bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5175: Novel approach for glioblastoma characterization via tumor specific extracellular vesicles
Authors: Hsia Tiffaney , Yekula Anudeep , Batool Syeda M. , Carter Bob S. , Balaj Leonora 
Published: June 2022

Abstract
INTRODUCTION: The utility of photosensitizers (PS), such as 5-Aminolevulinic acid (5-ALA), has been limited to fluorescence-guided surgery (FGS) and photodynamic therapy. The downstream metabolism of 5-ALA results in tumor-specific, highly selective accumulation of PpIX, an endogenous porphyrin, in tumor cells. We have previously reported evidence of PpIX in EVs derived from the plasma of glioblastoma (GBM) patients. Here, we characterize the tumor-specific nature of PpIX fluorescent EVs through quantification of their cargo, demonstrating their utility in the advancement of liquid biopsy for GBM diagnosis and management.
METHODS: Fluorescence activated cell sorting was adapted for nanoparticle isolation and PpIX fluorescent EVs were sorted from plasma collected from patients (N = 8) diagnosed with GBM, undergoing FGS. RNA cargo was extracted and quantified via low input RNA-Seq. Matching patient tumor and total plasma EVs along with healthy control plasma EVs (N = 8) were sequenced in parallel.
SUMMARY: Through sequencing analysis, we have demonstrated a distinct landscape of long RNAs (mRNA and lncRNA) in PpIX EVs, with isolation of this EV population resulting in an enrichment of lncRNAs. Considering the emerging diagnostic and prognostic potential of lncRNAs in GBM, exploration of such EVs provides valuable insight into the pathobiology of the tumor of origin. On a broader scale, gene expression analysis of PpIX EV cargo demonstrates at least a ten-fold enrichment of genes that are otherwise buried in the heterogeneous plasma EV background. Furthermore, downstream KEGG orthological analysis of PpIX EV cargo has revealed alignment of 78% of the significant pathways to processes implicated in cancer development and progression. We have identified a panel of genes unique to PpIX EVs, and reflective of the native tumor, that are implicated in GBM pathogenesis including GREM1, MAP4K4, and STAG2. Validation via quantitative and digital PCR of total plasma EVs from patient and healthy cohorts (N = 10, respectively) have yielded similar expression levels, as reflected in sequencing gene expression. Isolation of PpIX EVs, however, insinuates enriched genetic detection.
CONCLUSION: In summary, this preliminary cohort of GBM patients has demonstrated the utility of 5-ALA induced PpIX fluorescence outside of its original intentions: facilitating tumor-specific EV identification for the progression of liquid biopsy. These findings are an inviting breakthrough in the development of individualized disease detection and monitoring.
Citation Format: Tiffaney Hsia, Anudeep Yekula, Syeda M. Batool, Bob S. Carter, Leonora Balaj. Novel approach for glioblastoma characterization via tumor specific extracellular vesicles [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 5175.
Abstract 5243: 3-Bromopyruvate in combination with radiation inhibits pancreatic cancer growth by dismantling mitochondria and ATP generation in a preclinical mouse model
Authors: Roy Sanjit K. , Dukic Tijana , Bhandary Binny , Acharya Aneesh , Tu Kevin J. , Ko Young H. , Shukla Hem D. 
Published: June 2022

Abstract
3-Bromopyruvate (3 BP) is a promising anticancer drug against pancreatic cancer. It exerts potent anticancer effects by inhibiting hexokinase II enzyme of glycolysis pathway and ATP generation in cancer cells. In present investigation we have examined the effect of 3-BromoPyruvate employing panc-2 cancer cells, and syngeneic pancreatic cancer mouse model. The clonogenic survival assay demonstrated dose dependent inhibition of cell growth, and we observed 95% cell death at 15 uM conc. Further, ATP production was severely inhibited in cancer cells treated with same concentration of 3-BP. We also observed that 3-BP in combination with low doses of irradiation was more effective in killing cancer cells than 3-BP alone. Electron microscopy revealed that 3-BromoPyruvate severely damaged mitochondrial integrity which might have severely affected ATP generation in cancer cells. We further tested 3-BromoPyruvate (2.5-10.0 mg/kg) in syngeneic panc-2 tumor mouse model and observed that 3-BP at10.0 mg/kg dose significantly reduced tumor growth (volume) about 35-40%. Immunohistochemistry (IHC) data showed that 3-BP inhibits hexokinase II (HK2) and TGFbeta1 and enhanced active caspase-3 expression in tumor tissues as compared to untreated control. The disruption of the interaction between VDAC1 and HK2 due to 3BP treatment was confirmed by CO-IP. Interestingly, 3 BP at higher dose induces caspase-3 activation in tumor derived organoid without showing any effect on normal pancreatic organoid. Altogether, the results in this study demonstrated that 3 BP could be a promising anti-tumor drug against pancreatic cancer and its efficacy could be improved in combination with radiation therapy.
Citation Format: Sanjit K. Roy, Tijana Dukic, Binny Bhandary, Aneesh Acharya, Kevin J. Tu, Young H. Ko, Hem D. Shukla. 3-Bromopyruvate in combination with radiation inhibits pancreatic cancer growth by dismantling mitochondria and ATP generation in a preclinical mouse 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 5243.
Abstract 5259: Clinical feature of end-stage cerebral glioblastomas
Authors: Saito Norihiko , Hirai Nozomi , Kushida Naoki , Sato Sho , Hiramoto Yu , Fujita Satoshi , Nakayama Haruo , Hayashi Morito , Ito Keisuke , Sakurai Takatoshi , Iwabuchi Satoshi 
Published: June 2022

Abstract
Glioblastoma is the most common and aggressive primary brain tumor, and even with the best treatment, the tumor repeatedly recurs and grows, eventually invading the entire brain. There are few reports on the pathogenesis and pathological search in the terminal stage of glioblastoma. In this study, we report the pathological analysis of glioblastoma cases that we were able to perform from initial treatment to confirmation of death at our hospital. We analyzed 26 glioblastoma cases (including 18 autopsied cases) treated at our hospital from initial treatment to death. The mean age of the 26 patients was 60.7 years, and the mean overall survival was 16.7 months. The duration of clinical symptoms was 36.2 days from coma to death, and 12 days from the appearance of respiratory depression to death. Psychiatric symptoms and central fever were observed in patients with intrathecal dissemination. Steroids and antiepileptic drugs were often continued after completion of active treatment. Patients with intrathecal dissemination progressed rapidly and presented with a variety of symptoms, including psychiatric symptoms, headache, neck pain, and central fever. In addition, there was a case of diffuse infiltration from the brain parenchyma to the periventricular area in a patient treated with bevacizumab, suggesting the possibility of a change in the form of recurrence. In the terminal stage of glioblastoma, hypoxemia due to disturbance of respiratory center progresses from impaired consciousness to death. Convulsive seizures are rare in the dying stage, and continuation of antiepileptic drugs should be considered. Although many patients develop from local recurrence, it was suggested that new treatment may change the mode of recurrence or alter the trait of tumor cells. In recent years, the number of patients receiving home care and end-of-life care has been increasing due to the improvement of medical systems such as home care. Further investigation of the pathophysiology is necessary for better end-of-life care.
Citation Format: Norihiko Saito, Nozomi Hirai, Naoki Kushida, Sho Sato, Yu Hiramoto, Satoshi Fujita, Haruo Nakayama, Morito Hayashi, Keisuke Ito, Takatoshi Sakurai, Satoshi Iwabuchi. Clinical feature of end-stage cerebral glioblastomas [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 5259.
Abstract 526: Novel methylation-based, tissue-free ctDNA assay accurately quantifies longitudinal tumor burden changes for precision treatment monitoring
Authors: Ye Patrick Peiyong , Viens Robb , Bower Xavier , Riku Shan , Tsao David , Atay Oguzhan 
Published: June 2022

Abstract
As novel cancer treatments become available, the need to quickly and accurately evaluate whether these treatments are effective remains unaddressed. Obtaining earlier feedback on the efficacy of a cancer therapy could prevent a poor treatment outcome by switching to a more effective therapy sooner. Levels of circulating tumor DNA (ctDNA) have been found to be prognostic of tumor progression, suggesting that a non-invasive liquid biopsy assay could provide longitudinal ctDNA measurements that accurately track tumor progression. However, while there is interest in using existing minimal residual disease (MRD) detection and treatment selection liquid biopsy assays for treatment monitoring applications, they both suffer from limitations in their ability to precisely and sensitively quantify trends in tumor progression over the course of treatment. In addition, tumor-informed MRD detection assays are often infeasible for treatment monitoring due to unavailability of the initial tissue sample.
We have developed and validated a novel methylation-based liquid biopsy assay for pan-cancer treatment monitoring without the need to obtain a sample from the tumor itself. Methylation has long been shown to be a strong and consistent biomarker for cancer, and because tumor tissue has widespread differential methylation across the genome compared to normal tissue, we are able to overcome molecule sampling limitations. In analytical validation, our assay could detect as small changes as 0.05%, e.g., an elevation of tumor fraction from 0.5% to 0.55%, a level of precision that is an order-of-magnitude better than any available assays. Next, we tested our assay on clinical specimens by measuring ctDNA in serially collected blood samples from subjects with cancer. As would be expected from the high level of precision, we were able to successfully demonstrate the predictive power of ctDNA measurements for clinical outcomes. These results from our methylation-based liquid biopsy assay open the path to earlier and extremely precise treatment monitoring for oncologists and their patients.
Citation Format: Patrick Peiyong Ye, Robb Viens, Xavier Bower, Shan Riku, David Tsao, Oguzhan Atay. Novel methylation-based, tissue-free ctDNA assay accurately quantifies longitudinal tumor burden changes for precision treatment monitoring [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 526.
Abstract 5279: Prognostic serum biomarkers in cancer patients with COVID-19: A systematic review
Authors: Lai Yun-Ju , Lee Te-An , Wang Shih-Han , Li Chia-Wei , McCullough Louise D. , Bello Dhimiter 
Published: June 2022

Abstract
Purpose: COVID-19 has led to 4 million deaths worldwide since 2019. COVID-19 patients with cancers likely express biomarker changes in circulation. While many biomarker studies focused on COVID-19 diagnosis and prognosis, the panel of biomarkers used in SARS-CoV-2 infected cancer patients for COVID-19 severity and prognosis are largely unclear. Therefore, this systematic review aims to determine what biomarkers have been measured in cancer patients with COVID-19 and their prognostic utility.
Methods: A systematic literature review in PubMed, Embase, and Scopus was performed on June 16th, 2021. The search keywords coronavirus, neoplasm, biomarkers, and disease progression were used to filter out 17 eligible studies, which were then carefully evaluated.
Results: A total of 4,168 patients from 17 eligible articles were included in this study. Sixteen types of cancer and 60 biomarkers were identified. The majority of changed biomarkers in the cancer patients with COVID-19 compared to the healthy group and non-cancer patients with COVID-19 were biochemical and inflammatory markers. The up-regulated markers, including CRP, D-dimer, ferritin, IL-2R, IL-6, LDH, and PCT, were identified in eligible studies. Albumin and hemoglobin were significantly down-regulated in cancer patients with COVID-19. Additionally, we observed that the SARS-CoV-2 infected cancer patients with lower levels of CRP, ferritin, and LDH successfully survived from antiviral drug and immunotherapy for COVID-19 treatments.
Conclusion: Several important clinical biomarkers, such as CRP, ferritin, and LDH, may serve as the prognostic markers to predict the outcomes following COVID-19 treatment and monitor the deterioration of COVID-19 in cancer patients.
Citation Format: Yun-Ju Lai, Te-An Lee, Shih-Han Wang, Chia-Wei Li, Louise D. McCullough, Dhimiter Bello. Prognostic serum biomarkers in cancer patients with COVID-19: A systematic review [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 5279.
Abstract 5289: Activating p53 through MDM2 and WIP1 inhibition effectively inhibits tumors in liver adenocarcinoma
Authors: Chen Chiao-Ping , Yeh Chun-Nan , Pan Yi-Ru , Hsiao Yu-Tien , Lo Chih-Hong , Jhuang Cai-Jhen , Wu Chiao-En 
Published: June 2022

Abstract
Intrahepatic cholangiocarcinoma (iCCA) is an adenocarcinoma arising from the intrahepatic bile duct and accounts for the second most cases of primary liver cancers after hepatocellular carcinoma. Lacking effective treatment leads to a poor prognosis for advanced iCCA so new targeted therapy is warranted. Impaired wild-type (WT) p53 tumor suppressor function by its negative regulators frequently occurs in iCCA. Therefore, restoration of WT p53 function by inhibiting its negative regulators is a therapeutic strategy being explored for cancer treatment. Both MDM2 inhibitor (MDM2i, RG7388) stabilizing p53 and WIP1 inhibitor (WIP1i, GSK2830371) increasing p53 phosphorylation lead to maximize p53 function. The combination of MDM2i/WIP1i has been reported in severe cancer types but no in vivo study has been done. In the current study, both liver adenocarcinoma cell lines, RBE and SK-Hep-1, were treated with the RG7388 alone and in combination with GSK2830371. Cell proliferation, clonogenicity, protein and mRNA expressions, and cell cycle distribution were performed to investigate the effect and mechanism of growth suppression. To evaluate the antitumor efficacy of RG7388 and GSK2830371 in vivo, xenografts with SK-Hep-1 cells were treated with combination therapy for two weeks in NOD-SCID mice. The combination of MDM2i and WIP1i significantly increased the growth inhibition, cytotoxic activity, increased p53 protein expression, and phosphorylation (Ser 15), leading to transactivation of downstream targets (p21 and MDM2). The in vivo test demonstrated that the combination treatment can significantly inhibit tumor growth. In this study, liver adenocarcinoma cell lines were inhibited by the combination via reactivation of p53 function evidenced by increased p53 expression, phosphorylation and its downstream targets. This efficacy was also validated by in vivo study. The current research provides a novel strategy for targeting the p53 pathway in liver adenocarcinoma.
Citation Format: Chiao-Ping Chen, Chun-Nan Yeh, Yi-Ru Pan, Yu-Tien Hsiao, Chih-Hong Lo, Cai-Jhen Jhuang, Chiao-En Wu. Activating p53 through MDM2 and WIP1 inhibition effectively inhibits tumors in liver adenocarcinoma [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 5289.
Abstract 5299: A therapeutic antibody against G-protein-coupled receptor class 5 member D to treat multiple myeloma
Authors: He Feng , Wu Kefei , Liang Jiabei , Li Jianhui , Peng Hao , Wu Guojin , Ning Jinying 
Published: June 2022

Abstract
Multiple myeloma (MM) comprised 0.9% of all new cancer cases and 1.2% of cancer death in 2020 and is the second most common hematological neoplasm in adults. Primary refractory to treatment and relapse resulted in a high death rate of MM patients. Bispecific antibodies (BsAbs) are attracting candidate drugs against multiple myeloma by targeting CD3 on T cells and MM specific cell surface markers such as B cell maturation antigen (BCMA), CD38, and G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D). In the current study, we developed a humanized antibody targeting GPRC5D (clone number G-02-9D7). The antibody was derived from hybridoma of mouse immunized with GPRC5D overexpressed mouse cell line. Compared to the GPRC5D antibody in clinical (JNJ-64407564), this antibody has a higher affinity to 293T cells overexpressing GPRC5D (EC50=1.9nM vs. 3nM), MM cell lines, and MM patient samples. In addition, this antibody did not bind to GPRC5A, B, and C and had weaker non-specific binding to human serum albumin than JNJ-64407564. Bispecific antibody derived from the GRPC5D antibody and CD3 antibody (clone number: sp34) induced specific cytotoxicity of MM cells in the presence of T cells from PBMC. This bispecific antibody stimulated the release of cytokines from T cells such as INF-γ, IL-2, IL-8, and TNF-α. In NCI-H929 prophylactic xenograft mouse model with PBMC transplantation, tumor growth could be prevented by administration weekly with this bispecific antibody as low as 0.1ug per mouse. In the presence of T cells, the bispecific antibody also resulted in complete remission of established MM.1S tumor in xenografted NSG mouse with the injection of 1ug antibody weekly. At last, MM patient bone marrow samples cultured in vitro with this bispecific antibody increased cell death of the CD138+ population. In summary, the GPRC5D antibody could efficiently target Multiple myeloma tumor cells.
Citation Format: Feng He, Kefei Wu, Jiabei Liang, Jianhui Li, Hao Peng, Guojin Wu, Jinying Ning. A therapeutic antibody against G-protein-coupled receptor class 5 member D to treat multiple myeloma [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 5299.
Abstract 5307: Critical platforms of PROTAC validation
Authors: Wang Ruifeng 
Published: June 2022

Abstract
In recent years, proteolysis targeting chimeric (PROTAC) technology has become an effective endogenous protein degradation tool in drug discovery. As a class of heterobifunctional small molecules, PROTACs recruit an E3 ubiquitin ligase to a given substrate protein, resulting in its targeted degradation through the endogenous ubiquitin-proteasome system (UPS). PROTAC consists of three chemical elements: a ligand that binds to a target protein, a ligand that binds to an E3 ubiquitin ligase, and a linker that connects the two ligands. Compared with traditional drug development, PROTAC technology possesses unique advantages including overcoming drug resistance and targeting the “undruggable”. Here we generated a kind of PROTAC target, like KRAS, BRD4, ESR1, associated cell lines to accelerate the discovery of new protein degradation drugs and the target protein degradation therapeutics by an optimized insertion system. In the beginning, we develop a system of different tag targeted cell lines, which can be easy to introduce HiBiT, Flag, GFP and also Halo Tag, et.al to target protein by CRISPaint or CRISPR Cas9 mediated HDR system. We also developed an arbitrary point mutation system based on the optimized PE3 mutation system, which can randomly modify any point mutation to simulate in vivo disease models in vitro. During this process, we have also optimized a series of validation system, like Targeted Protein Degradation (TPD), High-throughput flow cytometry (HTFC) and In-Cell Western (ICW) to shorten the detection time and improve detection stability. It is worth mentioning that we also develop a HiBiT and GFP dual-signal system, which can easily validate the target protein degradation and cell viability. We hope that our detection system can speed up the development of new drugs and contribute to human anti-tumor.Keywords: PROTAC, UPS, drug development, therapeutics
Citation Format: Ruifeng Wang. Critical platforms of PROTAC validation [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 5307.
Abstract 5310: Physiochemical and biological characterization of anti-EGFR based bispecific antibodies in triple negative breast cancer (TNBC) models
Authors: Mohan Nishant , Luo Xiao , Shen Yi , Olson Zachary , Agrawal Atul , Endo Yukinori , Rotstein David , Pelosof Lorraine , Wu Wen Jin 
Published: June 2022

Abstract
Triple-negative breast cancer (TNBC) accounts for approximately 10-20% of all diagnosed breast cancer. Both epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) frequently overexpress in TNBC and cooperate with each other in autocrine and paracrine manner to enhance tumor growth and angiogenesis. Therapeutic mAbs targeting EGFR (cetuximab) and VEGFR2 (ramucirumab) are approved by FDA for numerous cancer indications, but none of them are approved to treat breast cancers. TNBC cells secrete VEGF-A, which mediate angiogenesis on endothelial cells in a paracrine fashion and promote cancer cell growth in autocrine manner. To disrupt autocrine/paracrine loop in TNBC models in addition to mediating anti-EGFR tumor growth signaling and anti-VEGFR2 angiogenic pathway, we generated a bispecific antibody co-targeting EGFR and VEGFR2 (designated as anti-EGFR/VEGFR2 BsAb), in which cetuximab IgG backbone is connected to the single chain variable fragment (scFv) of ramucirumab via a glycine linker. Physiochemical characterization data shows that anti-EGFR/VEGFR2 BsAb binds to both EGFR and VEGFR2 in a similar binding affinity comparable to parental antibodies. Anti-EGFR/VEGFR2 BsAb demonstrates potent in vitro and in vivo anti-tumor activity in TNBC models. Mechanistically, anti-EGFR/VEGFR2 BsAb not only directly inhibits both EGFR and VEGFR2 in TNBC cells but also disrupts autocrine mechanism in TNBC xenograft mouse model. Furthermore, anti-EGFR/VEGFR2 BsAb blocks paracrine pathway mediated by VEGF/VEGFR2 in endothelial cells. Collectively, our novel findings demonstrate that anti-EGFR/VEGFR2 BsAb inhibits tumor growth via multiple mechanisms of action and has potential to be developed as an attractive targeted therapy for TNBC.
Citation Format: Nishant Mohan, Xiao Luo, Yi Shen, Zachary Olson, Atul Agrawal, Yukinori Endo, David Rotstein, Lorraine Pelosof, Wen Jin Wu. Physiochemical and biological characterization of anti-EGFR based bispecific antibodies in triple negative breast cancer (TNBC) models [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 5310.