bluuebunny/crossref_metadata_2025 huggingface dataset:
Entropy Weight TOPSIS Evaluation of Corporate Internal Control Quality Based on Fuzzy Matter‐Element Model
Authors: Tian Tao , Li Xiaoning , Wang Qing , Tong Dajian
Published: June 2022

One of the core objectives of domestic and foreign regulation policies is to strengthen internal control and improve corporate risk management ability. To evaluate corporate internal control quality (CICQ), this paper constructs a composite fuzzy matter‐element model based on the fuzzy matter‐element theory and the data on 781 listed enterprises in China. By the entropy weight method, five evaluation indices of internal control were weighed and compared with the positive and negative ideal indices. Next, the internal control of the listed enterprises was measured by TOPSIS. The results show that the indices of laws and regulations (LR), financial statements (FS), assets safety (AS), operation (OP), and strategy (ST) are of different weights in terms of CICQ evaluation. The LR, OP, and ST indices are more important than the FS indices. Among the secondary indices, the most important indices, namely, major litigation and arbitration cases, turnover of total assets, and Tobin’s Q account for 66% of total weights. In addition, the CICQ varies with industries: the top‐10 enterprises in terms of CICQ mostly belong to industries with strict requirements on work safety. The research findings lay a methodological and practical basis for the CICQ evaluation of Chinese enterprises.
The Premechanism and Action Logic of Grassroots Rural Talents in the Rural Public Cultural Service System under the Development of Digital Technology
Authors: Wu Songjiang , Cao Min
Published: June 2022

At present, the rural public cultural service is facing the dilemma that the supply and demand are not in place. The participation of the local forces represented by the grassroots rural talents in the rural public cultural service provides a breakthrough. Based on the “dual-track supply” model, this paper studies the action logic of the grassroots rural elites in Dachengqiao Town, Ningxiang City. The study found that the grassroots rural talents’ participation in public cultural services has a pre-existing mechanism: villagers’ recognition is the foundation, government empowerment is the premise, and participation motivation is the focus. After reaching the critical point and generating the supply behavior, the policy guidance and the villagers’ demand, respectively, shaped the action logic of the grassroots rural talents: the grassroots rural talents acted as the bridge between the government and the villagers. Through big data, cloud services, and intelligent life, we can narrow the gap of rural, public, cultural services, and open up the last mile of public cultural services. The government should improve the incentive mechanism of rural talents to strengthen the grassroots rural talents’ participation motivation and give full play to the role of rural talents; rural talents should actively give feedback to villagers’ demand and actively explore villagers’ cultural needs to improve rural public cultural services.
Analysis of Insurance Marketing Planning Based on BD-Guided Decision Tree Classification Algorithm
Authors: Long Juan
Published: June 2022

The emergence and development of Chinese insurance companies are affected by their own unique national conditions. The modern marketing concept lags behind, lacks the practical experience of scientifically formulating marketing strategies, and insurance practitioners lack marketing knowledge and the ability to absorb modern marketing achievements to guide practice. Therefore, China’s insurance industry inevitably has many problems in insurance marketing. In recent years, with the rapid development of big data (BD) technology, artificial intelligence, and machine learning in engineering and academia, relevant data models have been well developed. The advantages of the decision tree are its good robustness, full sample mining, high precision, fast implementation, fast running speed, and low implementation cost. This paper studies the application of the decision tree classification algorithm under the guidance of BD in insurance marketing planning. The running results of the decision tree classification algorithm model show what factors will affect the accuracy and recall rate of customer churn decision-making. The predicted value and scoring value of users are extracted to test the model, and the results are within a reasonable range. The running time of this model is 2,320.36 s, which is more efficient than the 34 min 25 s of traditional SAS. Therefore, the model can be put into use, and it is necessary to establish a long-term and stable relationship with customers.
Combined Classifier-Demodulator Scheme Based on LSTM Architecture
Authors: Dampage Udaya , Amarasooriya S. M. R. P. , Samarasinghe R. A. S. M. , Karunasingha N. A.
Published: June 2022

When it comes to studies on smart receiver designs, using machine learning and deep learning techniques for the development of automatic modulation classifiers as well as demodulators which require little to no information about the transmitted signal or the channel state is an area of interest. Through this study, we have proposed a combined classifier-demodulator system that is entirely deep learning-based and one that is focused on higher-order quadrature amplitude modulation (QAM) schemes such as 64QAM and 256QAM that can be used in next-generation mobile technologies. The system was developed by training a bidirectional long-short-term memory (BiLSTM) and long-short-term memory (LSTM) network for the classifier and demodulator, respectively, using randomly generated data, demodulated using binary phase shift keying (BPSK), quadrature phase shift keying (QPSK), 16QAM, 64QAM, and 256QAM transmitted through a simulated additive white Gaussian noise (AWGN) channel of varying signal to noise ratio (SNR) levels. The classifier was then tested for its prediction accuracy while the demodulator models were tested against traditional mathematical models while calculating the effective capacity. The results showcased that the classifier worked extremely well for the QAM schemes across all SNR levels and less so with the PSK models. Considering the demodulator models’ performance, all schemes except the 256QAM demodulator were able to reach a zero or near zero bit error rate (BER) level within minimum acceptable SNR ranges.
Intramural Esophageal Hematoma Mimicking Acute Coronary Syndrome: Complication of Warfarin Use in a Mechanical Heart Valve Patient
Authors: Alirezaei Toktam , Irilouzadian Rana , Pirsalehi Ali , Nekooghadam Sayyed Mojtaba
Published: June 2022

A 59-year-old female with a history of mitral valve replacement presented to emergency department, complaining of sudden-onset retrosternal chest pain since 4 hours ago. Electrocardiogram, laboratory tests, and computed tomography (CT) angiography of aorta were performed and ruled out aortic dissection and cardiovascular events. However, new complaint of odynophagia, dysphagia, and incidental findings in CT angiography proposed esophageal pathologies. After initial workup including upper gastrointestinal endoscopy, intramural esophageal hematoma was diagnosed. Laboratory tests revealed significant reduction in the hemoglobin level. Management of warfarin-induced major bleeding in a patient whom anticoagulation was necessary for the prevention of mechanical heart valve thrombosis was challenging. The patient recovered fully with conservative treatment and was discharged on hospital day 14 with low molecular weight heparin. We described a case of intramural esophageal hematoma as a rare condition that could be misdiagnosed as a cardiovascular emergent disease and would be worsened by antiplatelet and anticoagulation therapy. Accordingly, it is important to differentiate intramural esophageal hematoma from cardiac ischemic events. Another challenge was correction of coagulation in the presence of mechanical mitral valve. Fortunately, we had a favorable outcome following conservative management.
Study the Mechanism of Gualou Niubang Decoction in Treating Plasma Cell Mastitis Based on Network Pharmacology and Molecular Docking
Authors: Wu Zhaojing , Yang Qing , Ma Hongbo
Published: June 2022

Objective. Explore the potential molecular mechanisms behind the therapeutic functions of Gualou Niubang decoction (GLNBD) in the treatment of plasma cell mastitis (PCM) by network pharmacology and molecular docking. Methods. GLNBD is a formula of Chinese traditional medicine consisting of 12 herbs. The potential active ingredients of GLNBD and their target genes were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database, and PCM‐related target genes were obtained from GeneCards, OMIM, and NCBI databases, using R language to obtain intersection targets; then, the STRING database and Cytoscape software were used to establish protein‐protein interaction networks and herb ingredient target networks. DAVID was used to perform GO and KEGG pathway enrichment analyses on the intersection target. PyMoL‐2.5.0 and AutoDock Tools‐1.5.6 were used to verify the molecular docking. Results. 164 ingredients and 58 intersection targets were obtained in the treatment of PCM by GLNBD. Four key active compounds and four key proteins were identified. Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that biological functions of potential target genes were associated with negative regulation of the apoptotic process, response to hypoxia, positive regulation of transcription, and DNA‐templated, with related pathways involving the pathway in cancer, phosphatidylinositol 3‐kinase (PI3K) Akt signaling pathway, and AGE‐RAGE signaling pathway in diabetic complications. Moreover, the binding activities of key target genes and essential active compounds of Chinese herbal medicines in GLNBD were further validated by molecular docking. The results showed that the docking results were stable and had good binding ability. Conclusion. This study suggested that four potential key active components, including quercetin, luteolin, fisetin, and kaempferol, were identified in GLNBD, which could interact with ALB, EGFR, IL‐6, and VEGFA modulating the activation of the pathway in cancer, PI3K‐Akt pathway, and AGE‐RAGE signaling pathway in diabetic complications.
Modeling of Hepatitis B Virus Transmission with Fractional Analysis
Authors: Khan Muhammad , Khan Tahir , Ahmad Imtiaz , Shah Zahir , Khan Alamzeb
Published: June 2022

Hepatitis B is one of the infectious diseases among other contagious diseases. In this paper, we analyze and discuss the time dynamics of hepatitis B under the effect of various infectious periods. We propose a model keeping in view the role of acute and chronic infections stages and analyze the temporal dynamics. To do this, first we develop the model and use the concept of fractional theory to fractionalize. We also study the qualitative analysis of both the integer and fractional order models. For the fractionalizing purpose, the Caputo–Fabrizio (CF) operator is utilized. We prove also, the existence and uniqueness of the solution to the considered fractional-order model to show that the epidemic problem is feasible and well possessed. For this, we use the fixed point theory and its applications. Moreover, we prove that the considered model possesses a positive as well as bounded solution. We calculate the basic reproductive number to find the equilibria of the model to execute the stabilities and to investigate that the proposed fractional model is stable asymptotically. We support our analytical findings with the use of some graphical visualization.
Optimization of Online Course Platform for Piano Preschool Education Based on Internet Cloud Computing System
Authors: Hu Qianru
Published: June 2022

This article focuses on introducing online piano teaching methods and has developed and implemented a preschool piano education online course platform. The system consists of four parts: backend, WeChat, client, and web page. Backend development uses PHP language and Laravel system framework, WeChat and web development both use JavaScript language and React framework, client development uses Objective-C language, and the system provides internal support for RESTful API, mainly for client, WeChat, and web. The client relies on the existing voice sensors of the research group to recognize and evaluate the performance of the students. The role of the client is to show the students their homework and demonstrate the activities performed by the teacher. The function of the WeChat terminal is to manage student work, user information, and user social interaction functions. The function of the web page is the score management and data analysis functions. Based on the knowledge of network course design, this article studies the design of piano preschool education platform and adds relevant components of the Internet cloud computer system and voice sensor to this platform, which provides great convenience for students to learn piano.
Oscillatory and Asymptotic Behavior of Nonlinear Functional Dynamic Equations of Third Order
Authors: Hassan Taher S. , Attiya Adel A. , Alshammari Mohammad , Abdel Menaem Amir , Tchalla Ayékotan , Odinaev Ismoil
Published: June 2022

The purpose of this work is to derive sufficient conditions for the oscillation of all solutions of the third-order functional dynamic equation

p

2

ξ

ϕ

γ

2

p

1

ξ

ϕ

γ

1

y

Δ

ξ

Δ

Δ

+
p

ξ

ϕ

β

y

g

ξ

=
0
,

on a time scale

T

. In addition, we present some Hille-type conditions for generalized third-order dynamic equations that improve and extend significant contributions reported in the literature without imposing time-scale restrictions. An example is given to demonstrate the essential results.
Chemotaxonomy and Antibacterial Activity of the Extracts and Chemical Constituents of Psychotria succulenta Hiern. (Rubiaceae)
Authors: Ngnokam Jouogo Darille Claudia , Tamokou Jean-De-Dieu , Teponno Rémy Bertrand , Matsuete-Takongmo Germaine , Voutquenne-Nazabadioko Laurence , Tapondjou Léon Azefack , Ngnokam David
Published: June 2022

The use of natural products for medicinal purposes is becoming more and more common nowadays, as evidenced by the presence in plants of secondary metabolites with different potentials such as antioxidant and antibacterial properties. We evaluated in this work the antimicrobial activities of the extracts and some isolated compounds from the seeds of Psychotria succulenta Hiern. (Rubiaceae), a Cameroonian medicinal plant traditionally used to cure microbial infections. The ethanol extract was prepared by maceration and extracted with ethyl acetate and n‐butanol. The EtOAc (m = 168 g) and n‐BuOH (m = 20 g) extracts were further fractionated by silica gel column chromatography to isolation of compounds. Their structures were elucidated by spectroscopic analysis and by comparison with published data. The antibacterial activity of extracts and compounds was assessed by evaluating the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against pathogenic bacteria. Thirteen compounds including four alkaloids (veprisine (1), naucleofficine III (2), vepridimerine B (3), and vepridimerine C (4)), three triterpenes (barbinervic acid (5), 3‐O‐α‐L‐rhamnopyranosyl quinovic acid (6), and oleanolic acid (7)), one steroid (β‐sitosterol‐3‐O‐β‐D‐glucopyranoside (8)), four phenolic compounds (scopoletin (9), gallic acid (10), quercetin‐3‐O‐β‐D‐glucopyranoside (11), and kaempferol 3‐O‐α‐L‐rhamnopyranoside‐7‐O‐α‐L‐rhamnopyranoside (12)), and one iridoid (borreriagenin (13)) were isolated from the EtOAc and n‐BuOH extracts. These compounds were identified by 1D and 2D NMR combined analysis as well as by melting point comparison. The EtOH, EtOAc, and n‐BuOH extracts exhibited significant antibacterial activities (MIC = 32‐128 μg/mL; MBC = 64‐256 μg/mL) against Staphylococcus aureus (Gram‐positive bacterium), Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumonia (Gram‐negative bacteria). Among the isolated compounds, scopoletin (9) showed a moderate activity against Klebsiella pneumoniae with MIC and MBC values of 16 μg/mL and 32 μg/mL, respectively. It appears that, chemotaxonomically, some of the isolated compounds have already been obtained from the genus Psychotria but to the best of our knowledge, this is the first report on the phytochemical investigation of P. succulenta. Although many other studies need to be achieved, our results support the use of P. succulenta in traditional medicine to cure infectious diseases particularly those caused by the tested bacteria.
Fall Detection and Direction Judgment Based on Posture Estimation
Authors: Yuan Chunmiao , Zhang Pengju , Yang Qingyong , Wang Jianming
Published: June 2022

For the problem of elderly people falling easily, it is very necessary to correctly detect the occurrence of falls and provide early warning, which can greatly reduce the injury caused by falls. Most of the existing fall detection algorithms require the monitored persons to carry wearable devices, which will bring inconvenience to their lives and few algorithms pay attention to the direction of the fall. Therefore, we propose a video‐based fall detection and direction judgment method based on human posture estimation for the first time. We predict the joint point coordinates of each human body through the posture estimation network, and then use the SVM classifier to detect falls. Next, we will use the three‐dimensional human posture information to judge the direction of the fall. Compared to the existing methods, our method has a great improvement in sensitivity, specificity, and accuracy which reaches 95.86, 99.5, and 97.52 on the Le2i fall dataset, respectively, whereas on the UR fall dataset, they are 95.45, 100, and 97.43, respectively.
Comprehensive Treatment of Urban Landscape Water Environment Based on Aquatic Plants Purification and Restoration
Authors: Li Ke
Published: June 2022

Water is the source of life and the foundation for the growth of all things. Water is also an important part of the urban ecological structure. A healthy water environment is the basis for human survival and development, and it is also one of the important conditions for the harmonious development of cities. With the rapid development of the economy and the improvement of the level of urbanization, the water environment pollution in the urban landscape has become more and more serious, such as serious water eutrophication and rapid algae reproduction in the water environment. As plants that can survive in water, aquatic plants have always been an important main body of the water ecological environment. It plays an unparalleled role in water environment purification and comprehensive treatment of water pollution. This paper aims to study the comprehensive management of urban landscape water environment based on the purification and restoration of aquatic plants. It combines the purification and restoration ability of aquatic plants and genetic algorithm to carry out the comprehensive management experiment of urban landscape water environment. The conclusion shows that after the purification and restoration of aquatic plants and comprehensive pollution control, the comprehensive eutrophic substance content of the urban landscape pond water body decreased by 21.7 mg, and the water body transparency increased by 20 cm.
Comparative Study of Flow Patterns around Rhizophora and Avicennia Mangrove Roots Using Computational Fluid Dynamics Simulation
Authors: Rahuman Sini , Ismail A. Mohamed , Varghese Shyla Manavalan , Toworfe George Kwamina
Published: June 2022

The goal of this research is to visualize and compare the patterns of the fluid flow around stilt roots of Rhizophora mangrove species and pneumatophore roots of Avicennia mangrove species in Pichavaram mangrove forest to better understand how mangrove roots can potentially slow down heavy wind flow and thereby offer protection to the coast from natural disasters. The flow around the roots is simulated and analyzed using ANSYS Computational Fluid Dynamics (CFD) software using an unsteady k-ε turbulence model. Wind and water flow velocities vary with respect to time during tsunami, cyclones, typhoons, or hurricanes. Hence, inlet velocity taken as the step function is applied to simulate the change in speed of fluid flow to study the flow behavior. Velocity and pressure are measured at various points around Rhizophora and Avicennia mangrove roots. The findings of the simulation reveal that the Rhizophora stilt roots and pneumatophore roots of Avicennia marina continuously lower the fluid velocity. The Rhizophora mangrove roots can largely decrease the flow velocity because of the complexity and its root dimensions in comparison to Avicennia roots. The data obtained from this research can be applied to increase the efficiency of breakwater models and, as a result, safeguard the shore from natural disasters.
Image Restoration using Nonlocal Regularized Variational Model with Spatially Adapted Regularization Parameter
Authors: Pan Chen , Feng Helin
Published: June 2022

Restoration of blurred images corrupted with impulse noise has attracted increasing attention due to its great potential toward practical applications. To guarantee the noisy image deblurring performance, total variation (TV), one of the most popular regularizers, has been extensively exploited in the literature. This local regularizer is known for its capability of preserving edges and penalizing oscillations but not sharp discontinuities. However, TV regularized variational models commonly suffer from undesirable staircase-like artifacts in homogeneous regions. The reason behind this phenomenon is that TV regularizer favors solutions that are piecewise constant in numerical experiments. To overcome the model-dependent deficiency, we proposed to replace the commonly used local regularizer by its nonlocal extension, i.e., nonlocal total variation (NLTV) regularizer. By taking advantage of the high degree of self-similarity within images, the proposed nonlocal variational model is able to remove both blurring and impulse noise while preserving meaningful image details. To guarantee solution stability and efficiency, the resulting nonsmooth image restoration problem was effectively dealt with using an alternating optimization algorithm. In addition, to further enhance the image quality, a local variance estimator-based automatic method was introduced to calculate the spatially adapted regularization parameters during image restoration. Extensive experiments have demonstrated that the proposed method could achieve superior imaging performance compared with several state-of-the-art image restoration methods.
The Asymmetric Utility of Cultural Distance in International Business based on the Cultural Bias
Authors: Fu Huawei , Li Hua , Wu Aiping
Published: June 2022

As an index to measure the cultural differences between countries, culture distance (CD) is a widely used construct in international business and postulated to be symmetric in previous studies. However, CD symmetry across different countries is been demonstrated to result in the national CD paradox. A new asymmetry index utility cultural distance (UCD) is proposed to replace the previous one in this study. The cultural utility function is applied to calculate the UCD for a particular country, where the cultural bias could cause the asymmetric change of cultural score. The index is verified to be a significant variable in the regression analysis of China’s outward foreign directing investment to 17 other countries in 15 years. The UCD demonstrated in this paper corrects the fallacious symmetry assumption on cultural distance and can maintain a consistent and effective conclusion on cultural differences in international business studies.
Effects of Monochromatic Blue Light on Reducing the Adverse Impact of Induced Cyclic Chronic Heat Stress during the Thermal Manipulation of Broiler Embryos
Authors: Zeng Li , Liu Qiong , Wang Tao , Yang Yefeng , Jado Ahmed , Elhadidi Yasser , Lin Wenfeng , Li Jian , Pan Jinming
Published: June 2022

Objective. The aim was to detect effects of blue light on reducing the adverse effect of heat stress in thermal manipulation (TM) of broiler embryos by subjecting embryos to heat stress during incubation development. Methods. Eggs were assigned to four treatments in which the TM (thermal manipulation) was exposed to 40°C for 4 h daily during five successive days, if TM was operated. The treatments were (1) normal temperature with white lighting group (37°C+W), (2) normal temperature with blue lighting group (37°C+B), (3) thermal manipulation with white lighting group (40°C+W), and (4) thermal manipulation with blue lighting group (40°C+B). Results. Blue light significantly lowered MDA and corticosterone concentrations in the embryonic liver. Additionally, the damage of embryonic liver tissue caused by heat stress could be reduced by blue light. HSPs and HSFs gene expression of chicken liver were modulated by blue light significantly, whereas the effects were different, respectively. Moreover, blue light modulated liver antioxidant enzyme activity and their gene expression in embryonic liver significantly. However, blue light did not exert significant effects on body weight, late hatch rectal temperature and tibia length of hatched chicks. Conclusions. The results suggest that monochromatic blue light can reduce the content of MDA and corticosterone of broiler embryos in heat stress and increase the relative expression of SOD and CAT genes. Moreover, the monochromatic blue light may reduce the metabolic heat production of broilers during the embryonic stage, thus reducing the damage of broilers due to heat stress during the embryonic heat acclimation stage.
Abstract 1008: Cell density-related variability in chemotherapeutic resistance patterns in human cancer cells
Authors: Brown Thomas , Punyamurtula Ujwal , Strandberg Jill , El-Deiry Wafik S.
Published: June 2022

Assessment of chemosensitivity and resistance varies with cancer cell of origin, drug and culture conditions. However, it is also not uncommon to find multiple different IC50 values for the same chemotherapeutic treatments acting on the same tumor cell lines. The aim of this research was to investigate this discrepancy in phenotypes and elucidate relevant variables that influence them. We assessed chemosensivity as a function of tumor cell density by plating TOV-21G ovarian, HT29 colorectal, and U2OS osteosarcoma cell lines in 96-well plates at various seeding densities per well and treated them with various concentrations of cisplatin, 5-fluorouracil (5-FU), and etoposide, respectively. CellTiter Glo assays were performed at 72 hours of treatment to determine IC50. Cisplatin IC50 for TOV-21G cells plated at 50,000, 20,000, 10,000, 5,000, 2,000, 1,000, and 500 cells/well were 12.00 μM, 5.47 μM, 3.16 μM, 2.45 μM, 2.54 μM, 2.83 μM, and 2.66 μM, respectively. Etoposide IC50 for U2OS cells plated at the same seeding densities were 6.50 μM, 5.19 μM, 3.23 μM, 2.98 μM, 2.49 μM, 2.13 μM, and 1.88 μM, respectively. IC50 values for HT29 cells treated with 5-FU at 2,000, 1,000, and 500 cells/well were 35.89 μM, 19.74 μM, and 13.42 μM, respectively. TOV-21G, U2OS, and HT29 cells all showed differences in IC50 values depending on cell plating density. TOV-21G and U2OS cells both showed a gradual decrease and plateau in IC50 as the cancer cell density decreased from 50,000 cells/well to 500 cells/well. HT29 cells displayed a sharper IC50 decrease as the cell density decreased from 2,000 cells/well to 500 cells/well. Our experiments demonstrate that IC50 values are not static at 72 hours and that tumor cell density is an important variable in influencing observed tumor resistance to traditionally effective drugs. As the density of cancer cells increases, the cells develop more resistance to the associated chemotherapy and require higher quantities of drug to achieve the same level of growth inhibition. We are currently exploring underlying molecular mechanisms that may influence these changes in IC50 including cell survival signaling proteins, cell-cell contact or growth factors that may influence cell density-related chemoresistance.

Citation Format: Thomas Brown, Ujwal Punyamurtula, Jill Strandberg, Wafik S. El-Deiry. Cell density-related variability in chemotherapeutic resistance patterns in human cancer 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 1008.
Abstract 1037: Targeting the RBM38-EIF4E complex to increase wild-type p53 as a novel cancer therapeutic strategy
Authors: Lucchesi Chris August , Zhang Jin , Chen Xinbin
Published: June 2022

To date, dysregulation of more than 450 RNA-binding proteins (RBPs) across a multitude of cancers has been implicated in tumorigenesis and chemoresistance. In fact, emerging evidence suggests RBPs are principal modulators of every hallmark of cancer progression. Functionally, RBPs are believed to modulate the stability, localization, and translation of transcripts encoding for virtually all known oncogenes and tumor suppressor genes. Consequently, aberrant expression of RBPs may contribute to the malignant transformation of cancer cells through enhancing the expression of oncogenes or decreasing the expression of tumors suppressor genes, such as TP53. As a potent transcription factor, TP53 is a leading regulator of numerous signaling pathways involved in tumor suppression. While mutation or deletion of TP53 contributes to tumorigenesis in more than half of all human cancers, suppression of wild-type TP53 expression also drives tumorigenesis. Thus far, multiple RBPs have been implicated in the repression of wild-type TP53, such as RNA-binding motif protein 38 (RBM38). Specifically, RBM38 interacts with eukaryotic translation initiation factor 4E (EIF4E) on the TP53 transcript, preventing EIF4E from binding to TP53 m7G cap, thus inhibiting TP53 translation. We previously demonstrated that Pep8, an 8 amino acid peptide derived from RBM38, disrupts the RBM38-EIF4E complex enhancing TP53 expression. Moreover, Pep8 alone or in combination with doxorubicin, significantly decreased tumor xenograft growth. As activation of wild-type TP53 by targeting non-genetic mechanisms that inhibit TP53 expression is a promising therapeutic tactic for malignancies that carry wild-type TP53, we are developing more efficacious Pep8 derivatives as a novel therapeutic approach for cancers that express wild-type TP53.

Citation Format: Chris August Lucchesi, Jin Zhang, Xinbin Chen. Targeting the RBM38-EIF4E complex to increase wild-type p53 as a novel cancer therapeutic strategy [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 1037.
Abstract 1074: Cellular uptake and metabolism of MT1-MMP-activated taxane prodrugs
Authors: Polykandritou Athina , Serre Alexandra , Spencer Hannah , Morais Goreti R. , Race Amanda , Shnyder Steven , Loadman Paul , Falconer Robert A.
Published: June 2022

ICT3205 is a targeted cytotoxic agent, comprised of an MT1-MMP-specific peptide and a paclitaxel warhead. Paclitaxel, originally approved in 1992, is one of the most commonly used chemotherapies for various cancer types, but is often characterized by its dose-limiting toxicity and low aqueous solubility. Tumor-targeted prodrugs are a promising strategy for the selective delivery of taxanes to prostate tumors, especially given the results of STAMPEDE trial1. Previous work has shown that ICT3205 is selectively metabolized in tumor tissue over the normal tissue, and that this is specifically mediated by MT1-MMP2. In vivo studies have demonstrated that when administered at an equimolar dose to paclitaxel, ICT3205 has a superior anticancer effect, with an absence of systemic toxicity. In this study we aim to further investigate the cellular uptake and metabolism of ICT3205 and other taxane analogues in MT1-MMP +ve (HT1080) and MT1-MMP -ve (MCF-7) cells in vitro. The compound will be also studied in the PC3 prostate cancer cell line, since it has been demonstrated before that there is a good correlation between MT1-MMP protein and mRNA expression. ICT3205 and analogues have been synthesized, and purified by semi-preparative HPLC. We report the tumor-specific metabolism of ICT3205 in prostate tumors ex vivo, and we are currently studying its cellular uptake and metabolism in MT1-MMP +ve and MT1-MMP -ve cancer cell-lines using HPLC, mass spectrometry and immunofluorescent microscopy. Moreover, ex vivo metabolism studies are performed on the analogues, while they will be also assessed for their metabolism and cellular uptake. These data will provide a better understanding of the mechanism of uptake and metabolism of this type of peptide prodrugs, and will provide the basis for the future synthesis and optimization of these prodrugs.

1.James ND et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomized controlled trial. Lancet. 2016;387(10024):1163-772.Loadman PM et al. Improved delivery of paclitaxel to prostate tumors: a membrane-type matrix metalloproteinase (MT-MMP)-targeted approach. Cancer Res. 2016;76:3

Citation Format: Athina Polykandritou, Alexandra Serre, Hannah Spencer, Goreti R. Morais, Amanda Race, Steven Shnyder, Paul Loadman, Robert A. Falconer. Cellular uptake and metabolism of MT1-MMP-activated taxane prodrugs [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 1074.
Abstract 1104: Loss of SUV420H2 drives EGFR inhibitor resistance in EGFR mutant NSCLC cell lines
Authors: Agredo Alejandra , Pal Arpita , Lanman Nadia , Son Jihye , Kasinski Andrea L.
Published: June 2022

Although important advancements have been achieved in the treatment of cancer, lung cancer is still the leading cause of cancer-related deaths in both men and women, with an estimated 1.6 million deaths each year. Non-small cell lung cancer (NSCLC), which makes up ~85% of lung cancer cases, is mainly treated with radiotherapy, chemotherapies, and targeted agents. Epidermal growth factor receptor (EGFR) is commonly mutated in NSCLC patients and leads to increased proliferation and cell survival. The standard-of-care treatment for patients harboring activating mutations in EGFR is treatment with tyrosine kinase inhibitors (TKI), such as erlotinib. While tumors initially respond to TKIs, after 1-2 years most of the patients develop resistance. In ~60% of patients, TKI resistance is the results of a secondary mutation in EGFR, leading to sustained receptor activation. Whereas, in the remaining 20%, tumors turn on bypass tracks-signals to overcome inhibition of the EGFR pathway. However, in 15-20% of the cases the mechanisms underlying resistance are unknown. Hence, there is a need to identify additional mechanisms involved in TKIs resistance.

Our laboratory performed a genome-wide CRISPR Cas9 knock-out screen to identify genes that when knocked-out would drive erlotinib resistance. Fold enrichment analysis of sgRNAs, identified the protein coding gene SUV420H2 as a top candidate. SUV420H2 is a histone methyltransferase that trimethylates H4K20 (H4K20me3), enabling the establishment of constitutive and facultative heterochromatin. The process by which SUV420H2 is reduced in tumors is unknown, yet data from human samples suggests that SUV420H2 is globally downregulated in NSCLC. Additionally, loss of H4K20me3, the modification made by SUV420H2, in preneoplasia influences prognosis of NSCLC, indicating that loss of SUV420H2 function is a crucial mechanism in carcinogenesis.

SUV420H2 expression has historically been associated with generating constitutive heterochromatin. However, more recently SUV420H2 was found to silence euchromatin regions. Our recent data suggests that SUV420H2 leads to reduced transcription of the oncogene MET by silencing the oncogenic long non-coding RNA LINC01510 upstream of MET. These findings led us to hypothesize that loss of SUV420H2 leads to erlotinib resistance through to upregulation of oncogenes including MET. Moreover, we aim to identify genes that are dynamically regulated by SUV420H2 using chromatin immunoprecipitation in NSCLC cell lines to further understand SUV420H2-mediated gene regulation and its role in TKIs resistance.

Citation Format: Alejandra Agredo, Arpita Pal, Nadia Lanman, Jihye Son, Andrea L. Kasinski. Loss of SUV420H2 drives EGFR inhibitor resistance in EGFR mutant NSCLC cell lines [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 1104.
Abstract 1108: Evaluation of heme inhibitory therapy in combination with chemotherapy drugs on SCLC progression
Authors: Ashrafi Adnin , Salamat Narges , Zhang Li
Published: June 2022

Lung cancer is the leading cause of cancer-related death in the US. It is mainly divided in two types: small cell lung cancer and non-small cell lung cancer. About 85-90% of cases are classified as non-small cell lung cancer (NSCLC). Small cell lung cancer (SCLC) is an aggressive neuroendocrine lung tumor representing 15% of lung cancers. Despite the advent of targeted therapies and chemotherapies, effective therapies for lung cancer are an unlikely outcome for most patients. SCLC is initially highly responsive to cisplatin and etoposide chemotherapy but, in almost every case, becomes rapidly chemo resistant. However, the mechanisms underlying initial sensitivity and subsequent resistance are not well investigated. Thus, alternative approaches and combination therapy is required for treating SCLCs. Recent studies in our lab show that NSCLC cells demonstrate elevated levels of heme via increased heme uptake and synthesis, and elevated oxidative phosphorylation (OXPHOS) and ATP generation which fuels NSCLC proliferation. Also, limiting heme via inhibition of heme uptake using heme sequestering peptides (HeSP2) can delay growth and progression of NSCLC tumors. This HeSP2 can also effectively inhibit angiogenesis, normalize tumor vasculature, and alleviate tumor hypoxia in NSCLC tumors and thereby inhibit lung tumor growth and progression. Tumor heterogeneity is critical for tumor growth, metastasis, and acquired therapeutic resistance. To understand if heme can effectively reduce tumor cell proliferation and growth and improve tumor microenvironment, we treated chemo resistant SCLCs with HeSP2 and in combination with commonly used chemo drugs cisplatin and etoposide. Our data shows that HesP2 can strongly inhibit cell proliferation and decreases oxygen consumption rate along with ATP generation in SCLCs. To gain insights into mechanism by which the heme sequestering peptides limit tumor growth and progression, we implanted subcutaneous or SCLC cell lines in NOD/SCID mice. Mice were treated with saline (control), HeSP2, HeSP2 and cisplatin, HeSP2 and etoposide. Tumor growth was monitored using caliper measurements. Tumors tissues were harvested, processed and paraffin embedded for immunohistochemistry (IHC) and histology experiments. These results indicate that heme sequestration can be a powerful strategy for suppressing lung tumors likely drug-resistant tumors that rely on oxidative phosphorylation for survival.

Citation Format: Adnin Ashrafi, Narges Salamat, Li Zhang. Evaluation of heme inhibitory therapy in combination with chemotherapy drugs on SCLC progression [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 1108.
Abstract 1147: A novel anti-Galectin-3 antibody therapeutic for the treatment of triple negative breast cancer
Authors: Zhang Li , Wu Heng , Palopo Karyssa , Hu Jie , Cadiente Marvin , Nguyen Anh , Mirabella Teodelinda , Sun Dongxu
Published: June 2022

About 43,600 women in the U.S. are expected to die in 2021 from breast cancer. Triple negative breast cancer (TNBC), which accounts for approximately 15% of all breast cancers, is diagnosed by exclusion of expression and/or amplification of three biomarkers (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]).Characterized by a high risk of relapse (one half of patients with early stages experience recurrence), short overall survival and progression-free survival (life expectancy of few months after failure of first-line chemotherapy), TNBC represents a high unmet medical need. Galectin-3 plays multiple roles in tumor initiation and development via a variety of cellular processes, spanning from angiogenesis to tumor migration. Galectin-3 (Gal3) expression is induced in TNBC patients and highly correlates with poor survival, as shown by our and others’ bioinformatics analysis from public database. We recently discovered and patented a series of antibodies with high specificity and affinity for Gal3, one of which is currently tested in human volunteers. This clinical candidate has shown superior pharmacokinetic properties and clean toxicity profile in GLP studies on non-human primates. Here, we show that anti-Gal3 inhibit both anchorage dependent and independent growth of TNBC cells, as well as Gal3-induced escape from NK cell killing. Also, anti-Gal3 proved to be efficacious in in vivo studies, where TNBC cells were implanted in mammary fat pads of mice and tumor progression, measured as growth of primary mass and presence of metastatic nodules in the lungs, was followed during the two months of treatment. The results presented herein support the conclusion that our therapeutic modality could offer an alternative promising treatment of TNBC.

Citation Format: Li Zhang, Heng Wu, Karyssa Palopo, Jie Hu, Marvin Cadiente, Anh Nguyen, Teodelinda Mirabella, Dongxu Sun. A novel anti-Galectin-3 antibody therapeutic for the treatment of triple negative breast 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 1147.
Abstract 1185: Survey of genomic alterations in Merkel cell carcinoma (MCC) in the AACR Project Genie real-world database
Authors: Brazel Danielle , Kumar Priyanka , Doan Hung , Moyers Justin T.
Published: June 2022

Introduction: MCC is a rare and highly aggressive cutaneous neuroendocrine carcinoma with increasing incidence over the last few decades. Cytotoxic chemotherapy and checkpoint inhibitors have provided modest treatment options, however, there are no approved or standard of care targeted treatment options. Here we surveyed the presence of targetable alterations in the AACR Project Genie Database

Methods: Individual patient data were accessed from the cBioPortal. Variables of interest include demographic data, alterations annotated by OncoKB therapeutic evidence level, and TCGA PanCancer pathway alterations.

Results: A total of 295 patients with MCC were cataloged in the database. Patients included were 34.6% (n=102) female with a median age of 71. Patients identified race as 91.2% (n=269) white, 2.4% (n=7) African American, and 0.4% (n=2) Asian.

The median number of alterations was 3.00 (SD 21.4, Range 0-178). Oncogenic alterations represented 17.4% (n=660 of 3799) of mutations. Sampled tissue originated from primary tumor in 54% (n=161) verses metastases in 42.4% (n=125).

NGS identified 18.5% (n=55) with an FDA approved drug for use in a biomarker approved indication or approved drug in another indication (Level 1-3). An additional 13.9% (n=41) had a Level 4 (L4) mutation. The most common Level 3B gene mutations include PIK3CA (4.1%, n=12), and BRCA1/2 (4.1%, n=12), HRAS (1.7%, n=5), TSC1/2 (1.7%, n=5). The most common L4 mutations include PTEN (4.4%, n=13), ARID1A (3.7%, n=11), and CDKN2A (2.4%, n=7).

Only three fusions were identified; L3B fusions ATM-CDK12 and TSC2 along with Level 4 PTEN.

Copy number alterations were identified in a small subset of patients. L3B CNAs include ATM, CHEK1 (n=1), BARD1 (n=1), BRCA2 (n=1), RAD51B (n=1), RAD51D (n=1). Level 4 CNAs identified CDKN2A (n=4) and PTEN (n=1).

In 60.7% cases, PanCancer pathways were altered and 28.5% had alterations in multiple pathways. The most commonly altered pathways were RTK-RAS (37.6%, n=111), TP53 (33.9%, n=100), Cell Cycle (33.9, n=100), PI3K (32.2%, n=95) and NOTCH (30.8%, n=91). Additionally, oncogenic DNA damage repair gene alterations (BRCA1/2, CHEK1/2, ATM, PALB2, BRIP1, RAD51) were present in 7.5% (n=22) of cases.

Conclusions: Here we identified a subset of patients with targetable mutations in MCC. The majority of patients had oncogenic alterations in cancer pathways which may support the investigation of kinase inhibitors as single agent or in combination with immunotherapy or cytotoxic chemotherapy in Merkel Cell Carcinoma.

Citation Format: Danielle Brazel, Priyanka Kumar, Hung Doan, Justin T. Moyers. Survey of genomic alterations in Merkel cell carcinoma (MCC) in the AACR Project Genie real-world database [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 1185.
Abstract 1215: pVACsplice: Predicting neoantigens from tumor-specific alternative splicing events derived from cis-acting regulatory mutations using whole exome and RNA sequencing data
Authors: Richters Megan M. , Cotto Kelsy C. , Kiwala Susanna , Xia Huiming , Carreno Beatriz M. , Dunn Gavin P. , Ribas Antoni , Griffith Obi L. , Griffith Malachi
Published: June 2022

Neoantigens are tumor-specific peptides on the cell surface that can be recognized by the adaptive immune system. Personalized immunotherapies, such as cancer vaccines, rely on neoantigen prediction to identify sequences that can activate T cells to recognize and destroy the tumor. The majority of cancer vaccine trials have utilized neoantigens derived from missense mutations and small insertions and deletions. However, other mutation types could contribute to the overall neoantigen landscape, such as aberrantly spliced transcripts arising from cis-acting regulatory mutations. In this study, we explore the potential immunogenicity of alternative splicing events by creating pVACsplice, a tool to expand the capability of pVACtools, a suite of tools for neoantigen prediction (http://www.pvactools.org). pVACsplice assembles alternative transcripts from tumor-specific splicing patterns, identifies sequence changes by comparison to a reference, and predicts neoantigens from the novel regions. To verify the accuracy of alternative transcript assembly, we ran pVACsplice with HCC1395 cell line samples and performed long-read sequencing to detect the transcripts in vitro. Matched whole exome sequencing and RNA sequencing datasets from glioblastoma, melanoma, and colorectal cancer cohorts will also be analyzed with pVACsplice to obtain binding affinity estimates. We will compare these results to neoantigen predictions from other mutation sources and across cancer types to discover the prevalence of immunogenic splicing events. Finally, we will perform immunogenicity testing with a set of high quality candidates to validate our predictions. We hope to increase the number of candidates for patients’ vaccines by adding this functionality to our standard neoantigen prediction workflow. This tool could help generate a more accurate portrait of the neoantigen landscape in tumors, and in turn, enhance responses to personalized immunotherapies.

Citation Format: Megan M. Richters, Kelsy C. Cotto, Susanna Kiwala, Huiming Xia, Beatriz M. Carreno, Gavin P. Dunn, Antoni Ribas, Obi L. Griffith, Malachi Griffith. pVACsplice: Predicting neoantigens from tumor-specific alternative splicing events derived from cis-acting regulatory mutations using whole exome and RNA sequencing data [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 1215.