bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5219: Telomere length distribution, metabolic trait association, and genome-wide association study among Singaporean cohorts
Authors: Nguyen Trang , Chan Penny , Lim Ives , Kennedy Brian , Karnani Neerja , Dorajoo Rajkumar , Ngeow Joanne 
Published: April 2023

Abstract
Leukocyte telomere length (LTL) is known as a heritable marker of cellular aging and is a risk factor for several chronic diseases. LTL distribution and association studies are essential in providing insights into telomere homeostasis, its relationship with different metabolic traits, and age-related conditions. Such studies have been underperformed in Asian population groups. Here we estimated LTL using whole-genome sequencing data in 8,045 Singaporean samples across three major ethnic groups - Chinese, Indian, and Malay divided into six cohorts: GUSTO, HELIOS, MEC, PRISM, SEED, and TTSH. LTLs were measured using TelSeq, with normalized LTL as phenotype in subsequent analyses. We demonstrated that average LTL was robustly longer in the childhood cohort (GUSTO) compared to the adult cohorts (P&lt;1.19 × 10−195). We observed ethnicity differences in LTL where adult Singaporean Chinese samples had the longest LTL (5.08kb) as compared to Malay (4.87kb) and Indian (4.65kb) samples in our datasets (P&lt;4.98 × 10−12). Our genetic association analyses replicated multiple variants previously reported to be associated with LTL (binomial P&lt;0.00001) in Asian population groups, providing added confidence in the methodologies used. At the same time, we identified a novel East-Asian-specific novel variant beyond genome-wide association levels (meta P=2.05 × 10−08) at the COL28A1/MIOS gene loci to be associated with LTL in our study. Individual analysis of the GUSTO childhood dataset highlighted a second novel genome-wide hit at RAD17 gene locus to be associated with LTL in our study and indicated that the previously reported variant at the TINF2 locus may have significantly opposing effects (compared to adults) during early developmental stages. Gene-level burden analysis for rare variants (MAF &lt;5%) in adult Chinese cohorts revealed potential cancer association with RET gene (SKAT, P=5.22 × 10−03) and MLH1 gene (SKAT, P=0.037), as well as telomere biology condition association with RECQL4 gene (CMC, P=0.0399, and VT, P=0.0379). Our findings have broadened the understanding of LTL distribution and the underlying associated genetic characteristics in both childhood and adult Singaporean populations.
Citation Format: Trang Nguyen, Penny Chan, Ives Lim, Brian Kennedy, Neerja Karnani, Rajkumar Dorajoo, Joanne Ngeow. Telomere length distribution, metabolic trait association, and genome-wide association study among Singaporean cohorts. [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 5219.
Abstract 5238: The functional role of promoter germline variants in breast cancer susceptibility genes
Authors: Arroyo Nelly Arlene , Godoy Lenin J. , Dutil Julie 
Published: April 2023

Abstract
It is estimated that inherited deleterious or pathogenic germline variants in high- to moderate- penetrance breast cancer (BC) susceptibility genes such as BRCA1, BRCA2, STK11, CDH1, ATM, PALB2, and CHEK2 may explain up to 27% of the BC cases. For the remaining cases, BC develops as a result of the complex interaction between environmental and lifestyle risk factors as well as inherited familial predisposition. While low penetrance genetic variants have limited impact on BC risk when taken individually, their combined effect on polygenic risk scores may provide a risk elevated enough to justify clinical actions. Most of the previous work in hereditary breast cancer research has focused on variants located in the coding region of the genes and as a result, there is an abundance of information on the functional interpretation of such variants, while information on regulatory variants remains limited. The goal of this study was to assess the functional impact of germline variants in the promoter region of BC susceptibility genes on gene expression level. Genes evaluated include CDH1, STK11, and bidirectional promoter genes ATM/NPAT and PALB2/DCTN5. A bioinformatics approach was developed to identify and prioritize variants based on conservation level and predicted binding of transcription regulatory proteins. Selected variants will be introduced into pGL3 constructs harboring the promoter of interest using site-directed mutagenesis followed by transfection into HEK293T cells. Dual-glo luciferase expression assays are used to measure levels of promoter activities. Expression levels from promoters containing genetic variants are compared with those from constructs containing the reference sequence. The reference constructs for STK11 and CDH1 containing the genes complete promoters demonstrated functional activity. For bidirectional promoters, forwards and reverse construct were tested. Forward ATM/NPAT and PALB2/DCTN5 constructs showed luciferase expression under the influence of ATM and DCTN5 respectively. Work is on the way to assess promoter activity of the reverse complement sequence of those promoters and determine the impact of 13 candidate variants on the strength of these promoters. At the clinical level, identifying germline variants that contribute to BC risk could help better define BC risk in women with negative hereditary cancer genetic test results.
Citation Format: Nelly Arlene Arroyo, Lenin J. Godoy, Julie Dutil. The functional role of promoter germline variants in breast cancer susceptibility genes. [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 5238.
Abstract 5243: Functional characterization of genetic loci in basal cell carcinoma
Authors: Li Mingyue , Turman Constance , Kraft Peter , Han Jiali 
Published: April 2023

Abstract
Background: Genome-wide association studies (GWAS) have identified over 30 loci associated with basal cell carcinoma (BCC) susceptibility. However, the causal variants and mechanisms at these loci remain unknown. We performed statistical fine mapping and functional enrichment to identify credible causal variants at 31 established BCC risk loci.
Methods: We performed statistical fine mapping by applying the sum of single effects (SuSiE) method to a previously published GWAS from 12,945 BCC cases and 274,252 controls. To identify genomic annotations enriched for BCC-associated variants, we compared high Posterior Inclusion Probability (PIP) variants from SuSIE to low PIP variants: we performed multivariable logistic regression of high-PIP status on 17 variant annotations from the Functional Annotation of Variants Online Resources (FAVOR) database, including sequence-contextual and functional annotations.
Results: We identified 6 variants with PIP&gt;0.99: rs1126809 (TYR), rs1805007 (MC1R), rs78378222 (TP53), rs12203592 (IRF4), rs35407(SLC45A2 a.k.a. MATP), rs12916300 (HERC2). Five of these six variants are in pigmentation genes; the sixth is in the tumor suppressor TP53. At a seventh region, the 95% credible set contained two variants in or upstream of RALY, which has previously been shown to be associated with pigmentation traits and multiple non-skin cancers. Another four regions had fewer than 10 variants in the credible set; the median size of the credible set was 11 (range: 1-76). After adjusting for sequence context (including location relative to exons, introns, UTRs; GC content; local mutation density, and nucleotide diversity) variants in active chromatin regions (as determined from multi-tissue methylation marks), variants in transcription factor binding sites, and skin eQTLs were significantly more likely to be high-PIP variants.
Conclusions: Our results identify candidate variants, genes, and mechanisms for further study in BCC carcinogenesis.
Citation Format: Mingyue Li, Constance Turman, Peter Kraft, Jiali Han. Functional characterization of genetic loci in basal cell carcinoma. [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 5243.
Abstract 5251: Skeletonema marinoi algae extract and carotenoid fucoxanthin are endowed with potential chemopreventive and angiopreventive properties for prostate cancer
Authors: Albini Adriana , Calabrone Luana , Noonan Douglas M. , Festa Marco , Ferrario Cinzia , Carlini Valentina , Macis Debora , Pistelli Luigi , Brunet Christophe , Sansone Clementina 
Published: April 2023

Abstract
Background: Research and production of natural anti-oxidants is growing and is developed both in experimental laboratories and in nutraceuticals and pharmaceutical industries. Marine microorganisms represent underestimated sources of bioactive compounds endowed with anti-oxidant, anti-inflammatory, cardiovascular protective and anti-angiogenic properties, all beneficial effects on human health.
Methods: Chemopreventive and anti-angiogenic activities of extracts from the marine coastal diatom Skeletonema marinoi (Sm) and carotenoid fucoxanthin, that is present in Sm, were evaluated in prostate cancer (PCa) and endothelial cell lines in in vitro. Morphogenesis assay was carried out to evaluate effects on HUVEC ability to form capillary-like structure on Matrigel. Gene expression analysis was performed by qPCR, measuring different inflammation and angiogenesis gene expression in cells treated with Sm extract and fucoxanthin. Membrane antibodies arrays were used to see alterations at protein level of pro- or anti-angiogenic factors.
Results: Sm extract and fucoxanthin were able to decrease cell viability, in MTT and Crystal violet assays. Furthermore, we observed that fucoxanthin enhanced the effects of chemotherapeutic drugs, 5-Fluorouracil (5-FU) and cisplatin (Cis-Pt), two of the most commonly used anti-cancer drugs. Sm extract and fucoxanthin hindered vascular mimicry of PCa cells and also inhibited capillary structure formation in endothelial cells. Finally, Sm extract and fucoxanthin shown a down-regulation of inflammation and angiogenesis associated genes.
Conclusions: Our study suggests promising potential chemopreventive and angiopreventive activities of Skeletonema marinoi extract and fucoxanthin for prostate cancer. Microalgae derived drugs can be a potential and relevant source of novel nutraceutical and preventive compounds, which can be considered as dietary supplements or in combination treatments in cancer prevention approaches.
Citation Format: Adriana Albini, Luana Calabrone, Douglas M. Noonan, Marco Festa, Cinzia Ferrario, Valentina Carlini, Debora Macis, Luigi Pistelli, Christophe Brunet, Clementina Sansone. Skeletonema marinoi algae extract and carotenoid fucoxanthin are endowed with potential chemopreventive and angiopreventive properties for 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 5251.
Abstract 5269: RF-1302, a novel dual inhibitor of PIM1 and FLT3 in preclinical treatment of acute myeloid leukemia
Authors: Qi Weiwei , Zhang Yanjun , Zhao Lei , Zhang Ailian , Zhang Chunze , Zhang Xiaoming , Li Lijuan , Wang Huaquan , Shao Zonghong , Fu Rong 
Published: April 2023

Abstract
It was reported that PIM (Proviral Insertion site in Moloney murine leukemia virus) proteins are family kinases (PIM1, PIM2, and PIM3), which are upregulated in several cancer types, especially PIM1 is highly expressed in hematopoietic malignancies. PIM kinase family are responsible for enhancement of cell cycle, inhibition of apoptosis, activation of transcription, and cell homing/migration. Fms-like tyrosine kinase 3 (FLT3) is part of a family of receptor tyrosine kinases (RTKs), and a molecular therapeutic target of acute myeloid leukemia (AML). There are three FTL3 inhibitors, midostaurin, gilteritinib, and quizartinib have been approved for clinical treatment of AML. We have developed a novel dual inhibitor of PIM1 and FLT3, RF-1302 and evaluated its inhibition of cell proliferation in vitro and antitumor activity in vivo. RF1302 was found to have a strong inhibitory activity against target enzymes (PIM1 IC50 at 1.0-2.3 nM and FLT3 IC50 at 0.8-2.2 nM), which were more potent than the tested positive control drugs gilteritinib, quizartinib, and midostaurin. RF-1302 showed to be highly cytotoxic to cultured human acute myeloid leukemia (AML) cells (MV4-11 and Molm-13) with IC50 at 5.7nM and 9.5 nM, respectively. The in vivo antitumor activity of RF-1302 was evaluated and compared with midostaurin and gilteritinib in the treatment of the two AML xenograft models. RF-1302 at 20 mg/kg/daily x 14, oral) significantly delayed tumor growth and resulted in a tumor growth inhibition (TGI) of 95% (p&lt;0.001 compared with the control group) in the Molm-13 AML model, and cured all of the tumor-bearing mice in the MV4-11 AML model. The antitumor activity of RF-1302 was superior to gilteritinib (TGI=46-55%) and midostaurin (TGI=63-75%). The treatment with RF-1302 showed very little toxicity (only 2% body weight loss) which were well below the maximum tolerated dose. These preclinical results suggest that RF-1302 represents a novel dual inhibitor of PIM1 and FLT3, which may constitute a highly efficacious modality for the treatment of FLT3 mutant AML, and is worthy of further clinical evaluation.
Citation Format: Weiwei Qi, Yanjun Zhang, Lei Zhao, Ailian Zhang, Chunze Zhang, Xiaoming Zhang, Lijuan Li, Huaquan Wang, Zonghong Shao, Rong Fu. RF-1302, a novel dual inhibitor of PIM1 and FLT3 in preclinical treatment of acute myeloid leukemia. [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 5269.
Abstract 5310: An expanded quantitative protein expression atlas of human cancers
Authors: Liang Han 
Published: April 2023

Abstract
The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) are the most widely used and deeply characterized resources for cancer research. Despite rich molecular and phenotypic data available for these cohorts, large-scale proteomic data across cancer lineages remain limited. Here we expanded our previous effort to generate high-quality protein expression data of 447 clinically relevant proteins for ~8,000 TCGA patient samples and ~900 CCLE cell line samples using reverse phase protein arrays. We show that the protein expression profiles provide deeper mechanistic insights into cancer dependency and serve as a sensitive functional readout for the fitness effect of somatic mutations, e.g., BRAF mutations. We develop a protein-centered strategy to identify synthetic lethality pairs with high confidence. We identify pro- and anti-metastasis protein markers and demonstrate their prognostic relevance in patient cohorts. Collectively, this dataset provides a valuable resource for elucidating cancer mechanisms, identifying protein biomarkers, and developing therapeutic strategies.
Citation Format: Han Liang. An expanded quantitative protein expression atlas of human cancers. [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 5310.
Abstract 5342: Assessment of polyphenolic secondary metabolites and small molecules against the xenobiotic metabolic and cell cycle regulatory proteins in prostate cancer
Authors: Sheoran Sumit , Arora Swati , Basu Tanmay , Subbarao Naidu , Upadhyay Atul Kumar , Vuree Sugunakar 
Published: April 2023

Abstract
Background: Prostate cancer (PCa) is the second most frequent kind of cancer in males globally after Lung Cancer. In clinical practice, medicines that act as antagonists/partial agonists of hormone receptors against prostate tissue are employed in PCa treatment. Cyproterone acetate, Flutamide, and Bicalutamide are prominent medications that induce acute and long-term toxicity and create drug resistance in patients and remission. We concentrated on flavonoids since they are non-cytotoxic and have substantial showing inhibitory action.
Methodology: We selected 560 flavonoids and small compounds along with 3 targets from the extensive literature review. Three-dimensional (3D) structures of selected proteins were obtained from Protein Data Bank, docked with 560 flavonoids and small molecules 3D structures, obtained from PubChem and CHEMBL database using Gold Docking Software. ADME characteristics were used to determine their bioactivities in the human body and drug-like investigations by using SwissADME and Zinc database, while Lipinski's rule of five was used to evaluate the flavonoids' anti-prostate cancer efficacy. Additionally, we have performed molecular simulation at 100ns and furthermore, we will perform cytotoxicity analysis.
Results: Diosmetin (58.72), Lapatinib Ditosylate (121.61), and Estramustine Phosphate Sodium (143.38) has the highest binding affinity for CDKN2 (4EK3), CYP17A1(3RUK), and CYP19A1(3S79), respectively, and are stable throughout 100ns simulation studies. At present, we are working on cytotoxicity studies on PC3 cell lines. As per the literature review by Ansar et al. 2022 quercetin and thymoquinone induce cytotoxicity in breast, lung, and prostate cancer cells effectively; MCF-7 cells were the most sensitive cells to quercetin with an IC50 value of 50 μM and PC3 cells were more sensitive to thymoquinone with an IC50 value of 20 μM.
Conclusion: As a result of our findings, these four Flavonoids may be viable candidates for additional research into PCa prevention or management.Keywords: Diosmetin, Lapatinib Ditosylatye, Prostate cancer, In-silico, Simulation
Citation Format: Sumit Sheoran, Swati Arora, Tanmay Basu, Naidu Subbarao, Atul Kumar Upadhyay, Sugunakar Vuree. Assessment of polyphenolic secondary metabolites and small molecules against the xenobiotic metabolic and cell cycle regulatory proteins in 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 5342.
Abstract 5427: Improving non-small cell lung cancer segmentation on a challenging dataset
Authors: Wei Yi , Selvaraj Balaji , Patwari Mayank , Li Qin , Xu Meng , Sidiropoulos Konstantinos , Zhang Zhenning , Fedden Leon , Madabhushi Anant , Khorrami Mohammadhadi , Viswanathan Vidya Sankar , Gupta Amit 
Published: April 2023

Abstract
When applied to different datasets, performance of the same deep learning tumor segmentation model can greatly vary. In a non-small cell lung cancer CT scan segmentation study that consists of two datasets, we found that the SwinUNETR model achieves state-of-the-art DICE score on a public dataset NSCLC but performs badly on a private dataset of curated data collected clinically. This performance variation reduces the applicability of such models. To mitigate this gap, through experimentation, we identified a set of techniques and applied them in the following order: (1) normalize a dataset to reduce differences between images. (2) stratify a dataset according to tumor sizes to form a more diverse training set. (3) isolate the lung area before training to help the model focus on the right area. (4) before training, initialize models with self-supervised pre-training weights (5) use a new loss function to give more weights on the cancerous area (6) after a model is trained, perform 3-axis test time flipping augmentation and ensemble the final predictions. In our experiments, our set of techniques improved the test DICE score for both datasets we tested on, where the best improvement was a 53% improvement from 0.32 to 0.49 DICE score.
Citation Format: Yi Wei, Balaji Selvaraj, Mayank Patwari, Qin Li, Meng Xu, Konstantinos Sidiropoulos, Zhenning Zhang, Leon Fedden, Anant Madabhushi, Mohammadhadi Khorrami, Vidya Sankar Viswanathan, Amit Gupta. Improving non-small cell lung cancer segmentation on a challenging dataset. [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 5427.
Abstract 5582: Liquid biopsy-based comprehensive genomic profiling reveal mutational landscape in real-world patients with unresectable NSCLC
Authors: Tang Haoran , Xie Feng , Zhang Yue , Jia Shidong 
Published: April 2023

Abstract
Introduction: NSCLC accounts for more than 80% of all lung cancer, and has been shown for clinical benefits from targeted therapies, according to tests of multiple genes, such as EGFR, KRAS, ALK, ERBB2. Previous studies revealed molecular characteristics and responses of targeted therapies in NSCLC. However, most studies used tissue biopsies. There is increasing interest to characterize the molecular profile of NSCLC through liquid biopsy. Hence, here we report a comprehensive genomic profiling study in unresectable NSCLC patients using liquid biopsy.
Methods: The prospective study is part of the Predicine’s Phoenix Program, a global molecular biomarkers screening program in multiple solid tumors. Currently, the study enrolled 352 unresectable advanced NSCLC patients from 24 centers in China, who were naïve to the 1st line treatment or recurrent after 1st line targeted therapies. 10ml of blood was collected from each patient and delivered to a central lab for ctDNA analysis. The study applied PredicineCARE, an NGS-based liquid biopsy assay, to profile somatic mutations, copy number variations, and gene fusions among these patients.
Results: The study identified 1614 somatic mutations and 202 copy number variants among blood samples from 352 patients. The most common altered genes were TP53(176/352, 50%), EGFR(144/352, 41%), PIK3CA(35/352, 10%), CDNK2A(35/352, 10%), KRAS(28/352, 8%), and RB1(28/352, 8%). Gene copy number gain incidents were identified on MYC(n=22), PIK3CA(n=16), EGFR(n=15), and MET(n=7), etc. Notably, the study also reported gene copy number loss incidents through liquid biopsy, such as CDKN2A(n=16), PTEN(n=11), and RB1(n=10). The study identified 12 gene fusion incidents, including 7 EML4-ALK fusions, 2 RET fusions(KIF5B-RET and NCOA4-RET), 2 NTRK fusions(ETV6-NTRK3 and NOS1AP-NTRK1), and 1 rare CD74-NRG1 fusion.
Conclusions: This study revealed the comprehensive mutational landscape of advanced NSCLC through liquid biopsy, providing novel biomarkers for clinical diagnosis and targeted therapy mechanism studies.
Citation Format: Haoran Tang, Feng Xie, Yue Zhang, Shidong Jia. Liquid biopsy-based comprehensive genomic profiling reveal mutational landscape in real-world patients with unresectable NSCLC. [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 5582.