bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1469: Optimizing the tolerability of intravenous oncolytic viral immunotherapy administration: investigation of a low-high-high dose schedule of enadenotucirev (EnAd) administration
Authors: McElwaine-Johnn Hilary , Illingworth Sam , Lear Rochelle , Brown Richard , Champion Brian 
Published: August 2019

Abstract
Background:EnAd is a tumor-selective oncolytic adenovirus with highly selective replication and cell killing in a broad range of carcinoma cell lines. Following intravenous dosing in clinical studies, uptake and replication of EnAd, associated with CD8+ cell infiltration, has been shown. It is currently in combination studies with nivolumab and paclitaxel. Intravenous delivery of EnAd stimulates an acute response characterised by an increase in cytokines in peripheral blood. As previously reported (ESMO IO 2017, abstr 203), the MTD of EnAd (3x1012 viral particles (vp) Days 1, 3 and 5, flat dosing schedule) has been determined primarily based on AEs occurring on first dose (C1D1), with the cytokine response, including interleukin-6 (IL-6), to subsequent doses of EnAd appearing attenuated when delivered within a few days of the first dose.
Methods: The effect of the first EnAd dose on subsequent acute particle-mediated cytokine (IL-6) responses in mice was investigated following administration of systemic doses equivalent to between 5.5 x 1012 vp and 5.5 x 1013 vp in humans.
Results: The magnitude of IL-6 response to a low first dose, which itself induces very low or undetectable levels of IL-6 cytokine, is sufficient to attenuate the response to subsequent high doses (10 times more vp). When administered as first dose these high doses induced a significant elevation in systemic IL-6.
Conclusions: Tolerability of EnAd is primarily determined by C1D1, correlating with the cytokine response across the patient cohort. The data from this in vivo pharmacology study support the concept of delivering a lower dose of enadenotucirev on Day 1 and administering higher doses thereafter, with the aim to deliver a higher viral load to tumour tissue and potentially optimise the overall risk:benefit of EnAd administration. This type of dosing regimen (low-high-high) has been successfully implemented in clinical studies of other systemically administered oncolytic viruses (Clin Cancer Res 2006;12:2555-2562) and is under clinical investigation as part of the ongoing combination study with nivolumab. (EudraCT:2013-001276-38).
Citation Format: Hilary McElwaine-Johnn, Sam Illingworth, Rochelle Lear, Richard Brown, Brian Champion. Optimizing the tolerability of intravenous oncolytic viral immunotherapy administration: investigation of a low-high-high dose schedule of enadenotucirev (EnAd) administration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1469.
Abstract 148: Analysis of the tumor microenvironment in seven cancer types by single-cell RNA-seq
Authors: Dean Michael , Li Guibo , Jin Jianhua , Hou Yong , Wu Kui , Zhu Shida , Zhou Hanlin , Lv Ruqian , Lin Feng , Liu Si , Dong Shichen , Wang Lei , Zhang Cuijuan , Zhao Yi 
Published: August 2019

Abstract
The tumor microenvironment (TME) is composed of tumor cells, as well as immune and stromal cells. Cancer cells can interact with the tumor microenvironment to suppress anticancer immunity and host inflammatory cells can modulate that immune response to the lesion. To better understand the TME across cancer types we used single-cell RNA-seq analysis of 224,330 cells from 77 patients with breast, gastric, nasopharyngeal carcinoma (NPC), diffuse large B-cell lymphoma (DLBCL), pancreatic, colorectal and lung cancer. The tumor cells and immune cells from individual patients were analyzed simultaneously at the single-cell level to identify distinct cell clusters and subtypes. Comparison of the profile of T cells, macrophages, dendritic cells (DC), B cells, mast cells, granulocytes and cancer-associated fibroblasts (CAFs) identifies unique profiles by tumor type. Breast tumors have high numbers of macrophages, colorectal tumors are elevated for CD4+-T cells, DLBCLs are low in CAFs, gastric cancers have high levels of mast cells, lung tumors high levels of CD4+-T cells and natural killer (NK) T cells, NPC have elevated levels of B cells and DCs and pancreatic cancers high levels of CAFs and granulocytes and low levels of DC and CD8+-T cells. However, within a tumor type, there is also considerable heterogeneity. Understanding how the TME evolves and changes with therapy or predicts response to treatment and survival may provide insight into tumorigenesis and cancer progression.
Note: This abstract was not presented at the meeting.
Citation Format: Michael Dean, Guibo Li, Jianhua Jin, Yong Hou, Kui Wu, Shida Zhu, Hanlin Zhou, Ruqian Lv, Feng Lin, Si Liu, Shichen Dong, Lei Wang, Cuijuan Zhang, Yi Zhao. Analysis of the tumor microenvironment in seven cancer types by single-cell RNA-seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 148.
Abstract 155: Cysteine-rich secretory protein 3 expression leads to invasive prostate cancer by modulating cell motility
Authors: Furic Luc , Volpert Marianna , Hu Jinghua , O'Connor Anne , Rebello Richard J. , Keerthikumar Shivakumar , Evans Jemma , Merriner Jo , Pedersen John , Risbridger Gail P. , McIntyre Peter , O'Bryan Moira K. 
Published: August 2019

Abstract
Cysteine-rich secretory protein 3 (CRISP3) is one of the most highly up-regulated proteins during the transition from a healthy human prostatic epithelium to prostate cancer. The role of CRISP3 within this process has not however, been defined. Here we show using a genetically engineered mouse model of prostate cancer, that CRISP3 production greatly facilitates disease progression from carcinoma in situ to invasive prostate cancer in vivo. This observation was further validated using both human and mouse prostate cancer cell lines, which showed that exposure to CRISP3 enhanced cell motility and invasion. Further,using mass spectrometry, we showed that this activity is induced, at least in part, via changes in cell-cell adhesion proteins, including LASP1 and TJP1 both in vivo and in vitro. Collectively, these data identify CRISP3 as being pro-tumorigenic in the prostate and validate it as a bona fide marker of aggressive prostate cancer and a potential target for therapeutic intervention.
Citation Format: Luc Furic, Marianna Volpert, Jinghua Hu, Anne O'Connor, Richard J. Rebello, Shivakumar Keerthikumar, Jemma Evans, Jo Merriner, John Pedersen, Gail P. Risbridger, Peter McIntyre, Moira K. O'Bryan. Cysteine-rich secretory protein 3 expression leads to invasive prostate cancer by modulating cell motility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 155.
Abstract 1564: Polymorphisms in nucleotide excision repair genes were associated with the survival of post-operative oral squamous cell carcinoma patients treated with adjuvant concurrent chemoradiotherapy
Authors: Yeh Chih-Ching , Senghore Thomas , Chien Huei-Tzu , Wang Wen-Chang , Chen You-Xin , Young Chi-Kuan , Huang Shiang-Fu 
Published: August 2019

Abstract
Background: The nucleotide excision repair (NER) pathway plays a major role in the repair of DNA damaged by exogenous agents including chemo-and radiotherapeutic agents. Thus, we investigate the association between key potentially functional single nucleotide polymorphisms (SNPs) in the NER pathway and clinical outcomes in oral squamous cell carcinoma (OSCC) patients treated with concurrent chemoradiotherapy (CCRT).
Methods: Thirteen SNPs in five key NER genes were genotypes in 319 OSCC patients using iPLEX MassARRAY. Multivariate Cox proportional hazards models and Kaplan-Meier survival curves were used to estimate risk of death or recurrence.
Results: Carriers of the XPC rs2228000 TT genotype showed a borderline significant increased risk for poor overall survival under the recessive model (hazard ratio [HR]=1.81, 95% confidence interval [CI]=0.99–3.29). The CC genotypes of ERCC5 rs17655 (HR=1.54, 95% CI=1.03–2.29) and ERCC1 rs735482 (HR=1.65, 95% CI=1.06–2.58) were associated with an increased risk for worse disease-free survival under the recessive model. In addition, participants carrying both CC genotype of ERCC5 rs17655 and ERCC1 rs735482 exhibited an enhanced susceptibility for recurrence (HR=2.60, 95% CI=1.11–6.09). However, no statistically significant interaction was observed between them.
Conclusion: Our findings show that the ERCC5 rs17655 CC and ERCC1 rs735482 CC genotypes were associated with an increased risk for recurrence in OSCC patients treated with CCRT. Therefore, CCRT may not be beneficial and alternative treatments are required for them.
Citation Format: Chih-Ching Yeh, Thomas Senghore, Huei-Tzu Chien, Wen-Chang Wang, You-Xin Chen, Chi-Kuan Young, Shiang-Fu Huang. Polymorphisms in nucleotide excision repair genes were associated with the survival of post-operative oral squamous cell carcinoma patients treated with adjuvant concurrent chemoradiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1564.
Abstract 1567: Race, RNA-based recurrence scores, and survival of early hormone receptor-positive breast cancer: A population-based study
Authors: Han Yunan , Colditz Graham A. , Liu Ying 
Published: August 2019

Abstract
Introduction: Compared with white women, black American women are less likely to develop hormone receptor-positive breast cancer, but experience higher mortality of the disease. The 21-gene recurrence scores (RS) predict individualized benefit of chemotherapy for early hormone receptor-positive breast cancer. We hypothesize that the RS scores in early hormone receptor-positive breast cancer are higher in black women than in white women and this contributes to the worse outcomes among black women with hormone receptor-positive breast cancer.
Methods: Utilizing the Surveillance, Epidemiology, and End Results database, we identified 75,861 women (75.7% non-Hispanic white, 7.9% non-Hispanic black, 8.0% Asian/Pacific Islander, and 8.5% Hispanic) with stage I-III hormone receptor-positive breast cancer diagnosed between 2004 and 2014. RS scores were categorized into low, medium, and high groups using traditional cutoffs (18 and 30) and the cutoffs used in the TAILORx clinical trial (11 and 25). We performed multivariable logistic regression to evaluate odds ratios (ORs) of RS categories, and Cox proportional hazard regression to estimate hazard ratios (HRs) for breast cancer-specific mortality and overall mortality.
Results: The multivariable adjusted least square mean of RS was significantly higher in black (23.2) than other racial/ethnic groups (white 22.9, Asian/PI 22.5, Hispanic 22.4; p&lt;0.0001). Compared with white women, black women were more frequently in the high RS category defined by a cutoff of 30 (case-only OR=1.24, 95% CI: 1.11-1.39), Asian/PI (OR=0.88, 95% CI: 0.79-0.98) and Hispanic (OR=0.80, 95% CI: 0.72-0.89) were less frequently in the high RS category defined by a cutoff of 25. Compared with white women, the HR of breast cancer-specific mortality was 1.37 (95% CI: 1.10-1.69) in black women, and 0.65 (95% CI: 0.48-0.90) in Asian/PI women, after adjustment for demographic factors, RS categories and other tumor characteristics, and treatment. This association did not significantly vary by RS categories. The multivariable-adjusted associations between race/ethnicity and overall mortality were similar to those for breast cancer-specific mortality.
Conclusions: Racial/ethnic differences in early hormone receptor-positive breast cancer outcomes could not be explained by RS scores. Potential differences in tumor biology that are not related to the genes in the 21-gene assay may contribute to the worse prognosis of black women with hormone receptor-positive breast cancer.
Citation Format: Yunan Han, Graham A. Colditz, Ying Liu. Race, RNA-based recurrence scores, and survival of early hormone receptor-positive breast cancer: A population-based study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1567.
Abstract 1570: Genome-wide association study identifies variants at 3p26.1 linked to survival in ovarian cancer patients among Chinese women
Authors: Dai Hongji , Chu Xinlei , Wang Wei , Yang Huijun , Wang Qiong , Li Mulin Jun , Wei Qingyi , Chen Kexin 
Published: August 2019

Abstract
Survival rates for ovarian cancer varies considerably among patients, and some of this variation could be explained by germline genetic variation. In order to identify genetic markers associated with ovarian cancer-specific survival, we performed a genome-wide association study (GWAS) of ovarian cancer survival among Chinese women. In a meta-analysis of 2,130 ovarian cancer patients from the southeast and north part of China, we found a significant association between SNPs at the 3p26.1 and overall survival (lead SNP rs3804994; combined P=9.8×10-9). Patients with the minor allele are at increased risk for mortality (HR: 1.55; 95% CI: 1.33-1.80) relative to patients with the major allele. Statistical fine-mapping and functional prioritization recommend a potential casual SNP rs9311399 that locates in the active chromatin region of ovarian tissue. Using EMSA, luciferase assay and ATAC-seq, we demonstrated that risk allele of rs9311399 could alter the regulatory activity of DNA sequence. Our findings suggest that genetic variants at the 3p26.1 may be promising prognostic biomarkers for ovarian cancer patients.
Citation Format: Hongji Dai, Xinlei Chu, Wei Wang, Huijun Yang, Qiong Wang, Mulin Jun Li, Qingyi Wei, Kexin Chen. Genome-wide association study identifies variants at 3p26.1 linked to survival in ovarian cancer patients among Chinese women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1570.
Abstract 1575: DNA methylation-derived neutrophil-to-lymphocyte ratio and survival among pediatric medulloblastoma patients
Authors: Arroyo Vidal M. , Lupo Philip J. , Scheurer Michael E. , Rednam Surya P. , Murray Jeffrey C. , Okcu M F. , Chintagumpala Murali M. , Brown Austin L. 
Published: August 2019

Abstract
Background/Objectives: Medulloblastoma is the most common malignant brain tumor diagnosed in children. Current risk-stratification methods of pediatric medulloblastoma do not fully explain the observed variability in clinical outcomes. Methylation-derived neutrophil-to-lymphocyte ratio (mdNLR) captures immune-specific information and has been identified as a potential prognostic biomarker of outcomes in various cancers, including adult brain tumors. Therefore, we evaluated the association between blood-derived mdNLR and overall survival in a cohort of patients with pediatric medulloblastoma.
Design/Methods: We identified pediatric patients diagnosed and treated for medulloblastoma at Texas Children’s Cancer Center between 1995 and 2015. Peripheral blood DNA methylation was measured using the Infinium Human Methylation 450K Beadchip. Methylation data underwent quality control, including beta-mixture quantile normalization and batch correction. Immune cell proportions (CD4+ T-Cells, CD8+ T-Cells, B-cells, natural killer cells, monocytes, and granulocytes) were estimated using cellular deconvolution methods and used to estimate mdNLR, which was then log-transformed to improve normality. Cox regression models were estimated to evaluate the association between mdNLR and overall survival.
Results: Of the 78 eligible patients include in this analysis, 83% (n=65) were alive at last follow-up (median follow-up=7.8 years). Deceased patients (n=13; median follow-up=2.6 years) had a higher mean mdNLR than patients who were alive at last contact (12.3 vs. 4.0, P = 0.046). Elevated log-transformed mdNLR was associated with an increased risk of death in both unadjusted models (HR=1.68, 95%CI: 1.11-2.55) and models accounting for age, sex, race, and clinical risk group (HR=1.97, 95%CI: 1.12-3.45).
Conclusion: We identified a significant association between peripheral blood mdNLR and survival in pediatric medulloblastoma. As a promising prognostic biomarker of outcomes, mdNLR captures immune-specific information and is a potential avenue of research in settings where cytologic determination of NLR may not be possible. Future work should investigate the relationship between elevated mdNLR and specific pediatric medulloblastoma molecular subtypes.
Citation Format: Vidal M. Arroyo, Philip J. Lupo, Michael E. Scheurer, Surya P. Rednam, Jeffrey C. Murray, M F. Okcu, Murali M. Chintagumpala, Austin L. Brown. DNA methylation-derived neutrophil-to-lymphocyte ratio and survival among pediatric medulloblastoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1575.
Abstract 158: Mutantp53, MAPK and STAT3 promote metastasis to the brain: Demonstrated by protein, gene, and functional analysis
Authors: Wainwright John V. , Cooper Jared B. , Chandy Anisha , Gandhi Chirag D. , Schmidt Meic H. , Jhanwar-Uniyal Meena 
Published: August 2019

Abstract
Metastatic tumors to the brain arise from a specific subset of neoplastic cells originating from primary tumors such as lung, breast, colon, etc which disseminate specifically to the cerebral gray/white matter junction. Genetic and epigenetic mechanisms of this complex metastatic transformation are yet to be defined. Inactivation of the tumor suppressor gene p53 is one of the most frequent genetic alterations seen in human cancers. Further, extracellular regulated kinase (ERK), a component of mitogen activated protein kinase (MAPK) and Signal transducer and activator of transcription 3 (STAT3) plays a crucial role in differentiation, proliferation and migration, and is aberrant in many tumors. We hypothesize that aberrant p53, ERK1/2 and STAT3 contribute to metastatic brain tumors. Results demonstrated that: 1. Immunohistochemical analysis (IHC) of mutant p53 (mt-p53), phosphorylated-ERK1/2 Thr202/Tyr204 (pERK 1/2) and phosphorylated-STAT3Tyr705 revealed that 66% of metastatic brain tumors expressed mt-p53, 86% of tumors expressed pERK 1/2, and 75% nuclear expression of pSTAT3Tyr705; 2. Gene expression profiling showed that 17, 44 and 21 differentially expressed genes in metastatic tumors were p53, MAPK and STAT3 associated, respectively with alterations in genes associated with cell cycle regulation, neurogenesis, and differentiation and reprogramming and metastases; and 3. Metastatic breast cancer cells grown in astrocytic media displayed increased cell proliferation and enhanced S-phase cell cycle entry. Migration of primary tumor cells was significantly enhanced in astrocytic media as well. Inhibitors of MAPK (U0126) and STAT3 (STAT3 inhibitor SVI-201) suppressed cell proliferation and migration. Metastatic tumor cells and astrocytes were shown to grow amicably together, forming cell-to-cell interactions. These findings suggest that mt-p53 and aberrant MAPK and STAT3 play a crucial role in brain metastasis, and that the cerebral milieu provides a suitable microenvironment for metastatic cells to grow and disseminate and inhibition of aforementioned pathway can provide suitable therapeutic strategies.
Citation Format: John V. Wainwright, Jared B. Cooper, Anisha Chandy, Chirag D. Gandhi, Meic H. Schmidt, Meena Jhanwar-Uniyal. Mutantp53, MAPK and STAT3 promote metastasis to the brain: Demonstrated by protein, gene, and functional analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 158.
Abstract 1593: Genetic interactions in lung cancer using machine-learning approaches in genome-wide association studies
Authors: Byun Jinyoung , Han Younghun , Amos Christopher I. 
Published: August 2019

Abstract
Genome-wide association studies (GWAS) consisting of hundreds of thousands or millions of single nucleotide polymorphisms (SNPs) have presented the complex inheritance patterns of disease/trait. Although GWAS have identified thousands of SNPS associated with diseases, few studies have explored interactions among these SNPs that may influence disease risks. Machine learning applications can identify SNPs that influence disease risk through interactions and define how these SNPs jointly influence disease risks. Tree-based machine-learning applications; classification and regression trees (CART) and random forest (RF) methods, have become increasingly popular and convenient tools for understanding interactions influencing disease development. Here we apply these methods to understand the genetic architecture of lung cancer. To elucidate the SNP-SNP interactions that influence lung cancer risk, we applied supervised tree-based approaches using 18,444 cases and 14,027 controls from lung cancer OncoArray GWAS data that is the largest lung cancer GWAS so far. To reduce the space of SNPs to consider in modeling, we first selected the SNPs very significantly (p&lt;0.00001) associated with lung cancer risk. Random Forests, which consists of systematically fitting classification trees, was run 1,000 times to identify the most influential SNPs that jointly influence lung cancer risk. Subsequently we applied a classification tree approach to summarize interactions that predict risk. The final parsimonious tree included effects from genetic variants in rs55781567(CHRNA5): rs452384(CLPTM1L): rs9258608(LOC105375010): rs6154144(DNAJC5): rs116506680(HLA-G): rs9271365(near HLADQA1): rs421629(CLPTM1L). The nodes of this tree had Odds ratios for lung cancer ranging from 0.87 to 1.63. Machine-learning approaches in genomics can provide an important genetic mechanism in lung cancer development.
Citation Format: Jinyoung Byun, Younghun Han, Christopher I. Amos. Genetic interactions in lung cancer using machine-learning approaches in genome-wide association studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1593.