bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 730: Annual hazard rate of recurrence in Middle-Eastern papillary thyroid cancer over a long-term follow-up
Authors: Siraj Abdul K. , Parvathareddy Sandeep K. , Qadri Zeeshan , Azam Saud , De Vera Felisa , Al-Rasheed Maha , Haqawi Wael , AlDossari Hassan , Al-Kuraya Khawla S. 
Published: July 2021

Abstract
Predicting the pattern of recurrence is necessary to establish optimal surveillance and treatment strategies. We identified patient population that remain at risk for an event and clarify changes in the hazard rate (HR) for tumor recurrence overtime in Middle Eastern patients with Papillary Thyroid Cancer (PTC). Data for 1201 PTC patients from single institute with median follow-up of 9.5 years were analyzed. Estimated HR were plotted overtime for the entire cohort, as well as for radioactive iodine (RAI) ablation in patients separately. The changes in risk were further analyzed according to clinical variable and factors predictive of early (≤ 5years) and late (&gt;5 years) recurrence were explored using Cox regression analysis. Tumor recurrence was noted in 18.4% (221/1201) patients. The annualized hazard of PTC recurrence was highest during the first 5 years (2.8%), peaking between 1 - 2 years (3.7%), with a second smaller peak between 13 - 14 years (3.2%). Patients receiving RAI therapy had a lower hazard of recurrence compared to those who did not receive RAI therapy (1.5% vs 2.7%, p = 0.0001). Importantly, this difference was significant even in the intermediate-risk PTC patients (0.7% vs 2.3%; p = 0.0001). Interestingly, PTC patients who were male, aged ≥ 55 years, with lymph node involvement and advanced stage disease were still at high risk for late recurrence. In conclusion, we confirmed the validity of double-peaked time-varying pattern for risk of recurrence in Middle-Eastern PTC patients. Furthermore, according to the time distribution of recurrence hazard, we could formulate individualized treatment and surveillance plans in PTC patients.
Citation Format: Abdul K. Siraj, Sandeep K. Parvathareddy, Zeeshan Qadri, Saud Azam, Felisa De Vera, Maha Al-Rasheed, Wael Haqawi, Hassan AlDossari, Khawla S. Al-Kuraya. Annual hazard rate of recurrence in Middle-Eastern papillary thyroid cancer over a long-term follow-up [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 730.
Abstract 731: Neurotensin causes tyrosine phosphorylation of HER3
Authors: Moody Terry W. , Ramosalvarez Irene , Jensen Robert T. 
Published: July 2021

Abstract
Neurotensin (NTS) is an autocrine growth factor for non-small cell lung cancer cells. NTS stimulates and the NTSR1 antagonist SR48692 inhibits NSCLC growth (Moody et al., Life Sci 2014; 100: 25). NSCLC patients, whose tumors have high NTSR1, have significantly lower relapse-free survival than those with low NTSR1 (Younes et al., Oncotarget 2014; 5: 8252). NTS addition to NSCLC cells increases the tyrosine phosphorylation of the EGFR and HER2 (Moody et al., Eur J Pharmacol 2019; 865:172735). Activation of HER3 in NSCLC mediates aggressive growth and drug resistance. Therefore the ability of NTSR1 to regulate transactivation of HER3 was investigated. By RT-PCR, HER3 and NTSR1 but not NTSR2 mRNA was present in NSCLC cells. NTS addition to NCI-H358 or H441 cells increased HER3 and ERK tyrosine phosphorylation by 210% and 240%, respectively and the increase caused by NTS was antagonized by SR48692 or mAb3481 (HER3 mAb). The increase is phosphorylation of Tyr1289-HER3 caused by NTS or neuregulin-1 addition to NSCLC cells was due to the formation of HER2-HER3 and EGFR-HER3 heterodimers. NTSR1 regulation of HER3 or Akt phosphorylation was impaired by PP2 (Src inhibitor) or GM6001 (MMP inhibitor). Because N-acetylcysteine (antioxidant) or Tiron (superoxide scavenger) inhibited the ability of NTS to increase HER3 phosphorylation, reactive oxygen species (ROS) are essential. Using a clonogenic assay, NTS increased NSCLC colony number whereas SR48692 or mAb3481 reduced colony number. The results indicate that NTS increased HER3 tyrosine phosphorylation in a ROS-/Src-/MMP-dependent manner. In summary, NTSR1 transactivates HER3 resulting in ERK and Akt phosphorylation increasing the proliferation and survival of NSCLC cells.
Citation Format: Terry W. Moody, Irene Ramosalvarez, Robert T. Jensen. Neurotensin causes tyrosine phosphorylation of HER3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 731.
Abstract 733: Significance of PELP1/SETDB1 axis in endocrine therapy resistance
Authors: Liu Zexuan , Liu Junhao , Tang Weiwei , Pratap Uday P. , Altwegg Kristin A. , Ebrahimi Behnam , Li Xiaonan , Sareddy Gangadhara R. , Viswanadhapalli Suryavathi , Vadlamudi Ratna K. 
Published: July 2021

Abstract
BACKGROUND: PELP1 is commonly overexpressed in breast cancer (BCa) and is implicated in endocrine therapy resistance. However, the mechanism by which PELP1 contributes to therapy resistance remains elusive. Our ongoing studies using yeast two hybrid screen identified histone methyltransferase SETDB1 as a novel interactor of PELP1. The objective of this study is to determine the significance of PELP1 interaction with SETDB1 in BCa endocrine therapy resistance.
METHODS: We used two ER+ BCa cell lines (MCF7 and ZR75) and three endocrine therapy resistant cell lines (Tamoxifen resistant MCF7-TamR, Fulvestrant resistant MCF7-FR, Tamoxifen resistant MCF7-PELP1-cyto). Additional BCa models with stable overexpression and under expression of SETDB1 and PELP1 (MCF7-SETDB1-PELP1shRNA, ZR75-SETDB1-PELP1shRNA, ZR75-SETDB1, MCF7-SETDB1, MCF7-TamR-SETDB1shRNA, MCF7-FR-SETDB1shRNA) were generated using lentiviral transduction. Functional significance of cross-talk was tested using MTT, soft agar, and colony formation assays. Mechanistic studies were conducted using immunoprecipitation, Western blotting, and RT-qPCR.
RESULTS: Analyses of TCGA databases showed that SETDB1 expression is positively correlated with PELP1 expression in ER+ BCa (r=0.30, p&lt;0.0001). Immunoprecipitation assays using multiple ER+ BCa cell lysates confirmed the interaction of SETDB1 with PELP1. Using ER+ BCa models with overexpression of SETDB1 or knockdown, we provided evidence that SETDB1 plays an important role in the proliferation of BCa cells. PELP1 knockdown attenuated SETDB1 mediated BCa cells proliferation. SETDB1 upregulation contributed to tamoxifen resistance, while PELP1 knockdown re-sensitized cells to tamoxifen therapy. Further, endocrine therapy resistant model cells (MCF7-TamR, MCF7-FR, MCF7-PELP1-cyto) showed increased expression of SETDB1, and its knockdown sensitized them to endocrine therapy. Mechanistic studies revealed that PELP1 is needed for SETDB1 mediated Akt phosphorylation and activation of its downstream targets such as S6, and Cyclin D1.
CONCLUSIONS: The results of study suggest that the PELP1/SETDB1 interactions contribute to endocrine therapy resistance via aberrant activation of Akt signaling. Targeting PELP1/SETDB1 axis could represent a new therapeutic avenue to mitigate endocrine resistance. Supported by VA grant I01BX004545 (R.K. Vadlamudi)
Citation Format: Zexuan Liu, Junhao Liu, Weiwei Tang, Uday P. Pratap, Kristin A. Altwegg, Behnam Ebrahimi, Xiaonan Li, Gangadhara R. Sareddy, Suryavathi Viswanadhapalli, Ratna K. Vadlamudi. Significance of PELP1/SETDB1 axis in endocrine therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 733.
Abstract 734: Macrophage tumor cell metabolic interactions induce therapeutic resistance in prostate cancer
Authors: El-Kenawi Asmaa , Viqueira William Dominguez , Liu Min , Awasthi Shivanshu , Dhillon Jasreman , Yamoah Kosj , Yu Xiaoqing , Koomen John , Gatenby Robert , Ruffell Brian 
Published: July 2021

Abstract
Castration-resistant prostate cancer (CRPC) is a lethal stage of disease. A wealth of clinical and experimental data supports the persistence of androgen receptor (AR) signaling in many cases of CRPC, despite androgen-deprivation therapy (ADT). Here we sought to determine the role of macrophage cholesterol in CRPC and androgen signaling using a syngeneic model that reflected the mutational landscape of the disease. A transcriptomic analysis of prostate tumors following macrophage depletion revealed lower molecular signatures for steroid and bile acid metabolism, indicating perturbation of cholesterol transport. Since cholesterol is the precursor of steroid hormones, we reasoned that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Indeed, macrophage depletion reduced the levels of androgens within prostate tumors and restricted androgen receptor (AR) nuclear localization in vitro and in vivo. Macrophages were cholesterol rich and had the ability to transfer cholesterol to tumor cells in vitro, and AR nuclear translocation was inhibited by activation of Liver X Receptor (LXR)-β, the master regulator of cholesterol homeostasis. Finally, combining macrophage depletion with androgen deprivation therapy increased survival, supporting the therapeutic potential of targeting macrophages in CRPC.
Citation Format: Asmaa El-Kenawi, William Dominguez Viqueira, Min Liu, Shivanshu Awasthi, Jasreman Dhillon, Kosj Yamoah, Xiaoqing Yu, John Koomen, Robert Gatenby, Brian Ruffell. Macrophage tumor cell metabolic interactions induce therapeutic resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 734.
Abstract 75: Determinants of tumor resistance to anti-angiogenic immunotherapy in mouse models of Kras-mutant NSCLC
Authors: Martinez-Usatorre Amaia , Kadioglu Ece , Cianciaruso Chiara , Guichard Alan , Torchia Bruno , Nassiri Sina , Schmittnaegel Martina , Ries Carola H. , Meylan Etienne , Keklikoglou Ioanna , De Palma Michele 
Published: July 2021

Abstract
Immune checkpoint blockade (ICB) with PD-1 or PD-L1 antibodies has been approved for the treatment of non-small cell lung cancer (NSCLC), often in combination with chemotherapy. However, only a minority of the patients respond and sustained remissions are rare. Anti-angiogenic therapy improves tumor response to ICB in mouse models of cancer and in patients with EGFR-mutant NSCLC, but the contribution of anti-angiogenic therapy to the clinical efficacy of ICB in patients with KRAS-mutant NSCLC remains unclear. We used genetically engineered mouse models of KrasG12D/p53null NSCLC, including a mismatch repair-deficient variant (KrasG12D/p53null/Msh2null) with higher mutational burden, and longitudinal imaging of individual tumors to study tumor response and resistance to combinations of ICB, anti-angiogenic therapy, and cisplatin chemotherapy. We found that anti-angiogenic blockade of VEGFA and angiopoietin-2 (ANGPT2) with the bispecific antibody A2V was superior to single VEGFA inhibition and markedly slowed tumor progression. But, contrary to findings in other tumor models, the addition of a PD1 antibody to A2V did not provide additive benefits and even accelerated growth of a fraction of the tumors. We implicated tumor-associated macrophages (TAMs) and PD-1+regulatory T cells (T-regs) in this growth-promoting response, and identified a pre-clinical strategy involving the differential targeting of two distinct TAM subsets that unleashed the therapeutic potential of anti-angiogenic immunotherapy and achieved regression of more than 80% of the lung tumors.
Citation Format: Amaia Martinez-Usatorre, Ece Kadioglu, Chiara Cianciaruso, Alan Guichard, Bruno Torchia, Sina Nassiri, Martina Schmittnaegel, Carola H. Ries, Etienne Meylan, Ioanna Keklikoglou, Michele De Palma. Determinants of tumor resistance to anti-angiogenic immunotherapy in mouse models of Kras-mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 75.
Abstract 750: Race differences in telomere length in benign prostate and subsequent risk of prostate cancer
Authors: Rybicki Benjamin A. , Sadasivan Sudha M. , Chen Yalei , Loveless Ian , Gupta Nilesh S. , Chitale Dhananjay A. , Williamson Sean R. , Rundle Andrew G. , Tang Deliang 
Published: July 2021

Abstract
Telomere shortening is linked to aging and thought to be associated with increased risk for cancer. Most cancer studies have used leukocyte telomere length as a surrogate measure for telomere length with few focused upon telomeres in the target tissue of cancer origin. To determine whether telomere length in pre-malignant prostate tissue is associated with subsequent prostate cancer risk, we conducted a case-control study of 530 case-control pairs matched on date, age at cohort entry, and race nested within a historical cohort of 10,478 men with a benign prostate biopsy. Overall mean telomere length assessed using modified quantitative real-time PCR was not different in benign prostate biopsies of prostate cancer cases vs. matched controls (1.65 ± 0.35 vs. 1.64 ± 0.39; p=0.41). However, race was significantly associated with telomere length with African American (AA) men having shorter telomeres in benign prostate biopsy compared with white men (1.59 ± 0.37 vs. 1.70 ± 0.37; p&lt;0.0001). In race-stratified analyses, telomere length only showed a suggestive association with prostate cancer risk in white men, wherein those with telomere length in the highest quartile had 1.5-fold greater risk of prostate cancer compared to men with prostate telomere lengths in the lowest quartile (OR=1.56; 95% CI = 0.89 - 2.73 ). In addition, white men in the highest prostate telomere length quartile had almost three-fold greater risk of aggressive prostate cancer, defined as Gleason group 3 and above, tumor stage 3 or above or PSA 20 ng/ml or higher , compared with men with telomere lengths in the lowest quartile (OR=2.73; 95% CI =1.05 - 7.15). In summary, white men have longer telomeres in benign prostate tissue compared with AA men, and those with the longest telomeres may be at increased risk for prostate cancer, particularly the more aggressive form of the disease.
Citation Format: Benjamin A. Rybicki, Sudha M. Sadasivan, Yalei Chen, Ian Loveless, Nilesh S. Gupta, Dhananjay A. Chitale, Sean R. Williamson, Andrew G. Rundle, Deliang Tang. Race differences in telomere length in benign prostate and subsequent risk of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 750.
Abstract 762: Clinical characteristics and prognostic value of the KRASmutation in Chinese colorectal cancer patients
Authors: Yuan Ye , Wang Wei , Zhao Jiemin , Zhang Junling , Chen Shiqing , Shen Chunti , Wu Changping , Hu Wenwei 
Published: July 2021

Abstract
Background: The KRAS mutation are high-frequency somatic mutations found in the colorectal cancer (CRC) patients both from Western and Asian countries, but except for exon 2 of KRAS, other prevalence and prognostic value have not been adequately assessed in Asian patients. The aim of this study was to determine the mutation frequencies of whole exon mutation of KRAS in Chinese CRC patients and to investigate their impact on prognosis.
Methods: 7189 tumor tissue samples (iCohort) were subjected to next-generation sequencing (NGS) for detection the KRAS mutation. All pathologic or likely pathologic mutations of KRAS were considered. In addition, clinical features and prognostic dates were collected from 145 patients at the third affliated Hospital of Soochow University (sCohort) and used ddPCR to detect KRAS mutations.
Results: In the iCohort, 2706 patients (37.6%) were confirmed harboring KRAS mutation. The most frequent mutations in KRAS were G12D (32.19%), G12V (17.96%) and G13D (17.59%). In the sCohort, 51 CRC patients (35.17%) had KRAS mutations, among which KRAS G12D (64.71%), G13D (29.41%) and G14D (3.92%) were high-frequency mutations. The KRAS mutation was associated with shorter median overall survival (OS) than wild-type tumors (mOS, 69 vs 55 months; HR, 1.80; 95% Cl 1.22-2.64; P=0.0003). In Cox multivariate analysis, age (HR, 1.562; 95% Cl 1.10-2.22; P=0.013), tumor differentiation (HR, 0.417; 95% Cl 0.19-0.90; P=0.026) and KRAS mutation (HR, 1.897; 95% Cl 0.19-0.90; P=0.001) remained independent predictor of shorter OS. Among the common KRAS mutations, G12D was significantly associated with shorter OS (HR, 2.17; 95% Cl 1.31-3.58; P &lt; 0.0001) compared with KRAS wild-type patients.
Conclusions: Our findings indicate that KRAS genes are frequently mutated and over 30% harbored the KRAS G12D mutation subtype. Our finding that KRAS G12D mutation is associated with inferior survival and a biomarker of poor prognosis in Chinese patients. Our data emphasizes the importance of molecular features in CRC patients, which could potentially be improved by G12D-specific related inhibitors.
Citation Format: Ye Yuan, Wei Wang, Jiemin Zhao, Junling Zhang, Shiqing Chen, Chunti Shen, Changping Wu, Wenwei Hu. Clinical characteristics and prognostic value of the KRASmutation in Chinese colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 762.
Abstract 764: Circulating tumor cell-based mRNA scoring system for prognostication of hepatocellular carcinoma - Translating HCC tissue-based mRNA profiling into a non-invasive setting
Authors: Lee Yi-Te , Sun Na , Kim Minhyung , Wang Jasmine J. , Tran Benjamin V. , Zhang Ryan Y. , Zhang Ceng , Sadeghi Saeed , Finn Richard S. , Saab Sammy , Busuttil Ronald W. , Zhu Yazhen , Tseng Hsian-Rong , You Sungyong , Yang Ju Dong , Agopian Vatche G. 
Published: July 2021

Abstract
Background and Aims Numerous studies in hepatocellular carcinoma (HCC) have proposed tissue-based gene signatures for individualized prognostic assessments. In this study, we aim to develop the HCC circulating tumor cell (CTC) mRNA Scoring System and the HCC-CTC Risk Score (RS) panel to translate tissue-based mRNA signatures into a liquid biopsy setting for non-invasive HCC prognostication.
Methods We developed the HCC CTC mRNA Scoring System by combining the NanoVelcro CTC Assay for enriching HCC CTCs and the NanoString nCounter platform for quantifying the HCC-CTC RS panel in enriched HCC CTCs. The prognostic role of HCC-CTC RS was assessed in the Cancer Genome Atlas (TCGA) HCC cohort (n=362) and validated in an independent CTC cohort (n=40).
Results The HCC-CTC RS panel was developed from 8 HCC tissue-based prognostic gene signatures. Through our integrated data analysis framework, the top 10 prognostic genes highly expressed in HCC cells and lowly expressed in white blood cells were selected as the HCC-CTC RS panel. The panel accurately discriminated overall survival in TCGA HCC cohort (hazard ratio [HR]: 2.01, 95% confidence intervals [CI]: 1.39-2.91). In addition, the combined use of Scoring System and panel successfully distinguished artificial blood samples spiked with an aggressive HCC cell type, SNU-387, from those spiked with PLC/PRF/5 cells (P=0.02). Finally, the prognostic value of HCC-CTC RS was further validated in the CTC cohort (HR: 8.48, 95% CI: 1.89-38.03) by multivariable analysis.
Conclusions Our pilot study demonstrates a novel interdisciplinary approach to translate tissue-based gene signatures into a liquid biopsy setting. This non-invasive approach will allow real-time disease profiling and dynamical prognostication of HCC.
Citation Format: Yi-Te Lee, Na Sun, Minhyung Kim, Jasmine J. Wang, Benjamin V. Tran, Ryan Y. Zhang, Ceng Zhang, Saeed Sadeghi, Richard S. Finn, Sammy Saab, Ronald W. Busuttil, Yazhen Zhu, Hsian-Rong Tseng, Sungyong You, Ju Dong Yang, Vatche G. Agopian. Circulating tumor cell-based mRNA scoring system for prognostication of hepatocellular carcinoma - Translating HCC tissue-based mRNA profiling into a non-invasive setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 764.
Abstract 782: Exploring the contribution of introgressed ancient DNA to prostate cancer racial disparity
Authors: Useh Evi O. , Venugopal Suresh , Molokwu Chidi N. 
Published: July 2021

Abstract
Introduction: Prostate cancer is the most common cancer in men and there is racial disparity in prostate cancer incidence and mortality globally, with greater disease burden in men of African ancestry, followed by European ancestry and least in men of Asian ancestry. The etiology of prostate cancer is not fully understood, but includes genetic and environmental factors. Present day non-Africans are reported to have introgressed DNA from Neanderthal and Denisovan ancestors. Over 170 prostate cancer associated single nucleotide polymorphisms (SNPs) have been identified from several genome-wide association studies (GWAS), with SNPS on chromosomes 2, 8 and 22 reported as showing variation between African and non-African men with prostate cancer. We performed analysis of prostate cancer associated SNPs on chromosomes 2, 8 and 22 to determine if DNA introgression could explain the racial variation.
Methods: We obtained data on prostate cancer associated SNPs from the GWAS catalog (https://www.ebi.ac.uk/gwas) and from reports that were not included in the catalog. Using an Ancient Genome Browser provided by the Max Plank Institute (https://www.eva.mpg.de/genetics/genomeprojects/neandertal/index.html), we determined whether SNPs on chromosomes 2, 8 and 22 were present in African, Neanderthal or Denisovan genomes. Based on the results, we inferred that SNPs were introgressed if they were present in Neanderthal or Denisovan genomes but absent from African genomes.
Results: 49, 59 and 17 prostate cancer SNPs were reported in chromosomes 2, 8 and 22 respectively. 23/49 in ch2, 25/59 in ch8 and 9/17 in ch22 were present in Neanderthal and or Denisovan genomes. SNPs in ch2 (rs13403657, rs12621278) and ch8 (rs7825414) were present in Neanderthal or Denisovan genomes but absent in African genomes. These SNPs lie in regions that have previously been reported to harbor introgressed DNA.
Conclusion: Our analyses identified prostate cancer associated SNPs that are likely to have been introgressed into present day non-Africans by extinct Neanderthal and Denisovan ancestors. Phenotypic changes caused by introgressed DNA could be contributing to racial disparities in prostate cancer in present day humans.
Citation Format: Evi O. Useh, Suresh Venugopal, Chidi N. Molokwu. Exploring the contribution of introgressed ancient DNA to prostate cancer racial disparity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 782.