bluuebunny/crossref_metadata_2025 huggingface dataset:
An Exploration of the Differences between Chinese and Western Costumes in the Archaeological Archaeology of Clothing Culture in Different Periods of Agriculture
Authors: Zhang Jiwen
Published: June 2022

Countries around the world have different historical development processes in different periods of agricultural economic environment, and have formed different costume culture characteristics. This study analyzes the differences in aesthetic standards in Chinese and Western clothing cultures, as well as the differences between Chinese and Western costumes in color design, structural design, and dress methods, and elaborates the main reasons for the differences between Chinese and Western clothing cultures. The study focuses on the characteristics and differences of traditional clothing art culture in various places, but because of the differences in historical conditions, lifestyles, psychological qualities, and traditional ideas and cultural concepts, there are great differences between the traditional costume art culture concepts in China and the West. Based on this, the study specifically explains the difference between the two through the comparison of the aesthetic characteristics of the traditional costume art culture concepts in the Middle East and the West, and the difference in the expression of the Middle East and Western clothing art.
Antioxidant, Antidiabetic, and Antibacterial Potentials and Chemical Composition of Salvia officinalis and Mentha suaveolens Grown Wild in Morocco
Authors: Al-Mijalli Samiah Hamad , Assaggaf Hamza , Qasem Ahmed , El-Shemi Adel G. , Abdallah Emad M. , Mrabti Hanae Naceiri , Bouyahya Abdelhakim
Published: June 2022

This work evaluated in vitro antioxidant, antidiabetic, and antibacterial properties of Salvia officinalis (S. officinalis) and Mentha suaveolens (M. suaveolens) essential oils (EO). The EOs were extracted, and their chemical composition was determined using GC-MS analysis. The in vitro antioxidant, antidiabetic, and antibacterial activities of S. officinalis and M. suaveolens EO were shown to be remarkable. Furthermore, S. officinalis EO demonstrated better antioxidant findings (using DPPH, ABTS, and FRAP test) than M. suaveolens EO (p<0.5). There were no significant differences in the inhibitory effects of the EOs on α-amylase and α-glucosidase activities in the antidiabetic assays. All of the examined bacterial strains (10 different strains), with the exception of P. aeruginosa, demonstrated significant sensitivity to the tested EOs, with M. suaveolens EO exhibiting better activity than S. officinalis EO. Thus, the research indicated that EO from these two medicinal plants has considerable potential for application in the formulation of antibacterial, antioxidant, and antidiabetic pharmaceuticals. However, more research studies are required to interpret the pharmacologic action of the studied EOs and their principal constituents and to confirm their safety.
An Efficient Geolocation Method for Malicious LBSD Users Based on Dynamic Adjustment of Probes
Authors: Shi Wenqi , Luo Xiangyang , Guo Jiashan , Liu Fenlin , Li Lingling
Published: June 2022

The integration of the Internet of Things (IoT) and social networks is a promising trend of network technology. However, the diversity of social networks also poses potential risks to IoT security. Researching on the geolocation of social network users can verify the effectiveness of location protection mechanisms adopted by service providers, as well as provide a means for geolocating miscreants in social networks. Most current research focuses on how to infer the true location of a target within a specific region, such as within a city, while less research has been done on how to achieve fast and accurate localization of targets under long-range conditions. In this manuscript, an efficient localization method for LBSD users at long distances based on dynamic adjustment of probes (DAPL) is proposed. Based on the analysis of factors that affect the accuracy and efficiency of the target location approximation, DAPL can approach the real location sustainability of the target by dynamically generating probe locations. By identifying abnormal fluctuations of the target’s reported distance, timely corrections of probe location are made to improve efficiency. In experimental results for Momo, a global popular LBSD social platform with more than 115 million active users show that even the initial probe is thousands of miles away from the target, DAPL can geolocate the target with a success rate close to 100% (99.5%), which is much higher than 70.6% of the existing method. Only about 12 times of LBSD service queries are needed, and DAPL can geolocate 88.9% of targets within 40 meters with an average error of 22.1 meters, which has higher efficiency and approximate accuracy compared with the existing typical method.
MicroRNA-877-5p Inhibits Cell Progression by Targeting FOXM1 in Lung Cancer
Authors: Liu Zhiguang , Wang Xinlian , Cao Liqiang , Yin Xiaowei , Zhang Qian , Wang Lan
Published: June 2022

Background. Many researches revealed that microRNAs (miRNAs) function as potential oncogene or tumor suppressor gene. As an antioncogene, miR-877-5p was reduced in many tumors. Objective. This research aimed to explore the biological role and mechanisms of miR-877-5p, which may help patients with non-small-cell lung cancer (NSCLC) find effective therapeutic targets. Methods. The downstream targets of miR-877-5p were predicted by Bioinformatics software. RT-qPCR and western blot were employed to analyze the gene levels. The impacts of miR-877-5p and FOXM1 were assessed by cell function experiments. Results. The miR-877-5p was reduced in NSCLC. In addition to this, it also inhibited cell progression of NSCLC cells in vitro. Moreover, the upregulation of FOXM1 expression restored the inhibitory effect of enhancement of miR-877-5p. Conclusions. Taken together, miR-877-5p inhibited cell progression by directly targeting FOXM1, which may provide potential biomarkers for targeted therapy of NSCLC.
Effect of Refined Perioperative Nursing on the Efficacy of Noninvasive Ventilation in Elderly Patients with Lung Cancer and Respiratory Failure
Authors: Huang Li , Feng Chun
Published: June 2022

NIV (noninvasive ventilation) is becoming more popular as a first-line treatment for older patients with lung cancer who are experiencing acute respiratory failure. In the ICU, older age is linked to worse results with mechanical breathing. When dealing with severely sick patients, noninvasive ventilation is beneficial. Due to the risk of NIV failure and the higher mortality induced by delayed intubation, it is difficult to apply to older patients, especially those with lung cancer and respiratory insufficiency. As a result, for a successful outcome, nurse interventions should be provided to patients during noninvasive ventilation. This paper proposes the application of integrated perioperative nursing models on the elderly patients with lung cancer and respiratory failure. We have applied three nursing models: peer support nursing model, multidisciplinary cooperative nursing model, and transcultural nursing theory. The effect of the proposed nursing model on the efficacy of NIV is evaluated using the Logical Decision Tree Regression (LDTR) model. It is optimized using Iterative Fruit Fly Optimization Algorithm (IFOA). The performance of the suggested system is analysed, and it is observed that the patients showed better surgical outcomes when provided with the integrated nursing models.
Empirical Analysis of Ensemble Learning for Imbalanced Credit Scoring Datasets: A Systematic Review
Authors: Lenka Sudhansu R. , Bisoy Sukant Kishoro , Priyadarshini Rojalina , Sain Mangal
Published: June 2022

Credit scoring analysis has gained tremendous importance for researchers and the financial industries around the globe. It helps the financial industries to grant credits or loans to each deserving applicant with zero or minimal risks. However, developing an accurate and effective credit scoring model is a challenging task due to class imbalance and the presence of some irrelevant features. Recent researches show that ensemble learning has achieved supremacy in this field. In this paper, we performed an extensive comparative analysis of ensemble algorithms to bring further improvements in the algorithm oversampling, and feature selection (FS) techniques are implemented. The relevant features are identified by utilizing three FS techniques, such as information gain (IG), principal component analysis (PCA), and genetic algorithm (GA). Additionally, a comparative performance analysis is performed using 5 base and 14 ensemble models on three credit scoring datasets. The experimental results exhibit that the GA-based FS technique and CatBoost algorithm perform significantly better than other models in terms of five metrics, i.e., accuracy (ACC), area under the curve (AUC), F1-score, Brier score (BS), and Kolmogorov-Smirnov (KS).
Construction of Data Mining Analysis Model in English Teaching Based on Apriori Association Rule Algorithm
Authors: Wang Shufei
Published: June 2022

How to create an English data mining analysis model based on prior association strategy algorithm is learned. First, the basic principles of data mining and organizational strategy are investigated, and the cooperative strategy algorithm in data mining technology is studied. This document makes a comprehensive analysis of the classical Apriori algorithm and studies the extension of organizational strategy and the technique of deleting participation strategy after decision-making. Then, the application of Apriori algorithm in instruction management is analyzed. There is often a lot of information in command management. We need to collect the data, then sort, and review it. Finally, taking the two adults' classes, class (39) and class (40) as the research objects, of which class (39) has 41 people and class (40) has 43 people. The two classes were brought to the board of directors. The results showed that over the course of 4 months, the students scored better on the mixed tests in the lab than those in the control room. The average score of the subjects before the experiment was 17.6, the average score of the subjects after the experiment was 20.1, and the significant

P

value of the corresponding t-test was

p
≤
0.001

, less than 0.05, indicating significant differences between the two groups of data. After studying data using writing styles in class, students focused more on complex patterns, concepts, technical expressions, and line patterns. Dynamic assessment of student writing is an effort to improve student writing by using interactive assessment techniques.
Optimal Model of Software Testing Path Selection Based on Genetic Algorithm and Its Evolutionary Solution
Authors: Zhan Lili
Published: June 2022

In software testing, the selection of test data is a difficult problem in structural testing. Whether the test data is appropriate or not is directly related to whether the error can be expected to be detected. In the process of software testing, the generation of test data is not only the core problem but also the key and difficulty of software testing. Because of the huge number of test cases and low test efficiency, a powerful optimization algorithm is needed to optimize the initial test cases. As a robust search method, genetic algorithm shows unique advantages and high efficiency in solving high-complexity problems such as large space, multipeak, nonlinear, and global optimization. Based on the application of genetic algorithm, this paper analyzes the optimization path by classifying and calculating the objective function and introducing NSGA-II algorithm, measures the distance between each branch on the processing path sample set, and sorts the path set to obtain the optimal solution. On the basis of the designed model, the experimental results show that the error control rate of the model is 89.4%. Moreover, because of the superiority of NSGA-II algorithm, the probability of comprehensive cross mutation is increased by 56.7%.
Rapid Screening of 352 Pesticide Residues in Chrysanthemum Flower by Gas Chromatography Coupled to Quadrupole-Orbitrap Mass Spectrometry with Sin-QuEChERS Nanocolumn Extraction
Authors: Wang Yuanyuan , Meng Zhijuan , Su Chunyan , Fan Sufang , Li Yan , Liu Haiye , Zhang Xuan , Chen Pingping , Geng Yunyun , Li Qiang
Published: June 2022

To analyze pesticide residues, GC coupled with quadrupole-Orbitrap MS (GC-Orbitrap-MS) has become a powerful tool because of its unique characteristics of accurate mass full-spectrum acquisition, high resolution, fast acquisition rates, and overcoming matrix interference. This paper presents an efficiency evaluation of GC-Orbitrap-MS for identification and quantitation in the 352 pesticide residues analysis of chrysanthemum flowers in full-scan mode. A streamlined pretreatment approach using one-step extraction and dilution was used, which provided high-throughput processing and excellent recovery. The samples were extracted using acetonitrile. The extracted solution was purified by a Sin-QuEChERS Nano column to suppress the matrix in chrysanthemum flowers and determined by GC-Orbitrap-MS. The calibration curves for the 352 pesticides obtained by GC-Orbitrap-MS were linear in the range of 0.5–200 μg·kg−1, with the correlation coefficients higher than 0.99. The limits of detection (LODs) and the limits of quantification (LOQs) for the 352 pesticide residues were 0.3–3.0 μg·kg−1 and 1.0–10.0 μg·kg−1, respectively. The average recoveries in chrysanthemum flower at three levels were 95.2%, 88.6%, and 95.7%, respectively, with relative standard deviations (RSDs) of 7.1%, 7.5%, and 7.2%, respectively. Lastly, the validated method and retrospective analysis was applied to a total of 200 chrysanthemum flower samples bought in local pharmacies. The proposed method can simultaneously detect multipesticide residues with a good performance in qualitative and quantitative detection.
Abstract 101: JAK-independent STAT5 signaling as a node of therapeutic vulnerability in glioblastoma
Authors: Blomquist Mylan , Tuncali Serdar , Sereduk Christopher , Kloss Jean , Loftus Joseph , Tran Nhan
Published: June 2022

Glioblastoma (GBM), the most common primary brain tumor in adults, comprises all WHO Grade IV gliomas of astrocytic origin. Despite extensive characterization of the molecular and genetic features of GBM, there remains a paucity of viable treatment options, and this disease confers a dismal 5% 5-year survival rate. Genomic amplification of epidermal growth factor receptor (EGFR) occurs in 40-60% of primary GBM. Half of all EGFR-amplified cases of GBM also harbor EGFRvIII, a constitutively active, truncated variant of EGFR. EGFR and EGFRvIII transduce oncogenic signals via cytoplasmic mediators, including the JAK/STAT signal transduction pathway. The oncogenic role of STAT3 has been well-studied in CNS malignancies; STAT3 has been found to induce the expression of target genes involved in the proliferative and invasive phenotypes of GBM. However, little is known about the mechanism and role of STAT5 activation in GBM progression. Microenvironmental cues and EGFRvIII signaling, lost in adherent cell culture, are required for STAT5 activation, making STAT5 difficult to study by conventional cell culture methods. Our recent data from patient-derived xenograft (PDX) cultures demonstrates that activation of STAT5 is important in GBM cell invasion and survival. Further, STAT5 activation is present predominantly at the invasive periphery of the tumor. In this study, we seek to characterize the mechanism and role of STAT5 activation downstream of EGFRvIII in GBM. RNA sequencing of PDX tumors expressing stable shRNA knockdown of STAT3 or STAT5 indicate both redundant and distinct transcriptional changes induced by STAT3 and STAT5 in GBM. We also find that while STAT3 activation is dependent upon JAK1/2, STAT5 activation is JAK-independent downstream of EGFRvIII in GBM. Depletion of JAK1/2 expression by siRNA oligonucleotides and pharmacologic inhibition of JAK1/2 suppressed STAT3 activation but not STAT5. In fact, targeting JAK2 with kinase inhibitor WP1066 suppressed STAT3 activation, but increased activation of STAT5 in GBM cells expressing EGFR/EGFRvIII. Inhibition of Src family kinases (SFK), a family of upstream signaling effectors of the JAK/STAT pathway, attenuates both STAT3 and STAT5 activation. These results suggest that activation of STAT5 may provide a therapeutic escape mechanism to JAK-STAT3 inhibition in GBM, necessitating dual STAT3 and STAT5 inhibition to successfully inhibit the distinct oncogenic signals transmitted by STAT3 and STAT5 to promote GBM cell survival and resistance.

Citation Format: Mylan Blomquist, Serdar Tuncali, Christopher Sereduk, Jean Kloss, Joseph Loftus, Nhan Tran. JAK-independent STAT5 signaling as a node of therapeutic vulnerability in 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 101.
Abstract 1014: A framework for research scientists to include patient advocates in cancer research
Authors: Stires Hillary , Bado Igor , Brown Thelma , Carlson Martha , Chan Isaac S. , Echeverria Gloria V. , Ewald Andrew J. , Lloyd Carla , Maues Julia , Oesterreich Steffi , Riter Robert N. , Shanahan Kelly , Welm Alana L. , Newby Josh
Published: June 2022

The inclusion of patient advocates in basic cancer research has emerged as a valuable practice to ensure research is intentional, to support effective communication with broader audiences, and to directly connect researchers with those whom they are striving to help. Despite this value, many researchers do not work with patient advocates. To understand why and build a roadmap for more engagement in the future, we hosted a workshop with patient advocates and research scientists then presented findings and discussed further at an international conference. We acknowledged four main barriers: 1) It is not clear to everyone why patient advocates should be included in research, 2) Researchers are worried about saying the wrong thing, 3) Researchers do not know where to meet patient advocates, and 4) Researchers do not know how to include patient advocates in research. We identified best practices from various organizations and opportunities to overcome these barriers in the short- and long-term. This is the first time a multi-stakeholder group has come together to provide ways to support research scientists with overcoming barriers to regularly working with patient advocates. Ultimately, these relationships will improve cancer research and more quickly accomplish our collective goal of improving lives of those who have been diagnosed with cancer.

Citation Format: Hillary Stires, Igor Bado, Thelma Brown, Martha Carlson, Isaac S. Chan, Gloria V. Echeverria, Andrew J. Ewald, Carla Lloyd, Julia Maues, Steffi Oesterreich, Robert N. Riter, Kelly Shanahan, Alana L. Welm, Josh Newby. A framework for research scientists to include patient advocates in cancer research [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 1014.
Abstract 1024: The challenge of standardizing the measurement of an imprecise biomarker like HRD
Authors: Konigshofer Yves , Butler Matthew G. , Nahlik Krystyna , Lowe Dana Ruminski , Huang Catherine , Clement Omoshile , Garlick Russell K.
Published: June 2022

Here we present data on the characterization and implementation of a set of reference materials for the standardization of homologous recombination deficiency (HRD) assessment. The safety and effectiveness profile of a drug can be improved by using it in patients where that drug is most likely to be effective. While PARP inhibitors are indicated for use in some patients with ovarian, breast, pancreatic, and prostate cancer, patients with other cancers that are deficient in homologous recombination repair (HRR) might also benefit from their use. However, determining whether a cancer is HRD-positive is neither trivial nor precise. While clinical trials have shown that patients with deleterious mutations in BRCA2 and BRCA1 are most likely to benefit from PARP inhibitors, determining that a given BRCA mutation (or set of such mutations) is in fact deleterious is frequently not straightforward. Therefore, assays are now looking for signs of HRD, such as genomic instability consistent with non-homologous end joining (NHEJ) being used for the repair of double-stranded breaks in DNA as opposed to HRR. For example, some assays look at the combination of loss of heterozygosity (LOH) and large-scale state transitions (LST) across chromosomes as well as telomeric allelic imbalance (TAI) when determining whether a cancer is HRD-positive, while other assays use alternative approaches. How those characteristics are measured, integrated, and distilled into a final determination of whether HRD is present or absent varies, which can create uncertainty around treatment options and enrollment into clinical trials. This also makes the path of follow-on companion diagnostics challenging because perfect agreement between imprecise measurements is unlikely. In order to enable more standardized reporting of HRD and to enable the assessment of HRD assays, we created a set of characterized reference materials composed of HRD negative, borderline, and positive tumor/normal matched cell lines that were analyzed using both array-based and next generation sequencing-based assays in order to characterize chromosomal changes across their genomes and obtain HRD scores. Because of differences in the results, assay imprecision should be taken into account in clinical trials that implement cutoffs in order to establish safety data for patients who are biomarker-negative but may be biomarker-positive in a future assay, which is similar to what is done for complementary diagnostics.

Citation Format: Yves Konigshofer, Matthew G. Butler, Krystyna Nahlik, Dana Ruminski Lowe, Catherine Huang, Omoshile Clement, Russell K. Garlick. The challenge of standardizing the measurement of an imprecise biomarker like HRD [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 1024.
Abstract 1029: The anti-androgen seviteronel sensitizes triple-negative breast cancer to chemotherapy
Authors: Juan Beatriz P. San , Hediyah-Zadeh Soroor , Rangel Laura , Rodriguez Vanina , Milioli Heloisa H. , Kohane Felix , Purcell Carley A. , Hickey Therese E. , Goldstein Leonard D. , Lock John G. , Davis Melissa J. , Chaffer Christine L.
Published: June 2022

Therapeutic strategies that improve survival outcomes for advanced-stage breast cancers have proven a major clinical challenge. Here, we define an androgen receptor (AR) signalling network that governs the maintenance and de novo formation of cancer stem cells in triple-negative breast cancer. In response to chemotherapy, AR activation switches cells into a cancer stem cell state, while AR antagonism suppresses cancer stem cell formation and function. In vivo, we validate that the AR antagonist, seviteronel, significantly improves chemotherapy-mediated inhibition of primary and metastatic tumour growth. Analysing three independent triple-negative breast cancer patient cohorts we identify that cytoplasmic AR expression prognosticates poor survival in treatment-naïve patients and predicts poor response to chemotherapy. Additionally, Phase II clinical trial data demonstrates that seviteronel treatment followed by chemotherapy improved survival outcomes in triple-negative breast cancer patients expressing high cytoplasmic AR levels. Seviteronel combined with chemotherapy represents a promising therapeutic strategy for triple-negative breast cancer patients.

Citation Format: Beatriz P. San Juan, Soroor Hediyah-Zadeh, Laura Rangel, Vanina Rodriguez, Heloisa H. Milioli, Felix Kohane, Carley A. Purcell, Therese E. Hickey, Leonard D. Goldstein, John G. Lock, Melissa J. Davis, Christine L. Chaffer. The anti-androgen seviteronel sensitizes triple-negative breast cancer to chemotherapy [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 1029.
Abstract 1085: PRO1184, a novel folate receptor alpha-directed antibody-drug conjugate, demonstrates robust anti-tumor activity in mouse carcinoma models
Authors: Zhao Baiteng , Wang Lei , Liu Haidong , Huang Suping , Shang Xiao , Han Tae
Published: June 2022

PRO1184 is an antibody-drug conjugate (ADC) directed toward folate receptor alpha (FOLR1), a glycosyl phosphatidylinositol anchored membrane protein. FOLR1 is overexpressed in many cancers with unmet medical need, including ovarian, lung, and breast cancers, while normal tissue expression is limited. PRO1184 is comprised of a 1) human monoclonal antibody that selectively binds to FOLR1, 2) a cleavable, hydrophilic linker, and 3) exatecan, a topoisomerase 1 inhibitor. Upon binding to FOLR1 on the surface of malignant cells, PRO1184 is internalized and exatecan released through enzymatic cleavage of the linker. Exatecan blocks the ligation step of the cell cycle and generates DNA single- and double-strand breaks, which leads to cell death. The mechanism of action and clinical potential of PRO1184 was tested in a series of studies. PRO1184 bound selectively and specifically to FOLR1 with nM affinity. PRO1184 was efficiently internalized and demonstrated cytotoxicity against multiple cell lines, in vitro. In mouse carcinoma models, PRO1184 demonstrated robust anti-tumor activity across multiple tumor types that represent ovarian, non-small cell lung, and breast cancer. In addition, PRO1184 was more potent with greater tumor growth inhibition than that of a DM4-conjugated ADC. PRO1184 was tolerated at the 60 mg/kg dose level in cynomolgus monkeys and the safety profile was generally more favorable than that for a DXd-based ADC. The pharmacokinetics (PK) of PRO1184 were similar to that of the unconjugated parent antibody in rats. PRO1184 has the potential for a meaningful therapeutic window to provide an appropriate benefit to risk profile for patients with FOLR1-expressing cancers.

Citation Format: Baiteng Zhao, Lei Wang, Haidong Liu, Suping Huang, Xiao Shang, Tae Han. PRO1184, a novel folate receptor alpha-directed antibody-drug conjugate, demonstrates robust anti-tumor activity in mouse carcinoma 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 1085.
Abstract 1090: Repurposing an overactive bladder drug to treat chemoresistant lung cancer
Authors: Bassett Joslyn , Bland Tyler
Published: June 2022

Background: Non-small cell lung cancer (NSCLC) is one of the most common types of cancer diagnosis among men and women leads the most cancer-related deaths in the United States. This is largely due to treatment failure which arises from therapy-resistant tumors. The current study investigates the role of muscarinic acetylcholine receptor 3 (CHRM3) in the development and treatment of NSCLC chemotherapy-resistance and the potential of the overactive bladder CHRM3 antagonist darifenacin to treat this lethal form of cancer.

Methods: Human NSCLC cell cultures were used to harvest protein for Western blot analyses of protein expression and activity of intracellular pathways. The chemotherapy drug docetaxel’s (DTX) ability to induce apoptosis was measured with crystal violet survival assay and colony formation assay.

Results: CHRM3 expression was measured in chemonaive NSCLC cells (A549) and chemoresistant cells (A549R), which showed increased expression in A549R cells. Chemoresistant A549R were pretreated with the CHRM3 antagonist darifenacin (Dari, 10 μM, 24 hrs) before treatment with DTX (48 hrs). Crystal violet survival assay and colony formation assays showed a significant reduction in cell survival in the Dari + DTX combination treatment group suggesting that CHRM3 signaling is necessary in a chemoresistant state. Chemonaive A549 cells and CHRM3 overexpressing A549 cells (A549 M3OE) were pretreated with carbachol (10 µM, 24 hrs) to activate CHRM3 before treatment with a set of serial dilutions of DTX (48 hrs). Crystal violet survival assay results showed that carbachol was not able to protect either cell line from DTX-induced cell death, suggesting that CHRM3 signaling alone is not sufficient to induce a chemoresistant state.

Conclusion: CHRM3 overexpression is observed in chemoresistant forms of NSCLC. While activation of CHRM3 does not instill a resistant state in chemonaive cells, its signaling is essential for maintenance of the chemoresistant state. The repurposing of the CHRM3 antagonist darifenacin shows strong potential as a therapeutic to treat lethal chemoresistant forms of NSCLC.The project described was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant #P20GM103408

Citation Format: Joslyn Bassett, Tyler Bland. Repurposing an overactive bladder drug to treat chemoresistant lung 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 1090.
Abstract 1098: Structure-activity relationship of pentacyclic triterpenes against chemoresistance and metastasis on non-small lung adenocarcinoma cells
Authors: Delgado Yamixa , Perez Daraishka , Torres Grace
Published: June 2022

Lung cancer is the second most common and leading cause of cancer-related death worldwide, 85% of these cases being non-small cell lung carcinoma (NSCLC). Although chemotherapy is the first-line treatment for lung cancer, its effectiveness is hampered by the dose-limiting toxic effects, chemoresistance, and metastatic process. Recently, plant-derived cyclic triterpenoids (eg, cholesterol-structure like compounds) have shown a wide spectrum of pharmacological activities, especially their potential against different cancer cells. Herein, we investigated the structure-activity relationship of several pentacyclic triterpenes: oleanolic acid (OleA), ursolic acid (UrA), betulinic acid (BeA), Asiatic acid (AsA), betulin (BeN), lupeol (Lupe), diosgenin (Dio), stigmasterol (Stg) and β-sitosterol (β-Sito) on NSCLC A549 cells. From our studies, the IC50 for OleA, UrA, BeA, AsA, BeN, Lupe, Dio were in the low µM range (from 10-75 µM) after 24h of incubation. β-Sito and Stg did not show any significant cytotoxic pattern in this µM range. In addition, BeA showed the highest cytotoxic pattern in these cells. We performed metabolic activity assays to determine the mechanism of action of these triterpenes. Mitochondrial membrane and caspases activity assays showed that all the cytotoxic triterpenes induced activation of caspase-3 and decline in the mitochondrial potential, except BeA and AsA. Our results also show that all the cytotoxic triterpenes disrupt cell membrane, except for OleA. However, there is no reactive oxygen species production for all of them. Gene expression assays of chemoresistance- and metastasis-related genes (EGFR, VEGF, MMP9, Pgp, TP53, NDRG1, CHD4) using qPCR demonstrated the downregulation of all of these genes after the incubation with the cytotoxic triterpenes. These results demonstrated that even slight structural changes in these triterpenes could influence the cytotoxic and metabolic pathways responses. This study opens promising perspectives for further research on the role of phytochemical triterpenes, which ultimately will contribute to a more rational application in lung cancer therapy.

Citation Format: Yamixa Delgado, Daraishka Perez, Grace Torres. Structure-activity relationship of pentacyclic triterpenes against chemoresistance and metastasis on non-small lung adenocarcinoma cells [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 1098.
Abstract 112: Epac signaling facilitates malignant transformation of melanocytes
Authors: Singh Mithalesh Kumar , Altameemi Sarah , Lares Marcos , Sadangi Shreyans , Setaluri Vijayasaradhi
Published: June 2022

Cyclic AMP (cAMP) signaling plays a critical role in melanocyte proliferation and differentiation. However, the role of cAMP signaling in malignant transformation of human melanocytes and initiation of melanoma is not fully understood. Previously, we demonstrated that cAMP signaling plays opposite roles in primary and metastatic melanoma cells, i.e., pro- and anti-proliferative roles, respectively. This switch in cAMP action is mediated by the alternative cAMP signaling axis involving EPAC-RAP1 (exchange protein directly activated by cyclic AMP-Ras-related protein 1). In this study, we tested the hypothesis that activation of EPAC signaling is an early event in malignant transformation of melanocytes and is required for survival and proliferation of malignant melanocytes. Here, we show that shRNA-mediated knockdown of PTEN alone or PTEN-KD with lentiviral transduction with BRAF(V600E) results in upregulation of EPAC expression and activation of RAP1 (i.e., RAP1-GTP) in human primary melanocytes. Interestingly, activation of phosphoinositide 3-kinase (PI3K) signaling alone is sufficient for stimulation of maximal EPAC expression as well as proliferation suggesting that EPAC activation is an early event associated with loss of PTEN and melanoma tumor initiation. Inhibition of EPAC activity by either EPAC 1/2 or EPAC2-selective inhibitors suppressed the growth of transformed melanocytes by inhibiting cell cycle progression as evident by downregulation of cyclins E, -A2 and -B1. Inhibition of EPAC signaling also increased cells expressing senescence-associate beta galactosidase activity suggesting that EPAC may contribute to the senescence escape mechanisms in BRAF(V600E) melanocytes. Our data suggest that activation of PI3K pathway alone or in combination with mitogen-activated protein kinase pathway activates EPAC signaling in melanocytes. Since primary but not metastatic melanoma cells remain dependent on EPAC signaling, understanding the mechanisms of action EPAC can open new avenues to prevent melanomagenesis and inhibit melanoma tumor progression.

Citation Format: Mithalesh Kumar Singh, Sarah Altameemi, Marcos Lares, Shreyans Sadangi, Vijayasaradhi Setaluri. Epac signaling facilitates malignant transformation of melanocytes [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 112.
Abstract 1143: ATG-022, an antibody-drug conjugate targeting Claudin 18.2, demonstrated potent in vivo efficacy in gastric cancer patient-derived xenografts
Authors: Chen Peng , Liu Yun , Deng Min , Tian Linjie , Lynch Kevin , Shan Bo , Mei Jay , Hou Bing
Published: June 2022

Background: Antibody-drug conjugates (ADCs) have become promising antitumor agents in recent years. ADCs are comprised of a monoclonal antibody, targeting antigens expressed at higher levels on tumor cells than on normal cells, cross-linked to small molecule payloads with cytotoxic activity. Human Claudin 18.2 (CLDN18.2) is overexpressed in a large proportion of gastric and pancreatic cancers, with restricted normal tissue expression. The monoclonal antibody targeting CLDN18.2 (IMAB362) has demonstrated promising clinical benefit in combination with chemotherapies for gastric cancer patients. However, the same antibody shows suboptimal efficacy in patients with low CLDN18.2 expression. Here we report the potent in vivo efficacy of ATG-022, a CLDN18.2 ADC, in multiple gastric cancer patient-derived xenograft (PDX) models, including those with low CLDN18.2 expression.

Methods: The binding affinity of ATG-022 with CLDN18.2 was detected by SPR and FACs analysis. The in vitro 50% inhibition concentration (IC50) of ATG-022 was determined in CLDN18.2 positive cell lines using CellTiter-Glo luminescent cell viability assay. In vivo efficacy of ATG-022 was evaluated in a series of gastric cancer PDX models with different expression level of CLDN18.2 The expression level of CLDN18.2 was determined using IHC staining. ATG-022 was dosed twice at 1 mg/kg, 3 mg/kg or 10 mg/kg every two weeks.

Results: ATG-022 binds to CLDN18.2 protein with sub-nM affinity. It induced potent in vitro cytotoxicity in CHOK1 cells overexpressing CLDN18.2, with an IC50 of 5-7nM. Bystander killing by ATG-022 was observed. ATG-022 demonstrated potent in vivo antitumor efficacy in a gastric cancer PDX model with high CLDN18.2 expression. Intravenous dosing of 1 mg/kg, 3 mg/kg, and 10 mg/kg ATG-022 induced 35.41%, 71.56% tumor growth inhibition (%TGI) and tumor regression respectively. In a PDX model with low CLDN18.2 expression, 3 mg/kg ATG-022 or 10 mg/kg clinical benchmark CLDN18.2-ADC did not inhibit tumor growth, while 10 mg/kg ATG-022 induced tumor regression.

Conclusions: ATG-022 demonstrated potent in vitro and in vivo antitumor effects, with in vivo efficacy observed in CLDN18.2-low expression PDX models, suggesting a promising therapeutic strategy for gastric cancer patients with a broad range of CLDN18.2 expression levels.

Citation Format: Peng Chen, Yun Liu, Min Deng, Linjie Tian, Kevin Lynch, Bo Shan, Jay Mei, Bing Hou. ATG-022, an antibody-drug conjugate targeting Claudin 18.2, demonstrated potent in vivo efficacy in gastric cancer patient-derived xenografts [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 1143.
Abstract 1157: Uncovering transcriptional changes related to cisplatin treatment and mixing of TNBC subclones using single-cell RNA sequencing
Authors: Nicholas Shadae , Mukashyaka Patience , Kumar Pooja , Chuang Jeffrey , Liu Edison
Published: June 2022

Triple negative breast cancer (TNBC) has long been characterized by having a high degree of intratumoral heterogeneity. While significant contributions have been made in understanding the components of TNBC tumors, examining the dynamics of interaction between subclones in TNBC is relatively unexplored. By using single-cell RNA sequencing (scRNA-seq) technology, this study aims to focus on understanding changes in gene expression of two TNBC subclones: the cisplatin-resistant subclone (A50) and cisplatin-sensitive subclone (B), when cocultured in 3D organoids in the presence and absence of cisplatin. We hypothesized that there will be significant differentially expressed genes (DEGs) due to various concentrations of cisplatin and mixing effect. We found DEGs (ACTB, FOS, EIF5, BRD2, MAFG, SF3B4, ID1, MGMT, DDIT4 and LPP) due to treatment with cisplatin in both subclones, with the largest clear effect present at a high concentration of cisplatin. Additionally, the network analysis showed that cisplatin was an upstream regulator for 11 DEGs. Even though, gene expression changes due to mixing are much more subtle than effects due to treatment, we saw some DEGs caused by the mixing effect like MT1X which is related to cisplatin resistance. Taken together, the findings of this project will help in future studies when deducing which genes to target in TNBC chemotherapy treatments based on predictive molecular biomarkers.

Citation Format: Shadae Nicholas, Patience Mukashyaka, Pooja Kumar, Jeffrey Chuang, Edison Liu. Uncovering transcriptional changes related to cisplatin treatment and mixing of TNBC subclones using single-cell RNA sequencing [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 1157.
Abstract 1162: A systematic analysis of RET mutations and their sensitivity to different RET inhibitors
Authors: Rotkopf Shay , Haham DIkla , Fillipov-Levy Natalie , Birnbaum Lea , Dehan Elinor , Kifer Ilona , Barbash Zohar , Tarcic Gabi
Published: June 2022

The RET oncogene is a receptor tyrosine kinase, mainly expressed in neural crest-derived tissues, that plays a role in cell growth and differentiation. Since the first identification of inherited mutations in RET as the cause of Multiple endocrine neoplasia type 2 (MEN2), somatic RET alterations have been identified as actionable drivers in subtypes of lung and thyroid, among other cancer types. This enabled the development of several RET targeted treatments, such as pralsetinib and selpercatinib, showing meaningful clinical benefit. To understand the full scope of RET alteration frequency and heterogeneity we used the AACR-GENIE database. We found that the frequency of RET alterations pan-cancer is 3%, of which two-thirds are missense mutations. The major cancer types with RET alterations are medullary thyroid, papillary thyroid and NSCLC, as expected, but also breast, colorectal and melanoma. An important distinction between NSCLC and thyroid cancer compared to colorectal, breast and melanoma is the fraction of missense vs. fusion events, with 30%-40% of samples in the former group containing RET fusions. This is in contrast with >80% of samples in the latter group containing RET missense mutations. Moreover, the heterogeneity of RET alterations is large, with over 1,000 unique types of missense mutations identified. The vast majority of mutations are classified as variants of uncertain significance (VUS). To better understand the potential activity of these mutations, we assayed over 200 different missense mutations and fusions using a high-throughput cell-based functional assay. Results were analyzed using a novel machine learning model consisting of a multi-scale deep convolutional neural net, followed by a tree-based regressor. Our results show that the assay correctly predicted the activity of both known activating alterations as well as of loss of function mutations. Interestingly, only ~3% of over 150 VUS tested were found to be activating. Furthermore, we show that the active alterations are sensitive to the FDA-approved targeted agents pralsetinib and selpercatinib, with varying IC50 values. Taken together, these results uncover the full extent of actionable RET alterations, differentiating between active and non-active variants, as well as the effectiveness of RET inhibitors.

Citation Format: Shay Rotkopf, DIkla Haham, Natalie Fillipov-Levy, Lea Birnbaum, Elinor Dehan, Ilona Kifer, Zohar Barbash, Gabi Tarcic. A systematic analysis of RET mutations and their sensitivity to different RET inhibitors [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 1162.
Abstract 1165: Therapeutic targeting of glucocorticoid receptor in ETS rearranged cancer
Authors: Sekar Arunachalam , Nataraj Nishanth Belugali , Yarden Yosef
Published: June 2022

The Nuclear receptor Glucocorticoid receptor (GR) acts as a ubiquitous hormone-dependent transcription factor, which regulates many cellular functions. Here, we discovered that some ETS (E-twenty-six) family transcription factors form physical complexes with GR. Two members of the family, FLI1 and ERG exhibited stronger binding with the ligand-activated GR. GR-FLI1 interaction enhance the transcriptional activity of DNA-bound GR. Antagonizing GR or lowering cortisol levels in Ewing sarcoma (ES) animal models, a pediatric bone malignancy driven by EWS-FLI1 fusion, robustly retarded tumor growth, as well as inhibited bone to lung metastasis. These findings prompted us to identify prognostic, GR-regulated gene signature in ES. Because the genomic binding sites of GR in ES are still unknown, using chromatin immunoprecipitation followed by high-throughput DNA sequencing in A673 cells we found previously known and new target genes of GR. By utilizing the protein-fragment complementation assay (PCA), we discovered that GR physically interacts with additional ETS factors. Disruption of this complex is enabled by clinically approved GR antagonist RU486 or newly developed selective GR modulators (i.e., SGRMs without AR or PR cross-reactivity). ETS proteins has been strongly associated with tumor progression and metastasis in several cancers. Taken together, we hypothesised that these mechanisms are also relevant for other ETS rearranged cancers. Results of co-immunoprecipitation analysis confirm the interaction of GR and ERG/ETV4 in ETS-positive prostate cancer cells. In addition, migration and proliferation were reduced when we knocked-down or antagonized GR. It is important noting that the pharmacology of GR is very well developed and some GR-targeting drugs are among the most prescribed medicines. These discoveries will open the way to clinical tests and eventual application of anti- hormone therapy in the discipline of pediatric sarcomas and ETS-rearranged cancers.

Citation Format: Arunachalam Sekar, Nishanth Belugali Nataraj, Yosef Yarden. Therapeutic targeting of glucocorticoid receptor in ETS rearranged 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 1165.
Abstract 1197: Refining the drug-gene interaction database for precision medicine pipelines
Authors: Cannon Matthew , Stevenson James , Kuzma Kori , O'Sullivan Colin , Miller Katherine , Grischow Olivia , Coffman Adam , Kiwala Susanna , McMichael Joshua F. , Morrissey Dorian , Cotto Kelsy , Griffith Obi , Griffith Malachi , Wagner Alex
Published: June 2022

The Drug-Gene Interaction Database (DGIdb, www.dgidb.org) is a publicly accessible resource that aggregates 102,426 gene records and 57,498 drug records from 40 drug-gene interaction data sources to aid both researchers and clinicians in identifying associations between genes of interest and available drugs and therapeutics. By using peer-reviewed data sources and publications, DGIdb represents a stand-alone resource with over 100,000 drug-gene interaction claims across 30 interaction types to drive hypothesis generation in precision medicine and interpretation pipelines. The background process that normalizes drugs to a harmonized ontological concept has been upgraded. These improvements have increased concept normalization for drugs by 20% and are now available as a stand-alone service for use (https://normalize.cancervariants.org/therapy/). Leveraging our platform’s ability to find relationships between disease-critical genes and available therapeutics, DGIdb has been used in clinical interpretation pipelines to find drugs for specific diseases with an emphasis on regulatory approval status. DGIdb now uses annotations from Drugs@FDA as an additional source to provide more accurate descriptors for market and maturity status of drugs, when available. Lastly, to enhance the annotation potential for DGIdb in precision medicine pipelines, we have updated our druggable gene category sources with an additional curated list of 2,217 genes. Used alone or in combination with existing categories-such as the heavily-utilized ‘clinically actionable’ category-this additional source will give precision medicine and interpretation pipelines the power to find concise, actionable annotations for specific diseases including pediatric cancers and epilepsy. These lists are managed and maintained as a publicly-available resource to provide up-to-date annotations on disease-associated genes as they become available.

Citation Format: Matthew Cannon, James Stevenson, Kori Kuzma, Colin O'Sullivan, Katherine Miller, Olivia Grischow, Adam Coffman, Susanna Kiwala, Joshua F. McMichael, Dorian Morrissey, Kelsy Cotto, Obi Griffith, Malachi Griffith, Alex Wagner. Refining the drug-gene interaction database for precision medicine pipelines [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 1197.