bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 688: Anti-CNTN4 antibody, GENA-104A07 suppresses tumor growth in murine syngeneic tumor models by regulating T cell function
Authors: Cha Mi Young , Houh Youn Kyung , Kim Yun Yeon , Kim Hyunuk , Chung Joo-Yeon , Park Kyung Mi , Park Hansoo 
Published: July 2021

Abstract
Vast improvements in tumor treatment have been achieved with immune checkpoint inhibitors. They have been approved for use in monotherapy or combinations for patients with different types of cancer. However, the treatments often yield limited benefits and strong responses are observed only in a minority of treated patients. For this reason, enormous efforts have been made to explore primary or acquired resistance mechanisms to improve the available current therapies. CNTN4 (contactin 4, alias BIG-2) is a neuronal cell adhesion molecule, which is mainly expressed in the human brain and functions in axonal growth and guidance. Some genetic evidence has indicated that CNTN4 may be associated with non-neurological disorders such as cancer and cardiovascular conditions as well as neurodevelopmental disorders. Recently we identified CNTN4 as a novel immunomodulatory protein, which is expressed on tumors. In this study, we investigate the potential of CNTN4 as a cancer immunotherapeutic target, using GENA-104A07 to target it. GENA-104A07 is a humanized IgG4 monoclonal antibody that specifically binds to human and mouse CNTN4 with sub-nanomolar binding affinity by ELISA assay, not to any other related proteins having similar sequences. This molecule competitively interferes with the binding of CNTN4 and its receptor protein. The in vitro functional effect showed that the treatment of GENA-104A07 alleviates the immune suppressive effect induced by CNTN4 on T cells. Consequently, the administration of GENA-104A07 induces significant suppression of the tumor growth as monotherapy in syngeneic mouse models with a high expression level of CNTN4. GENA-104A07 treatment increases the expression of activation markers and pro-inflammatory cytokines on T cells. Taken together with in vitro and in vivo studies, the efficacy of GENA-104A07 demonstrated that CNTN4 blockage with monoclonal antibody may provide an immunotherapeutic strategy for human cancer. Currently, the preliminary safety study is ongoing in mice, and IND enabling studies will be initiated early next year with the optimized antibody.
Citation Format: Mi Young Cha, Youn Kyung Houh, Yun Yeon Kim, Hyunuk Kim, Joo-Yeon Chung, Kyung Mi Park, Hansoo Park. Anti-CNTN4 antibody, GENA-104A07 suppresses tumor growth in murine syngeneic tumor models by regulating T cell function [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 688.
Abstract 711: Repurposing 2nd generation androgen receptor antagonist Proxalutamide to treat COVID-19
Authors: Ma Liandong , Tong Youzhi , Guo Qiang , Zhou Yifeng , Zhou Qianxiang , Yan Honghua 
Published: July 2021

Abstract
To date, as of 17 November 2020, there have been 55 million confirmed cases of COVID-19, including 1,4 million deaths globally, as reported to WHO. It is, therefore, very critical to discovery and development of the available treatment options for COVID-19. We here discuss the repurposing 2nd generation androgen receptor antagonist Proxalutaminde to treat COVID19. We analyzed the gender disparity of disease severity and progression in 1339 patients with COVID-19 and investigated the mechanism of gender disparity in male vs female patients with COVID 19. As androgen-androgen receptor pathway may contribute to the difference in severity and disease progression in male and female patients with COVID-19, we used cell lines derived from lung, prostate cancer and normal lung epithelial cells to determine the effect of androgen and androgen receptor antagonist Proxalutamide on the expression of two key proteins for SARS-CoV-2 to infect and enter the host cells. Angiotensin converting enzyme 2 (ACE2), a host transmembrane protein provides the binding sites for SARS-CoV-2 on the host cell surface, transmembrane protease serine 2 (TMPRSS2), a cellular serine protease, prims the S protein of SARS-Cov-2 to facilitate the viral entry into the host cells. As cytokine store plays a major role in the disease progression of COVID-19, we examined the effect of GT0918 on inducible nitric oxide synthase (iNOS) and Tumor necrosis factor-alpha (TNF-α), the macrophage polarization/activation markers, in mouse macrophage cells. In this study, we demonstrated higher rates of disease progression and mortality of male COVID-19 patients than female patients. Furthermore, we revealed that androgen-AR activation induced the expression of ACE2 and TMPRSS2 under the androgen-dependent condition in cells derived from prostate and lung cancer, which was inhibited by the blockage of AR signaling with Proxalutamide. Importantly, Proxalutamide also inhibited the expression of iNOS and TNF-α, the biomarkers for macrophage polarization/activation. These results support the role of androgen-AR signaling in the disease progression and mortality in male patients with COVID-19. We are currently conducting clinical study in COVID-19 patients with Proxalutamide in Brazil (NCT04446429).
Citation Format: Liandong Ma, Youzhi Tong, Qiang Guo, Yifeng Zhou, Qianxiang Zhou, Honghua Yan. Repurposing 2nd generation androgen receptor antagonist Proxalutamide to treat COVID-19 [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 711.
Abstract 760: Analysis of ERG and SPOP subtypes in prostate cancer in the Colombian population and their possible implications on prognosis
Authors: Ovalle Wendy Montero , Moreno Yenifer Segura , Sanabria-Salas María Carolina , de Mesa Jorge Mesa López , Ramírez Rodolfo Varela , Boada Vilma Medina , López Martha Lucía Serrano 
Published: July 2021

Abstract
Prostate cancer (PCa) is the type of cancer with the highest incidence and mortality in our country. Current disease prognostic factors do not differentiate aggressive from indolent cases with sufficient certainty and for this reason, it has worked on a characterization of molecular subtypes that allows for a better classification. In localized PCa, fusions between the gene regulated by androgens TMPRSS2 and ERG, or mutations in SPOP (speckle type POZ, the gene that codes for an adapter protein of the Cullin-3-RING-Box1 complex) have been detected in different populations, which has been related to prognosis; however, we do not know the relevance of these molecular alterations in affected Colombians. These two alterations are described within the 7 subtypes reported by the TCGA and are considered mutually exclusive.
Objective: Evaluate the presence of ERG and SPOP subtypes in prostate cancer in the Colombian population and correlate these findings with clinicopathological parameters.
Methodology: For this study, FFPE radical prostatectomy samples from 112 patients with PCa were used, where the TMPRSS2-ERG fusions were studied by FISH, and in negative cases for fusion, mutations in exons 6 and 7 of SPOP were evaluated by sanger sequencing.
Results: Fusion was detected in 71 patients (63.4%), this frequency of the ERG subtype was similar to that observed in the Caucasian population (40-60%). No statistically significant differences were found between the fusion state and the clinicopathological variables analyzed such as age, initial PSA, Gleason score, Gleason grade group, clinical and pathological tumor stage, lymph node involvement, biochemical recurrence-free survival, and overall survival. In the 41 (36.6%) cases negative for fusion, only one mutation (F133L) was detected in exon 7, which has previously been reported in 34 cases.
Conclusions: The frequency of fusion of the ERG subtype detected in our population was 63.4%, no associations were found between the fusion state and the prognosis of the disease. Until now, 1 case has been detected a mutation of exon 7 of SPOP (2.4%). The low frequency of this subtype in Colombians could be explained by the reported variability in the frequency of these mutations according to the population (5% -20%).
Citation Format: Wendy Montero Ovalle, Yenifer Segura Moreno, María Carolina Sanabria-Salas, Jorge Mesa López de Mesa, Rodolfo Varela Ramírez, Vilma Medina Boada, Martha Lucía Serrano López. Analysis of ERG and SPOP subtypes in prostate cancer in the Colombian population and their possible implications on prognosis [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 760.
Abstract 772: A novel recurrence-associated metabolic prognostic model for risk stratification and therapeutic responses prediction in patients with stage I lung adenocarcinoma
Authors: Liu Chengming , Sun Nan , He Jie 
Published: July 2021

Abstract
Background: The proportion of patients with stage I lung adenocarcinoma (LUAD) has dramatically increased with the prevalence of low-dose computed tomography use for screening. Up to 30% of patients with stage I LUAD experience recurrence within 5 years after curative surgery. A robust risk stratification tool is urgently needed to predict the patients who might benefit from adjuvant treatment.
Methods: In this first investigation of the relationship between metabolic reprogramming and recurrence in stage I LUAD, we developed a recurrence-associated metabolic signature (RAMS). This RAMS was based on metabolism-associated genes to predict cancer relapse and overall prognosis of patients with stage I LUAD. The clinical significance and immune landscapes of the signature were comprehensively analyzed.
Results: Based on a gene expression profile from the GSE31210 database, functional enrichment analysis revealed a significant difference in metabolic reprogramming that distinguished patients with stage I LUAD with relapse from those without relapse. We then identified a metabolic signature (i.e., RAMS) represented by two genes (ACADM and RPS8) significantly related to recurrence-free survival and overall survival times of patients with stage I LUAD using transcriptome data analysis of a training set. The training set was well-validated in a test set. The discriminatory power of the two-gene metabolic signature was further validated using protein values in an additional independent cohort. The results indicated a clear association between a high-risk score and a very poor patient prognosis. Stratification analysis and multivariate Cox regression analysis revealed that the RAMS was an independent prognostic factor. We also found that risk score was positively correlated with inflammatory response, the antigen-presenting process, and the expression levels of many immunosuppressive checkpoint molecules (e.g., PD-L1, PD-L2, B7-H3, galectin-9, and FGL-1). These results suggested that high-risk patients had immune response suppression. Further analysis revealed that anti-PD-1/PD-L1 immunotherapy did not have significant benefits for high-risk patients. However, they could respond better to chemotherapy.
Conclusion: This study was the first to highlight the relationship between metabolic reprogramming and recurrence in stage I LUAD and develop a clinically feasible signature. This signature may be a powerful prognostic tool and help further optimize the cancer therapy paradigm.
Citation Format: Chengming Liu, Nan Sun, Jie He. A novel recurrence-associated metabolic prognostic model for risk stratification and therapeutic responses prediction in patients with stage I lung adenocarcinoma [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 772.
Abstract 788: Differences in somatic TP53 mutation type in breast tumors by race and receptor status
Authors: Pollock Nijole , Ramroop Johnny , McElroy Joseph , Toland Amanda E. 
Published: July 2021

Abstract
Somatic driver mutations in TP53 are associated with triple negative breast cancer (TNBC) and poorer outcomes. African American women with breast cancer are more likely to have TNBC and TP53 driver mutations. Missense driver mutations in TP53 can be loss-of function (LOF) or gain-of-function (GOF). Additionally, some variants show dominant negative (DNE) activity. There are a number of hot-spot TP53 mutations, many occurring at CpG sites. Given the differences in TNBC status and TP53 driver mutation frequency by race, we wanted to determine if there are differences in TP53 mutation type by race. From multiple databases and a literature review, we identified 98 studies with patient race and TP53 mutation details. We compiled TP53 mutations from 2964 breast tumors from these 98 studies. The cohort included 715 (24.1%) Asian, 258 (8.7%) African (AA), and 1931 (65.1%) European (EA) ancestry individuals. Additionally, 60 patients (2%) had Hispanic or Latina ethnicity. Of the somatic TP53 mutations, 939 (31.7%) were GOF, 1739 (58.7%) were LOF, while the remaining 286 (9.6%) were not able to be classified by existing literature. With respect to DNE activity, 1246 (42%) showed DNE, 1190 (40.1%) showed no DNE, and 528 (17.8%) were unknown DNE status. CpG hotspots accounted for 613 (20.6%) mutations. Using Fisher's Exact test, we did not identify significant associations between any of the functional categories and overall race. However, 35.8% of tumors from EA individuals had GOF mutations compared to 29% in AA individuals (p=0.04). Mutations with DNE activity were positively associated with TNBC (OR=1.37, p=0.03) and negative estrogen receptor (ER) status (OR=1.38; p=0.005). Patients with hotspot mutations were slightly younger (mean age 53.61) compared to those with non-hotspot mutations (mean age 55.04), and this association neared significance (p=0.065). Larger cohorts are needed, in particular the AA cohort, to further elucidate some of these borderline findings. In summary, ER negative and TNBC breast tumors are more likely to have DNE TP53 mutations which could reflect biological processes.
Citation Format: Nijole Pollock, Johnny Ramroop, Joseph McElroy, Amanda E. Toland. Differences in somatic TP53 mutation type in breast tumors by race and receptor status [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 788.
Abstract 797: Cancers of unknown primary: A descriptive study in the U.S. military health system
Authors: Bytnar Julie A. , Lin Jie , Moncur Joel T. , Shriver Craig D. , Zhu Kangmin 
Published: July 2021

Abstract
Background: Cancers of unknown primary (CUP) are defined as histologically confirmed metastatic cancers that do not have an identified primary site of origin despite an appropriate diagnostic work-up. It is known that accessibility to and quality of medical care are associated with cancer diagnosis. This study aimed to describe the demographic, histologic, and temporal trend characteristics of CUP patients in the Military Health System (MHS), which provides universal healthcare access.
Methods: The data were obtained from the Department of Defense (DoD)'s Automated Tumor Registry (ACTUR) which collects cancer data from beneficiaries who were diagnosed or received treatment in the (MHS). We described the demographic and histologic distributions in CUP patients aged 18 or older diagnosed from 1987-2013. We calculated the proportion of CUP patients among all metastatic cancers and the most common histologic categories of those tumors. We then evaluated whether the proportion of histologic types changed over time.
Results: CUP comprised 15.1% of all metastatic cancers in ACTUR during the study period. The majority of CUP within ACTUR was well and moderately differentiated adenocarcinoma (51.3%) and poorly differentiated carcinomas (23.2%) followed by squamous cell carcinomas (12.5%). The percentages of CUP among metastasized cancers of the same histologic category ranged 12-15% for well and moderately differentiated adenocarcinomas, squamous cell, and poorly differentiated carcinomas, and 41-46% for malignant neuroendocrine carcinomas and undifferentiated neoplasms. However, the percentages varied by sex, race, and age for certain pathologies. The proportion of CUP patients among all metastatic cancer patients has steadily declined from 22.4% to 8.3% from 1987 to 2013.
Conclusion: The proportion and trends of CUP in the MHS were generally consistent with other descriptive CUP studies. This study provides a description of CUP in a healthcare system with universal access and provides a foundation for future studies on CUP.
Citation Format: Julie A. Bytnar, Jie Lin, Joel T. Moncur, Craig D. Shriver, Kangmin Zhu. Cancers of unknown primary: A descriptive study in the U.S. military health system [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 797.
Abstract 813: Clinical significance of pathogenic variants in germline BRCA1/2 wild type patients at risk for hereditary breast cancer
Authors: Kuang Xiaying , Shao Nan , Lin Ying 
Published: July 2021

Abstract
Objectives: Approximately, 5-10% of breast cancer (BC) are related to inherited germline mutations. Homologous recombination repair (HRR) of DNA is the most important theory in hereditary cancer, in which BRCA1/2 are the most recognized and tested genes. Genetic testing for hereditary BC has changed significantly. Increasing evidence suggests parallel multigene testing of HRR gene.
Methods: NGS-based germline multigene-panel testing of 105 HRR gene was performed on 159 high risk BC patients with at least one of the following risk factors: triple negative BC, early onset (≤45y), family history of BC and bilateral BC. Capture-base targeted sequencing was performed on white blood cells using a panel consisting of 105 genes related to homologous recombination repair of DNA.
Results: Among the 159 patients of median age 40, All the patients had early stage infiltrating ductal carcinoma. 12 patients (7.55%) had pathogenic BRCA1/2 mutation. We investigated the prevalence of 21 pathogenic germline pathogenic mutations beyond BRCA1/2 from 21 patients spanning 13 HRR genes, resulting in a prevalence rate of 13.21% for pathogenic germline mutations in high risk germline BRCA1/2 WT BC patients. PALB2 is the most common gene with pathogenic mutation (n=5). In these 21 patients, 18 (85.71%) were diagnosed with BC before the age of 45, within 7 patients (33.33%) even younger than 35 years old. 7 of them (33.33%) had bilateral BC; one had triple negative BC (4.76%) and 5 patient (23.81%) had a family history of BC. Nearly half of the patients (n=9) presented at least 2 of the risk factors.
Conclusions: Our study confirms the clinical significance of testing non-BRCA genes, and suggests multigene panel testing for patients at risk for hereditary BC as a routine in patients with those risk factors, especially young and bilateral BC patients even without family history of BC.
Citation Format: Xiaying Kuang, Nan Shao, Ying Lin. Clinical significance of pathogenic variants in germline BRCA1/2 wild type patients at risk for hereditary breast 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 813.
Abstract 840: Gallstones and risk of cancers of the liver, biliary tract, and pancreas: A prospective study within two U.S. cohorts
Authors: Luo Xiao , yang wanshui , Joshi Amit , Wu Kana , Simon Tracey , Yuan Chen , Jin Lina , Long Lu , Kim Mi Na , Lo Chun-Han , Liu Xing , Abrams Thomas A. , Wolpin Brian M. , Chan Andrew T. , Giovannucci Edward L. , Zhang Xuehong 
Published: July 2021

Abstract
Background: As one of the most common gastrointestinal diseases, gallstones may result in inflammation,altered bile flow, and changes in metabolic hormone levels, thereby increasing cancer risk. Previous studiesfor gallstones and cancers of the liver, biliary tract, and pancreas from the different data sources, inadequateconfounding adjustment, and whether the association varied by potential risk factors is unclear.
Objective: We examined the association of gallstones and cholecystectomy with the risk of cancers of theliver, biliary tract, and pancreas in the United States.
Methods: We followed 115 036 women from the Nurses' Health Study (1982-2012) and 49 729 men fromthe Health Professionals Follow-up Study (1986-2012). History of gallstones, including with or withoutperformed cholecystectomy, was reported at baseline and updated through biennial questionnaires. The Coxproportional hazard regression model was used to calculate multivariable hazard ratios (HRs) and 95%confidence intervals (95%CIs).
Results: During up to 30-year follow-up, we identified 204 incident liver cancer, 225 biliary tract cancer, and1 147 pancreatic cancer cases. Compared to those without gallstones diagnosis, the multivariable HRs forindividuals with gallstones (untreated or with cholecystectomy) were 1.60 for liver cancer (95%CI: 1.14-2.26),4.79 for biliary tract cancer (95%CI: 3.02-7.58), and 1.13 for pancreatic cancer (95%CI: 0.96-1.32). Themultivariable HRs for individuals with cholecystectomy were 1.33 for liver cancer (95%CI: 0.90-1.95) and1.15 for pancreatic cancer (95%CI: 0.98-1.36).
Conclusions: Gallstones were associated with a higher risk of cancers of the liver, biliary tract, and possiblypancreas. Cholecystectomy was associated with a suggestive increased risk of liver and pancreatic cancer.Our findings provide further evidence for a positive association of gallstones with the risk of cancers in thehepato-pancreato-biliary area.
Citation Format: Xiao Luo, wanshui yang, Amit Joshi, Kana Wu, Tracey Simon, Chen Yuan, Lina Jin, Lu Long, Mi Na Kim, Chun-Han Lo, Xing Liu, Thomas A. Abrams, Brian M. Wolpin, Andrew T. Chan, Edward L. Giovannucci, Xuehong Zhang. Gallstones and risk of cancers of the liver, biliary tract, and pancreas: A prospective study within two U.S. cohorts [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 840.