bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6386: Phosphomimetic Dicer rewires glutamine metabolism and gemcitabine resistance in pancreatic ductal adenocarcinoma
Authors: Chiu Ching-Feng , Park Ji Min , Shen Yu-Shiuan , Lin Chia-Ying , Hsu Tung-Wei , Su Yen-Hao , Chen Hsin-An 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a common malignancy that shows high cancer-mortality and poor prognosis, in the absence of obvious symptoms and biomarkers for early diagnosis. Gemcitabine is a type of chemotherapy drug which commonly used to treat PDAC, however, the rapid acquisition of resistance to gemcitabine treatment has been observed in many of PDAC patients. The miRNA-producing enzymes Dicer is crucial for the maturation of miRNAs, and we found previously that ERK/Sp1 signaling transactivate both gene and protein expressions of Dicer, leading an acquisition of gemcitabine resistance in pancreatic cancer cells both in vitro and in vivo. In this study, we further identified that phosphomimetic S1016E of Dicer may regulate miRNAs maturation, resulting an imbalance of glutaminase (GLS) and glutamine synthetase (GS/GLUL). Metabolism analysis revealed that gemcitabine-resistant PANC-1 (PANC-1/GEM) cells have high glutamine dependence and GLS/GLUL ratio. Our study suggests that phosphomimetic Dicer S1016E plays a critical role in glutamine metabolism reprogramming and gemcitabine resistance of pancreatic cancer.
Citation Format: Ching-Feng Chiu, Ji Min Park, Yu-Shiuan Shen, Chia-Ying Lin, Tung-Wei Hsu, Yen-Hao Su, Hsin-An Chen. Phosphomimetic Dicer rewires glutamine metabolism and gemcitabine resistance in pancreatic ductal adenocarcinoma [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 6386.
Abstract 643: Non-classical sources of tumour specific antigen in checkpoint inhibitor response
Authors: Thakkar Krupa , Qian Danwen , Cha Hongui , Watkins Thomas B. , Swanton Charles , Litchfield Kevin 
Published: June 2022

Abstract
A large-scale meta-analysis of over 1000 CPI (immune checkpoint blockade) treated patients across multiple cancer types broadly categorised biomarkers into four categories: sources of antigen leading to T-cell responses, host-derived factors, immune evasion and infiltration mechanisms. Our analyses established tumour mutation burden (TMB) as the strongest predictor of CPI response, alongside clonal TMB and CXCL9 expression. However, over half of the patients in our cohort who responded to CPI treatment did not have high-TMB and showed no evidence of oncogenic viral infections, hence suggesting alternative sources of antigen could be driving the immune response. As well as this, data from the CPI1000 cohort suggested that the biomarkers identified in an extensive systematic review only accounted for ~60% of the variance in CPI response, promoting the search for non-classical sources of antigen.
Extending the cohort to encompass 2500+ patients, using available genomic and transcriptomic data from checkpoint inhibitor trials and industry partners, the previously published multivariate predictor will be further validated in a larger patient cohort inclusive of more cancer types. The CPI1000 cohort utilised primarily whole exome-sequencing therefore, had limited ability to discern non-coding sources of tumour antigen and cell-type specific predictors of response. The CPI2500+ cohort will incorporate several additional cohorts as well as single-cell and T-cell reactivity data. The raw data will be harmonised across studies and processed using a robust bioinformatics pipeline. As well as this, alternative (non-classical) sources of tumour specific antigen will be studied. Alternative sources of antigen can originate from a diverse range of biological processes including retained introns, stop codon loss mutations and cancer associated bacterial/viral epitopes. Data from this exploratory analysis will be coupled with peptide reactivity assays from local UCL patient TIL (tumour infiltrating lymphocyte) and PMBC (peripheral blood mononuclear cells) samples to validate immunogenicity.
Current analysis has identified a novel subgroup of CPI-responders with low-TMB who have significantly higher rates of microbial diversity, consistent with a diverse tumour microbiome providing a source of immunogenic antigens in the absence of high-TMB. Here we will present insights from CPI2500+ and highlight the importance of emerging non-classical sources of tumour specific antigen.
Citation Format: Krupa Thakkar, Danwen Qian, Hongui Cha, Thomas B. Watkins, Charles Swanton, Kevin Litchfield. Non-classical sources of tumour specific antigen in checkpoint inhibitor response [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 643.
Abstract 707: Mahanine, a carbazole alkaloid attenuates lung cancer progression
Authors: Kandimalla Raghuram , Aqil Farrukh , Moholkar Disha N. , Samanta Suman K. , Gupta Ramesh C. 
Published: June 2022

Abstract
Lung cancer continues to be a major cause of cancer mortality. Emerging evidence suggests that cancer likely involves multiple mutations. Therefore, compounds targeting multiple signal transduction pathways would be ideal for the prevention and treatment of cancer. Mahanine, a carbazole alkaloid isolated from an Indian folklore medicinal plant Murraya koenigii (known as Curry Patta), widely consumed in traditional dishes, have been shown to possess anticancer activities and confound many oncogenic signaling events in breast, colon, and prostate cancers. In the current study, we determined the anticancer potential of mahanine against drug-sensitive and drug-resistant lung cancer cells and postulate the possible mechanism of action. Mahanine was isolated from the dried leaves of Murraya koenigii by hydro alcoholic extraction and fractionation with ethyl acetate, followed by preparative UPLC to isolate pure (&gt;95%) compound and its identity was confirmed by LC-MS/MS and NMR spectroscopy. Antiproliferative activity of mahanine was determined against drug- sensitive (A549 and H1299) and taxol-resistant (A549-TR) human lung cancer cells. Mahanine showed a dose- and time-dependent inhibition of both drug-sensitive and drug-resistant lung cancer cell growth. Interestingly, the IC50 values of mahanine were essentially the same for drug sensitive (A549) (12.5 µM) and drug- resistant (12.5 µM) lung cancer cells; the IC50 value was somewhat lower (10 µM) against highly metastatic H1299 lung cancer cells. Mahanine attenuated the colony formation and reduced the wound healing of lung cancer cells. Mechanistically, mahanine dose dependently impeded the oncogenic markers such as KRAS, MET, AKT, mTOR and cMYC. Together, mahanine demonstrate ability to inhibit both drug- sensitive and drug-resistant lung cancer cells and modulate distinct oncogenic molecular targets providing potential to be developed for the treatment of drug-resistant and metastatic NSCLC (Supported from Duggan Endowment funds).
Keywords: Mahanine, Lung cancer, Oncogenes, Plant therapeutics.
Citation Format: Raghuram Kandimalla, Farrukh Aqil, Disha N. Moholkar, Suman K. Samanta, Ramesh C. Gupta. Mahanine, a carbazole alkaloid attenuates lung cancer progression [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 707.
Abstract 709: Metabolomic differences between pulmonary metastasis of Lewis lung carcinoma and normal lungs from C57BL/6 mice fed an obesogenic high-fat diet
Authors: Yan Lin , Sundaram Sneha , Rust Bret M. , Picklo Matthew J. , Bukowski Michael R. 
Published: June 2022

Abstract
Metastasis, the spread of malignant cells from a primary tumor to distant organs, is the most devastating aspect of cancer. To understand the metabolism of metastases, we compared the metabolomes of pulmonary metastases of Lewis lung carcinoma (LLC) with that of normal lung tissues from mice fed an obesogenic high-fat diet. In a 2x2 design, male C57BL/6 mice, with or without a subcutaneous LLC inoculation, were fed the standard AIN93G diet or a high-fat diet (HFD), which provided 16% or 45% of energy from soybean oil, for 12 weeks. At the end of the study, lung metastases from injected mice and the lungs from non-injected mice were harvested for untargeted metabolomic analysis of primary metabolism by gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). We identified 91 metabolites, 70 of which differed among the four groups. Pathway and network analyses along with the discriminant analysis showed that amino acid and carbohydrate metabolism were altered the most in metastases compared to the normal lung tissue (e.g., aminoacyl-tRNA biosynthesis pathways and the citric cycle). A 60% decrease in glutamine and a 25-fold elevation in sorbitol were observed in metastases. Cholesterol and its metabolite dihydrocholesterol were 50% lower in metastases than in the lungs. The HFD elevated arachidonic acid and its precursor linoleic acid in the lungs from non-LLC-bearing mice, which reflected dietary fatty acid composition of the HFD. However, such elevation did not occur in metastases from HFD-fed LLC-bearing mice, suggesting alterations in fatty acid metabolism during LLC metastatic progression. Differences in metabolomes between LLC pulmonary metastases and the normal healthy lungs identified in the present study can be useful in designing targeted studies for prevention and treatment of metastasis using this spontaneous metastasis model.
Citation Format: Lin Yan, Sneha Sundaram, Bret M. Rust, Matthew J. Picklo, Michael R. Bukowski. Metabolomic differences between pulmonary metastasis of Lewis lung carcinoma and normal lungs from C57BL/6 mice fed an obesogenic high-fat diet [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 709.
Abstract 713: Monoclonal antibodies for the detection of the uropathogenic specific protein (USP): A bacterial genotoxin linked to colorectal cancer
Authors: Martínez-Ramírez Rachell , Toro-Díaz Valeria Toro-Díaz , Akamine Pearl , Ruiz-Rosado Kimberly , Pino Ignacio , Baerga-Ortiz Abel 
Published: June 2022

Abstract
The Uropathogenic Specific Protein (USP) is an E. coli genotoxin nuclease primarily associated with urinary tract infections. Previous efforts in our laboratory found the USP gene in stool samples; more frequently found in stool samples from adenoma and CRC patients than in samples from healthy individuals. New efforts in our laboratory aim to find the USP protein in the same population of patient samples and this may require anti-USP antibodies, which at present are not commercially available. In this work, we report the first anti-USP monoclonal antibodies (mAbs) for the detection of USP in human samples. A total of 38 hybridoma supernatants containing mAbs were assayed by immunoblotting and biolayer light interferometry (BLI) for their ability to recognize purified USP(∆HNH). Results from BLI showed that the pair AB-A10 and AB-D5 presented the highest affinity with slow dissociation, moving forward for the development of a sandwich ELISA. Using AB-A10 as the capture antibody, and AB-D5 as the top antibody, results from the ELISA showed signals that were concentration-dependent above 6 ug/mL of USP. We also used the AB-D5 and AB-D10 in immunoblots for the detection of USP in proteins extracted from stool samples of patients with adenoma and CRC. The immunoblots reveal the detection of a 25 kDa protein that remains unidentified but is present only in some of the samples. This could be the first detection of USP protein directly in a biological sample. Efforts are underway to identify this protein band and confirm its identity as USP. Additional efforts are aimed at increasing the number of stool samples analyzed to establish whether USP protein is a risk factor for CRC or adenoma.
Citation Format: Rachell Martínez-Ramírez, Valeria Toro-Díaz Toro-Díaz, Pearl Akamine, Kimberly Ruiz-Rosado, Ignacio Pino, Abel Baerga-Ortiz. Monoclonal antibodies for the detection of the uropathogenic specific protein (USP): A bacterial genotoxin linked to 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 713.
Abstract 724: Examining the effects of obesity and weight loss on mammary tumor inflammation and fibrosis
Authors: Kuziel Genevra M. , Arendt Lisa M. 
Published: June 2022

Abstract
Obesity significantly increases risk of breast cancer development, and following diagnosis, obese breast cancer patients have an overall worsened prognosis. The complex relationship of obesity to breast cancer growth and aggressiveness must continue to be examined. Within breast adipose tissue, obesity causes a state of chronic, macrophage-driven inflammation. Chronic inflammation is associated with increased extracellular matrix (ECM) deposition. Increased collagen within the mammary microenvironment is a risk factor for tumor formation, as well as more aggressive tumors, in mouse models. In breast tumors from obese patients, tumor desmoplasia is also found to be increased. To better understand how obesity affects mammary tumor growth, inflammation, and fibrosis, we used a diet-induced obesity mouse model paired with the estrogen receptor alpha (ERα)+ TC2 mammary tumor cell line in female FVB mice. We observed that TC2 mammary tumors grew significantly faster in obese mice compared to lean mice and had significantly more macrophage infiltration. TC2 tumors from obese mice also had significantly more collagen deposition than TC2 tumors from lean mice, indicating that obesity leads to more fibrotic tumors. To identify how weight loss alters the mammary gland and mammary tumor microenvironments, obese mice were switched from a high-fat diet to a low-fat diet for six weeks, to induce weight loss. In non-tumor-bearing mammary glands, weight loss led to a significantly decreased number of crown-like structures, a marker of adipose tissue inflammation, similar to observations in human adipose tissue. TC2 mammary tumors grew at an intermediate rate between tumors from lean and obese mice, indicating that weight loss may be a viable option to reduce tumor aggressiveness, particularly for obese patients with other breast cancer risk factors. Understanding these weight-related changes in the mammary gland and mammary tumor microenvironments will provide greater insight into possible interventions for obese breast cancer patients.
Citation Format: Genevra M. Kuziel, Lisa M. Arendt. Examining the effects of obesity and weight loss on mammary tumor inflammation and fibrosis [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 724.
Abstract 832: Breast cancer plasticity is restricted by a LATS1-NCOR1 repressive function
Authors: Aylon Yael , Furth Noa , Mallel Giuseppe , Nataraj Nishanth , Friedlander Gilgi , Hassan Ori , Zoabi Rawan , Cohen Benjamin , Salame Tomer , Mukherjee Saptaparna , Johnson Randy , Shema Efrat , Oren Moshe 
Published: June 2022

Abstract
Purpose of study: Understanding the epigenetic mechanism underlying luminal-to-basal plasticity of breast cancer subtypes
Experimental procedures: Epigenetic focused CyTOF, ATAC-seq, RNA-seq, FACS-sorting, Proximity Ligation Assay, orthotopic syngeneic injections of tumor cells to mouse mammary gland, and others.
Summary: Breast cancer is the most frequent cancer in women. It is defined by specific types of tumors that are classified into distinct histological and molecular subtypes. However, lately, with the advent of single-cell technologies, the extent of cellular and functional intratumoral heterogeneity within breast cancer subtypes is being appreciated. Much of this heterogeneity, including transitions of luminal-to-basal cell identity, can be attributed to alterations in the activity of chromatin remodelers. The transcriptional corepressor, NCOR1, and the tumor suppressor, LATS1, are downregulated in luminal breast cancer tumors with poor prognosis. Here, we show that LATS1 impedes the emergence of an epigenetically distinct basal-like population in luminal B tumors by augmenting NCOR1 repressive activity and facilitating deacetylation of H3K27ac.
Conclusion: Rigorous repression of ERα-repressed genes facilitated by LATS1-NCOR1 maintains luminal cell identity and restricts progression of luminal breast cancer.
Citation Format: Yael Aylon, Noa Furth, Giuseppe Mallel, Nishanth Nataraj, Gilgi Friedlander, Ori Hassan, Rawan Zoabi, Benjamin Cohen, Tomer Salame, Saptaparna Mukherjee, Randy Johnson, Efrat Shema, Moshe Oren. Breast cancer plasticity is restricted by a LATS1-NCOR1 repressive function [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 832.
Abstract 84: Sensitive and unbiased detection of clinically actionable gene fusions from FFPE tumor biopsies using the Arima-HiC platform
Authors: Hermel David Jacob , Sikkink Kristin , Reid Derek , Schmitt Anthony , Sigal Darren S. 
Published: June 2022

Abstract
Accurate and sensitive identification of gene fusions is critical to understanding disease mechanisms and the development and selection of optimal treatment regimens for cancer patients. Typically, these fusions are detected using low-resolution karyotyping, low throughput and biased FISH assays, or RNA sequencing approaches; however, the accuracy and sensitivity of gene fusion detection can be limited by factors such as low transcript abundance, transcript length, RNA degradation from formalin fixed paraffin embedded (FFPE) tissues, or the limited availability of fresh biopsy samples for RNA extraction. To address these limitations, we developed a novel approach to identifying gene fusions from FFPE samples using the Arima-HiC platform and short-read sequencing. We performed pan-cancer analysis on 12 FFPE adult tumor biopsies, each with gene fusions known to be clinically actionable. With this newly developed Hi-C workflow we identified all the known gene fusions with 100% sensitivity in the samples including those involving ALK, NTRK3, ROS1, FGFR2, and SS18 genes. This approach also revealed that the NTRK3 gene fusion was the result of a more complex rearrangement within chr12, within chr15, and between chr12 and chr15. Additionally, we detected the presence of numerous structural variants per sample in addition to the known gene fusion in each sample. For example in a bile duct tumor, Arima-HiC detected an FGFR2-EEA1 gene fusion, as well as 25 other structural variants genome-wide including in a CPD-LASP1 gene fusion This gene fusion has not been reported to our knowledge, however, LASP1 is a reported 3’ fusion partner with MLL in leukemia. While these findings are not clinically actionable today, the unbiased, accurate, and sensitive detection of structural variants from frozen and FFPE solid tumor biopsies may facilitate further research into their relationship between disease mechanisms and clinical outcomes. Taken together, these findings demonstrate the analytical utility of Arima Hi-C sequencing technology to provide both chromosome-scale and gene-level resolution for the detection of structural variants in tumor biopsies samples. This workflow can provide improved access to critical genomic information from FFPE blocks for the identification of pathognomonic and druggable gene fusion events and other structural variants across tumor types.
Citation Format: David Jacob Hermel, Kristin Sikkink, Derek Reid, Anthony Schmitt, Darren S. Sigal. Sensitive and unbiased detection of clinically actionable gene fusions from FFPE tumor biopsies using the Arima-HiC platform [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 84.
Abstract 866: Translational repression by a novel partner of human cytoplasmic poly(A) binding protein
Authors: Li Naren , Hu Liang , Liu Qinfang , Xiong Yulan , Yu Jianzhong 
Published: June 2022

Abstract
In higher eukaryotes, post-transcriptional regulation of gene expression, which is accomplished by an ensemble of RNA-binding proteins (RBPs), is critical for cellular homeostasis. Unkempt (UNK) is an evolutionarily conserved Zinc Finger/RING domain RNA-binding protein that was originally identified as a developmental regulator in Drosophila. Recent studies suggest that UNK targets specific mRNAs through its two compact zinc finger clusters and regulates their translation. However, the underlying molecular mechanisms by which UNK represses translation remain unclear. To examine UNK interactions, we purified Flag-tagged UNK and subjected the preparations to Mass spectrometry (MS) and identified an enriched protein Cytoplasmic poly(A)-binding protein(PABPC1), a key component of the translation machinery that binds to the poly(A) tail of mRNAs to promote translation and mRNA turnover. GST Pull down assay and reciprocal immunoprecipitations in HEK293 cells further confirmed the strong interaction between UNK and PABPC1 and showed that the interaction is RNA-dependent. Notably, the structural analysis, along with mutational studies proved that the interaction is mediated by the C-terminal MLLE domain of PABPC1 and the C-terminal Domain of UNK both in vitro and in vivo. Further MS2 tethering assay indicated that UNK inhibits PABPC1-stimulated translation activity. Our studies identified Unkempt as a novel partner of PABPC1 that functions to represses PABPC1-stimulated translation. The findings provide novel insight into the molecular function of Unkempt and PABPC1-mediated translational machinery.
Citation Format: Naren Li, Liang Hu, Qinfang Liu, Yulan Xiong, Jianzhong Yu. Translational repression by a novel partner of human cytoplasmic poly(A) binding protein [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 866.
Abstract 869: Post-transcriptional control of androgen receptor expression
Authors: Likos Eviania , Shukla Girish C. 
Published: June 2022

Abstract
The Androgen Receptor (AR) is a ligand-dependent transcription factor that modulates the expression of androgen-regulated genes involved in the proliferation and differentiation of normal prostate epithelial cells. However, in Prostate Cancer (PCa), these cellular events are dysregulated upon significant changes in AR, such as AR overexpression, leading to uncontrolled cell growth and proliferation. To elucidate the molecular mechanisms by which AR expression and function are controlled, we have explored the post-transcriptional regulatory RNA elements of AR, particularly the 3’ untranslated region (UTR). The AR 3’UTR is 6.8 Kilobases (Kb) long, which indicates that this region is likely a site for multitudinous levels of post-transcriptional regulation. We found that the length of AR 3’UTR negatively correlates with AR expression, with the full length 3’UTR leading to the most downregulation of expression. Currently, we are exploring cis-acting noncoding RNAs and RNA binding proteins (RBPs) predicted to interact with the AR 3’UTR.
Citation Format: Eviania Likos, Girish C. Shukla. Post-transcriptional control of androgen receptor expression [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 869.