cancer cells
Authors: Phatak Pornima , Tulapurkar Mohan E. , Donahue James M. 
Published: June 2022

Abstract
Objectives: MiR-199a-5p has been shown to be downregulated in multiple malignancies and function as a tumor suppressor. We have previously demonstrated that miR-199a-5p is markedly downregulated in esophageal cancer cell lines compared to esophageal epithelial cells. In several miR-target sequence analysis programs, miR-199a-5p is predicted to bind JUN-B mRNA with high affinity. JUN-B is an important component of the AP1 transcription factor. The objective of this study was to determine expression of JUN-B in esophageal cancer cells as well as to investigate the interaction between miR-199a-5p and JUNB in these cells and to characterize the functional implications of this interaction.
Methods: Studies were performed in human esophageal epithelial (hESO) cells and in TE7, SK-GT-4 and OE21 human esophageal cancer cells. Expression of miR-199a-5p and JUNB mRNA in these cell lines was measured by real-time PCR. JUNB protein expression levels were examined by Western blot. Function of miR-199a-5p was tested through its overexpression and silencing. Cellular proliferation was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
Results: Levels of miR-199a-5p in TE7, SK-GT-4, and OE21 esophageal cancer cells are markedly reduced compared to hESO cells. JUN-B mRNA and protein expression are correspondingly elevated in these cells compared to hESO cells. JUN-B mRNA and protein expression levels were decreased following miR-199a-5p overexpression in TE7, SK-GT-4 and OE21 cells. In reciprocal experiments, silencing miR-199a-5p in hESO cells resulted in increased JUN-B protein and mRNA levels. Forced expression of miR-199a-5p in TE7, SK-GT-4 and OE21 cells led to a marked decrease in cellular proliferation.
Conclusions: MiR-199a-5p expression is significantly reduced in TE7, SK-GT-4, and OE21 esophageal cancer cells relative to hESO cells. Forced expression of miR-199a-5p results in significantly decreased JUN-B mRNA and protein expression in these cells, leading to decreased cellular proliferation. These results add our understanding of the roles by which miR-199a-5p functions as a tumor suppressor in esophageal cancer cells. Further studies will investigate the association of miR-199a-5p with JUN-B mRNA using biotinylated RNA pull-down and luciferase reporter assays, in addition to determining the effect of Jun-B downregulation on AP1 promoter activity.
Citation Format: Pornima Phatak, Mohan E. Tulapurkar, James M. Donahue. MicroRNA (miR)199a-5p targets JUN-B to decrease cell proliferation in esophageal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1486.
Abstract 1490: Development of a 5-FU modified miR-129 mimic as a novel therapeutic for non-small cell lung cancer
Authors: Hwang Ga-Ram , Yuen John G. , Farley Hannah , Ju Jingfang 
Published: June 2022

Abstract
Lung cancer is the leading cancer type of cancer-related deaths in the U.S., with non-small cell lung cancer (NSCLC) accounting for a majority of cases. Despite innovations in cancer therapeutics, due to resistance to these therapeutics, the 5-year survival rate for patients with metastatic lung cancer has remained poor. As a result, there is an urgent need to develop new and effective therapeutics, including the study of RNA-based therapeutics. Previous studies from our laboratory have shown that 5-fluorouracil (5-FU) modified tumor suppressor miRNAs significantly enhance the therapeutic efficacy, stability, and deliverability of miRNAs in colorectal cancer (CRC) and pancreatic cancer. In this study, we have characterized the therapeutic potential of miR-129 modified with 5-FU (5-FU-miR-129) in non-small cell lung cancer in vitro via Annexin V staining, cell cycle analysis, and Western Blot. 5-FU-miR-129’s therapeutic potential was also assessed in vivo via IVIS imaging of NSCLC xenografts. We have demonstrated that 5-FU-miR-129 can induce apoptosis (7.2-fold in A549 and 2.9-fold in Calu-1) and cell cycle arrest (12.7-fold change in G1/S phase ratio in A549) in NSCLC in vitro. Furthermore, 5-FU-miR-129 has been found to retain target specificity by downregulating miR-129 targets BCL2 and HMGB1 in a cell line-dependent manner. As was observed in previous studies, we have also demonstrated the ability of 5-FU-miR-129 to be delivered in cancer cells without the use of a transfection vehicle in vitro. Finally, we were also able to demonstrate the therapeutic potential of 5-FU-miR-129 in inhibiting NSCLC tumor growth in vivo, as seen by a significantly decreased change in tumor growth by 37 days post-treatment in the 5-FU-miR-129 treated group compared to the negative control group (79.8% reduction in tumor growth). In addition, we observed a significant increase in survival probability and a reduced hazard ratio in mice treated5-FU-miR-129 when compared to the negative control group. Furthermore, we did not observe any visible side effects (hair loss) of mice treated with 5-FU-miR-129 compared to chemotherapeutic drugs 5-FU and gemcitabine (Gem). 5-FU-miR-129’s therapeutic potential in NSCLC further demonstrates the potential for modified miRNAs as a platform technology in cancer therapeutics.
Citation Format: Ga-Ram Hwang, John G. Yuen, Hannah Farley, Jingfang Ju. Development of a 5-FU modified miR-129 mimic as a novel therapeutic for non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1490.
Abstract 1495: Bioengineered RNAi molecules for cancer research and experimental therapy
Authors: Yu Ai-Ming 
Published: June 2022

Abstract
RNAs have emerged as a novel group of medications, with distinct chemistry and pharmacology from conventional small molecules and proteins or antibodies. Indeed, some RNAi products (e.g., siRNAs) have been approved for clinical practice by the United State Food and Drug Administration while many others, including genome-derived miRNAs, are under active investigations. However, current research and development relies predominantly on the use of chemo-engineered RNA mimics made in vitro that are different from natural RNA molecules produced and folded in vivo. This is also in sharp contrast to protein research and therapy that primarily uses bioengineered or recombinant proteins produced and folded in vivo, instead of synthetic polypeptides or proteins made in vitro. Therefore, we have devoted large efforts to producing true biologic RNA molecules to better recapitulate the properties of natural RNA molecules for research and drug development. Herein I will present our one-of-a-kind RNA bioengineering technology that achieves high-yield, large-scale and cost-effective, in vivo fermentation production of biologic RNAs (BioRNAs) consisting of target RNAi molecules (e.g., miRNAs or siRNAs). Examples will be presented to demonstrate the precise release of payload RNAi molecules from BioRNAs in human cells and subsequently, modulate target gene expression and various cancer cellular processes. In addition, biologic RNAi prodrugs are effective to control tumor growth and metastasis in clinically relevant xenograft mouse models. Our results demonstrate that bioengineered RNA molecules are a novel class of agents for cancer research and drug development. Acknowledgements: This study was supported by grants R01CA225958, R01CA253230 and R35GM140835 from NIH.
Citation Format: Ai-Ming Yu. Bioengineered RNAi molecules for cancer research and experimental therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1495.
Abstract 1504: Mouse model and human patient data suggest critical roles for Pten and p53 in suppressing POLE mutant tumor development
Authors: Sun Meijuan J. , Park Vivian S. , Frey Wesley D. , Williams Leonard G. , Hodel Karl P. , Strauss Juliet D. , Wellens Sydney J. , Jackson James G. , Pursell Zachary F. 
Published: June 2022

Abstract
Mutations in the exonuclease domain of POLE are associated with tumors harboring very high mutation burdens. The mechanisms linking this significant mutation accumulation and tumor development remain poorly understood. Pole+/P286R;Trp53+/- mice showed accelerated cancer mortality compared to Pole+/P286R;Trp53+/+ mice. Cells from Pole+/P286R mice showed increased p53 activation, and subsequent loss of p53 permitted rapid growth, implicating canonical p53 loss of heterozygosity in POLE mutant tumor growth. Somewhat surprisingly, however, p53 status had no effect on tumor mutation burden or single base substitution signatures in POLE mutant tumors from mice or humans. Pten has important roles in maintaining genome stability. We find that PTEN mutations are highly enriched in human POLE mutant tumors, including many in POLE signature contexts. One such signature mutation, PTEN-F341V, was previously shown in a mouse model to specifically decrease nuclear Pten and lead to increased DNA damage. We found tumors in Pole+/P286R mice that spontaneously acquired PtenF341V mutations and were associated with significantly reduced nuclear Pten and elevated DNA damage. Further analysis in cells suggests the presence of the mutant polymerase triggers DNA damage in specific contexts. Taken together, our analysis supports the idea that POLE-mediated hypermutagenesis is necessary, but not entirely sufficient, for tumorigenesis. Disabling surveillance of nuclear DNA damage is a likely sufficient factor.
Citation Format: Meijuan J. Sun, Vivian S. Park, Wesley D. Frey, Leonard G. Williams, Karl P. Hodel, Juliet D. Strauss, Sydney J. Wellens, James G. Jackson, Zachary F. Pursell. Mouse model and human patient data suggest critical roles for Pten and p53 in suppressing POLE mutant tumor development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1504.