bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4543: Phenotypic screening of bispecific antibodies in 3D tumor immune cell cocultures
Authors: Daszkiewicz Lidia , Goverse Gera , Beztsinna Nataliia , Visser Benjamin , van der Drift Lois , Yan Kuan , Price Leo 
Published: September 2020

Abstract
INTRODUCTION
The co-culture of tumor and immune cells in 3D enables a better recapitulation of the complex interactions between cells and the tumor microenvironment. High content analysis can be used to evaluate the effects of diverse immunotherapeutics on anti-tumor immune responses in a 3D setting. Functional read-outs can include active migration of immune cells towards tumoroids, infiltration of immune cells into the tumoroids and tumor killing. Here, we have applied high content analysis to quantify the effects of bi-specific antibodies targeting both the tumor and the T cells in 3D culture in a 384 well plate format.
MATERIAL and METHODS
Tumoroids generated from various cancer cell types were cultured in 3D in an extracellular matrix-rich protein hydrogel. Partially HLA-matching T cells isolated from healthy PBMCs donors were added with or without activation to the 3D culture and their infiltration into tumoroids and subsequent killing was visualized using high-content microscopy. Quantification of effects on immune cells and tumoroids was achieved with morphometric analysis with OMinerTM software.
RESULTS and DISCUSSION
Image-based analysis enabled the assessment of tumor-immune cell interactions and tumor killing in 3D co-cultures. The activation status of T cells determined the level of immune cell infiltration and killing of the tumoroids. T cell engaging bi-specific antibodies enhanced infiltration and tumor killing and was associated with increased IFNγ levels in culture supernatants.
CONCLUSION
Here we demonstrated the enhanced immune cell infiltration and tumor killing induced by bi-specific antibodies that simultaneously engage both T cells and tumors in a 3D setting. This assay represents a more physiologically relevant approach to enable cancer immunotherapy drug developers to evaluate the activity of novel immunotherapeutic molecules and better understand their mechanism of action.
Citation Format: Lidia Daszkiewicz, Gera Goverse, Nataliia Beztsinna, Benjamin Visser, Lois van der Drift, Kuan Yan, Leo Price. Phenotypic screening of bispecific antibodies in 3D tumor immune cell cocultures [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4543.
Abstract 4569: DNA vaccine targeting BARF1 induces potent antitumor immunity against Epstein-Barr virus-associated carcinomas
Authors: Zhu Xizhou 
Published: September 2020

Abstract
Epstein-Barr Virus (EBV) is an oncogenic pathogen, with which more than 90% of world population has been infected. It is associated with several types of cancer, and no EBV-specific therapies are available for these diseases. Recent studies targeting EBV latent proteins have shown limited efficacy, for their moderate immunogenicity. Therefore, the development of effective anti-EBV immunotherapies is in need. In this study, we screened a group of EBV proteins and selected BARF1 as a vaccine candidate, for its strong immunogenicity and high expression in EBV positive nasopharyngeal and gastric carcinomas. The BARF1 vaccine was developed through a synthetic DNA approach and delivered in vivo by electroporation. The vaccine induced potent BARF1-specific antibody and polyfunctional effector T cell responses in both C57BL/6 and BALB/c mice. We next established two carcinoma models by generating BARF1-expressing CT26 and MC38 cell lines. In the therapeutic model where mice were challenged with cancer cells and then treated, BARF1 vaccine was able to suppress cancer progression alone and showed synergy when combined with anti-PD1 antibody. In the minimal residual disease model where mice were immunized and then challenged with cancer cells, one dose of BARF1 vaccine was able to generate 100% complete response in treated animals. CD8 T cell was shown to be necessary for this protection. Finally, using the in vivo imaging system, we found that the BARF1 vaccine-induced immune responses cleared tumor in 60% of subjects as soon as 48 hours post tumor challenge. Tumors were cleared in all animals by day 10. In summary, BARF1 DNA vaccine provides a novel tool of immunotherapy that is highly specific to EBV positive malignancies and combining it with checkpoint inhibitors might open up new avenues for precision and combination immunotherapy against EBV-associated cancer. In the future, we will also target other viral-specific cancer antigens with our DNA vaccine platform, exploiting its capability to induce potent cytotoxic T lymphocyte response.
Citation Format: Xizhou Zhu. DNA vaccine targeting BARF1 induces potent antitumor immunity against Epstein-Barr virus-associated carcinomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4569.
Abstract 4576: Oncolytic vaccinia virus TG6010 expressing cytidine deaminase induces DNA damage and shows potent anti-tumor effects
Authors: Foloppe Johann , Kempf Juliette , Pichon Christelle , Findeli Annie , Farine Isabelle , Hortelano Julie , Moreau Baptiste , Klein Michèle , Cochin Sandrine , Brandely Renée , Koerper Véronique , Silvestre Nathalie , Machon Christelle , Guitton Jérôme , Quéméneur Eric , Erbs Philippe 
Published: September 2020

Abstract
The recombinant Vaccinia virus Copenhagen strain deleted in Thymidine Kinase and Ribonucleotide Reductase (VVCOPTK−RR−) is a potent and versatile oncolytic platform that has demonstrated strong activity in various preclinical models. The deletion of such VV genes inhibits viral replication in normal cells, while retaining therapeutic replication in tumor cells. TG6002, a VVCOPTK−RR− expressing the suicide gene FCU1, is under investigation in Phase I trials in patients with advanced gastrointestinal tumors.
We have developed a new product based on the VVCOPTK−RR− vector, named TG6010, expressing the human cytidine deaminase (CDA) that efficiently catalyzes the deamination of cytidine and deoxycytidine to uridine and deoxyuridine, respectively.
The tumor specific expression of CDA by the VV leads to a depletion of cytidine and deoxycytidine. This cytidine/deoxycytidine depletion resulting from CDA overexpression, activated a DNA damage response highlighted by an induction of H2AX phosphorylation.
Next, to validate the potential therapeutic use of TG6010, we analyzed the effects of the virus on human xenograft tumors implanted in mice. We observed, after systemic injection of TG6010, high expression of CDA in the tumors with a significant increase in DNA damage in vivo as revealed by the γH2AX foci assay. In addition, intraperitoneal administration of TG6010 in a xenograft model of human ovarian carcinomatosis resulted in significantly prolonged animal survival.
In conclusion, the oncolytic vaccinia virus expressing the cytidine deaminase (TG6010) has shown potent anti-tumor effects. Mechanistically, due to the cytidine deaminase overexpression, we observed induction of a DNA damage response. These are data encouraging of clinical development for this highly potent oncolytic Vaccinia virus TG6010 against ovarian cancer.
Citation Format: Johann Foloppe, Juliette Kempf, Christelle Pichon, Annie Findeli, Isabelle Farine, Julie Hortelano, Baptiste Moreau, Michèle Klein, Sandrine Cochin, Renée Brandely, Véronique Koerper, Nathalie Silvestre, Christelle Machon, Jérôme Guitton, Eric Quéméneur, Philippe Erbs. Oncolytic vaccinia virus TG6010 expressing cytidine deaminase induces DNA damage and shows potent anti-tumor effects [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4576.
Abstract 4584: A novel combination of a multipeptide KRAS vaccine and an ACAT1 inhibitor to prevent lung cancer
Authors: Pan Jing , Zhang Qi , Palen Katie , Johnson Bryon , Wang Li , Sei Shizuko , Shoemaker Robert H. , Lubet Ronald A. , Wang Yian , You Ming 
Published: September 2020

Abstract
Kirsten rat sarcoma viral oncogene homolog (KRAS) gene encodes a small GTPase that cycles between GDP and GTP-bound states, which modulates important cell surface receptors essential for cell proliferation and survival. It is one of the most common drivers for many types of cancers, is present in up to 25% all human tumors, and 80% of mutation occurs in codon12. Efforts to target KRAS-driven cancers preventively or therapeutically have been unsuccessful. We recently formulated a multi-peptide KRAS vaccine (KVAX), which targets both wild-type and G12D mutant forms of KRAS and has 100% sequence homology between human and mouse. KVAX elicited strong immunologic response and exhibited striking cancer preventive efficacy when administered prior to KRAS mutation induction. However, clinical high-risk individuals may already express mutant KRAS, which has known to promote an immunosuppressive environment. Therefore, we combined KVAX with avasimibe (AVA), an ACAT1 inhibitor that modulates lipid metabolism in T cells and facilitates better TCR/peptide/MHC interactions, in syngeneic lung cancer mouse model and genetically engineered mouse model, in which mutant KRAS initiated lung tumorigenesis before vaccination. We found that the combination significantly decreased the presence of regulatory T cells in the tumor microenvironment, facilitated CD8+ T cell infiltration in tumor sites, and ultimately led to enhanced anti-cancer efficacy. Using 10X Genomics, we performed single cell RNA-seq on lung tumors from mice treated with KVAX and AVA and found significant increases in APC monocytes and CD4+ Th1 cells, especially increases in the effector/memory T cell population. Meanwhile, KVAX also decreased Tregs and M2 macrophages. These studies include the evaluation of tumor-infiltrating immune cells by single-cell RNA-seq (scRNA-seq) and provide a more detailed mechanisms of action of KVAX alone or in combination with AVA in modulating the tumor immune microenvironment.
Citation Format: Jing Pan, Qi Zhang, Katie Palen, Bryon Johnson, Li Wang, Shizuko Sei, Robert H. Shoemaker, Ronald A. Lubet, Yian Wang, Ming You. A novel combination of a multipeptide KRAS vaccine and an ACAT1 inhibitor to prevent lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4584.
Abstract 4595: SERGE- the development of an optical sensor for the detection glioblastoma recurrence
Authors: Fischer Igor , Hänggi Daniel , Kahlert Ulf Dietrich 
Published: September 2020

Abstract
Objective: Total gross resection is the clinical most positive prognostic treatment of brain cancer. Tumor recurrence is a frequent event in patients undergone neurosurgical removal of the primary cancer. Current surveillance of the disease requires cost-intensive and infrastructural sophisticated means and is applied in an infrequent manner. Better tools to monitor the therapy success in order to increase the chances of total gross resection of the recurrent lesion are of high clinical need.
Concept and Results: Photodynamic diagnosis (PDD) is a clinical applied procedure that exploits metabolic alterations in brain tumor cells to discriminate of cancerous tissue from healthy brain parenchyma. This project aims to develop an implant-prototype that enables the surveillance of any tumor recurrence at the primary tumor resection cavity by applying the principles of PDD. We present initial electro-engineering details and the study design to probe its functionality in vitro and in vivo. Supported by the Volkswagen Foundation the project aims to create evidences for the technological feasibility and therapeutic benefit of SERGE as a future class III medical device.
Citation Format: Igor Fischer, Daniel Hänggi, Ulf Dietrich Kahlert. SERGE- the development of an optical sensor for the detection glioblastoma recurrence [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4595.
Abstract 4601: Toward the development of a $100 screening test for 6 major cancer types
Authors: Xu Linhao , Wang Jun , Yang Ting , Tao Jinsheng , Liu Xin , Ye Zhujia , Zhao Dezhi , Jiang Zeyu , Chen Zhiwei , Fan Jian-Bing 
Published: September 2020

Abstract
Introduction: Early cancer detection remains a critical challenge to improve patients' survival rate and clinical outcomes. Alterations in DNA methylation play a key role in tumor initiation, development, progression and metastasis. Cell-free DNA (cfDNA) methylation analysis on liquid biopsies (e.g., blood and urine) holds a great promise for early detection of cancers even without symptoms. In this context, we are developing a non-invasive, cost-effective test that can detect several major cancer types, including lung (LnC), breast (BrC), colorectal (CRC), gastric (GC), esophageal (EC) and liver (LvC) cancers with high specificity (Sp) and sensitivity (Sn). These six cancer types represent two third of the newly diagnosed cancer patients and 72% of cancer deaths every year in China.
Methods: In order to identify highly effective DNA methylation markers for early detection, we have conducted genome-wide methylation profiling on more than 2,000 benign and malignant tissue samples, including large number of early stage (Stage I/II) tumors and pre-cancerous lesions from lung, breast, colorectum, liver, stomach and esophagus. We then developed a high performance assay, Aurora, to capture cancer-specific DNA methylation signatures in plasma. Specifically, cfDNA was extracted from each of the plasma samples, bisulfite-converted, and analyzed by NGS on Illumina MiSeq system.
Results and Discussion: To date, methylation profiles of plasma samples derived from, 1) 58 normal and 106 malignant pulmonary nodule patients, 2) 31 normal and 85 malignant CRC patients, and 3) 81 normal and 78 malignant breast nodule patients, were analyzed. Overall performances (Area Under Curve, AUC) of the Aurora test are 90%, 98% and 92% for LnC, BrC and CRC, respectively. Further clinical validation and evaluation are being conducted in larger independent cohorts of these three types of cancers as well as additional cohorts for the other cancers (GC, EC and LvC). The superior performance and low cost (~$100) make the Aurora test very promising for simultaneous screening of multiple major cancers in symptom-free, average risk populations.
Citation Format: Linhao Xu, Jun Wang, Ting Yang, Jinsheng Tao, Xin Liu, Zhujia Ye, Dezhi Zhao, Zeyu Jiang, Zhiwei Chen, Jian-Bing Fan. Toward the development of a $100 screening test for 6 major cancer types [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4601.
Abstract 4626: TBX1 functions as a potential oncogene in breast cancer
Authors: Huang Shuya , Shu Xiang , Wu Jie , Wang Jifeng , Guo Xingyi , Ping Jie , Bauer Joshua A. , Long Jirong , Shu Xiao-Ou , Zheng Wei , Cai Qiuyin 
Published: September 2020

Abstract
We have previously identified a genetic variant, rs34331122 in the 22q11.21 locus, to be associated with breast cancer risk in genome-wide association studies. This SNP is located in the intronic region of the T-box transcription factor 1 (TBX1) gene. TBX1 is a member of the T-box transcription factor gene family, which plays important roles in embryogenesis and organogenesis. Previous studies have indicated that TBX1 exerted potential tumor suppressor functions in mouse skin tumors and human thyroid cancer. However, the biological functions and molecular mechanisms of TBX1 in breast cancer remain largely unknown. In this study, we investigated whether the association of the 22q11.21 locus with breast cancer risk was mediated by the TBX1 gene. Using The Cancer Genome Atlas (TCGA) data, we found that TBX1 expression was significantly upregulated in breast cancer tissues compared to adjacent normal breast tissues. To investigate the biological functions of the TBX1 gene in breast cancer, we knock-downed TBX1 gene expression using siRNAs in MDA-MB-231, MCF-7 and T47D breast cancer cell lines. Our results showed that knocking down TBX1 expression significantly inhibited breast cancer cell proliferation, migration and invasion. We further performed RNA sequencing in both TBX1 knocked-down and control MDA-MB-231 cells. Our differential gene expression and gene set enrichment analyses showed that knocked-down TBX1 expression significantly downregulated cell cycle-related genes, including CDC6, CDK6, DHFR, CIT, ORAI1 and TOP2A (P &lt; 10−30). These six downregulated genes in TBX1 knocked-downed MDA-MB-231 cells were further confirmed by quantitative real-time PCR (qPCR). Furthermore, using the JASPAR database to predict TBX1 binding motif, we found that TBX1 may bind to the promoter regions of these six genes. In summary, our results suggest that TBX1 acts as a potential oncogene in breast cancer through regulating the expression of cell cycle-related genes, and the associations between genetic variants in the 22q11.21 locus and breast cancer risk may be mediated through altered expression of the TBX1 gene.
Citation Format: Shuya Huang, Xiang Shu, Jie Wu, Jifeng Wang, Xingyi Guo, Jie Ping, Joshua A. Bauer, Jirong Long, Xiao-Ou Shu, Wei Zheng, Qiuyin Cai. TBX1 functions as a potential oncogene in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4626.
Abstract 4647: Diet quality indexes and risk of hepatocellular carcinoma: Findings from the Singapore Chinese Health Study
Authors: Luu Hung N. , Neelakantan Nithya , Geng Ting-ting , Wang Renwei , Adams-Haduch Jennifer , Jin Aizhen , Van Dam Rob M. , Koh Woon-Puay , Yuan Jian-Min 
Published: September 2020

Abstract
Background. There is a limited research on the association between combined dietary measures and liver cancer risk. We investigated the association between the four diet-quality index (DQI) scores, the Alternative Health Eating Index-2010 (AHEI-2010), Alternate Mediterranean Diet (aMED); Dietary Approaches to Stop Hypertension (DASH) and Heathy Diet Indicator (HDI) with liver cancer risk, using data from the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese men and women aged 45-74 at enrollment in 1993-1998 with up to 25 years of follow-up.
Methods. The Cox proportional hazard regression method was used to estimate hazard ratio (HR) and its 95% confidence interval (CI) of HCC with each DQI after adjustment for multiple potential confounders. The unconditional logistic regression method was used to evaluate the associations between the DQIs and HCC risk among a subset of individuals who tested negative for hepatitis B surface antigen (HBsAg).
Results. During an average 17.7 years of follow-up, 561 incident HCC cases were identified. High scores of AHEI-2010, aMED and DASH, representing higher dietary quality, were associated with lower risk of HCC (all Ptrend&lt;0.05). Compared with the lowest quartile, HRs (95% CIs) of HCC risk for the highest quartile of AHEI-2010, aMED and DASH were 0.71 (0.55-0.91), 0.73 (0.54-0.98), and 0.68 (0.52-0.89), respectively. These inverse associations were stronger in men than in women. No significant association between HDI and HCC risk was observed. Among HBsAg-negative individuals, similar inverse associations were observed, and the strongest inverse association was for aMED that reached statistically significance level (HRQ4vsQ1=0.48, 95% CI: 0.24-0.98).
Conclusion. Higher scores of AHED, aMED, and DASH were significantly associated with reduced risk of HCC in this Asian population. The findings support the notion that adherence to a healthier diet may lower the risk of HCC, suggesting that dietary modification may be an effective approach for primary prevention of HCC.
Funding: The Singapore Chinese Health Study was supported by the National Institutes of Health (NIH) of the United States (grants # R01 CA144034 and UM1 CA182876).
Citation Format: Hung N. Luu, Nithya Neelakantan, Ting-ting Geng, Renwei Wang, Jennifer Adams-Haduch, Aizhen Jin, Rob M. Van Dam, Woon-Puay Koh, Jian-Min Yuan. Diet quality indexes and risk of hepatocellular carcinoma: Findings from the Singapore Chinese Health Study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4647.
Abstract 4682: Influence of PI3K/AKT pathway on imatinib mesylate treatment outcome in chronic myeloid leukemia patients
Authors: Banapuram Swathi , Gorre Manjula , Digumarti Raghunadha Rao , Satti Vishnupriya , Palle Komaraiah , Annamaneni Sandhya 
Published: September 2020

Abstract
Chronic myeloid leukemia (CML) is a common myeloproliferative disorder characterized by cytogenetic abnormality [t(9;22)(q34;q11)] that generates BCR-ABL oncogene with aberrant tyrosine kinase activity, the driver event in CML origin. Tyrosine kinase inhibitors (TKIs) are remarkably effective; yet, treatment failure is common in some cases due to the accumulation of mutations in BCR-ABL itself and other genes causing drug resistance/relapse, which indicates that BCR-ABL inhibition alone may not be sufficient to combat CML. The PI3K/Akt/mTOR signaling pathway downstream of BCR-ABL has been proven to be an important survival mechanism in leukemias. In vitro studies demonstrated that targeting this pathway could be a viable strategy, but needs further validation in CML patients. In this study, we examined the critical PI3K/AKT/mTOR pathway genes (PIK3CA, PTEN, AKT1, SHIP1, mTOR, and FOXO3A) in CML patients (n=51) using qPCR method at diagnosis and after treatment, and analyzed with respect to BCR-ABL status, and JAK2, STAT5, and STAT3 levels. Interestingly, significant upregulation of AKT1 (p=0.012) and PIK3CA (p=0.026) and downregulation of PTEN (P=0.06) and SHIP1 (p=0.039) was observed in samples at diagnosis compared to their post imatinib treated. Remarkably, these elevated AKT1 and PI3KCA transcript levels were significantly associated with increased BCR-ABL and JAK2 transcript levels, but not STAT3 and STAT5 suggesting PI3K pathway as a prominent target in CML. However, with respect to the clinical phase and imatinib response, none of the genes showed significant differences except for PTEN, which was significantly downregulated in advanced phase (p&lt;0.042) and in cases with poor imatinib response. Overall, these results indicate a critical role for PI3K pathway in CML and its maintenance.
Citation Format: Swathi Banapuram, Manjula Gorre, Raghunadha Rao Digumarti, Vishnupriya Satti, Komaraiah Palle, Sandhya Annamaneni. Influence of PI3K/AKT pathway on imatinib mesylate treatment outcome in chronic myeloid leukemia patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4682.