bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1286: Oral administration of poly gamma glutamic acid significantly enhances the antitumor immune response of doxorubicin in a murine cancer model through regulating tumor microenvironment
Authors: Choi Joungwoo , Jung Solmin , Oh Yena , Jang Jaepyeong , Cho Yeondong , Lee Do young , Park Youngcheol , Jeong Kwangil 
Published: June 2022

Abstract
Immunogenic cell death (ICD) is a type of cancer cell death triggered by certain chemotherapeutic drugs, oncolytic viruses, and other therapies. In particular, doxorubicin (DOX), one of the chemo-drugs, is well known to induce ICD, which involves the activation of the immune system against cancer in immunocompetent hosts. ICD comprises the release of damage-associated molecular patterns (DAMPs) from dying tumor cells that result in the activation of tumor-specific immune responses, thus eliciting long-term efficacy of anticancer drugs by combining direct cancer cell killing and antitumor immunity. However, the antitumor immunity can be achieved by overcoming the immunosuppressive tumor microenvironment (TME). Most current treatment strategies harnessing the tumor microenvironment focus on T cell-immune response, either by promoting activating signals or suppressing inhibitory ones.We here present a novel approach to cope with the inhibitory TME, combinatory treatment of DOX with poly gamma glutamic acid (γ-PGA). PGA, a safe edible biomaterial secreted by B. subtillis, has been evaluated in the clinical trials with the patients diagnosed as cervical intraepithelial neoplasia 1 (CIN 1). From the study using murine cancer models, including MC38, we found the combinatory treatment with γ-PGA restored the downregulation of NK cell activity caused by DOX, enhanced ICD and T cell responses, and reduced proinflammatory cytokines in the tumor tissues. Taken together, co-administration of γ-PGA exhibited synergistic anti-cancer effects by favoring the immunosuppressive TME in the combinatory treatment with conventional chemo-drugs.
Citation Format: Joungwoo Choi, Solmin Jung, Yena Oh, Jaepyeong Jang, Yeondong Cho, Do young Lee, Youngcheol Park, Kwangil Jeong. Oral administration of poly gamma glutamic acid significantly enhances the antitumor immune response of doxorubicin in a murine cancer model through regulating tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1286.
Abstract 1338: Humanized mouse model for in vivo evaluation of bispecific antibody efficacy
Authors: Yao Li-Chin , Keck James G. , cai Danying 
Published: June 2022

Abstract
Bispecific antibodies have shown several promising advantages over monoclonal antibodies and are emerging as one of growing cancer immunotherapies. Preclinical in vivo models to assess efficacy associated with immune cell engagement are needed. Here we evaluated an EGFR bispecific T cell engager (EGFRXCD3 BiTE) using xenograft models in humanized NSG™ (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice that have been engrafted with human CD34+ HSC and have human T cells in circulation. Three EGFR+ tumor models were used in this report including LG1202 lung PDX and two triple negative breast cancer cell lines MDA-MB-231 with a high EGFR expression level and MDA-MB-453 with a low EGFR expression. Interestingly we found that all three models were resistant to EGFR monoclonal antibody drug cetuximab despite the expression of EGFR but responded to EGFRXCD3 BiTE. BiTE-induced T cell activation was evident through the analysis of tumor infiltrated lymphocytes by flow cytometry at the end of the study. BiTE treatment for 3 weeks effectively reduced the LG1202 tumor growth whereas the effect of cetuximab on the tumor growth was minimal. In the BiTE-treated group, CD3+ T cell percentage increased as compared to the vehicle group, and both CD4+ and CD8+ T cell subsets showed an increased frequency of CD69+ cells. We also observed elevated levels of human cytokines IFN-γ, IL-6, IL-2, and IL-10 in circulation 4 h after animals received the first BiTE dose. We evaluated the dose response of BiTE treatments on MDA-MB-231 model with a high EGFR expression. Low dose BiTE reduced tumor growth whereas high dose BiTE effectively prevented or even regressed some tumor growth. Flow analysis showed that tumor CD3+ T cell frequency remained similar to the vehicle group but CD8+ T frequency increased after high dose BiTE. High CD69+CD8+ T cell frequency was found in the vehicle group and the percentage further increased after high dose BiTE. For the low EGFR-expressing MDA-MB-453 model, BiTE treatment for 4 weeks also effectively reduced the tumor growth. In comparison, while cetuximab treatment decreased EGFR expression on tumor cells, it did not reduce the tumor growth. Flow analysis showed that BiTE-treated group had increased T cell infiltration into the tumors when compared to the PBS and cetuximab groups. The frequency and cell number of CD25+ and CD69+ CD4+ T and CD8+ T cells in the tumor increased after BiTE treatment. Together, these data support our humanized mouse model to be used to validate T-cell dependent bispecific antibody efficacy.
Citation Format: Li-Chin Yao, James G. Keck, Danying cai. Humanized mouse model for in vivo evaluation of bispecific antibody efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1338.
Abstract 135: Age-related immunosenescence and cancer drug toxicity and efficacy in C57BL/6J syngeneic model
Authors: Yang Jiwon , Schile Andrew , Cheng Mingshan , Keck James G. 
Published: June 2022

Abstract
Cancer has a higher incidence in the elderly and immunotherapy is widely applied to this population. However, the majority of preclinical studies assessing drug toxicity and efficacy have been done in young healthy mice. Immunosenescence is a state of aging-related gradual deterioration of the immune system in the elderly. Here, we established tumor models in aged mice that show immunosenescence for a better representation of cancer patients, and to examine the effects of aging and immunosenescence on cancer drug efficacy and toxicity. Young (7 weeks), mid-aged (54-58 weeks), and aged (76-78 weeks) C57BL/6J female mice were used for this study. Syngeneic tumor models were established using three different mouse cancer cell lines, B16-F10 melanoma, MC38 colon adenocarcinoma, and E0771 breast cancer. Age-related tumor growth kinetics varied based on tumor models. Specifically, aging did not affect tumor growth kinetics of B16-F10 tumors, while aged mice showed slowed growth of MC38 tumors and faster growth of E0771 tumors. To evaluate the maximum tolerated dose, young and aged mice were dosed with the standard of care cancer drugs (docetaxel, cisplatin, and doxorubicin) and body weight was monitored three times a week. Aged mice showed higher toxicity against standard care cancer drugs compared to young counterparts. Next, we performed efficacy study using checkpoint inhibitor. Young, mid-aged, and aged mice bearing MC-38 tumor were treated with isotype control or Anti-PD1 (8 mg/kg), intravenously, twice weekly for 3 weeks. Whole blood and tumor samples were collected for immune cell profiling. Comparisons of PD-1 response in the various age groups showed that anti-PD1 treatment showed significant suppression of tumor growth in all age groups with the MC38 tumors, with the greatest effect in aged mice. We also found that anti-PD1 treatment increased T cell infiltration into the tumor, and that regulatory T cells in the tumor are decreased in aged mice. In conclusion, we established syngeneic tumor models using aged mice, and found aged mice exhibit higher toxicity against drugs. The effect of aging on tumor growth kinetics varies depending on the models. Differences in immune cell infiltration in the tumor might be an underlying event that causes age-related differences in response to anti-PD1 treatment. The integration of aging in cancer research could potentially bridge the gap between preclinical studies and clinical outcomes.
Citation Format: Jiwon Yang, Andrew Schile, Mingshan Cheng, James G. Keck. Age-related immunosenescence and cancer drug toxicity and efficacy in C57BL/6J syngeneic model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 135.
Abstract 1363: Preclinical development of bispecific CAR-T cells for canine B cell malignancies
Authors: Atherton Matthew J. , Rotolo Antonia , Mason Nicola J. 
Published: June 2022

Abstract
Chimeric antigen receptor (CAR)-T cells targeting CD19 have revolutionized the treatment of B cell malignancies in people. However, post-treatment loss of CD19 has emerged as an adaptive mechanism of resistance. Pet dogs that develop tumors spontaneously in an immune competent setting represent a compelling parallel population of patients to study next generation cancer immunotherapies. Comparative trials at the University of Pennsylvania are investigating the activity of canine CAR-T cells targeting either CD19 or CD20 in canine B cell lymphoma patients and have revealed a favorable safety profile with early signs of anti-tumor activity. Aligned with experiences in human trials, expansion of CD20-negative B cells has been observed in dogs treated with anti-CD20 CAR-T cells. Bispecific CAR-T cells that simultaneously target two antigens to mitigate antigen escape have encouraging efficacy profiles in human patients. Thus, we designed a dual-targeting CAR specific for canine B cell antigens. A second-generation canine CAR construct targeting both CD19 and CD20 with a 28z signaling domain was cloned into the MSGV1 backbone. Chimeric retrovirus encoding RD114 and VSV-G envelope proteins and the CAR construct was made using GP2-293 cells. Jurkat NFAT-GFP reporter cells and primary T cells from dogs diagnosed with high grade B cell lymphoma were retrovirally transduced with bispecific CARs. Antigen specific reactivity was assessed against cell lines with variable CD19 and CD20 expression patterns. The CD19-CD20 CAR was efficiently transduced, with stable expression in both Jurkat and primary canine T cells. Jurkat reporters revealed dual-specific CAR signaling after co-culture with CD19+ and/or CD20+ target cells. Primary canine CAR-T cells expanded in vitro and exhibited CAR-specific proliferation and cytotoxicity against CD19+ CD20+ target cells. Preclinical manufacture of functional, bispecific anti-CD19 anti-CD20 canine CAR-T cells is feasible. A clinical trial recruiting dogs diagnosed with B cell cancer will assess safety and efficacy of this approach in vivo, with the aim of establishing the dog as a compelling model to appraise the ability of bispecific CAR-T cells to overcome therapeutic failures secondary to antigen loss.
Citation Format: Matthew J. Atherton, Antonia Rotolo, Nicola J. Mason. Preclinical development of bispecific CAR-T cells for canine B cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1363.
Abstract 1393: A Novel platform providing automated, consistent and gentle cell isolation from tissues for downstream applications
Authors: Yu Liping 
Published: June 2022

Abstract
Tumor biologists have long studied tumor tissue to understand cancer progression and to ultimately treat the disease. The gold standard would be to analyze tumor and immune cells from the same sample, providing purified cells that are interacting within the tumor. Many tissue homogenization techniques have been developed to release cells for downstream analysis, however, an automated and gentle process of purifying multiple cell types from the same processed tissue has remained elusive. The industry-standard workflows, such as centrifugation, have presented long-standing performance issues in terms of low cell recovery and inefficient removal of molecular debris, which often leads to sequencing results that are difficult to interpret. To ensure the quality of sequencing data from tissues, upstream processes need to improve to get the most from the precious patient tissue. Applied Cells has developed an integrated system based on multiple physics principles to achieve cell wash, concentration, and target cell isolation, with high recovery at an unprecedented flow rate. This platform combines tunable, acoustic cell purification and in-flow, column-free immuno-magnetic separation technologies, enabling automation of the entire cell sample preparation workflow for genomics and transcriptomics analysis. By harnessing the power and precision of acoustic cell manipulation, the MARS System can process a variety of samples including dissociated solid tissue in enzymatic buffer with high cell recovery and superior molecular debris removal compared to standard methods. For instance, when purifying leukocytes from a lung cancer biopsy tissue samples, MARS can remove 99.50% debris and 91% of dead cells in one single step, which is supreme than the conventional centrifuge cell wash while having &gt;90% leukocyte recovery at 1mL/min flow rate. The in-flow microfluidics design drastically reduces residual DNA and RNA fragments that are difficult to remove using centrifuge wash methods. Furthermore, the system enables parallel cell purification and concentration for high throughput sample processing. Tumor or TIL cells can be further enriched by means of positive magnetic selection for genomic or cell biology applications. This novel platform allows improved tumor and TIL recovery in a gentle, consistent manner while having minimal interference with downstream applications, all from a single source starting material.
Citation Format: Liping Yu. A Novel platform providing automated, consistent and gentle cell isolation from tissues for downstream applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1393.
Abstract 1439: Meta-analysis of the NQO1 gene C609T polymorphism: Increased risk of colorectal cancer
Authors: Ganji Chaithanya , Basha Raasil R. , Bhaskar Lakkakula V.K.S. , El-Rayes Bassel F. 
Published: June 2022

Abstract
Background/objective: Colorectal cancer (CRC) is aggressive and widespread (3rd among malignancies) in the United States. Recent studies suggest that metabolic pathways play an essential role in CRC. NQO1 is an enzyme that contributes to chemoprotection for CRC. Previous studies showed that the link between the NQO1 polymorphisms and CRC risk yielded conflicting results. The aim of this meta-analysis is to test the connection between NQO1 C609T polymorphisms and CRC risk.
Methods: PubMed, Web of Science, and Google Scholar were used in bibliographic searches until July 17, 2021. For the NQO1 C609T analysis, a total of 18 studies (7568 CRC cases and 9003 controls) were considered. Data was gathered and subsequently calculated using the pooled odds ratio (OR) (95% confidence interval, CI).
Results: The relation between NQO1 polymorphism and CRC risk (T vs. C: OR=1.17, 95% CI=1.07-1.29, p&lt;0.001; TT + CT vs. CC: OR=1.19, 95% CI=1.06-1.34, p&lt;0.001) was significant. Furthermore, stratified investigation based on ethnicity indicated significant association between NQO1 polymorphism and CRC risk in only Caucasian populations (T vs. C: OR=1.15, 95% CI=1.08-1.24, p&lt;0.001; TT + CT vs. CC: OR=1.17, 95% CI=1.08-1.27, p&lt;0.001). No proof of bias in publications was found for NQO1 polymorphism (Eggers p=0.929).
Conclusion: This study indicates that the C609T polymorphism of NQO1 is linked with CRC risk in Caucasian populations.
Citation Format: Chaithanya Ganji, Raasil R. Basha, Lakkakula V.K.S. Bhaskar, Bassel F. El-Rayes. Meta-analysis of the NQO1 gene C609T polymorphism: Increased risk of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1439.
Abstract 1445: Influence of neighborhood deprivation on the DNA epigenome in cancerous breast tissue from African American and European American women
Authors: Lord Brittany D. , Rossi Emily , Dorsey Tiffany , Kiely Maeve , Hutchinson Ruby , Ambs Stefan 
Published: June 2022

Abstract
Low socioeconomic status (SES) associates with early onset of chronic diseases and reduced life-expectancy. This relationship is only partly explained by unhealthy behavioral habits and inadequate access to health care. Chronic life stress is more prevalent in low SES communities and has been shown to affect DNA methylation and the immune system. Yet, the biological processes that mediate the impact of SES on health to promote the development of chronic diseases like cancer remain poorly understood. Our study aims to uncover whether DNA methylation is linked to neighborhood socioeconomic deprivation and to a biology that causes inflammation and changes to the immune environment, thereby promoting breast cancer progression and affecting response to therapy. These differences have been characterized in 181 breast tumors (108 African American (AA), 73 European American (EA)). We geocoded the addresses of our participants and linked these data to a Census-level neighborhood deprivation index (NDI). Statistically significant associations between NDI, race and methylation beta values were determined using linear regression followed by Benjamini-Hochbergcorrection. Of the 18 CpG sites that differed between individuals with low and high neighborhood deprivation, 3 were hypermethylated in women with high neighborhood deprivation. We also used methylCIBERSORT to estimate immune subpopulation differences by race group, breast cancer subtype, and ND. For AA women with aggressive triple negative breast cancer, neighborhood deprivation was significantly positively correlated with absolute immune cell scores (p=0.011), including a higher absolute score for endothelial cell expression (p=0.006) and eosinophils (p=0.049). Our findings give insight into how socioeconomic position and neighborhood deprivation may affect cancerous mammary gland biology by altering DNA methylation patterns.
Citation Format: Brittany D. Lord, Emily Rossi, Tiffany Dorsey, Maeve Kiely, Ruby Hutchinson, Stefan Ambs. Influence of neighborhood deprivation on the DNA epigenome in cancerous breast tissue from African American and European American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1445.
Abstract 1547: LncRNA UCA1 modulates glucose metabolism proteins in colorectal cancer
Authors: Leslie Sophia , Doxtater Kyle , Lopez Samantha , Anilkumar Adithya , Jaggi Meena , Chauhan Subhash , Tripathi Manish 
Published: June 2022

Abstract
Colorectal cancer (CRC) is the primary cause of cancer-related deaths worldwide. According to the American Cancer Society, it is the third most common cancer diagnosed in adults in the United States. It will have an estimated 149,500 new cases of colon cancer in 2021. In addition, studies show CRC has increased morbidity with obesity and obesity-related diseases such as diabetes. In a geographical area of The Rio Grande Valley which has a high incidence of diabetes, understanding the connection between CRC and diabetes is essential. Our lab identified LncRNA UCA1, a poor prognosis marker in CRC, responsible for increased proliferation and upregulating glucose metabolic pathway. First, we investigated the possible role of UCA1 in glucose metabolism, finding that UCA1 overexpressing cells (SW480+UCA1) showed a higher glucose consumption than their vector. The inverse of this trend was established when we knockdown UCA1 (SW620+shUCA1). Further, we found that overexpressing UCA1 increases the migration, invasion, and proliferation of SW480 cells. A vital aspect of the metastatic progression is when the cell survives detachment from the extracellular matrix. A route in which they overcome apoptosis is through modulation of the metabolic pathways, upregulating such markers as GLUT1, FDFT1, SGK1, and HIF1α. At 36hrs of anchorage-independent stimulation, we found an uptick in glucose consumption and lactate production and an increase in the expression of GLUT1, FDFT1, SGK1, and HIF1α compared to 0hrs. The Warburg effect is when glycolysis is no longer connected to the tricarboxylic acid cycle or oxidative phosphorylation. The increase in expression of the markers GLUT1, FDFT1, SGK1, and HIF1α indicates aerobic metabolic activity during anchorage-independent growth with UCA1 expression. This relationship needs to be further examined and could lead to understanding the increased morbidity associated with diabetes and CRC.
Citation Format: Sophia Leslie, Kyle Doxtater, Samantha Lopez, Adithya Anilkumar, Meena Jaggi, Subhash Chauhan, Manish Tripathi. LncRNA UCA1 modulates glucose metabolism proteins in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1547.
Abstract 1559: Repurposing of pimavanserin tartrate for the treatment of glioblastoma
Authors: Zabel Carson , Ramachandran Sharavan , Srivastava Sanjay 
Published: June 2022

Abstract
Glioblastoma is a highly aggressive brain tumor that has a median survival of 15 months. We aim to give a substitute to the current chemotherapeutic drug temozolomide by using the FDA-approved anti-psychotic pimavanserin tartrate (PVT). To uncover the effectiveness of PVT, we did cytotoxicity assays using SRB to determine the percentage of cell survival in a dose-dependent and time-dependent manner. The apoptotic effects were measured using Annexin-V/APC assay. The mechanism of action was determined utilizing Western Blotting. In different glioblastoma tumor cell lines, the IC50 for 24 hours was between 6 µM and 10 µM. 48 and 72 hours had an IC50 between 4 µM and 6 µM. SF188 glioblastoma cell line had approximately 70% to 80% more apoptotic cells in 10 µM PVT when compared to control in Annexin-V/APC assay. PVT causes a strong modulation of the PI3K/AKT and MAPK pathways when given in increasing concentration at 48 hours. The level of apoptosis was confirmed through Western Blot as well using apoptotic markers. The preliminary data show the ability of PVT to cause apoptosis of glioblastoma tumor cells in vitro through the AKT and MAPK signaling.
Citation Format: Carson Zabel, Sharavan Ramachandran, Sanjay Srivastava. Repurposing of pimavanserin tartrate for the treatment of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1559.