bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 536: The role of CCN1 in mutant K-RAS addiction in pancreatic ductal adenocarcinoma
Authors: De Archana , Gupta Vijayalaxmi , Das Amlan , Ghosh Arnab , Haque Inamul , Lau Laster , Banerjee Sushanta K. , Banerjee Snigdha 
Published: June 2023

Abstract
Mutant K-RAS addiction of pancreatic ductal adenocarcinoma cells (PDAC) coordinates their transformation, proliferation, and survival. Therefore, initially, it had an impression that targeting mutant K-RAS could be an ideal strategy for treating PDAC. However, after decades of studies, no effective RAS inhibitors reached the clinic, indicating that RAS-oncoprotein is an undruggable target in PDAC. Thus, identifying a new target linked with K-RAS signaling was most needed. Using genetically engineered cell lines and K-RAS-driven genetically engineered mouse models (KC or KPC) with or without pancreas-specific CCN1 conditional knockout background, we identified a positive feedback circuit between CCN1 and mutant K-RAS expression. Moreover, blocking this feedback via conditional knockout of CCN1 in the pancreas significantly reduced invasive phenotypes, PDAC growth, and metastasis in the lung in KC and KPC mice. Mechanistically we found that the K-RAS-CCN1 feedback circuit is regulated by microRNA miR-145 via a feedforward mechanism. Collectively, these studies highlight the clinical potential of targeting CCN1 in PDAC. (This work is supported by VA Merit grants).
Citation Format: Archana De, Vijayalaxmi Gupta, Amlan Das, Arnab Ghosh, Inamul Haque, Laster Lau, Sushanta K. Banerjee, Snigdha Banerjee. The role of CCN1 in mutant K-RAS addiction in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 536.
Abstract 5398: Optimization generator app (OpGen) for radiotherapy treatment planning using case-based reasoning
Authors: Reiazi Reza , Prajapati Surendra , Mohamed Abdallah Sherif , Fuller Clifton David , Salehpour Mohammad 
Published: June 2023

Abstract
Case-based reasoning (CBR) means adopting previous experiences (i.e, data from previous patients) to meet new demands (new patients). In this scenario, we developed an application named OpGen to generate optimization objective values for head and neck radiotherapy inverse treatment planning, using the previously treated patient with an acceptable outcome. OpGen will be helpful in radiotherapy treatment planning automation and efficiently reducing the required time to reach the target goals and improving the quality and safety of the treatment.OpGen has been developed in Python and has four main modules: 1- Analyzing radiotherapy treatment planning parameters of the previous patients in the database. We have developed (a) a powerful graphical user interface (GUI) that allows quantitative and qualitative analysis of the previous knowledge, including the type of frequently used objective parameter (Min Dose, Max Dose, Min DVH dose, etc.); (b) The range of values used for each specific objective type, and (c) Histogram of the number of patients vs. values used for a specific objective type. 2- Importing patients from treatment planning and retrieving a user-defined number of treatment planning information from the previously treated patients in the database corresponding to the given patient using the user-defined quantitative features (geometrical, distance or geo-distance) and retrieval algorithms (k-Nearest Neighbor and Random Forest). 3- Generating optimization objective values based on the following available options: (a) The most similar patient in the database; (b)- Average or median value over the number of patients retrieved from the database; and (c) Deep learning generated values using a model trained over 100 similar cases retrieved from the database. 4- Generate a portable database of the objective values and patient geometric information for any inter- or intra-institutional usage of the algorithm. OpGen is compatible with RayStation (RaySearch Laboratories™) treatment planning and can retrieve, analyze and generate treatment planning optimization parameters in less than 3 minutes. OpGen can potentially increase the quality and safety of radiotherapy treatment planning by improving the efficiency of the optimization process.
Citation Format: Reza Reiazi, Surendra Prajapati, Abdallah Sherif Mohamed, Clifton David Fuller, Mohammad Salehpour. Optimization generator app (OpGen) for radiotherapy treatment planning using case-based reasoning. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5398.
Abstract 547: Role of KDM4A in bladder cancer
Authors: Warren Bailey O. , Abdelfattah Ammar Y. , Ghoneum Alia , Salsbury Freddie , Said Neveen A. 
Published: June 2023

Abstract
Bladder cancer (BCa) is the most common malignancy of the urinary system in the United States. Most patients present with non-muscle invasive bladder cancer (NMIBC) that is treated with bladder preserving approaches. However, recurrence is high with a 50% chance to progression into muscle invasive bladder cancer (MIBC). Patients with MI disease are treated with aggressive surgery and/or systemic chemo-radiation, and more recently immune- and targeted therapies. Patients with BCa require life-long surveillance with expensive imaging, and repeated treatment courses, making BCa one of the most expensive malignancies throughout the patients’ lifespan. BCa therapies have been stagnant for almost four decades until 2016 when new immune and targeted therapies were approved for patients with locally advanced, recurrent, or metastatic disease, with an overall response of 15-29%. Thus, better understanding of the pathobiology of BCa is needed to identify actionable targets and develop novel therapeutics. In this respect, we have identified histone lysine demethylase 4A (KDM4A), also known as Jumanji D2A (JMJD2A) as a BCa onco-protein. We found that the expression of nuclear KDM4A significantly correlated with disease stage in patients’ tumors and in tobacco carcinogen-induced murine bladder tumors. KDM4A transcript expression significantly increased in bladder tumors compared to normal in TCGA data and three independent publicly available datasets. Knockdown of KDM4A in BCa cell lines significantly inhibited their proliferation and invasiveness. Interestingly, KDM4A transcripts exhibited significant inverse correlation with BCa tumor suppressor SPARC in five independent datasets. In addition, using phenotypic screening and computational modeling, we found that KDM4A is a direct target of verteporfin, a potent inducer of SPARC expression in BCa cell lines. Mechanistically, knockdown of KDM4A in BCa cell lines increased SPARC expression, whereas its overexpression inhibited basal and verteporfin-induced SPARC expression. Chromatin immune-precipitation (ChIP) assays indicated that verteporfin significantly inhibited the association of KDM4A with SPARC promoter. Together, our data underscore the oncogenic role of KDM4A in BCa and its potential as an actionable target.
Citation Format: Bailey O. Warren, Ammar Y. Abdelfattah, Alia Ghoneum, Freddie Salsbury, Neveen A. Said. Role of KDM4A in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 547.
Abstract 5487: Synergy between FAK and PI3K inhibitors in cervical and pancreatic cancer cells
Authors: Chen Chao-Cheng , Wang Suyang , Yang Jr-Ming , Huang Chuan-Hsiang 
Published: June 2023

Abstract
The Ras/PI3K/ERK signaling network is frequently mutated in many cancer types including cervical cancer and pancreatic cancer. Our previous study suggested that PI3K and FAK form a positive feedback loop to modulate ERK activation. We tested combined inhibition of FAK and PI3K on the growth of cervical and pancreatic cancer in vitro. We found that FAK and PI3K inhibitors synergistically inhibited the growth of some cervical cancer and pancreatic cancer cell lines. The synergy was due to both increased apoptosis and decreased cell proliferation. Molecularly, FAK inhibition caused downregulation of PI3K and ERK signaling in cervical cancer but not pancreatic cancer cells. Interestingly, PI3K inhibitors induced activation of several RTK including insulin R and IGF-1R in cervical cancer cells, as well as EGFR, Her2, Her3, Axl, and EphA2 in pancreatic cancer cells. Together, our results show the promise of combining FAK and PI3K inhibition for cervical cancer and pancreatic cancer treatment, but biomarkers for sensitivity to the combination are needed, and concomitant RTK inhibition may be required to combat potential resistance to the combination.
Citation Format: Chao-Cheng Chen, Suyang Wang, Jr-Ming Yang, Chuan-Hsiang Huang. Synergy between FAK and PI3K inhibitors in cervical and pancreatic cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5487.
Abstract 5509: The PI3K inhibitor Paxalisib combines synergistically with the MEK inhibitor Mirdametinib to target atypical teratoid/rhabdoid tumors
Authors: Malebranche Kristen J. , Findlay Tyler , Geethadevi Anupa , Eberhart Charles , Raabe Eric , Rubens Jeffrey 
Published: June 2023

Abstract
Atypical teratoid/rhabdoid tumors (AT/RT) are aggressive pediatric brain tumors and the most common malignant brain tumors of infancy. The four-year event-free survival rate is only 37%. For patients with relapsed AT/RT there are limited treatment options, but precision therapies may help improve survival for patients with this deadly disease. We have previously identified strong activation of the PI3K-AKT-mTOR (mTOR) signaling pathways in AT/RT. Paxalisib is a highly brain-penetrant PI3K inhibitor acting upstream of mTOR. We find that Paxalisib slows tumor growth in orthotopic xenograft models of AT/RT and extends median survival from 40 to 54 days (p=0.001, log-rank test). RNASeq after mTOR pathway inhibition identifies reflexive activation of the RAS-RAF-MEK-ERK (MAPK) pathway as a possible mechanism of therapy resistance (KEGG pathway analysis). The RAS-RAF-MEK-ERK (MAPK) pathway plays a pivotal role in regulating cell growth and survival and activation of the pathway contributes to the aggressive growth of numerous cancers. Mirdametinib is a small, allosteric MEK inhibitor currently used in clinical trials for both pediatric low- and high-grade gliomas (PD0325901). We find that dual inhibition of both the mTOR and MAPK pathways by Paxalisib and Mirdametinib synergize to reduce AT/RT growth and viability (Bliss synergy score 16.77). Paxalisib also combines with Mirdametinib to induce high levels of apoptosis and cell senescence (as determined by western blot: cPARP, pRB, P21, P16). Naïve treatments in mice bearing AT/RT orthotopic tumors suggests the combination therapy decrease mTOR and MAPK pathway activation (as determined by western blot). These data support the use of Paxalisib and Mirdametinib combination therapy as a promising novel combination therapy to treat relapsed AT/RT.
Citation Format: Kristen J. Malebranche, Tyler Findlay, Anupa Geethadevi, Charles Eberhart, Eric Raabe, Jeffrey Rubens. The PI3K inhibitor Paxalisib combines synergistically with the MEK inhibitor Mirdametinib to target atypical teratoid/rhabdoid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5509.
Abstract 5518: Use of antihypertensive drugs and the risk of cancer, findings of a population-based cohort study in Shanghai
Authors: Wang Suna , Xie Li , Qian Ying , Wang Jie , Zhang Guanglu , Li Lei , Zhang Weituo , Yu Herbert , Zhao Wensui , Qian Biyun 
Published: June 2023

Abstract
Background: The widespread use of antihypertensive drugs has raised concerns on whether the use increases the risk of cancer. Although multiple studies have addressed this issue, it remains unclear if hypertension patients who are on antihypertensive medications are at higher risk for cancer.
Methods: Between 2013 and 2017, we enrolled 101,370 individuals with hypertension from community healthcare centers in Changning Shanghai, followed through December 31, 2019. Drug administration was defined as the class and number of ever use the major antihypertensives. The main outcomes included the incidences of all cancer and major types of cancer in Shanghai (lung, colorectum, thyroid, and stomach).
Results: During a mean follow-up of 5.1 (SD 1.3) years, 4970 cancer cases were newly diagnosed in the cohort. CCBs were the most frequently used antihypertensives which were associated with a moderately increased risk of all cancer (hazard ratio, HR: 1.11, 95% CI: 1.05-1.18). The second commonly used drug ARBs were also associated with increased risk of all cancer (HR: 1.10, 95%CI: 1.03-1.17) as well as lung and thyroid cancers (HR: 1.21, 95%CI: 1.05-1.39; HR: 1.66, 95%CI: 1.22-2.27, respectively). No cancer association was found with other antihypertensives. Individuals who use more than one class of antihypertensives had a higher risk of all cancer, and a possible dose-response relationship was suggested.
Conclusions: Use of ARBs or CCBs may be associated with an increased risk of cancer. Taking more than one class of antihypertensives appeared to have a higher risk for cancer.
Citation Format: Suna Wang, Li Xie, Ying Qian, Jie Wang, Guanglu Zhang, Lei Li, Weituo Zhang, Herbert Yu, Wensui Zhao, Biyun Qian. Use of antihypertensive drugs and the risk of cancer, findings of a population-based cohort study in Shanghai. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5518.
Abstract 5525: Community cancer research advocates: Helping underrepresented minority groups become research ready
Authors: Been Sarah , Gertz Susan , Hershberger Susan , Kovacic Melinda Butsch ,   We Engage 4 Health Community-Academic Partnership
Published: June 2023

Abstract
Even though certain racial/ethnic minority groups get cancer more often, are diagnosed at younger ages, and are at risk for earlier death, clinical trials fail to include adequate proportions of representatives from these groups. Encouraging equitable participation in research becomes an important tool in the fight against cancer disparities. Therefore, we co-created with community representatives a graphic-style story entitled “Research Ready” that is used by trained Community Research Advocates (including some survivors or family of survivors themselves) to hold brief discussions to help eligible hesitant participants to learn the 3 P’s: the purpose of cancer research, how they are kept safe while participating, and why people from diverse backgrounds are needed to participate. Importantly, advocates use a Research Review activity to discuss factors that influence their willingness to participate as well as identify questions they have for the research study’s staff. Focus group and survey-based evaluation data show these discussions to be useful in increasing hesitant patients’ willingness to consider participation in research and increase perception of safety. Advocates too appreciate the opportunity to serve. While this pilot is small, additional partnerships within the University of Cincinnati Cancer Center to expand the program will be developed. Future partnership with a community patient navigator program will also enable additional support and transportation to research appointments. Collectively, we anticipate that this program will ultimately support hesitant patients’ decision-making and improve cancer research participation particularly among racial/ethnic minorities.
Citation Format: Sarah Been, Susan Gertz, Susan Hershberger, Melinda Butsch Kovacic, We Engage 4 Health Community-Academic Partnership. Community cancer research advocates: Helping underrepresented minority groups become research ready. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5525.
Abstract 5551: Cancer associated PSA-glycoforms as prostate cancer markers
Authors: Koistinen Hannu , Kovanen Ruusu-Maaria , Lehto Timo-Pekka , Rannikko Antti , Mirtti Tuomas 
Published: June 2023

Abstract
Changes in protein glycosylation have been observed in several cancers, where they affect cellular growth behavior, invasiveness and acquisition of metastatic potential. Such changes are not random and have been found to associate with cancer aggressiveness. Thus, detection of protein glycosylation may offer novel opportunities for cancer biomarker development. Since prostate-specific antigen (PSA) is glycosylated, assessing different PSA-glycoforms may provide valuable diagnostic and prognostic information. We recently established a novel in situ proximity ligation-based method for the detection of different protein-glycoforms in tissue sections. This method utilizes protein-specific antibody and glycan-binding lectins. We have optimized this method for the detection of different PSA-glycoforms in formalin-fixed paraffin-embedded prostatic tumor samples. We found that PSA is, indeed, differently glycosylated in prostate cancer (n=23) compared to benign prostate tissue (n=4). Two of the 25 studied lectins showed prominent staining only in cancer tissues (p&lt;0.0001 for both), although the total PSA staining was stronger in benign tissues (p=0.006). We are currently validating these results in large, well-curated clinical cohorts, with intention to test whether PSA-glycoforms in tissue offer improved detection of clinically significant prostate cancer. These studies facilitate development of tools for identification of cancer-specific PSA-isoforms in serum samples. Detection of such isoforms is likely to provide independent diagnostic and prognostic information.
Citation Format: Hannu Koistinen, Ruusu-Maaria Kovanen, Timo-Pekka Lehto, Antti Rannikko, Tuomas Mirtti. Cancer associated PSA-glycoforms as prostate cancer markers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5551.
Abstract 5552: MAGE-A3 and MAGE-A4 protein show co-expression in tumor of lung, bladder, and colon cancer
Authors: Gonzalez Rachel 
Published: June 2023

Abstract
Melanoma Antigen Gene Family (MAGE-A) are part of the cancer-testis antigens whose limited expression in normal tissues and high expression in cancer make them excellent targets for immunotherapy. Clinical trials have already begun targeting MAGE-A3 and MAGE-A4 proteins in tumors. Should these trials lead to new treatment protocols, it is important to develop a diagnostic immunohistochemistry (IHC) tool for pre-screening patients who would benefit. The MAGE-A family consists of 12 members that share up to 85% sequence homology presenting a challenge for finding highly specific antibodies for IHC. Using CytoSections, a new screening control tool for IHC, ICC, IF, and in-situ hybridization, highly specific IHC MAGE-A3 and MAGE-A4 antibodies were developed and screened. The MAGE-A3 and MAGE-A4 antibodies were assessed on twenty-two lung cancers, twenty-one colon cancer, and more than thirty bladder cancers which resulted in cases that co-express MAGE-A3 and MAGE-A4 proteins in all three types of tumors. Using immunofluorescence, tumors positive for both proteins were double stained for MAGE-A3 and MAGE-A4 to show the proteins were co-expressed in the same tumor cells. Immunohistochemistry continues to be a rapid and reproducible method for the detection of proteins in tumors. Antibodies specific to MAGE-A3 and A4 proteins for IHC may be a useful tool in predicting outcomes or benefits for patients.
Citation Format: Rachel Gonzalez. MAGE-A3 and MAGE-A4 protein show co-expression in tumor of lung, bladder, and colon cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5552.
Abstract 557: EGFR-targeted mesenchymal stem cells for enhanced tumor retention and inhibition
Authors: Nethi Susheelkumar , Bhatnagar Shubhmita , Li Xiaolei , Prabha Swayam 
Published: June 2023

Abstract
MSCs have been studied as gene therapy vehicles, and several preclinical and clinical studies support the use of genetically modified MSCs to deliver therapeutics to tumor tissues. We were one of the early groups to demonstrate that MSCs can be engineered to carry cytotoxic drugs by using nanoparticle-encapsulated form of the drug. However, tumor homing of MSCs is inefficient. We hypothesized that the targeting effectiveness of MSCs can be significantly improved by incorporating tumor-targeting ligands on the MSC surface that will allow for enhanced arrest and binding within the tumor tissue. In this study, we designed anti-EGFR Ab (cetuximab, Cmab) functionalized MSCs and studied the comparative therapeutic efficacy of paclitaxel-loaded, Cmab functionalized MSCs relative to that of paclitaxel-loaded, unfunctionalized MSCs. Cmab functionalized MSCs demonstrated improved binding to A549 adenocarcinoma cells. Mice bearing orthotopic A549 tumors were dosed i.v. with the various treatments. Similar to what we have shown previously, MSCs loaded with paclitaxel nanoparticles were effective in slowing tumor growth and improving the overall survival relative to that of other controls. However, the greatest inhibition of tumor growth was observed in mice that received anti-EGFR Ab functionalized, paclitaxel-loaded MSCs. Compared to a median survival of 21 days for saline and 27 days for paclitaxel-loaded MSC treated group and paclitaxel-loaded IgG functionalized MSCs, Cmab Ab functionalized, paclitaxel-loaded MSCs treated mice resulted in significantly improved median survival of 35 days (p&lt;0.001). Biodistribution studies revealed a sixfold higher retention of functionalized MSCs when compared to unfunctionalized MSCs. These results demonstrate the potential for improved tumor targeting with EGFR-targeted MSCs.
Citation Format: Susheelkumar Nethi, Shubhmita Bhatnagar, Xiaolei Li, Swayam Prabha. EGFR-targeted mesenchymal stem cells for enhanced tumor retention and inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 557.