bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2569: miR520a inhibits Fzd9 in bronchial epithelial cells and NSCLC
Authors: Smith Alex J. , Do Paulina , Sompel Kayla M. , Elango Alamelu 
Published: July 2021

Abstract
Non-small cell lung cancer (NSCLC) continues to be the most diagnosed cancer type worldwide and has the highest mortality rate. Treatment is highly researched, but 5 year survival remains around 20%. Chemoprevention could combat the development of lung cancer in individuals who are at high risk, such as former cigarette smokers. Iloprost is a prostacyclin analogue demonstrated to reduce the presence of endobronchial dysplasia in former smokers. Increased Frizzled-9 (Fzd9) expression is induced by Iloprost, resulting in activation of peroxisome proliferator activated receptor γ (PPARγ) and inhibition of transformed growth. The goal of this study is to elucidate the relationship of cigarette smoke, NSCLC, and miRNA regulation of Fzd9 expression. We hypothesized that miRNA regulate Fzd9 expression when NSCLC cells are exposed to both cigarette smoke condensate (CSC) and Iloprost. miR520a5p was predicted in silico to bind Fzd9 and we validated binding with a miR520a5p mimic and Fzd9 3'UTR luciferase in an immortalized human bronchial epithelial cell line (HBEC) and NSCLC cell lines. A549 and H322 NSCLC cells and HBEC were exposed to cigarette smoke condensate (CSC) and Iloprost. CSC increased miR520a expression, while the opposite was observed in Iloprost treated cells. We also measured Fzd9 3'UTR activity and demonstrated that CSC decreases both Fzd9 3'UTR and PPRE activity, while Iloprost does the opposite. We investigated the effect of miR520a5p on targets downstream of Fzd9, including PPARγ response element (PPRE), a direct measure of PPARγ activity, and epithelial to mesenchymal transition (EMT) gene expression, including Cox2, E-cadherin, and CRB3. We found that when Fzd9 is inhibited by miR520a5p, PPRE activity and epithelial gene expression are inhibited, while mesenchymal gene expression is stimulated. Rescue experiments combining CSC with a miR520a5p inhibitor or iloprost with a miR520a5p mimic supported a role for miR-520a-5p in inhibition of Fzd9 in a CSC carcinogenic pathway in lung epithelial cells that is reversed with iloprost treatment. Overall, these findings suggest a mechanism for miRNA regulation of Fzd9 in lung epithelial cells exposed to cigarette smoke and a potential chemoprevention target.
Citation Format: Alex J. Smith, Paulina Do, Kayla M. Sompel, Alamelu Elango. miR520a inhibits Fzd9 in bronchial epithelial cells and 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 2569.
Abstract 2605: A natural history study of men with high-risk genetics for prostate cancer (PCa) using multiparametric MRI (mpMRI)
Authors: Karzai Fatima , Couvillon Anna , McKinney Yolanda , Lee-Wisdom Katherine , Choyke Peter L. , Giri Veda N. , Morgan Todd M. , Cheng Heather H. , Merino Maria J. , Pinto Peter A. , Turkbey Baris , Dahut William L. 
Published: July 2021

Abstract
Introduction: The understanding of molecular genetics in PCa provides insight into disease progression and treatment. Less is known about PCa development in men with known high-risk germline pathogenic/likely pathogenic variants in PCa related genes, particularly DNA damage repair (DDR). mpMRI can localize and detect PCa lesions in this population. We are conducting a multicenter natural history study of male participants (prts) with documented germline variant(s) in BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, HOXB13, ATM, NBN, TP53, CHEK2, PALB2, RAD51D, BRIP1, or FANCA who do not have a PCa diagnosis using mpMRI (NCT03805919).
Methods: Up to 500 men, 30-75 years old (y/o) will undergo mpMRI evaluation at baseline and every 2 years (yrs). Prts are followed at 12-mo intervals to determine PSA, PCa diagnosis, and/or disease/survival status until death. Indication for prostate biopsy includes PSA &gt;2.0 for 30 - 49 y/o; &gt;2.5 ng/mL for 50 - 75 y/o and/or PIRADS 3+ MRI lesion or clinical discretion. Tissue obtained will undergo full transcriptome analysis.
Results: 100 prts have enrolled. Median age is 47 y/o. Median on-study PSA is 0.87 (0.16-10.05 ng/mL). Median PSA density is 0.029. Gene mutations are BRCA2 (40%), BRCA1 (33%), MSH2 (9%), and CHEK2 (4%). Mutations in ATM, HOXB13, MLH1, MSH6, PMS2, and EPCAM are ≤3%. No significant AEs have been observed. Of 96 prts, 25 (26%), had indication for biopsy [PIRADS 4 lesion: 16 (64%), PIRADS 3 lesion: 4 (16%), elevated PSA: 6 (24%), or clinical indication 1: (4%)]. 22 prostate biopsies were performed and 6 prts were diagnosed with PCa. One prt was upstaged on radical prostatectomy (RP).
Conclusions: We found mpMRI-based PCa screening in men with high-risk gene mutations, especially DDR genes, is feasible and can be used to identify clinically significant PCa and monitor for disease progression. Future guidelines should consider age, mutation specificity and mpMRI. Accrual and correlative studies (biomarkers, PBMCs) are on-going.
AgeMutationPSA (ng/mL)Biopsy Gleason ScoreTreatment65BRCA22.253+3RP52BRCA10.693+3Active Surveillance (AS)62CHEK22.493+3AS59PMS21.033+3AS59CHEK22.243+4Radiation55BRCA21.683+3RP: 4+4=8
Citation Format: Fatima Karzai, Anna Couvillon, Yolanda McKinney, Katherine Lee-Wisdom, Peter L. Choyke, Veda N. Giri, Todd M. Morgan, Heather H. Cheng, Maria J. Merino, Peter A. Pinto, Baris Turkbey, William L. Dahut. A natural history study of men with high-risk genetics for prostate cancer (PCa) using multiparametric MRI (mpMRI) [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 2605.
Abstract 2610: A high performance blood test for multiple cancer early screening
Authors: Xu Linhao , Wang Jun , Ma Weifeng , Liu Xin , Yang Ting , Li Sihui , Hu Qian , Tao Jinsheng , Ye Zhujia , Chen Zhiwei , Fan Jian-Bing 
Published: July 2021

Abstract
Introduction: Early detection is critical to improving cancer patient survival and quality of life. Cell-free DNA (cfDNA) methylation profiling is a promising diagnostic approach for early detection of cancer, even before symptoms appear. We previously reported a non-invasive and cost-effective methylation test, Aurora, which is able to detect three major cancer types with high specificity and sensitivity especially at early stages (I/II), including lung cancer (LC), breast cancer (BC), colorectal cancer (CRC). We have improved this test to include two additional major cancer types, gastric cancer (GC) and esophageal cancer (EC). Taking together, these five cancer types represent 56% of new cancer cases and 60% of cancer-related deaths in China.
Methods: We developed a novel high-throughput targeted methylation profiling platform, Aurora 2.0 (an improved version of Aurora 1.0, as presented in AACR 2020), to efficiently enrich and capture cancer-specific DNA methylation markers in plasma, prior to analysis via next-generation sequencing on a MiSeqDx system. About 100 cases each for GC and EC patients (mostly at Stage I/II), together with ~200 healthy controls, have been analyzed by using Aurora 2.0 and used for model development and validation.
Results and Discussion: cfDNA methylation profiles have been obtained from 409 plasma samples, comprising 206 healthy controls, 98 GC and 105 EC patients. Logistic regression model has been developed with the Area Under Curve (AUC) of 94.0% and 93.5% for GC and EC, respectively. Overall, the performance (AUC) of Aurora 2.0 for LC/BC/CRC/GC/EC are 97.3%, 96.2%, 92%, 94% and 93.5%, respectively. An independent cohort (~2,000 plasma samples, five cancer types including lung, breast, colorectal, gastric and esophageal cancers with healthy controls) study is undergoing to further validate this test prospectively. The superior performance and cost-effectiveness (~$100) of the test could make early cancer screening of multiple major cancers in symptom-free and average-risk populations more achievable.
Citation Format: Linhao Xu, Jun Wang, Weifeng Ma, Xin Liu, Ting Yang, Sihui Li, Qian Hu, Jinsheng Tao, Zhujia Ye, Zhiwei Chen, Jian-Bing Fan. A high performance blood test for multiple cancer early screening [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 2610.
Abstract 2612: Personalized cancer risk and prevention: analysis of risk factors for specific cancers and integration into cancer risk assessment paradigms
Authors: Elespuru Rosalie K. , Fischer Catherine 
Published: July 2021

Abstract
Cancer risk assessment is performed generally in relation to assessment of the safety of new medical products or environmental exposures, especially when DNA modification is a factor. The risk assessment paradigms used for products subject to regulatory review are independent of specific cancers, multiple exposures, and individual risk factors. A default cancer risk assessment for regulatory review includes “uncertainty factors” to account for differential susceptibility and other variables involved in extrapolating from experimental systems to human risk. However, there is a growing amount of evidence that suggests differing risk for different types of cancer as well as the importance of combinations of risk factors not limited to genetic or environmental effects. In the era of personalized medicine and cancer genomics, can we begin to assess personalized cancer risk, instead of overall cancer risk? What models would assist in this paradigm shift? There are several cancers for which specific genetic, environmental, viral and other associations have been established and could be used in personalized cancer risk assessments, including colon, liver, and lung cancer. A search was conducted on PubMed for available literature on epidemiology, genetic susceptibility, and risk factors associated with the major types of cancer, including ~25 pathological types of cancer in 17 different organs. Risk factors associated with each included chemical exposures and tobacco, as well as genetic, epigenetic, microbial, viral, dietary, exercise, and other factors known for involvement in the development of cancer in humans. The diversity of cancers and evidence for specific risk factors is summarized. Common risk factors, including smoking and obesity, are supplemented with a substantial set of individual, often non-overlapping risk factors for diverse cancers. Surprisingly, little evidence was found that genetic-environmental interactions are significant risk factors for most cancers. From this assessment we can begin to ask whether and for what cancers a personalized risk approach seems feasible.
Disclaimer: The findings and conclusions in this presentation are those of the authors and should not be construed to represent any agency determination or policy.
Citation Format: Rosalie K. Elespuru, Catherine Fischer. Personalized cancer risk and prevention: analysis of risk factors for specific cancers and integration into cancer risk assessment paradigms [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 2612.
Abstract 2613: Cryptotanshinone and dihydrotanshinone epigenetically suppress human colorectal cancer cell growth
Authors: Su Zheng-Yuan , Chen Yu-Hsin Chen , Wu Tien-Yuan 
Published: July 2021

Abstract
Most cancer cases are closely related to many risk factors such as environment and diets. Carcinogenesis may also be controlled by epigenetic regulation. Salvia miltiorrhiza Bunge (Danshen) is a common Chinese herbal medicine, and it has been reported that it has anti-cancer, anti-inflammatory, anti-coagulant, and anti-thrombotic activities. In this study, we studied the effect and epigenetic mechanisms of cryptotanshinone (CTS) and dihydrotanshinone (DHTS), the major active ingredients in Danshen, against human colorectal cancer HCT116 cells. The results showed that CTS and DHTS suppressed the proliferation of HCT116 cells for 72-hour treatment and induced mRNA and protein expressions of p21 and DLEC1. Pro-apoptosis proteins such as PARP, caspase-3, and caspase-9 are cleaved and activated in HCT116 cells treating CTS and DHTS. Moreover, CTS and DHTS also increased the protein levels of epigenetics regulating enzymes, including histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) in HCT116 cells. Therefore, it is suggested that CTS and DHTS may affect tumor suppressor genes, such as p21 and DLEC1, by regulating epigenetic mechanisms, which induce apoptosis of colorectal cancer HCT116 cells.
Citation Format: Zheng-Yuan Su, Yu-Hsin Chen Chen, Tien-Yuan Wu. Cryptotanshinone and dihydrotanshinone epigenetically suppress human colorectal cancer cell growth [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 2613.
Abstract 2647: HOXB7, a key transcriptional regulator in triple negative breast cancer progression
Authors: Jin Kideok 
Published: July 2021

Abstract
Despite major advances in breast cancer treatment and management one-third of women with ER-positive, and nearly 30% of women with ER-negative breast cancer will have recurrent disease within fifteen years. Our laboratory and others have accumulated a large body of evidence for the involvement of HOXB7 in various aspects of breast cancer progression: tamoxifen resistance, DNA repair, epithelial-mesenchymal transition, promotion of metastasis in a transgenic mouse model and human cells as well as angiogenesis suggesting a role for HOXB7 not only in the epithelium but also strongly implicating its control on the microenvironment of the tumor. In this project, we focused on understanding factors driven by HOXB7 that lead to triple-negative breast cancer (TNBC). In the previous studies, we found that HOXB7 expression results in the recruitment of stromal components and enhances the formation of lung metastasis in transgenic crosses of HOXB7xHER2 mice. Interestingly, HOXB7 expression was increased in MDA-MB-231 Bone and Brain metastatic cells. Therefore, we hypothesize that HOXB7, through its ability to mediate EMT and recruit pro-angiogenic molecules, is capable of promoting invasion and metastasis. In this report, we established HOXB7 overexpressing MDA-MD-231 cells. We screened secretomes from MB231-HOXB7 cells using Human Cytokine Array Q440 to quantitatively detect 440 human inflammatory factors, growth factors, chemokines, receptors, and cytokines simultaneously. We identified upregulation of IL-8, IL-6, VEGF, ARG2, CXCL1, CF XIV, Procalcitonin, Syndecan-3, AMICA, IL-11, CXCL14, ROBO3, Follistatin, SOST, and ALCAM in the secretomes from MB231-HOXB7 cells. We ranked the expression level of each factor by real-time qRT-PCR and determined that IL-8 and CXCL1 were the top candidates. We confirmed by ELISA that IL-8 and CXCL1 secreted from tumor conditioned medium (TCM) was upregulated compared to the control cells. Our data showed that the HUVEC tube formation was increased by MDA-MD-231-HOXB7 conditioned media. Furthermore, fibroblast and M2 type macrophage migration were promoted by TCM of MDA-MD-231-HOXB7 cells. Significantly, Depletion of IL-8 and CXCL1 using specific shRNAs in MDA-MD-231-HOXB7 cells decreased the HUVEC tube formation and the cell migration of fibroblast and macrophage. In addition, CXCL1 and IL-8 signaling pathway by Reparixin, an inhibitor of the CXCR1/2 abrogated the tube formation and migration induced by MDA-MD-231-HOXB7 cells. These findings implicate IL-8 and CXCL1 signaling as a critical event in HOXB7 overexpression TNBC growth and metastasis via crosstalk between cancer cells and stromal components.
Citation Format: Kideok Jin. HOXB7, a key transcriptional regulator in triple negative breast cancer progression [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 2647.
Abstract 2651: Combination of an anti-angiogenic antibody with PD1/PDL1 blockade agents produces synergistic anti-tumor efficacy in preclinical models
Authors: Xue Liting , Zhang Haoyu , Wang Qian , Li Feng , Li Xinxin , Yu Xiaohong , Lu Zhihong , Huang Yue , Yang Wenqing 
Published: July 2021

Abstract
Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play a fundamental role in tumor growth and angiogenesis. Signalling through VEGF/VEGFR not only induces cancer angiogenesis but also affects immune cells, making VEGF/VEGFR a pair of well-documented cancer therapeutic targets. Recently more and more studies have focused on combination of anti-VEGF/VEGFR agents and immune checkpoint inhibitors in preclinical and clinical settings. BD0801 is a humanized rabbit anti-VEGF monoclonal antibody currently in clinical development stage. In this study, we have revealed that BD0801 presents more potent activity than Bevacizumab in blockade of VEGF/VEGFR2 binding (IC50=275 ng/ml for BD0801; IC50=1451 ng/ml for Bevacizumab) and VEGFR2 activation in HUVEC assays. BD0801 also showed enhanced inhibitory effects on the proliferation (IC50=87 ng/ml for BD0801; IC50=476 ng/ml for Bevacizumab) and migration of the HUVECs, compared to Bevacizumab. We found that BD0801 exhibits dose-dependent tumor growth inhibitory activities in both lung cancer PC9 xenograft and lung cancer 3LL murine syngeneic tumor models. In addition, we obtained PK parameters of BD0801 using lung cancer PC9 tumor bearing mice and successfully made correlations between the in vitro function, PK profile and in vivo efficacy of BD0801. Notably, combination of BD0801 with either anti-PD-1, or anti-PD-L1 antibodies showed synergistic anti-tumor efficacy in both lung and colorectal cancer mouse models. Mechanistic studies were conducted to reveal possible mechanism of actions (MOA) underlying the modification in tumor microenvironment. Our data demonstrated that the MOA of the anti-tumor synergy may involve enhanced T-cell mediated immunity, including increased tumor infiltration of CD8+ and CD4+ T cells and reduced double positive CD8+PD-1+ T cells, as well as improved vasculature normalization. Taken together, these data provide a foundation for combining BD0801 with immunotherapy for cancer treatment and support further clinical development plans for BD0801 toward this direction.
Citation Format: Liting Xue, Haoyu Zhang, Qian Wang, Feng Li, Xinxin Li, Xiaohong Yu, Zhihong Lu, Yue Huang, Wenqing Yang. Combination of an anti-angiogenic antibody with PD1/PDL1 blockade agents produces synergistic anti-tumor efficacy in preclinical models [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 2651.
Abstract 2654: Differential effect of MGMT methylation between moderate or high vascular profile in IDH wild-type glioblastoma
Authors: del Mar Álvarez-Torres Maria , Fuster-García Elies , Juan-Albarracín Javier , Puig Josep , Balaña Carmen , Capellades Jaume , Emblem Kyrre Eeg , García-Gómez Juan Miguel 
Published: July 2021

Abstract
A significant association between MGMT methylation and prolonged overall survival (OS) was observed for patients with glioblastoma (GB) that present moderately relative cerebral blood volume (rCBV) 1. However, that study should be updated to the current glioma WHO classification. In the current study we assess the combined effect of rCBV and MGMT methylation combined on OS in patients with IDH wild-type GB.
An independent cohort of 95 IDH wild-type GB patients with OS&gt;30 days and with tumor resection was included for this study. The rCBV values of the highest angiogenic tumor regions were automatically calculated using ONCOhabitats analysis services2. Finally, the whole cohort was divided into moderately and highly vascularized GB by the median of the previously calculated rCBVs (rCBVmedian=9.56).
We observed a significant association between MGMT methylation and prolonged OS for the whole cohort (p = 0.003, HR = 0.49), as well as for patients with moderate rCBV (p = 0.002, AUC = 0.30). The difference in OS between patients with MGMT methylated and patients with MGMT unmethylated was 4 times higher in the group with moderate rCBV than for the group with high rCBV (205 vs. 42 days). Finally, no association was found between MGMT methylation and OS in patients with high rCBV (p &gt; 0.05) (Table below).
Our results highlight the combined prognostic effect of MGMT methylation and moderate vascularity in IDH wild-type GB patients. As demonstrated, non-invasive MRI perfusion markers may identify those patients who will mostly benefit in terms of prolonged OS owing to their MGMT methylation status.
1: doi.org/10.1007/s00330-020-07297-4
2: doi.org/10.1016/j.ijmedinf.2019.05.002
Number of patientsMedian OS (days)ResultsStatistical resultsTotalMeth MGMTUnmethMGMTMeth MGMTUnmethMGMTΔOSHR [95% CI]pAUCAll9551445894501390.49 [0.30-0.78]0.0028*0.61Moderate rCBV4221216534482050.30 [0.14-0.64]0.0020*0.72High rCBV533023493451420.68 [0.37-1.26]0.21800.52
Citation Format: Maria del Mar Álvarez-Torres, Elies Fuster-García, Javier Juan-Albarracín, Josep Puig, Carmen Balaña, Jaume Capellades, Kyrre Eeg Emblem, Juan Miguel García-Gómez. Differential effect of MGMT methylation between moderate or high vascular profile in IDH wild-type glioblastoma [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 2654.