bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3619: The role of CXCR4 in progression of malignant glioma
Authors: Liu Mingli 
Published: August 2018

Abstract
High grade malignant gliomas are devastating, uniformly fatal cancers for which no effective therapies exist. Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Recent studies have shown that cytokines/chemokines can regulate many malignant features of tumor cells. CXCL12/CXCR4 axis activates various signaling pathways that promote chemotaxis, adhesion and migration, cell proliferation and survival. PI3 kinase, Ras, stress-activated protein kinase (SAPK)/c-Jun Nterminal kinase (JNK), phospholipase C (PLC)/mitogen-activated protein kinase (MAPK), p38 MAPK and AKT are all downstream effectors of CXCL12/CXCR4 axis, through which tumor cell growth, dissemination and migration are facilitated. To enhance our understanding of the development and progression of glioma which may lead to novel and useful biomarkers and/or therapeutic targets in the context of GBM, we analyzed the role of CXCR4 in glioma using the published data and literature. (1).To determine the prognostic role of CXCR4 in malignant glioma, we analyzed the microarray data from Rembrandt Databases by Affymetrix HG U133 v2.0 Plus on 523 glioma patients. Kaplan-Meier analysis of overall survival showed that glioma patients with high CXCR4 expression (n=329) have short overall survival compared to those with low CXCR4 expression (n=54), logrank test: P=2.2e-8 9. Among GBM, high CXCR4 expression (n=178) have short overall survival compared to those with low CXCR4 expression (n=9), logrank test: P=0.044. Among Astrocytoma, high CXCR4 expression (n=102) have short overall survival compared to those with low CXCR4 expression (n=33), logrank test: P=0.0247 (http://www.betastasis.com/glioma/rembrandt/kaplan-meier_survival_curve/). (2).To determine the relationship between glioma progression and chemokine receptor CXCR4, we made a meta-analysis based on 14 published articles. All 14 eligible studies having 805 patients from China and USA were included. These studies showed that CXCR4 expression in glioma was correlated to high WHO grade glioma (OR=8.26, 95% CI=3.42-19.93, P&lt;0.00001). Our results indicate that CXCR4 is a predictive marker for malignant glioma progression and survival. Suppression of CXCR4 inhibited proliferation, migration, and invasion of malignant human gliomas indicating that CXCR4 may represent a novel and promising target for therapeutic intervention of malignant glioma.
Citation Format: Mingli Liu. The role of CXCR4 in progression of malignant glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3619.
Abstract 3622: Identify prognostic biomarkers for colorectal cancer by human villi development model
Authors: Zhang Botao , Feng Lin , Xiao Ting , Cheng Shujun 
Published: August 2018

Abstract
Background Tumorigenesis and embryogenesis have many similar biological characteristics, such as proliferation, invasion, metabolism and immunity. The development of villi is a physiological process, it will stop after the fetus is born. Trophoblast have been defined as "physiological metastasis" or "pseudo-malignant". However, tumorigenesis is a pathological process that will go on indefinitely. We hypothesize that if the interactions between gene and gene in tumors deviate from the interactions in villi, it is more likely to develop into malignant tumors and have worse prognosis.
Methods We collected tissue samples including human chorionic villus samples at 6 to 10 weeks of gestation (n = 15) and leaf chorionic samples from postpartum placental tissue (n = 6), then extracted RNA and carried out RNA sequencing. We processed bioinformatics analysis in combination with multi-stage colorectal cancer (CRC) transcriptome data, including normal (n = 12), low-grade adenoma (n = 21), high-grade adenoma (n = 30), cancer (n = 25).
Results We found that CRC progress and villi development involve many genes with similar biological behaviors, such as proliferation, immunity, metabolism and invasion, but the genes of the relevant biological behavior are different between CRC and villi. Then we filtered those genes, of which the interactions in CRC are far from that in villi. Twenty-four genes, such as CBL, COL1A1, ATP5C1, CDC42 etc were finally selected. Abnormal expression of the 24 genes was significantly associated with poor survival in six independent CRC cohorts (The Cancer Genome Atlas, P&lt;0.001; GSE39084, P= 0.002; GSE14333, P&lt;0.001; GSE17536, P=0.003; GSE39582, P&lt;0.001; GSE29621, P=0.001).
Conclusions Villi development is a reliable and strictly regulated model that can illuminate the trajectory of human cancer development. Our study indicated that the interactions between gene and gene in CRC development deviate from that in villi, the deviation interactions of gene may have some substantial impacts on CRC development and reveal novel prognostic biomarkers.
Citation Format: Botao Zhang, Lin Feng, Ting Xiao, Shujun Cheng. Identify prognostic biomarkers for colorectal cancer by human villi development model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3622.
Abstract 3628: PD-1 checkpoint blockade therapy enhances adoptive immunotherapy by human Vγ2Vδ2 T cells against prostate tumors in a preclinical model
Authors: Nada Mohanad H. , Wang Hong , Morita Craig 
Published: August 2018

Abstract
Cancer immunotherapy is an effective treatment against a variety of malignancies. Checkpoint blockade with anti-PD-1 or anti-CTLA-4 antibodies has resulted in durable clinical responses. However, targeting PD-1 or PD-L1 provides clinical benefits for only a minority of patients. Moreover, the effectiveness of checkpoint blockade correlates with the numbers of nonsynonymous mutations present in the tumor explaining the poor responsiveness of certain tumors such as prostate cancers. Therefore, additional therapies are needed for patients not currently responding.
Unlike αβT cells, the anti-tumor activity of Vγ2Vδ2 T cells does not require MHC and is independent of the number of tumor mutations. Instead, Vγ2Vδ2 T cells use their TCRs to surveil tumor cells for alterations in isoprenoids metabolism induced by bisphosphonate treatment in a process requiring butyrophilin 3A1. This allows Vγ2Vδ2 T cells to recognize and kill all types of tumors. In clinical trials involving more than 200 patients, adoptive immunotherapy with Vγ2Vδ2 T cells has been proven to be safe. However, there have been few partial or complete responses with the most common beneficial response being stable disease. To find ways to increase its effectiveness, we have now assessed the benefits of combining PD-1 checkpoint blockade with the adoptive transfer of human Vγ2Vδ2 T cells. Vγ2Vδ2 T cells were found to express the major inhibitory receptors, PD-1, CTLA-4, LAG3, and TIM3 at varying times during the fourteen day ex vivo expansion period. To assess the effect of checkpoint blockade in vivo, immunodeficient NSG mice were inoculated with human PC-3 prostate cancer cells that naturally express the PD-L1 ligand. After 2 weeks, weekly treatments were started with intravenous pamidronate followed a day later by purified Vγ2Vδ2 T cells combined with either anti-PD-1 (clone J116) or control IgG1 mAbs. The addition of anti-PD-1 mAb treatment, markedly enhanced Vγ2Vδ2 T cell immunity to PC-3 tumors. Combination treatment was able to reduce tumor volume almost to zero after 5 weeks. These results demonstrate that PD-1 checkpoint blockade can greatly enhance adoptive immunotherapy with γδ T cells in a preclinical tumor model and suggests that combination therapy with anti-PD1 and Vγ2Vδ2T cells could be an effective strategy to treat patients with a variety of cancers.
Citation Format: Mohanad H. Nada, Hong Wang, Craig Morita. PD-1 checkpoint blockade therapy enhances adoptive immunotherapy by human Vγ2Vδ2 T cells against prostate tumors in a preclinical model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3628.
Abstract 3629: Repeated abscopal effect with radiation and anti-PD-1 blockade in MMR deficient endometrial cancer
Authors: Oh Michael S. , Chae Young 
Published: August 2018

Abstract
The combination of radiation therapy and immune checkpoint inhibitors has raised interest as possibly having synergistic antitumor effects. Radiation can induce both a local response as well as a systemic one that stimulates immune cells, which then can be further potentiated by immunotherapy. This abscopal effect has been validated in preclinical studies and is currently being studied in clinical trials, though it has yet to be reported in gynecologic cancers. A 64-year-old woman initially presented with vaginal bleeding and was subsequently diagnosed with stage IIIC endometrial adenocarcinoma with pelvic and para-aortic lymphadenopathy. She underwent surgical resection with adjuvant carboplatin and paclitaxel. Follow-up CT scans showed progression of disease, and over the next 18 months, the patient was sequentially treated with doxorubicin, topotecan, melphalan, docetaxel, and capecitabine. Analysis of a tumor biopsy demonstrated an MMR deficient phenotype with absent MLH1 and PMS2. Based on the recently-published data on the efficacy of PD-1 inhibitors in MMR deficient solid tumors, the patient was started on nivolumab. Meanwhile, she was given palliative radiation therapy to the following areas: painful cutaneous metastases on her left thigh; an L3 spinal metastasis; lymph nodes in the retroperitoneum, external iliacs, and left inguinal chain; and a symptomatic bladder mass. After radiation, the patient exhibited a strong partial response not only in the targeted lesions but also throughout her tumor burden, consistent with an abscopal effect. This response was sustained over many months and repeatable with each radiation session. The synergistic use of radiation therapy and immune checkpoint blockade may thus represent a powerful treatment modality in endometrial cancer and warrants further clinical investigation.
Citation Format: Michael S. Oh, Young Chae. Repeated abscopal effect with radiation and anti-PD-1 blockade in MMR deficient endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3629.
Abstract 363: Role of the SAGA histone acetylation module in lung cancer
Authors: Mustachio Lisa Maria , Roszik Jason , Dent Sharon YR 
Published: August 2018

Abstract
Lung cancer causes the highest mortality in cancer-related deaths. Definition of novel molecular targets is needed since these cancers often become resistant to existing therapies. Epigenetic modifications may provide such targets. Recent reports suggest that the histone acetyltransferase (HAT) module within the transcriptional coactivator SAGA complex plays a role in cancer, creating a new link between epigenetic regulators and this disease. We are working to define the role of the SAGA HAT protein GCN5 in the regulation and function of oncogenes in lung cancers. Since our prior work indicates that GCN5 serves as a coactivator for MYC target genes, we hypothesize that inhibition of GCN5 will reduce lung oncogenesis by suppressing MYC functions. We also propose that inhibition of GCN5 will reduce lung cancer formation and progression in mouse models of lung cancer. Our preliminary data indicate that both GCN5 and MYC expression levels are upregulated and positively associated in mouse and human lung cancers. Both proteins are also associated with MYC target genes in lung cancer tissues. Inhibition of the GCN5 active site or bromodomain significantly (p &lt; 0.05) reduces cell proliferation compared to normal lung epithelium cells. Studies investigating how GCN5 inhibition affects other lung cancer phenotypes are underway. Specific genes and pathways affected by GCN5 loss will be determined using RNA-Seq and RPPA assays to identify mechanisms behind observed phenotypes. In addition, we will determine whether knockout of Gcn5 reduces lung formation and progression in the KrasLA2 lung cancer mouse model. Our ongoing studies will determine whether targeting GCN5 represses multiple oncogenic pathways in cancer and whether it inhibits oncoproteins difficult to directly target, such as MYC. We expect that our findings will highlight the importance of epigenetic regulators in carcinogenesis and extend beyond our current research focus to other cancer types.
Citation Format: Lisa Maria Mustachio, Jason Roszik, Sharon YR Dent. Role of the SAGA histone acetylation module in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 363.
Abstract 3631: Passenger fusion genes are novel predictive biomarker of anti-PD-1 antibody nivolumab for ovarian cancer
Authors: Hamanishi Junzo , Murakami Ryusuke , Brown John B. , Baba Tsukasa , Abiko Kaoru , Suzuki Eiji , Mandai Masaki 
Published: August 2018

Abstract
Background: Immune checkpoint PD-1 signal blockade provides significant clinical efficacy and durable response for several cancer patients. However it is crucial to identify a biomarker to predict the response to PD-1 signal blockade. Herein we analyzed the somatic mutanomes and transcriptomes of tumor samples from ovarian cancer patients treated with nivolumab to identify potential biomarkers of antitumor response.
Methods: We previously reported a phase II clinical trial for resistant ovarian cancer with nivolumab (UMIN000005714) and showed disease control rate was 45% including 2 complete responders. To estimate the somatic mutation burden (TMB) of tumor samples, the number of non-synonymous single nucleotide variants (nsSNVs), insertions and deletions of genes was analyzed by whole exome sequencing of formalin fixed paraffin embedded tumor tissues. Next, to evaluate whole transcriptome of these samples, we performed an RNAseq analysis and detected several fusion genes in some patients. We evaluated the correlation between clinical anti-tumor response for nivolumab treatment with the numbers of somatic mutations or transcriptomic alignments containing gene fusions.
Results: 16 tumor samples (7 responders, 9 non-responders and 1 loss) for whole exome sequencing and 17 samples (7 responders and 10 non-responders) for RNA sequencing were available. Contrary to expectations generated by previously reported papers in melanoma or lung cancers, the levels of TMB including nsSNVs, insertions and deletions of genes were not significantly correlated to antitumor response. However, more than 2 fusion genes were detected (mean=6.3, range 0-15) in 6 of 7 responders, while 8 of 10 non-responders did not have any fusion genes and the remaining non-responders had only 1 fusion gene each (mean=0.2, range, 0-1). Therefore an antitumor response to nivolumab was strongly correlated to the number of fusion genes in ovarian cancer (p=0.0003, sensitivity: 86% [6/7] specificity: 100% [10/10]).
Conclusions: This study, to our knowledge, is the first to describe passenger fusion genes of tumors, and might provide a clinically useful and novel predictive biomarker of antitumor response to anti-PD-1/PD-L1 antibody therapy for ovarian cancer.
Citation Format: Junzo Hamanishi, Ryusuke Murakami, John B. Brown, Tsukasa Baba, Kaoru Abiko, Eiji Suzuki, Masaki Mandai. Passenger fusion genes are novel predictive biomarker of anti-PD-1 antibody nivolumab for ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3631.
Abstract 364: Differentially methylated super-enhancers regulate gene expression in human papillomavirus-related head and neck squamous cell carcinoma
Authors: Flam Emily L. , Kelley Dylan Z. , Stavrovskaya Elena , Danilova Ludmila , Guo Theresa , Considine Michael , Qian Jiang , Califano Joseph A. , Favorov Alexander V. , Fertig Elana J. , Gaykalova Daria A. 
Published: August 2018

Abstract
Human papillomavirus-related head and neck squamous cell carcinoma (HPV+ HNSCC) is characterized by abundant gene expression changes, which cannot be explained by limited genetic alterations alone. We hypothesized that epigenetically regulated super-enhancers (SEs) are the drivers of aberrant gene expression in HPV+ HNSCC. We used integrated analysis of DNA methylation and gene expression data for cancer and noncancer oropharyngeal tissues to discover actionable SEs that regulate expression of target genes in HPV+ HNSCC. Since no SEs are currently defined for any HNSCC samples; we investigated 6196 SE elements that were obtained from the public domain for closely related tissues, including normal and tumor lung, and cervical cancer cell lines. We analyzed the methylation of these elements and gene expression of their nearby genes for 47 HPV+ HNSCC and their 25 noncancer controls. Overall, we found 122 differentially methylated SEs that had putative target (nearby) genes whose expression was correlated with enhancer methylation in HPV+ HNSCC. Of these, 107 were hypermethylated, and 15 were hypomethylated in tumors relative to normal samples. The pathway analysis revealed that the inferred SE-regulated genes were associated with pathways known to regulate carcinogenesis. Our data demonstrate that gene expression in HPV+ HNSCC may be regulated by epigenetic alterations in SE elements of related tissues.
Citation Format: Emily L. Flam, Dylan Z. Kelley, Elena Stavrovskaya, Ludmila Danilova, Theresa Guo, Michael Considine, Jiang Qian, Joseph A. Califano, Alexander V. Favorov, Elana J. Fertig, Daria A. Gaykalova. Differentially methylated super-enhancers regulate gene expression in human papillomavirus-related head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 364.
Abstract 3643: Utility of peritoneal and pleural lavages for detection of somatic alterations: A proof-of-concept study
Authors: Ariza Núria Jordana , Ibañez Mónica Garzón , Martinez-Bueno Alejandro , Caldero Sonia Gatius , casas Clara Mayo de las , Velasco Ana , Ruiz Maria , Canal Berta Roman , Alamillo Jordi Bertran , Rodríguez Muñoz Sonia , Fuentes Raquel Campos , García Beatriz , Bel Ariadna Balada , Villatoro Sergi , Molina-Vila Miguel Ángel , Matias-Guiu Xavier 
Published: August 2018

Abstract
Background: Surgical resection remains the best treatment option for early-stage endometrial (CE), colorectal (CRC) and lung cancer (LC) patients. However, a proportion of patients (p) develop tumor recurrence, even after curative resection. Peritoneal or pleural lavages may be performed during surgery but little data is available about their potential as liquid biopsies with predictive value for recurrence. This proof-of concept study aimed to determine if somatic mutations can be detected in these lavages.
Methods: We analyzed mutations in paired surgical biopsies, blood and peritoneal or pleural lavages supernatants in an early-stage cohort of 25 EC, 12 CRC and 19 LC p. Molecular characterization of surgical biopsies was performed using the GeneReader NGS platform (Qiagen) and the Actionable Insight Tumor Panel, which includes 12 genes (KRAS, NRAS, KIT, BRAF, PDGFRA, ALK, EGFR, ERBB2, PIK3CA, ERBB3, ESR1, and RAF1). cfDNA was purified from blood and lavages using an automatic extractor and the hotspot mutations identified in tumor tissue were tested using a sensitive Taqman assay for codons 12, 13, and 61 in KRAS, codons 542, 545 and 1047 in PIK3CA and codon 600 in BRAF.
Results: NGS of tumor biopsies revealed hotspot KRAS, PIK3CA or BRAF mutations in a total of 11/25 (44%) early-stage EC p, 7/12 (58%) early-stage CRC p and 6/19 (32%) early-stage LC p. In peritoneal lavages, hotspot mutations were found in 6/11 (55%) EC p and 2/7 (29%) CRC p and, in pleural lavages, hotspot mutations appeared in 2/6 (33%) LC p. Furthermore, 2/11 (18%) blood samples from EC p, 1/7 (14%) blood samples from CRC p and 1/6 (17%) blood samples from LC p were positive.
Conclusions: Our study reveals that mutational analysis in peritoneal or pleural lavages from early stage tumors is feasible and that mutations are more frequently detected in lavages than in blood. Further research will determine if positivity in blood or lavages is associated with early relapse.
Citation Format: Núria Jordana Ariza, Mónica Garzón Ibañez, Alejandro Martinez-Bueno, Sonia Gatius Caldero, Clara Mayo de las casas, Ana Velasco, Maria Ruiz, Berta Roman Canal, Jordi Bertran Alamillo, Sonia Rodríguez Muñoz, Raquel Campos Fuentes, Beatriz García, Ariadna Balada Bel, Sergi Villatoro, Miguel Ángel Molina-Vila, Xavier Matias-Guiu. Utility of peritoneal and pleural lavages for detection of somatic alterations: A proof-of-concept study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3643.