bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel Compound Q-1 Alleviates Type II Collagen-Induced Arthritis in Rats through the NF-κB Pathway
Authors: Xu Ting , Guo Jia-Chen , Wu Sha-Sha , Wang Yan , Liu Xiao-Long , Qian Hai-Bing
Published: July 2021

Background. Q-1 is a novel compound extracted from the Miao medicine Tiekuaizi. Although Q-1 is known to be a coumarin derivative, its structure has not been deposited in the ACX library. Our previous study showed that Q-1 inhibits the activity of inflammatory cells. This study explores the efficacy of Q-1 in regulating rheumatoid arthritis (RA). The findings show that Q-1 acts through the NF-κB signaling pathway. Methods. The effects of Q-1 were explored using a bovine type II collagen-induced arthritis (CIA) rat model. The CIA rats were intragastrically administered with high (30 mg·kg−1) or low (15 mg·kg−1) doses of Q-1. The control group was administered with an equal volume of drinking water, while the positive control group was administered with Tripterygium glycoside (9.45 mg·kg−1) for 28 consecutive days. The arthritis indices and ankle joint swelling rates were determined. The levels of IL-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1) in serum and sialic acid (SA) in liver homogenate were determined by enzyme-linked immunosorbent assay (ELISA). The pathological features of the ankle joint were analyzed by hematoxylin and eosin (HE) staining. The IκB, P-IκB, P65, and P-P65 protein levels in synovial tissue were assayed by western blotting. Results. The arthritis index, ankle joint swelling rate, IL-1β, IL-6, and MCP-1 levels in serum, SA level in liver tissue, and IκB, P-IκB, P65, and P-P65 protein levels in synovial tissues were significantly higher (

P
<
0.01

) in the CIA model compared to the control group. RA was successfully replicated by the CIA model, as shown by the joint swelling results and histopathological sections of the ankle. Notably, all the above indicators decreased significantly (

P
<
0.01

) after treatment with Q-1 compared to the model. In addition, animals treated with Q-1 showed lower inflammation in the ankle joints than the model rats. Conclusion. The findings indicate that Q-1 effectively inhibited RA in rats by downregulating IκB, P-IκB, P65, and P-P65, inhibiting the excessive release of inflammatory factors, and inhibiting the overactivation of the NF-κB signaling pathway.
Analysis of Plant Growth and Yield in Varieties of Tomato (Solanum lycopersicum L.) Grafted onto Different Eggplant Rootstocks
Authors: Latifah Evy , Krismawati Amik , Saeri Mohammad , Arifin Zainal , Warsiati Bas , Setyorini Dwi , Prahardini Paulina Evy Retnaning , Subagio Herman , Sihombing Donald , Antarlina Sri Satya , Widaryanto Eko , Ariffin  , Maghfoer Moch Dawam
Published: July 2021

This study aimed to examine plant growth of tomato grafted onto different eggplant rootstocks. We applied a randomized block design comprising twelve treatments with three replicates. Three varieties of tomato—Cervo, Karina, and Timoty—and three rootstocks—Gelatik, EG203 line, and Solanum torvum—were selected for this study. Nongrafted tomato plants of the same varieties were used as controls. The variables recorded were the number of branches, the diameter of scions and rootstocks, root length, and root dry weight at 4, 6, 8, and 10 weeks after planting (WAT) and relative growth rate, specific leaf area, and net assimilation rate at 4, 8, and 12 WAT. Grafted tomato plants demonstrated better growth than controls. There was a significant relationship between yield, plant growth parameters, and photosynthetic organs, expressed by higher production, greater scion diameter, longer roots, and increased relative growth rate, leaf area ratio, and net assimilation rate of grafted plants, compared to the controls.
Evaluation of Risk of Building Damage due to Deep Excavations via Numerical Modelling
Authors: Zhang Xingxing , Zhan Zhifeng
Published: July 2021

In the densely populated urban environment, ground movements induced by deep excavations inevitably present a risk of damage to adjacent buildings and structures. An important and necessary aspect to justify the engineering design is to evaluate the degree of risk of such damage. This paper presents a specific procedure to evaluate the engineering design by assessing the risk level of building damage based on the deformation profiles along the ground surface which are calculated via numerical modelling and verified by empirical methods. This procedure is afterwards applied to justify the engineering design of the extension line construction of a metro project between PK0 + 344.00 and PK0 + 407.00 with the cut‐and‐cover excavation method. The results demonstrate that the damage risk levels of all the buildings adjacent to the excavations are within category level 0 indicating that the relevant design is acceptable while considering the risk of building damage induced by deep excavations.
Design of a Real-Time Monitoring System for Smoke and Dust in Thermal Power Plants Based on Improved Genetic Algorithm
Authors: Wang Bo , Yao Xuliang , Jiang Yongqing , Sun Chao , Shabaz Mohammad
Published: July 2021

The major health hazards from smoke and dust are due to microscopic fine particles present in smoke as well as in dust. These fine particles, which are microscopic in nature, can penetrate into human lungs and give rise to a range of health problems such as irritation in eyes, a runny nose, throat infection, and chronic cardiac and lung diseases. There is a need to device such mechanisms that can monitor smoke in thermal power plants for timely control of smoke that can pollute air and affects adversely the people living nearby the plants. In order to solve the problems of low accuracy of monitoring results and long monitoring time in conventional methods, a real-time smoke and dust monitoring system in thermal power plants is proposed, which makes use of modified genetic algorithm (GA). The collection and calibration of various monitoring parameters are accomplished through sampling control. The smoke and dust emission real-time monitoring subsystems are employed for the monitoring in an accurate manner. A dual-channel TCP/IP protocol is used between remote and local controlling modules for secure and speedy communication of the system. The generic GA is improved on the basis of the problem statement, and the linear programming model is used to avoid the defect of code duplication with genetic operations. The experimental results show that the proposed smoke and dust monitoring system can effectively improve the accuracy of the monitoring results and also reduce the time complexity by providing solutions in a faster manner. The significance of the proposed technique is to provide a reliable basis for the smoke and dust emission control of thermal power plants for safeguarding the human health.
Research and Application of Hydraulic Punching Pressure Relief Antireflection Mechanism in Deep “Three‐Soft” Outburst Coal Seam
Authors: Gu Beifang , Wu Yanling
Published: July 2021

To solve the problems of gas predrainage in deep seams with “three softs” and low‐air permeability, hydraulic punching pressure relief antireflection technology is proposed on the basis of the research background of gas predrainage technology in Lugou Mine to alleviate technical problems, such as low gas drainage efficiency, in this mine. Through the analysis of the mechanism of hydraulic punching and coal breaking, combined with FLAC3D software, a hydraulic punching pressure relief antireflection model is established. Then, the fracture radii of coal rock are simulated and calculated. The results show that, under hydraulic punching with a water pressure of 10 MPa and coal outputs of 3 m3, 6 m3, 9 m3, and 12 m3, the fracture radii of coal and rock are 3.4 m, 4.8 m, 5.5 m, and 5.9 m, respectively. Using the software to fit the relationship between coal output V and hydraulic punching fracture radius R under the same water pressure, R = 2.32479 V0.3839 is obtained. The field test is carried out in the bottom drainage roadway of 32141 in Lugou Mine. The application effect is as follows: the gas concentration of hydraulic punching with a coal output of 3 m3 is twice that of ordinary drilling, and the coal output of hydraulic punching with a coal output of 6 m3 is four times that of ordinary drilling. The extraction concentration is four times that of ordinary drilling, and the extraction concentration of hydraulic punching with a coal output of 9 m3 is 6.4 times that of ordinary drilling. Combining the results of the numerical simulation and taking into account the actual construction situation on site, the coal output of water jetting from the borehole is 9 m3, and the fracture radius is 5.5 m. This outcome means that the effective half radius is 5.5 m, and the borehole spacing is 7.7 m. These values are the construction parameters for large‐scale applications. This proposal provides effective technology and equipment for gas drainage in the deep three‐soft coal seam. Consequently, it has promotion and reference significance for gas drainage in coal seam of the same geological type.
Cost-Effectiveness Analysis of a Mobile-Based Intervention for Patients with Type 2 Diabetes Mellitus
Authors: Li Jing , Sun Li , Hou Yabing , Chen Liming
Published: July 2021

Objective. The aim of this study was to evaluate the cost effectiveness of a mobile-based intervention for patients with type 2 diabetes mellitus (T2DM) and compare it with the usual management mode. Method. A total of 215 patients with T2DM in a tertiary-care hospital specific to diabetes were selected as the study population. This study was conducted from January 1, 2019 to January 1, 2020. Of the 215 patients, 130 were randomly assigned to the mHealth group and 85 were assigned to the usual care group. IBM SPSS 25.0 software was used for descriptive statistics, t tests, chi-square tests, and correlation analyses. Haemoglobin A1c (HbA1c) was the effectiveness parameter adopted. Cost-effectiveness analyses were performed, and incremental cost-effectiveness ratios (ICERs) were calculated. Results. Of the 215 patients with T2DM, the proportion of male patients was 66.0%. The mean age of the patients was 47.2 (SD 9.95). Differences in baseline information were not statistically significant between the two groups (

P
>
0.05

). At the 3-, 6-, and 12-month follow-ups, the mHealth group reported higher control rates of HbA1c than the usual care group, 67.9% versus 46.2% (

P
<
0.001

), 72.4% versus 45.4% (

P
<
0.001

), and 74.6% versus 47.1% (

P
<
0.001

), respectively. The value of HbA1c was positively related to total patient cost, material fee, Western medicine fee, and hospitalization expenses (

P
<
0.05

), with correlation coefficients of 0.202, 0.200, 0.172, and 0.183, respectively. The costs of the mHealth group and usual care group were CNY¥ 1169.76 and CNY¥ 1775.44 per patient/year, respectively. The incremental cost of the mHealth intervention was CNY¥ −605.68 per patient/year. The ICER was CNY¥ −22.02 per patient/year. Conclusion. Compared with the usual care mode, the mHealth management model for patients with T2DM improved the control rate of HbA1c, and the mHealth management mode had better cost effectiveness.
Correlation of Clinical, Endoscopic, and Pathological Findings among Suspected Peptic Ulcer Disease Patients in Abuja, Nigeria
Authors: Okoye Onyedika Godfrey , Olaomi Oluwole Olayemi , Nwofor Alexander M.E. , Jibrin Paul , Batta Cephas Shallangwa , Yaú Abubakar Gagarawa , Badejo Olawale A.
Published: July 2021

Background. Peptic ulcer disease (PUD) remains one of the most prevalent gastrointestinal diseases and has been linked to Helicobacter pylori (H. pylori) infection. This condition may be suspected on clinical grounds, but diagnosis is established using upper gastrointestinal endoscopy. Aims. To determine the correlation between the endoscopic and pathological findings among suspected PUD patients who have been referred for diagnostic upper gastrointestinal endoscopy in National Hospital Abuja. Methods. This is a hospital-based prospective study conducted among suspected PUD patients at National Hospital Abuja over a one-year period. Clinical, endoscopic, and histological findings were ascertained and documented. Data obtained were analyzed using SPSS version 21.0. Tests of significance were done using the chi-square test and Student

t

-test at 95% confidence intervals. Results. One hundred and thirty-two patients were included in the study. The ages ranged from 15 to 87 years, mean age

43.30
±
11.94

years. Seventy-seven (58.3%) patients had abnormal endoscopic findings, of whom 37 (28.0%) had PUD. Prevalence of H. pylori infection was 42.2% and was found in 81.1% of PUD patients. H. pylori was significantly associated with confirmed PUD (

p
<
0.001

) and abnormal endoscopic findings (

p
<
0.001

). No association was found between normal endoscopic findings and histological findings (

p
=
0.924

). Conclusion. There is a poor correlation between clinical and endoscopic diagnoses of PUD. H. pylori was found to be significantly associated with PUD and abnormal endoscopic findings. Endoscopic facilities should therefore be made available and accessible for proper PUD diagnosis. Empirical treatment of H. pylori in patients with diagnosed PUD is strongly recommended.
Evaluation and Management of Intangible Assets of High-Tech Enterprises from the Perspective of Monte Carlo and Network Security
Authors: Wan Xinya , Li Yonghai
Published: July 2021

High-tech enterprises are knowledge- and technology-intensive economic entities. These entities are considered intangible assets and an essential part of the enterprises. The fast and effective development of high-tech enterprises requires scientific evaluation of intangible assets. Therefore, the evaluation of intangible assets of high-tech enterprises has become more significant in the evaluation industry. This article uses the Monte Carlo method to evaluate the intangible assets of high-tech enterprises from the perspective of network security. This paper combines the weighted average cost of capital (WACC) with the capital asset pricing model (CAPM) to determine the rate of return. It uses the analytic hierarchy process (AHP) method to determine the weight. It determines the value of various intangible assets based on the contribution of various intangible assets to the overall intangible asset value. Moreover, the Monte Carlo model is used in the probability determination process to evaluate intangible assets. In practical applications of a high-tech enterprise, the advancement and practicability of this method are verified by comparing it with the income method.
A Blind Signature‐Aided Privacy‐Preserving Power Request Scheme for Smart Grid
Authors: Zhang Weijian , Guo Zhimin , Li Nuannuan , Li Mingyan , Fan Qing , Luo Min
Published: July 2021

Smart grid is an emerging power system capable of providing appropriate electricity generation and distribution adjustments in the two‐way communication mode. However, privacy preservation is a critical issue in the power request system since malicious adversaries could obtain users’ daily schedule through power transmission channel. Blind signature is an effective method of hiding users’ private information. In this paper, we propose an untraceable blind signature scheme under the reputable modification digital signature algorithm (MDSA). Moreover, we put forward an improved credential‐based power request system architecture integrated with the proposed blind signature. In addition, we prove our blind signature’s blindness and unforgeability under the assumption of Elliptic Curve Discrete Logarithm Problem (ECDLP). Meanwhile, we analyze privacy preservation, unforgeability, untraceability, and verifiability of the proposed scheme. Computational cost analysis demonstrates that our scheme has better efficiency compared with other two blind signatures.
[Retracted] An Intelligent Code Search Approach Using Hybrid Encoders
Authors: Meng Yao
Published: July 2021

The intelligent code search with natural language queries has become an important researching area in software engineering. In this paper, we propose a novel deep learning framework At‐CodeSM for source code search. The powerful code encoder in At‐CodeSM, which is implemented with an abstract syntax tree parsing algorithm (Tree‐LSTM) and token‐level encoders, maintains both the lexical and structural features of source code in the process of code vectorizing. Both the representative and discriminative models are implemented with deep neural networks. Our experiments on the CodeSearchNet dataset show that At‐CodeSM yields better performance in the task of intelligent code searching than previous approaches.
3D Virtual Animation Instant Network Communication System Design
Authors: Liu Jing , Chen Qixing , Tian Xiaoying
Published: July 2021

This project uses Openfire to implement a virtual 3D animation instant messaging system, which is easier to use and more expandable. The main work of the client is to implement the Extensible Messaging and Presence Protocol (XMPP) and use XMPP to transmit data to the server side and receive data from the server side, while Openfire is built by the server side to use. To address the problem that the current mainstream face key point localization model is less robust to complex environments, this project adopts a deep learning‐based approach to design and implement the face key point localization model, through data preprocessing, model design, and model training, to achieve a robust model that can locate 68 face key points and complete the migration of the model to mobile. The current video communication often suffers from delay and lag, so this project uses face key point data instead of video stream data transmission to reduce the pressure on the network. This topic also uses voice coding and decoding, noise reduction, echo cancellation, and other processing to solve the problems of noise interference and echo interference in voice transmission. This paper also introduces the creation, import, and loading of 3D virtual models, and explains how to use face key point association to drive 3D animation models, how to make the drive smoother and more natural, and using individual face key points as an example.
Transición social en niñas, niños, niñes y adolescentes con incongruencia de género: revisión y sugerencias de intervención a profesionales
Authors: Retamal Parra María Dorca , Hermosilla Rubio Wladimir , Medel Arriagada Miguel , Retamal Vargas Catalina
Published: July 2021

Introducción: la transición social en niñas (os, es) y adolescentes con incongruencia de género, es una intervención no médica, completamente reversible, que genera beneficios en la salud mental, pero que ha sido poco estudiada. El objetivo es realizar una revisión bibliográfica al respecto y desde ahí derivar recomendaciones a las(os) profesionales que intervienen en el apoyo a estas (os, es) niñas (os, es), adolescentes y sus familias. Métodos: ll presente trabajo corresponde a una revisión entre los años 2010 – 2021 en revistas científicas en habla inglesa e hispana indexadas en PUBMED, SciELO y en Google Académico. Resultados: se describe la trayectoria en el desarrollo de la incongruencia de género. En las (os, es) prepúberes el interés está centrado en la persistencia y desistencia de la incongruencia de género y las distintas trayectorias. La transición social y la persistencia se pueden manifestar diferencialmente para niñas y niños trans. Realizar transición social en niñas (os, es) que lo solicitan favorece la salud mental. La familia y la comunidad viven sus propias transiciones. En Chile se han ido dando las condiciones en salud, educación y a nivel legislativo para apoyar la afirmación de género de las niñas (os, es) y adolescentes, pero falta educación respecto a la transición social en infancia y adolescencia.
Conclusiones: dado los beneficios que genera la transición social en niñas (os, es) y adolescentes transgénero, se requiere que las(os) profesionales se eduquen e intervengan adecuadamente.
Suplementos ergogénicos: la evidencia más allá de una moda
Authors: Martorell Miquel , Ramírez-Alarcón Karina , Labraña Ana María , Lanuza Fabián , Martínez-Sanguinetti María Adela , Leiva-Ordóñez Ana María , Troncoso-Pantoja Claudia , Villagrán Marcelo , Mardones Lorena , Celis-Morales Carlos , Petermann-Rocha Fanny
Published: July 2021

Los suplementos deportivos que se etiquetan como ergogénicos son muchos, pero pocos son los que realmente han demostrado su efectividad como tal. Actualmente, su uso se ha masificado, tanto por falta de regulación en uso y venta, así como por su utilización en la población general, y no sólo en deportistas de alto rendimiento. Frente a estas limitantes ¿cuál es la efectividad de estos productos más allá de la moda? En esta comunicación breve se abordan algunos de los suplementos y plantas más utilizados como ergogénicos; no obstante, es necesario tener precaución al momento de generalizar los resultados obtenidos por algunos ergogénicos, ya que su efecto podría ser secundario y/o estar condicionado por otros factores.
Estudio de la relación entre estrategias de aprendizaje y desempeño académico en estudiantes de medicina
Authors: López Mildred , Heredia Escorza Yolanda
Published: July 2021

Introducción: las estrategias de aprendizaje utilizadas por los estudiantes de medicina han evolucionado con el paso del tiempo, avanzando de modelos más tradicionales hacia la autodirección y autonomía del aprendizaje, propios de un aprendiz de por vida. El objetivo de este estudio fue evaluar la relación entre estas estrategias de aprendizaje y el desempeño académico de estudiantes de medicina. Materiales y métodos:  el enfoque y diseño de la investigación es cuantitativo y correlacional. La muestra consistió en 144 estudiantes de una universidad privada del norte de México. Como instrumento se utilizó el cuestionario para la evaluación de las estrategias de aprendizaje de los estudiantes universitarios, y una pregunta donde los estudiantes reportaban su desempeño académico con el promedio acumulado. El análisis de datos considera el uso de estadística descriptiva a fin de explorar el desempeño académico y estrategia, y correlacional para entender la vinculación entre escalas. Como factor de interés para el análisis se integraron también las variables de género, edad, y grado de escolaridad del padre y madre. Resultados: los estudiantes muestran una media y desviación estándar (DE) de 9,22±0,41 en el desempeño académico (escala del 1 al 10). Las estrategias de aprendizaje con medias más altas fueron motivación intrínseca con una media de 4,69±0,56 y valor de la tarea con una media de 4,67±0,54. Las tendencias menos favorables fueron en atribuciones externas con media de 2,55±0,78 y repetición simple con una media de 2,82±1,12. La correlación entre las variables de desempeño académico y las subescalas de estrategias es débil, varían entre -0,01 con la subescala de componentes afectivos y 0,16 con la subescala de estrategias de control del contexto, interacción social y manejo de recursos. Discusión: los resultados del desempeño académico reportados por los estudiantes son congruentes con los altos parámetros de selección del programa de medicina. La falta de relación entre esta variable y las estrategias de aprendizaje contradicen la creencia de que la selección y activación de estas estrategias determina el desempeño.  Es importante que al interior de los programas se estudien las estrategias utilizadas por los estudiantes, a fin de facilitar recursos para movilizarlos y potenciar su aprendizaje.
Abstract 1030: CENP-E inhibition generates micronucleus formation activating the cGAS-STING pathway in cancer cells
Authors: Hakozaki Yumi , Kashima Yukie , Morita Tomoko Y. , Tanaka Kosuke , Kobayashi Susumu S. , Ohashi Akihiro
Published: July 2021

Background: Micronuclear formation has been reported to activate innate immune response in tumor through the cGAS-STING pathway, which monitors cytosolic DNA primarily to detect bacteria or virus infection. We have developed a novel small molecule inhibitor targeting CENP-E, termed Cmpd-A, which intensively generate micronucleus formation in a broad range of cancer cells, causing a potent antiproliferation by aneuploid-mediated cellular stresses. In this study, using Cmpd-A as a tool compound, we aim to determine that micronucleus formation induced by CENP-E inhibitor could activate the cGAS-STING pathway in cancer cells, which may potentially induce an immunological conversion from cold to hot in cancer cells.

Method: We generated micronuclear formation in cancer cells by Cmpd-A treatment. Phosphorylations of TBK1 and IRF3, indexes of the cGAS-STING pathway activation, were determined by immunoblotting. Gene set enrichment analysis of RNA-seq data was performed, comparing DMSO (control) and Cmpd-A treatment. Reporter assays for IRF and NF-kB were also performed.

Results: Immunoblotting revealed that phosphorylations of TBK1 and IRF3 were remarkably upregulated in Cmpd-A-treated cells concordantly with micronuclear formation. Transcriptome analysis revealed that the down-stream genes in the cGAS-STING pathway (innate immune pathways) are elevated: IL6, IP10, CXCL1, IL8, TNF, IFNA families, and IFNB1. The Gene Set Enrichment Analysis (GSEA) also demonstrated that innate immune-associated pathways were significantly enriched in Cmpd-A-treated cells: cytosolic DNA sensing pathway, cytokine-cytokine receptor interaction pathway, and Toll-like receptor signaling pathway. Furthermore, the IRF-Lucia and NF-kB-SEAP reporter activity assays revealed that both IRF and NF-kB were significantly activated in Cmpd-A-treated cells in a time-dependent manner.

Conclusions: The CENP-E inhibitor generates micronucleus formation to activate the cGAS-STING pathway in cancer cells. These findings suggest the CENP-E inhibitor could potentially induce the immunological conversion from cold to hot in cancer cells.

Citation Format: Yumi Hakozaki, Yukie Kashima, Tomoko Y. Morita, Kosuke Tanaka, Susumu S. Kobayashi, Akihiro Ohashi. CENP-E inhibition generates micronucleus formation activating the cGAS-STING pathway in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1030.
Abstract 106: Assessing the impact of staggered light exposure on breast cancer risk and metabolism
Authors: Palluth Lauren , Harlow Brittany , McCellan Bryan , Jolly Christopher , Bray Molly , deGraffenried Linda
Published: July 2021

Background: Numerous epidemiological studies, including the Nurses' Health Study II, found that shift workers have a higher risk for breast cancer. These studies hypothesize that suppressed melatonin and disrupted clock gene expression likely lead to an immune compromised, proliferative phenotype. However, the majority of studies to date rely on correlative evidence. With the onset of the COVID-19 pandemic, shift work has become increasingly prevalent, making the need to understand the mechanisms promoting disease, including breast cancer, even more important.

Objective: The objective of this study is to analyze the impact of staggered light exposure on the immune function and breast tissue gene expression in order to identify how breast cancer risk is mediated.

Methods: An 18-week study with 10 C57BL/6 female mice was conducted whereby half of the mice were exposed to a staggered light/dark (LD) cycle, as would be experienced by shift workers, and half were exposed to a regular LD cycle. Body weight was monitored weekly and sera and mammary tissues were collected at termination. The sera from each group was pooled and cytokine levels assessed using an antibody-pair-based assay.

Results: Intriguingly, although the mice from the two study groups did not significantly differ in average body weight, the staggered LD exposure group had higher levels of inflammatory cytokines indicative of chronic, low-grade inflammation. Notably, the staggered LD group had 75% higher IL-6 levels, 157% higher IL-10 levels, and 49% higher TNF-alpha levels compared to the control group. To determine the impact of staggered light exposure on localized breast tissue gene expression, qPCR arrays of breast cancer risk and inflammatory genes will be done comparing expression levels between the control and staggered LD groups. IHC techniques will be used to determine Ki67 and macrophage subtype infiltration in the breast tissue of the two groups.

Conclusion: Our data show that staggered LD exposure induces chronic, low-grade inflammation independent from body mass, which can be indicative of increased breast cancer risk. These data help elucidate the metabolic and immune responses induced by staggered light exposure, helping to define the mechanisms promoting health risks imposed by shift work, with the ultimate goal to develop preventive measures to limit breast cancer development.

Citation Format: Lauren Palluth, Brittany Harlow, Bryan McCellan, Christopher Jolly, Molly Bray, Linda deGraffenried. Assessing the impact of staggered light exposure on breast cancer risk and metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 106.
Abstract 1076: Hormonal regulation of SEMA7A promotes therapeutic resistance in ER+ breast cancer
Authors: Crump Lyndsey S. , Wyatt Garhett L. , Rutherford Taylor R. , Richer Jennifer K. , Porter Weston W. , Lyons Traci R.
Published: July 2021

Background: The majority of all breast cancers (BC) are estrogen receptor positive (ER+). While ER-targeting endocrine therapies have improved patient survival, many tumors become drug resistant and recur within 20 years. Thus, novel targets are needed to treat recurrent ER+BC. Previous reports have described tumor-promotional effects of Semaphorin 7A (SEMA7A) in ER- disease; however, the role of SEMA7A in ER+ disease is not well-characterized.

Hypothesis: SEMA7A promotes cell survival and drug resistance in ER+ BC.

Methods: We measured expression of SEMA7A in drug resistant cells via immunoblotting. We then overexpressed SEMA7A and used ER-targeting drugs (fulvestrant and tamoxifen) to test how SEMA7A-expressing cells respond to endocrine therapy. In vitro, we utilized cell proliferation and survival assays. In vivo, we implanted ER+ BC cells, then treated the animals with fulvestrant to assess how SEMA7A affects primary tumor volume and metastasis. We also measured markers of “stemness” and multi-drug resistance via flow cytometry.

Results: We found that SEMA7A expression correlated with decreased relapse free survival in patients who received endocrine therapy for ER+BC (Kmplotter; p=0.042). We also observe that SEMA7A can be hormonally regulated in ER+BC, but expression did not consistently decrease with endocrine therapy. Instead, long term estrogen deprivation and ER-targeting treatments increased SEMA7A expression, likely through signaling via other hormone receptors such as the androgen receptor, which also increases with long term estrogen deprivation. Additionally, overexpression of SEMA7A promoted in vitro growth and survival of ER+ cells during estrogen-deprivation, tamoxifen, or fulvestrant treatments. In vivo, SEMA7A promoted fulvestrant resistance in the primary tumor and also induced lung metastases. Finally, we identified pro-survival signaling as a therapeutic vulnerability of ER+SEMA7A+ tumors.

Conclusion: These studies show that SEMA7A can promote drug resistance in ER+ BC. We suggest that targeting pro-survival signaling may prove efficacious for treating SEMA7A+ tumors, which are less likely be resistant to endocrine therapies.

Citation Format: Lyndsey S. Crump, Garhett L. Wyatt, Taylor R. Rutherford, Jennifer K. Richer, Weston W. Porter, Traci R. Lyons. Hormonal regulation of SEMA7A promotes therapeutic resistance in ER+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1076.
Abstract 114: Loss of BMPR1a in fibroblasts restricts breast cancer progression and alters the immune tumor microenvironment
Authors: Ihle Claire Louise , Provera Meredith D. , Karimpour Parvanee A. , Straign Desiree M. , Smith Erin , Owens Philip
Published: July 2021

The Bone Morphogenetic Protein (BMP) pathway is a member of the TGFβ signaling family and has complex roles in cancer. The dichotomous role of BMPs as both tumor promoters and suppressors appears to be largely context based in both the cancer cell and the surrounding microenvironment. Fibroblasts who are activated in the tumor microenvironment to become cancer associated fibroblasts (CAFs) also carry out diverse functions to support tumor progression, including matrix generation and remodeling as well as angiogenesis and immune cell regulation. We found that conditional deletion of the BMP signaling receptor BMPR1a in mammary fat pad derived fibroblasts (via FSP-Cre) restricts tumor progression in a C57BL/6 syngeneic mammary fat pad MMTV-PyMT breast cancer mouse model. Specific changes in the architecture of collagen were found in the tumors with loss of BMPR1a signaling in CAFs. We analyzed these mammary fat pad tumors using Vectra multiplexed immunohistochemistry (mIHC) to evaluate differential cell phenotypes, spatial distribution, and high-dimensional cell clustering dependent on BMP signaling in CAFs. Vectra mIHC panels were designed to perform tumor and stromal cell classification, immune cell profiling, immune cell function, cell signaling and vascular analysis. Based on Vectra mIHC, changes in myeloid cell populations and immune cell interactions in the tumors were observed with differential BMPR1a expression in CAFs. We profiled the secretome of mammary fat pad fibroblasts and found distinct chemokine and cytokine secretion was altered related on BMPR1a loss. These results indicate a unique necessity for BMP signaling in fibroblasts during tumor progression to influence the stroma, matrix, and immune components of the tumor microenvironment.

Citation Format: Claire Louise Ihle, Meredith D. Provera, Parvanee A. Karimpour, Desiree M. Straign, Erin Smith, Philip Owens. Loss of BMPR1a in fibroblasts restricts breast cancer progression and alters the immune tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 114.
Abstract 1150: CARG-2020 artificial oncolytic virus delivering three immune-modulators prevents tumor recurrence in a syngeneic model of ovarian cancer
Authors: Alvero Ayesha B. , Fox Alexandra , Madina Bhaskara , Nakaar Valerian , Yarovinsky Timur , Krady Marie , Almassian Bijan , Mor Gil
Published: July 2021

Background: Ovarian cancer is the most lethal of all gynecologic malignancies with a grim 5-year survival rate of ~47%. Mortality occurs in the setting of recurrent disease wherein the co-presentation of chemoresistance and carcinomatosis limits the value of standard of care. It is therefore imperative to develop approaches that can prevent recurrent ovarian cancer. Oncolytic viruses are genetically modified replication competent viruses that can selectively infect cancer cells to induce cell lysis and death. This approach has proven to be clinically safe making it a promising approach to complement standard of care. The objective of this study is to evaluate the efficacy of CARG-2020, a virus-like vesicles (VLV) delivering three immune-modulators including IL-12, IL-17 antagonist and shRNA-PD-L1 in preventing recurrent disease in a syngeneic mouse model of recurrent ovarian cancer.

Materials and Methods: In vitro: Triple knockout (TKO; p53LSL-R172H/Dicerflox/flox/Ptenflox/flox) mouse ovarian cancer cells were seeded in 96-well plates and treated with different doses of CARG-2020. Cell death was determined using the Incucyte imaging system. In vivo: TKO ovarian cancer cells stably expressing the mCherry fluorescent protein were injected i.p. in C57bl/6 mice (day 0) to mimic the establishment of recurrent disease. Treatment commenced on day 3 with the treatment group receiving three doses of 1x10^8 PFU of CARG-2020 given every other day (n=5). Control group received PBS (n=5). Both treatments were given i.p. Tumor growth was monitored by live imaging using mCherry fluorescence ROI area. Progression-free survival (PFS) was defined as the day ROI area reached 2,000.

Results: CARG-2020 (1x10^5 PFU) demonstrated cytolytic effect in vitro and induced 100% cell death within 24h. In vivo, CARG-2020 induced significant decrease in i.p. tumor growth (p = 0.0128) compared to PBS control. Treatment with CARG-2020 completely delayed the establishment of recurrent disease (PFS, p = 0.0003). Whereas PBS control group demonstrated median PFS of 20 days, mice in the CARG-2020 group remained disease-free until day 60.

Conclusion: CARG-2020 is able to prevent the establishment of recurrent disease in a syngeneic mouse model of recurrent ovarian cancer. Our results provide rationale for the further development of this platform as a therapeutic modality for ovarian cancer patients.

Citation Format: Ayesha B. Alvero, Alexandra Fox, Bhaskara Madina, Valerian Nakaar, Timur Yarovinsky, Marie Krady, Bijan Almassian, Gil Mor. CARG-2020 artificial oncolytic virus delivering three immune-modulators prevents tumor recurrence in a syngeneic model of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1150.
Abstract 1153: Targeting CA125 transcription for ovarian cancer treatment
Authors: Yue Er , Yang Guangchao , Yao Yuanfei , Wang Guangyu , Zhang Yanqiao , Wang Edward W.
Published: July 2021

CA125 coded by MUC16 gene is highly expressed in most ovarian cancer cells and serves as a tumor marker to monitor disease progression or response to treatment of ovarian cancer patients. However, targeting CA125 for ovarian cancer treatment has never been successful. We performed multiple steps of high-fidelity PCR and obtained a 4.2kb DNA fragment upstream of the human MUC16 gene, which included a region upstream from the transcription start site (TSS) and a region downstream from the TSS that contains both the 5' untranslated region and the first 136bp of the open reading frame. Reporter assays showed that this DNA fragment possesses strong transactivation activity in CA125-high cancer cells, but not in CA125-low cells, indicating that the DNA fragment we cloned contains the transactivation region that controls specific expression of MUC16 gene in ovarian cancer cells. We further refined the promoter and found a 1040bp fragment with similar transcriptional activity and specificity. We used this refined MUC16 promoter to replace the E1A promoter in the adenovirus type 5 genome DNA to control expression of E1A, an essential gene for adenovirus replication, and successfully generated a conditionally replication-competent adenovirus that can replicate in and lyse CA125-high-expressing cancer cells, including CAOV3, Kuramochi, MADH2774, OVCAR3, OVCAR4, and TOV112D cells, but not in CA125-low or -negative cancer cell lines, such as A2780, OVCAR5, PEO4, or SKOV3 cells. In vivo studies showed that intraperitoneal virus injection prolonged survival of NSG mice inoculated intraperitoneally with MADH2774 cells. Preliminary experiment showed that a mouse ovarian cancer cell line, ID8, infected with the virus might elicit a protective immune response to rechallenge of parental cancer cells. Our data indicate that targeting MUC16 transactivation for ovarian cancer treatment by conditionally replicative adenovirus development is feasible and practical.

Citation Format: Er Yue, Guangchao Yang, Yuanfei Yao, Guangyu Wang, Yanqiao Zhang, Edward W. Wang. Targeting CA125 transcription for ovarian cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1153.
Abstract 1155: Subcutaneous intratumoral administration of a novel oncolytic virus leads to eradication of peritoneal disseminated pancreatic cancer in nude mice
Authors: Zhang Zhifang , Yang Annie , Chaurasiya Shyambabu , Kim Sang-In , Park Anthony K. , Lu Jianming , Warner Susanne G. , Fong Yuman , Woo Yanghee
Published: July 2021

Introduction: We investigated a novel oncolytic virus, CF33-hNIS-antiPDL1, which has shown robust preclinical activity against numerous solid tumors, for its ability to track and kill distant peritoneal metastases after local virus administration in vivo.

Methods: In this study, we used CF33-hNIS-antiPDL1, a replication competent orthopoxviral chimera engineered to express the human sodium iodine symporter (hNIS) and anti-human programmed death ligand 1 (PD-L1) antibody. To create our mouse model, we inoculated the human pancreatic cell line - AsPC1-ffluc (5x106 cells/site) in both the subcutaneous space and the peritoneum in nude mice. After confirming presence of tumor, the mice were divided into two groups; and treated with either 1) three doses of intratumoral (IT) CF33-hNIS-antiPDL1 (3x105 plaque forming units; (n=8) or 2) PBS (n=4). Each mouse was assessed for the following: tumor burden (bioluminescence imaging); CF33-hNIS-antiPDL1 tracking and replication in tumors (124I based PET imaging); and survival (time to death).

Results: By week 2, the animals in the CF33-hNIS-antiPDL1 treated group compared to the PBS treated group had significantly decreased tumor burden both in the peritoneal tumors (2.5e9±2.498e9 %/ID/cc versus 1.6e10 ±1.3e10 %/ID/cc, respectively; p<0.05) and SC tumors (5.2e8 ±4.3e8 %/ID/cc versus 2.6e9 ±2.6e9 %/ID/cc; p<0.05). With a median survival of 35 days, all PBS treated mice died from disease between 21 to 47 days. In the CF33-hNIS-antiPDL1 treated group, the median survival was 49 days; and two out of eight mice were still alive at 220 days (p<0.05). These two surviving animals had no evidence of cancer; there was complete eradication of SC and peritoneal tumors. At one week after the first CF33-hNIS-antiPDL1 administration, significantly increased PET avidity for 124I uptake in the SC tumors (6.4±1.5 photons/second of regions of interest) and PC tumors (3.5±0.14 photons/second of regions of interest) were visible in the CF33-hNIS-antiPDL1 treated mice.

Conclusion: After local SC tumor injection, CF33-hNIS-antiPDL1 can efficiently kill local tumor and kill distant peritoneal metastases to improve survival. Successful therapy of SC and peritoneal tumors using CF33-hNIS-antiPDL1 can be visualized by 124I-based PET imaging.

Citation Format: Zhifang Zhang, Annie Yang, Shyambabu Chaurasiya, Sang-In Kim, Anthony K. Park, Jianming Lu, Susanne G. Warner, Yuman Fong, Yanghee Woo. Subcutaneous intratumoral administration of a novel oncolytic virus leads to eradication of peritoneal disseminated pancreatic cancer in nude mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1155.
Abstract 1160: SAM competitive PRMT5 inhibitor PF06939999 demonstrates antitumor activity in splicing dysregulated NSCLC with decreased liability of drug resistance
Authors: Jensen-Pergakes Kristen , Tatlock John , Maegley Karen , McAlpine Indrawan , McTigue Michele , Xie Tao , Dillon Christopher , Wang Yuli , Yamazaki Shinji , Spiegel Noah , Shi Manli , Nemeth Amy , Miller Natalie , Hendrickson Eleanore , Lam Hieu , Sherrill John , Liu Wei , Deng Ya-Li , Chung Chi-Yeh , McMillan Elizabeth A. , Palde Prakash , Brooun Alexei , Braganza John , Kephart Susan E. , Kumpf Robert , Patman Ryan , Rui Eugene , Scales Stephanie , Tran-Dube Michelle , Wang Fen , Wythes Martin , Paul Thomas
Published: July 2021

Protein arginine methyltransferase 5 (PRMT5) overexpression in hematological and solid tumors promotes symmetrical di-methyl arginine (SDMA) on cellular proteins involved in important cancer functions including cell cycle regulation, mRNA splicing, cell differentiation, cell signaling, and apoptosis. PRMT5 methyltransferase function has been linked with high rates of tumor cell proliferation and decreased overall survival, and PRMT5 inhibitors are currently being explored as an approach for targeting cancer-specific dependencies due to PRMT5 catalytic function. Here we describe the discovery of potent and selective S-adenosylmethionine (SAM) competitive PRMT5 inhibitors, including the clinical candidate PF-06939999. Acquired resistance mechanisms were explored through the development of drug resistant cell lines. Our data highlight compound-specific resistance mutations in the PRMT5 enzyme that demonstrate structural constraints in the co-factor binding site that prevent emergence of complete resistance to SAM site inhibitors. PRMT5 inhibition by PF-06939999 treatment reduced proliferation of NSCLC cancer cells, with dose-dependent decreases in SDMA levels and changes in alternative splicing of numerous pre-mRNAs. Drug sensitivity associates with cancer pathways including MYC, cell cycle and splicing. Translation of efficacy in mouse tumor xenograft models with splicing mutations provides rationale for therapeutic use of PF-06939999 for treatment of splicing dysregulated NSCLC.

Citation Format: Kristen Jensen-Pergakes, John Tatlock, Karen Maegley, Indrawan McAlpine, Michele McTigue, Tao Xie, Christopher Dillon, Yuli Wang, Shinji Yamazaki, Noah Spiegel, Manli Shi, Amy Nemeth, Natalie Miller, Eleanore Hendrickson, Hieu Lam, John Sherrill, Wei Liu, Ya-Li Deng, Chi-Yeh Chung, Elizabeth A. McMillan, Prakash Palde, Alexei Brooun, John Braganza, Susan E. Kephart, Robert Kumpf, Ryan Patman, Eugene Rui, Stephanie Scales, Michelle Tran-Dube, Fen Wang, Martin Wythes, Thomas Paul. SAM competitive PRMT5 inhibitor PF06939999 demonstrates antitumor activity in splicing dysregulated NSCLC with decreased liability of drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1160.