bluuebunny/crossref_metadata_2025 huggingface dataset:
Hybrid Electromagnetic Signal Feature Extraction
Authors: Dong Jianming
Published: May 2022

In the complex electromagnetic environment, the large number of pulse loss (data loss) and the serious overlap of signal parameter space destroy the signal regularity used by the traditional sorting method and finally make the existing signal sorting algorithm difficult to obtain satisfactory sorting effect or even completely invalid. On the basis of considering several key characteristic indexes (pulse width, carrier frequency, and arrival time), a multiparameter and five-layer mutual coupling sorting algorithm is designed. In particular, a new key feature index extraction method is proposed to study the feature vectors contained in the data and establish the corresponding mathematical model, which is finally applied to the sorting of various communication signals. The numerical results show that the five-step sorting method can be used to separate signals with serious overlap and partial missing data.
Design and Research of Dynamic Evolution System in Football Tactics Under Computational Intelligence
Authors: Wang Jianming , Chen Jing
Published: May 2022

With the rapid development of computer vision, it has been widely used in football. Aiming at the problems of incomplete collection of information, poor operability of system, and bad practical application in the field of football match, an analysis system of football tactics is designed in this paper. Combining the requirements of functions and performance, the analysis system is divided into management of basic information, collection of tactical information, detection of passing pattern, inquiry of tactical information, and visual display, which puts forward the method of the detection of passing pattern based on model. Through the intelligent design, the visual display of the information of athlete, team, competition, tactics, and passing pattern is realized under computational intelligence, which has certain practical value in application.
Finite Element Analysis of a Novel Fusion Strategy in Minimally Invasive Transforaminal Lumbar Interbody Fusion
Authors: Han Zhenchuan , Ren Bowen , Zhang Long , Ma Chao , Liu Jianheng , Li Jiantao , Liu Xiao , Liu Qingzu , Mao Keya , Tang Peifu
Published: May 2022

Purpose. To evaluate the biomechanics of a novel fusion strategy (hybrid internal fixation+horizontal cage position) in minimally invasive transforaminal lumbar interbody fusion (MIS‐TLIF). Methods. MIS‐TLIF finite element models for three fusion strategies were created based on computed tomography images, namely, Model‐A, hybrid internal fixation (ipsilateral pedicle screw and contralateral translaminar facet screw fixation)+horizontal cage position; Model‐B, bilateral pedicle screw (BPS) fixation+horizontal cage position; and Model‐C, BPS fixation+oblique 45° cage position. A preload of 500 N and a moment of 10 Nm were applied to the models to simulate lumbar motion, and the models’ range of motion (ROM), peak stress of the internal fixation system, and cage were assessed. Results. The ROM for Models A, B, and C were not different (P > 0.05) but were significantly lower than the ROM of Model‐INT (P < 0.0001). Although there were subtle differences in the ROM ratio for Models A, B, and C, the trend was similar. The peak stress of the internal fixation system was significantly higher in Model‐A than that of Models B and C, but only the difference between Models A and B was significant (P < 0.05). The peak stress of the cage in Model‐A was significantly lower than that of Models B and C (P < 0.01). Conclusion. Hybrid internal fixation with horizontal single cage implantation can provide the same biomechanical stability as traditional fixation while reducing peak stress on the cage and vertebral endplate.
Construction and Evaluation of Prognosis Prediction Model for Patients with Brain Contusion and Laceration Based on Machine Learning
Authors: Li Shaoquan , Bai Limei , Zheng Zhixia
Published: May 2022

Objective. Finding valuable risk factors for the prognosis of brain contusion and laceration can help patients understand the condition and improve the prognosis. This study is aimed at analyzing the risk factors of poor prognosis in patients with brain contusion after the operation. Methods. A total of 136 patients with cerebral contusion and laceration combined with cerebral hernia treated by neurosurgical craniotomy in our hospital were retrospectively selected and divided into a training set (

n
=
95

) and a test set (

n
=
41

) by the 10-fold crossover method. Logistic regression and back-propagation neural network prediction models were established to predict poor prognosis factors. The receiver operating characteristic curve (ROC) and the calibration curve were used to verify the differentiation and consistency of the prediction model. Results. Based on logistic regression and back-propagation neural network prediction models,

GCS
 
score
≤
8

on admission,

blood
 
loss
≥
30

 ml,

mannitol
≥
2

weeks, anticoagulants before admission, and surgical treatment are the risk factors that affect the poor prognosis of patients with a cerebral contusion after the operation. The area under the ROC was 0.816 (95% CI 0.705~0.926) and 0.819 (95% CI 0.708~0.931), respectively. Conclusion. The prediction model based on the risk factors that affect the poor prognosis of patients with brain contusion and laceration has good discrimination and accuracy.
A Cost-Effective Identity-Based Signature Scheme for Vehicular Ad Hoc Network Using Hyperelliptic Curve Cryptography
Authors: Iqbal Asad , Ullah Insaf , AlSanad Abeer Abdulaziz , Haq Muhammad Inam Ul , Khan Muhammad Asghar , Khan Wali Ullah , Rabie Khaled
Published: May 2022

A Vehicular Ad Hoc Network (VANET) is a subset of the Mobile Ad Hoc Network (MANET) that allows vehicles to communicate with each other and with roadside stations to offer efficient and safe transportation. Furthermore, when VANET is used in connection with the Internet of Things (IoT) devices and sensors, it can help with traffic management and road safety by allowing vehicles to interact with one another at any time and from any location. Since VANET’s event-driven communications are carried out via an open wireless channel, there are significant security concerns. In this paper, we use Hyperelliptic Curve Cryptography (HECC) to offer a cost-effective identity-based signature for secure communication over VANET. The proposed scheme does not need certificate management, and we found that it is more secure against a variety of cryptographic threats after conducting a thorough security analysis. In addition, comparisons of communication and computational costs are made, demonstrating that the proposed scheme is more efficient in both respects than existing schemes.
Efficacy of Dialectical Comprehensive Treatment of Traditional Chinese Medicine in Patients with Chronic Stable Heart Failure: A Randomized Controlled Trial
Authors: Yang Lixiang , Chen Yuanyuan , Lou Fei , Zhao Xiaoxia , Zhou Jia
Published: May 2022

The treatment of chronic stable heart failure (CSHF) with integrated traditional Chinese and Western medicine has been of wide concern. We mainly discuss the clinical efficacy of TCM decoction combined with acupuncture and moxibustion (A&M) in CSHF treatment on the basis of syndrome differentiation and treatment (SDT). The control group was given conventional cardiac rehabilitation (CCR), and the treatment group was given TCM decoction combined with A&M treatment based on SDT on the basis of conventional cardiac rehabilitation. The clinical efficacy and cardiopulmonary exercise testing (CPET) indicators were evaluated. Left ventricular ejection fraction (LVEF), NT-proBNP, myocardial ischemia threshold (MIT), and 6-minute walking distance (6MWD) were measured by ultrasound, ELISA, electrocardiogram, and 6MWD test. After treatment, the clinical efficacy, LVEF, and 6MWD of the treatment group were better than in the control group. The NT-proBNP plasma level and MIT in the treatment group were lower than in the control group. The treatment group had enhanced AT, VO2 Peak, VO2 Peak/HR, and Peak power and decreased resting systolic pressure and peak systolic pressure, and the difference was statistically significant. Dialectical comprehensive treatment of TCM could effectively improve cardiac function and clinical treatment effect, which was worthy of clinical application.
PSOWNNs-CNN: A Computational Radiology for Breast Cancer Diagnosis Improvement Based on Image Processing Using Machine Learning Methods
Authors: Nomani Ashkan , Ansari Yasaman , Nasirpour Mohammad Hossein , Masoumian Armin , Pour Ehsan Sadeghi , Valizadeh Amin
Published: May 2022

Early diagnosis of breast cancer is an important component of breast cancer therapy. A variety of diagnostic platforms can provide valuable information regarding breast cancer patients, including image-based diagnostic techniques. However, breast abnormalities are not always easy to identify. Mammography, ultrasound, and thermography are some of the technologies developed to detect breast cancer. Using image processing and artificial intelligence techniques, the computer enables radiologists to identify chest problems more accurately. The purpose of this article was to review various approaches to detecting breast cancer using artificial intelligence and image processing. The authors present an innovative approach for identifying breast cancer using machine learning methods. Compared to current approaches, such as CNN, our particle swarm optimized wavelet neural network (PSOWNN) method appears to be relatively superior. The use of machine learning methods is clearly beneficial in terms of improved performance, efficiency, and quality of images, which are crucial to the most innovative medical applications. According to a comparison of the process’s 905 images to those of other illnesses, 98.6% of the disorders are correctly identified. In summary, PSOWNNs, therefore, have a specificity of 98.8%. Furthermore, PSOWNNs have a precision of 98.6%, which means that, despite the high number of women diagnosed with breast cancer, only 830 (95.2%) are diagnosed. In other words, 95.2% of images are correctly classified. PSOWNNs are more accurate than other machine learning algorithms, SVM, KNN, and CNN.
Deep Learning for Treadmill-Oriented Cardiorespiratory Endurance Testing and Training
Authors: Zhu Yanying
Published: May 2022

The aim of this paper was to study deep learning for treadmill-oriented cardiorespiratory endurance testing and training. This paper designs a cardiorespiratory endurance test system for the general public based on ordinary exercise bikes, which can be used to execute training programs and improve cardiorespiratory endurance levels, system design, and implementation. Through the analysis and summary of the design principle, and the design of software and hardware, the heart rate measurement, power measurement, and constant power control are realized, and the human-computer interaction software integrated into the cardiorespiratory endurance test scheme is designed. The results show that the Pearson correlation coefficient verification results of the maximum oxygen uptake VO2max of the two groups are the correlation coefficient r = 0.938, |r > 0.8, indicating that the two groups of data have a high correlation; the significance coefficient p < 0.0S, lpl <0.0S, and the accuracy and validity of the system test are verified by the comparison experiment with the gold standard equipment Monaco MONARK power car.
Multi‐Frequency Information Flows between Global Commodities and Uncertainties: Evidence from COVID‐19 Pandemic
Authors: Asafo-Adjei Emmanuel , Frimpong Siaw , Owusu Junior Peterson , Adam Anokye Mohammed , Boateng Ebenezer , Ofori Abosompim Robert
Published: May 2022

Owing to the adverse impact of the COVID‐19 pandemic on world economies, it is expected that information flows between commodities and uncertainties have been transformed. Accordingly, the resulting twisted risk among commodities and related uncertainties is presumed to rise during stressed market conditions. Therefore, investors feel pressured to find safe haven investments during the pandemic. For this reason, we model a mixture of asymmetric and non‐linear bi‐directional causality between global commodities and uncertainties at different frequencies through the information flow theory. Consequently, we utilise the complete ensemble empirical mode decomposition with adaptive noise (CEEMDAN) and the Rényi effective transfer entropy techniques to establish the dynamic flow of information. The intrinsic mode functions (IMFs) from the CEEMDAN are carefully extracted into multi‐frequencies through cluster analysis to reconstruct the series into high, medium, and low frequencies in addition to the residue. We utilise daily data from December 31st, 2019, to March 31st, 2021, to provide insights into the COVID‐19 pandemic. The correlation coefficients and variances demonstrate that the high frequency (IMFs 1–4) which measures the short‐term dynamics is the dominant frequency, suggesting short‐lived market fluctuations relative to real economic growth for institutional investors. Moreover, outcomes from the multi‐frequency entropy indicate a negative bi‐directional causality of information flow between global commodities and uncertainties, especially in the long term. Generally, the findings present pertinent inferences for portfolio diversification, policy decisions, and risk management schemes for global commodities and markets volatilities. We, therefore, advocate that market volatilities act as effective hedges for global commodities, and they clearly act as balancing assets rather than substitutes in the long‐term dynamics of the COVID‐19 pandemic. Investors who delayed in investing within financial markets of commodities and market volatilities are likely to minimise their portfolio risks.
Truck and Unmanned Vehicle Routing Problem with Time Windows: A Satellite Synchronization Perspective
Authors: Li Hongqi , Zhao Jiamin , Zhan Zhuopeng
Published: May 2022

We consider an important feature of satellite synchronization in the practical scenario of using unmanned vehicles (UVs) carried by trucks for “last-meter” delivery and introduce the truck and UV routing problem with time windows (TUVRP-TW) for optimizing the routes of a homogeneous fleet of truck-UV combinations. A UV that has been dispatched from its truck must be picked up by the same truck or must return by itself to the depot. Customers with time windows are classified into two types: truck-UV customers (TUCs) and UV customers (UCs). The TUCs where trucks dispatch or pick up the carried UVs are regarded as satellites. Fleet coordination and satellite synchronization are essential for modelling the TUVRP-TW. We classify satellite synchronization into inner-satellite synchronization and intersatellite synchronization. The inner-satellite synchronization generally considered in the literature focuses on synchronization operations at the same satellite. Intersatellite synchronization, which focuses on synchronization operations at various satellites, allows UVs to not return to the dispatched locations, if necessary. In the mixed-integer linear programming model of the TUVRP-TW, both binary variables for identifying the appointed satellites and continuous variables for time continuity constraints are introduced to ensure the interaction between truck routes and UV routes. A hybrid algorithm based on a greedy randomized adaptive search procedure (GRASP) and a variable neighborhood search (VNS) is provided. Based on generated instances and benchmark instances, computational experiments are conducted to evaluate the performance of the intersatellite synchronization, the performance of the developed formulation, and the applicability of the hybrid algorithm.
Recommendation of English Reading in Vocational Colleges Using Linear Regression Training Model
Authors: Xie Haibo
Published: May 2022

High-quality vocational education is a vital basis for China’s efforts to develop high-quality teachers and technical and skilled workers. The increasing development of contemporary vocational education is given higher importance in the new era. We proposed the stick to moral education while carefully integrating it with the requirements of changes in technology and modernization, continuous improvements in the quality of college vocational education, and the development of more conceptual and skilled talented individuals with both political integrity and the capacity to build modernization. Using artificial intelligence technology to challenge these difficulties in the context of social informatization can play important role in enhancing the teaching quality of high vocational education. With the advent of the Internet era, students and parents have an increasingly strong demand for online independent vocational English reading materials, although there is some English learning software that provides online vocational English reading materials in the education market. However, most of this software only changes the reading form of paper vocational English reading materials but fails to completely meet the real demand of students for vocational English reading materials, so how to carry out personalized recommendation reading according to the real reading situation and reading preferences of students is a vital problem to be resolved. In this background, this paper studies the personalized recommendation technology, in the use of recommendation algorithms on the based association rules to obtain higher vocational English reading content recommended the strongest association rules, on the based combination of user-based collaborative clarifying recommendation algorithm. The linear regression model combined with the users reading interest and personalized recommendation of higher vocational English reading process is optimized, improving the accuracy of English reading recommendation in vocational colleges.
Cisapride versus Maren Pill for Functional Constipation: A Meta-Analysis
Authors: Sun Yanming , Zhu Ying , Ye Rui
Published: May 2022

Background. The efficacy and safety of cisapride in functional constipation (FC) remain unclear. This meta-analysis aimed at investigating the efficacy and safety of cisapride and Maren pill in the treatment of FC. Material and Methods. PubMed, Web of Science, Embase, Cochrane Library, WANFANG DATA, VIP, and CNKI databases were searched from inception to December 2021 for eligible comparative studies investigating the effects and safety of cisapride and Maren pill for FC. The primary outcome was the therapeutic effectiveness rate. The secondary outcomes were recurrence rate and incidence of adverse events. Results. A total of 526 studies were screened out by searching the electronic databases and by manually searching the relevant reference lists. According to the four-step process (identification, screening, eligibility, and inclusion) to select studies for meta-analysis, 521 articles were excluded. Finally, 5 studies with a total of 414 patients with FC were included in the quantitative analysis after sequential exclusion. The cisapride group had a significantly higher effectiveness rate than the control one (90.78% vs 64.97%,

P
<
0.05

). The incidence of adverse events in the cisapride group was lower than that in the Maren pill group (10.08% vs 13.95%,

P
<
0.05

). Similarly, the recurrence rate of the cisapride group was lower than that of the Maren pill group (32.31% vs 53.16%,

P
<
0.05

). Conclusion. For FC patients, cisapride is more effective than Maren pill; the recurrence rate and adverse event rate are lower than the latter, which makes it a better choice. The combination of cisapride and Maren pill is a direction of future research studies, which may increase the efficiency and reduce the dosage of cisapride.
Rehabilitation Training and Prevention of Athlete’s Hind Thigh Muscle Injury Based on IoT Intelligent Data
Authors: Sun Peng
Published: May 2022

With the rapid development of information science today, the Internet of Things technology is gradually being applied to all walks of life, and the multifunction and intelligentization of instruments have gradually become the focus of people’s attention. In recent years, domestic track and field sports have developed to a certain extent, but at the same time, it must also be noted that there are still some difficulties and problems in the development of domestic track and field sports. This article was aimed at studying the application of the rehabilitation training and prevention of athletes’ hind thigh muscle group injury based on the intelligent data of the Internet of Things and puts forward the idea of using the intelligent data of the Internet of Things to better use in sports rehabilitation and prevention. This article describes in detail track and field training, athletes’ hindquarters muscle injury, and so on. The application experiment of rehabilitation training and prevention of athlete’s hind thigh muscle group injury based on the intelligent data of the Internet of Things has been made. The experimental results show that the rehabilitation training and prevention program of athletes’ hind thigh muscle injury based on the intelligent data of the Internet of Things can effectively reduce the athlete’s muscle injury during training, and it is more than 10% higher than the traditional prevention program. It can effectively improve the bad and wrong movement patterns of athletes, improve their own stability, flexibility, and balance, optimize the transmission of the body’s power chain, and improve the athletes’ ability to perform competitively.
Research on Precision Marketing Based on Consumer Portrait from the Perspective of Machine Learning
Authors: Zhang Mengmeng
Published: May 2022

With the advent of the big data era and the development of artificial intelligence, the traditional marketing model has undergone dramatic changes, and precision marketing has become the focus of current research. Consumer portrait is a labeled consumer model abstracted from the basic attributes, social attributes, behavior characteristics, and psychological characteristics of consumers, which can reflect the real needs of consumers well. Precision marketing based on consumer portraits is a fine division of consumers on the premise of in-depth understanding of consumer-related data. Based on the public dataset of a bank in a certain region, this paper extracts a series of data features such as basic attributes and social attributes of consumers to draw consumer portraits. BP neural network, SVM, and random forest algorithm in machine learning algorithm are used to model and predict whether consumers should take out personal loans, and then, the prediction effect of these algorithms is compared to judge which algorithm has better prediction effect. The results show that the random forest algorithm has the highest prediction accuracy, reaching an average of 94% in 10 calculations, which can help banks to select potential target customers to some extent.
Analysis of the lncRNA-Associated Competing Endogenous RNA (ceRNA) Network for Tendinopathy
Authors: Huang Bing-Zhe , Jing-Jing Yang , Dong Xiao-Ming , Zhuan Zhong  , Xiao-Ning Liu
Published: May 2022

Background. We aimed to construct the lncRNA-associated competing endogenous RNA (ceRNA) network and distinguish feature lncRNAs associated with tendinopathy. Methods. We downloaded the gene profile of GSE26051 from the Gene Expression Omnibus (GEO), including 23 normal samples and 23 diseased tendons. Differentially expressed mRNAs (DEmRNAs) and differentially expressed lncRNAs (DElncRNAs) were identified, and functional and pathway enrichment analyses were performed. Protein-protein interaction (PPI) network was constructed and further analyzed by module mining. Moreover, a ceRNA regulatory network was constructed based on the identified lncRNA–mRNA coexpression relationship pairs and miRNA–mRNA regulation pairs. Results. We identified 1117 DEmRNAs and 57 DElncRNAs from the GEO data. The downregulated DEmRNAs were particularly associated with muscle contraction and muscle filament, while the upregulated ones were linked to extracellular matrix organization and cell adhesion. From the PPI network, 11 modules were extracted. Genes in MCODE 2 (such as TPM4) were significantly involved in cardiomyopathy, and genes in MCODE 4 (such as COL4A3 and COL4A4) were involved in focal adhesion, ECM-receptor interaction, and PI3K-Akt signaling pathway. The ceRNA network contained 7 lncRNAs (MIR133A1HG, LINC01405, PRKCQ-AS1, C10orf71-AS1, MBNL1-AS1, HOTAIRM1, and DNM3OS), 63 mRNAs, and 41 miRNAs. Downregulated lncRNA MIR133A1HG could competitively bind with hsa-miR-659-3p and hsa-miR-218-1-3p to regulate the TPM3. Meanwhile, MIR133A1HG could competitively bind with hsa-miR-1179 to regulate the COL4A3. Downregulated C10orf71-AS1 could competitively bind with hsa-miR-130a-5p to regulate the COL4A4. Conclusions. Seven important lncRNAs, particularly MIR133A1HG and C10orf71-AS1, were found associated with tendinopathy according to the lncRNA-associated ceRNA network.
Nucleotide Sequence Variation Is Frequent in the Mitochondrial DNA Displacement Loop Region of Individual Human Tumor Cells
Authors: Yoneyama Haruko , Hara Toshiko , Kato Yo , Yamori Takao , Matsuura Etsuko T. , Koike Katsuro
Published: May 2022

The mitochondrial DNA (mtDNA) displacement loop (D-loop) regions of 76 various tumor cell lines were examined to investigate the existence of a specific relationship between a somatic mtDNA sequence and initiation and/or progression of a tumor. Based on molecular cloning-sequencing analysis, a nucleotide sequence in the D-loop region in each cell line was found to be homoplasmic. Several site-specific nucleotide variations were found in stomach and liver tumor cell lines more frequently than those in other tumor cell lines. Subsequently, 20 pairs of noncancerous and cancerous parts from stomach and liver tumor tissues were examined. In the liver tumor tissue, 80% of the noncancerous parts exhibited slightly higher heterogeneity than the corresponding cancerous parts. Several site-specific nucleotide variations found in 76 tumor cell lines were also detected in noncancerous or cancerous parts of stomach and liver tumor tissues. However, it remains unclear why the mtDNA D-loop sequence is homoplasmic in each tumor cell line. The data indicate that mtDNA exhibits heterogeneity even in the noncancerous part and a slight decrease in heterogeneity during tumorigenesis and/or tumor progression. Homoplasmy of the mtDNA population in the tumor cell line would be acquired in the cloning process of establishing a cell line. Site-specific nucleotide substitutions might not be directly involved in the tumorigenesis process.
E2F1 Uses the ATM Signaling Pathway to Induce p53 and Chk2 Phosphorylation and Apoptosis
Authors: Powers John T. , Hong SungKi , Mayhew Christopher N. , Rogers Pamela M. , Knudsen Erik S. , Johnson David G.
Published: May 2022

The p53 tumor suppressor protein is phosphorylated and activated by several DNA damage-inducible kinases, such as ATM, and is a key effector of the DNA damage response by promoting cell cycle arrest or apoptosis. Deregulation of the Rb-E2F1 pathway also results in the activation of p53 and the promotion of apoptosis, and this contributes to the suppression of tumor development. Here, we describe a novel connection between E2F1 and the ATM DNA damage response pathway. In primary human fibroblasts lacking functional ATM, the ability of E2F1 to induce the phosphorylation of p53 and apoptosis is impaired. In contrast, ATM status has no effect on transcriptional activation of target genes or the stimulation of DNA synthesis by E2F1. Cells containing mutant Nijmegen breakage syndrome protein (NBS1), a component of the Mre11-Rad50 DNA repair complex, also have attenuated p53 phosphorylation and apoptosis in response to E2F1 expression. Moreover, E2F1 induces ATM- and NBS1-dependent phosphorylation of the checkpoint kinase Chk2 at Thr68, a phosphorylation site that stimulates Chk2 activity. Delayed γH2AX phosphorylation and absence of ATM autophosphorylation at Ser1981 suggest that E2F1 stimulates ATM through a unique mechanism that is distinct from agents that cause DNA double-strand breaks. These findings identify new roles for several DNA damage response factors by demonstrating that they also participate in the oncogenic stress signaling pathway between E2F1 and p53.
Enhanced Growth of Pancreatic Tumors in SPARC-Null Mice Is Associated With Decreased Deposition of Extracellular Matrix and Reduced Tumor Cell Apoptosis
Authors: Puolakkainen Pauli A. , Brekken Rolf A. , Muneer Sabeeha , Sage E. Helene
Published: May 2022

SPARC, a matricellular glycoprotein, modulates cellular interaction with the extracellular matrix (ECM). Tumor growth and metastasis occur in the context of the ECM, the levels and deposition of which are controlled in part by SPARC. Tumor-derived SPARC is reported to stimulate or retard tumor progression depending on the tumor type, whereas the function of host-derived SPARC in tumorigenesis has not been explored fully. To evaluate the function of endogenous SPARC, we have examined the growth of pancreatic tumors in SPARC-null (SP−/−) mice and their wild-type (SP+/+) counterparts. Mouse pancreatic adenocarcinoma cells injected s.c. grew significantly faster in SP−/− mice than cells injected into SP+/+ animals, with mean tumor weights at sacrifice of 0.415 ± 0.08 and 0.086 ± 0.03 g (P < 0.01), respectively. Lack of endogenous SPARC resulted in decreased collagen deposition and fiber formation, alterations in the distribution of tumor-infiltrating macrophages, and decreased tumor cell apoptosis. There was no difference in microvessel density of tumors from SP−/− or SP+/+ mice. However, tumors grown in SP−/− had a lower percentage of blood vessels that expressed smooth muscle α-actin, a marker of pericytes. These data reflect the importance of ECM deposition in regulating tumor growth and demonstrate that host-derived SPARC is a critical factor in the response of host tissue to tumorigenesis.
HMG-I/Y Is a c-Jun/Activator Protein-1 Target Gene and Is Necessary for c-Jun–Induced Anchorage-Independent Growth in Rat1a Cells
Authors: Hommura Fumihiro , Katabami Motoo , Leaner Virna D. , Donninger Howard , Sumter Takita F. , Resar Linda M.S. , Birrer Michael J.
Published: May 2022

The transcription complex activator protein-1 (AP-1) plays a role in a diverse number of cellular processes including proliferation, differentiation, and apoptosis. To identify AP-1–responsive target genes, we used a doxycycline-inducible c-Jun system in Rat1a cells. The HMG-I/Y chromatin binding protein was found to be up-regulated by c-Jun. Following induction of c-Jun expression, Rat1a cells under nonadherent growth conditions have sustained HMG-I/Y mRNA expression and 2-fold higher protein than uninduced cells. HMG-I/Y promoter reporter assays show that HMG-I/Y promoter activity increases in the presence of c-Jun expression, and gel mobility shift assays demonstrate that induced c-Jun binds to an AP-1 consensus site at position −1,091 in the HMG-I/Y promoter. Suppression of HMG-I/Y expression by its antisense sequence significantly reduces the ability of c-Jun–overexpressing Rat1a cells to grow in an anchorage-independent fashion. HMG-I/Y transforms Rat1a cells (although the colonies are smaller than that observed for the cells overexpressing c-Jun). Taken together, these results suggest that HMG-I/Y is a direct transcriptional target of c-Jun necessary for c-Jun–induced anchorage-independent growth in Rat1a cells.
Chromatin Association of Rad17 Is Required for an Ataxia Telangiectasia and Rad-Related Kinase-Mediated S-Phase Checkpoint in Response to Low-Dose Ultraviolet Radiation
Authors: Garg Renu , Callens Shannon , Lim Dae-Sik , Canman Christine E. , Kastan Michael B. , Xu Bo
Published: May 2022

Activation of the S-phase checkpoint results in an inhibition of DNA synthesis in response to DNA damage. This is an active cellular response that may enhance cell survival and limit heritable genetic abnormalities. While much attention has been paid to elucidating signal transduction pathways regulating the ionizing radiation–induced S-phase checkpoint, less is known about whether UV radiation initiates the process and the mechanism controlling it. Here, we demonstrate that low-dose UV radiation activates an S-phase checkpoint that requires the ataxia telangiectasia and Rad-related kinase (ATR). ATR regulates the S-phase checkpoint through phosphorylation of the downstream target structural maintenance of chromosomal protein 1. Furthermore, the ATPase activity of Rad17 is crucial for its chromatin association and for the functional effects of ATR activation in response to low-dose UV radiation. These results suggest that low-dose UV radiation activates an S-phase checkpoint requiring ATR-mediated signal transduction pathway.
Mice Expressing SV40 T Antigen Directed by the Intestinal Trefoil Factor Promoter Develop Tumors Resembling Human Small Cell Carcinoma of the Colon
Authors: Gum James R. , Hicks James W. , Crawley Suzanne C. , Yang Stacey C. , Borowsky Alexander D. , Dahl Christine M. , Kakar Sanjay , Kim Dong Hoon , Cardiff Robert D. , Kim Young S.
Published: May 2022

The colonic epithelium contains three major types of mature cells, namely, absorptive, goblet, and enteroendocrine cells. These cells are maintained by a complex process of cell renewal involving progenitor and stem cells, and colon cancers develop when this process goes awry. Much is known about the genetic and epigenetic changes that occur in cancer; however, little is known as to the specific cell types involved in carcinogenesis. In this study, we expressed the SV40 Tag oncogene in the intestinal epithelium under the control of an intestinal trefoil factor (ITF) promoter. This caused tumor formation in the proximal colon with remarkable efficiency. ITFTag tumors were rapidly growing, multifocal, and invasive. ITFTag tumor cells express synaptophysin and contain dense core secretory granules, markers of neuroendocrine differentiation. The cell type involved in the early steps of ITFTag tumorigenesis was studied by examining partially transformed crypts that contained populations of both normal and dysplastic cells. The dysplastic cell population always expressed both Tag and synaptophysin. Cells expressing Tag alone were never observed; however, normal enteroendocrine cells expressing synaptophysin but not Tag were readily visualized. This suggests that ITFTag tumor cells originate from the enteroendocrine cell lineage following a transforming event that results in Tag expression. ITFTag tumors closely resemble human small cell carcinomas of the colon, suggesting the possibility that these tumors might be derived from the enteroendocrine cell lineage as well.
Peroxisome Proliferator-Activated Receptor γ Ligands Improve the Antitumor Efficacy of Thrombospondin Peptide ABT510
Authors: Huang Hanhua , Campbell Steven C. , Bedford Dhugal F. , Nelius Thomas , Veliceasa Dorina , Shroff Emelyn H. , Henkin Jack , Schneider Andrew , Bouck Noel , Volpert Olga V.
Published: May 2022

An expanding capillary network is critical for several pathologic conditions. In cancer, the decrease of antiangiogenic thrombospondin-1 (TSP1) often enables an angiogenic switch, which can be reversed with exogenous TSP1 or its peptide derivative ABT510. TSP1 acts by inducing endothelial cell apoptosis via signaling cascade initiated at CD36, a TSP1 antiangiogenic receptor. Here, we show that the ligands of nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), 15-deoxy-Δ12,14-prostaglandin J2, troglitazone, and rosiglitazone increased PPARγ and CD36 expression in endothelial cells and improved the efficacy of TSP1 and ABT510 in a CD36-dependent manner. The ABT510 and PPARγ ligands cooperatively blocked angiogenic endothelial functions in vitro and neovascularization in vivo. In tumor xenografts, 15-deoxy-Δ12,14-prostaglandin J2 and troglitazone synergistically improved antiangiogenic and antitumor effects of ABT510. Our data provide one mechanism for the in vivo angioinhibitory effect of PPARγ ligands and show fine-tuning of the antiangiogenic efficacy via targeted up-regulation of the endothelial receptor.
Bcl-2-Mediated Cell Survival Promotes Metastasis of EpH4 βMEKDD Mammary Epithelial Cells
Authors: Pinkas Jan , Martin Stuart S. , Leder Philip
Published: May 2022

The majority of patients who succumb to cancer die from metastatic disease progression rather than from the primary tumor. Elucidation of the mechanisms underlying tissue-specific metastasis is essential to the development of effective therapies. The mitogen-activated protein kinase kinase (MEK) pathway is frequently activated in human tumors and has been shown to regulate genes involved in proliferation, migration, and invasion. Studies with MEK-transformed EpH4 mouse mammary epithelial cells showed that these cells are highly tumorigenic but have a limited metastatic ability. Detachment of epithelial cells from the extracellular matrix causes disruption of the actin cytoskeleton and induces apoptosis. Several metastatic breast carcinoma cell lines have been shown to be resistant to cell death following actin disruption. This death-resistant phenotype can be modeled by overexpressing the antiapoptotic Bcl-2 protein in cells. This suggests that mechanisms that regulate survival of extravasated tumor cells may enhance metastatic efficiency. Therefore, we examined whether expression of Bcl-2 in MEK-transformed EpH4 mammary epithelial cells could provide a survival advantage and promote metastasis. Expression of Bcl-2 in parental EpH4 mammary epithelial cells or MEK-transformed cells was insufficient to induce increased migration, invasion, or tumor development. However, Bcl-2 expression markedly enhanced spontaneous lung metastasis from orthotopically implanted primary tumors. These results clearly show that mechanisms that regulate primary tumor development are distinct from those that promote metastasis and that assays designed to isolate genes involved in transformation may fail to identify genes that are critical regulators of metastasis.
Low-Dose Radiation Hypersensitivity Is Associated With p53-Dependent Apoptosis
Authors: Enns Louise , Bogen Kenneth T. , Wizniak Juanita , Murtha Albert D. , Weinfeld Michael
Published: May 2022

Exposure to environmental radiation and the application of new clinical modalities, such as radioimmunotherapy, have heightened the need to understand cellular responses to low dose and low-dose rate ionizing radiation. Many tumor cell lines have been observed to exhibit a hypersensitivity to radiation doses <50 cGy, which manifests as a significant deviation from the clonogenic survival response predicted by a linear-quadratic fit to higher doses. However, the underlying processes for this phenomenon remain unclear. Using a gel microdrop/flow cytometry assay to monitor single cell proliferation at early times postirradiation, we examined the response of human A549 lung carcinoma, T98G glioma, and MCF7 breast carcinoma cell lines exposed to γ radiation doses from 0 to 200 cGy delivered at 0.18 and 22 cGy/min. The A549 and T98G cells, but not MCF7 cells, showed the marked hypersensitivity at doses <50 cGy. To further characterize the low-dose hypersensitivity, we examined the influence of low-dose radiation on cell cycle status and apoptosis by assays for active caspase-3 and phosphatidylserine translocation (Annexin V binding). We observed that caspase-3 activation and Annexin V binding mirrored the proliferation curves for the cell lines. Furthermore, the low-dose hypersensitivity and Annexin V binding to irradiated A549 and T98G cells were eliminated by treating the cells with pifithrin, an inhibitor of p53. When p53-inactive cell lines (2800T skin fibroblasts and HCT116 colorectal carcinoma cells) were examined for similar patterns, we found that there was no hyperradiosensitivity and apoptosis was not detectable by Annexin V or caspase-3 assays. Our data therefore suggest that low-dose hypersensitivity is associated with p53-dependent apoptosis.
Src Regulates Actin Dynamics and Invasion of Malignant Glial Cells in Three Dimensions
Authors: Angers-Loustau Alexandre , Hering Ramm , Werbowetski Tamra E. , Kaplan David R. , Del Maestro Rolando F.
Published: May 2022

Malignant glioma is the major brain tumor in adults and has a poor prognosis. The failure to control invasive cell subpopulations may be the key reason for local glioma recurrence after radical tumor resection and may contribute substantially to the failure of the other treatment modalities such as radiation therapy and chemotherapy. As a model for this invasion, we have implanted spheroids from a human glioma cell line (U251) in three-dimensional collagen type I matrices, which these cells readily invade. We first observed that the Src family kinase-specific pharmacologic inhibitors PP2 and SU6656 significantly inhibited the invasion of the cells in this assay. We confirmed this result by showing that expression of two inhibitors of Src family function, dominant-negative-Src and CSK, also suppressed glioma cell invasion. To characterize this effect at the level of the cytoskeleton, we used fluorescent time-lapse microscopy on U251 cells stably expressing a YFP-actin construct and observed a rapid change in actin dynamics following addition of PP2 in both two-dimensional and three-dimensional cultures. In monolayer cultures, PP2 caused the disappearance of peripheral membrane ruffles within minutes. In three-dimensional cultures, PP2 induced the loss of actin bursting at the leading tip of the invadopodium. The inhibition of Src family activity is thus a potential therapeutic approach to treat highly invasive malignant glioma.
Enhancement of the Antiangiogenic Activity of Interleukin-12 by Peptide Targeted Delivery of the Cytokine to αvβ3 Integrin
Authors: Dickerson Erin B. , Akhtar Nasim , Steinberg Howard , Wang Zun-Yi , Lindstrom Mary J. , Padilla Marcia L. , Auerbach Robert , Helfand Stuart C.
Published: May 2022

We engineered a fusion protein, mrIL-12vp [mouse recombinant interleukin (IL)-12 linked to vascular peptide], linking the vascular homing peptide CDCRGDCFC (RGD-4C), a ligand for αvβ3 integrin, to mrIL-12 to target IL-12 directly to tumor neovasculature. The fusion protein stimulated IFN-γ production in vitro and in vivo, indicating its biological activity was consistent with mrIL-12. Immunofluorescence techniques showed mrIL-12vp specifically bound to αvβ3 integrin-positive cells but not to αvβ3 integrin-negative cells. In corneal angiogenesis assays using BALB/c mice treated with either 0.5 μg/mouse/d of mrIL-12vp or mrIL-12 delivered by subcutaneous continuous infusion, mrIL-12vp inhibited corneal neovascularization by 67% compared with only a slight reduction (13%) in angiogenesis in the mrIL-12-treated animals (P = 0.008). IL-12 receptor knockout mice given mrIL-12vp showed a marked decrease in the area of corneal neovascularization compared with mice treated with mrIL-12. These results indicate that mrIL-12vp inhibits angiogenesis through IL-12-dependent and IL-12-independent mechanisms, and its augmented antiangiogenic activity may be due to suppression of endothelial cell signaling pathways by the RGD-4C portion of the fusion protein. Mice injected with NXS2 neuroblastoma cells and treated with mrIL-12vp showed significant suppression of tumor growth compared with mice treated with mrIL-12 (P = 0.03). Mice did not show signs of IL-12 toxicity when treated with mrIL-12vp, although hepatic necrosis was present in mrIL-12-treated mice. Localization of IL-12 to neovasculature significantly enhances the antiangiogenic effect, augments antitumor activity, and decreases toxicity of IL-12, offering a promising strategy for expanding development of IL-12 for treatment of cancer patients.
Tumor-Stroma Interaction: Positive Feedback Regulation of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) Expression and Matrix Metalloproteinase-Dependent Generation of Soluble EMMPRIN
Authors: Tang Yi , Kesavan Prabakaran , Nakada Marian T. , Yan Li
Published: May 2022

Matrix metalloproteinases (MMPs) are metal-dependent endopeptidases that play pivotal roles in tumor disease progression. In many solid tumors, MMPs are indeed produced by tumor stromal cells, rather than by tumor cells. This expression pattern is, at least in part, regulated by tumor-stroma interaction via tumor cell-associated extracellular matrix metalloproteinase inducer (EMMPRIN). In vitro, recombinant EMMPRIN dose-dependently stimulated MMP-1 production by primary human fibroblast cells. Interestingly, in addition to stimulating MMP expression, EMMPRIN also induced its own gene expression. To further explore this potential positive feedback regulatory mechanism, we generated human breast cancer cells expressing different levels of EMMPRIN. Coculture of EMMPRIN-positive tumor cells with fibroblast cells resulted in a concomitant stimulation of MMP-2, MMP-9, and EMMPRIN production. This induction was EMMPRIN dependent, was further enhanced by overexpression, and was reduced by antisense suppression of EMMPRIN expression in tumor cells. Increased expression of membrane-associated EMMPRIN was accompanied by an MMP-dependent generation of a soluble form of EMMPRIN representing a proteolytic cleavage product lacking the carboxyl terminus. On the basis of these findings, we propose a model in which tumor cell-associated EMMPRIN stimulates MMPs, as well as EMMPRIN expression in tumor stroma. Increased MMP activity in tumor local environment results in proteolytic cleavage of membrane-associated EMMPRIN, releasing soluble EMMPRIN. Soluble EMMPRIN in turn acts in a paracrine fashion on stroma cells that are both adjacent and distant to tumor sites to further stimulate the production of MMPs and additional EMMPRIN, which consequently contributes to tumor angiogenesis, tumor growth, and metastasis.
Tumor-Derived Lysophosphatidic Acid Blunts Protective Type I Interferon Responses in Ovarian Cancer
Authors: Chae Chang-Suk , Sandoval Tito A. , Hwang Sung-Min , Park Eun Sil , Giovanelli Paolo , Awasthi Deepika , Salvagno Camilla , Emmanuelli Alexander , Tan Chen , Chaudhary Vidyanath , Casado Julia , Kossenkov Andrew V. , Song Minkyung , Barrat Franck J. , Holcomb Kevin , Romero-Sandoval E. Alfonso , Zamarin Dmitriy , Pépin David , D'Andrea Alan D. , Färkkilä Anniina , Cubillos-Ruiz Juan R.
Published: May 2022

Lysophosphatidic acid (LPA) is a bioactive lipid enriched in the tumor microenvironment of immunosuppressive malignancies such as ovarian cancer. Although LPA enhances the tumorigenic attributes of cancer cells, the immunomodulatory activity of this phospholipid messenger remains largely unexplored. Here, we report that LPA operates as a negative regulator of type I interferon (IFN) responses in ovarian cancer. Ablation of the LPA-generating enzyme autotaxin (ATX) in ovarian cancer cells reprogrammed the tumor immune microenvironment, extended host survival, and improved the effects of therapies that elicit protective responses driven by type I IFN. Mechanistically, LPA sensing by dendritic cells triggered PGE2 biosynthesis that suppressed type I IFN signaling via autocrine EP4 engagement. Moreover, we identified an LPA-controlled, immune-derived gene signature associated with poor responses to combined PARP inhibition and PD-1 blockade in patients with ovarian cancer. Controlling LPA production or sensing in tumors may therefore be useful to improve cancer immunotherapies that rely on robust induction of type I IFN.

Significance:

This study uncovers that ATX–LPA is a central immunosuppressive pathway in the ovarian tumor microenvironment. Ablating this axis sensitizes ovarian cancer hosts to various immunotherapies by unleashing protective type I IFN responses. Understanding the immunoregulatory programs induced by LPA could lead to new biomarkers predicting resistance to immunotherapy in patients with cancer.

See related commentary by Conejo-Garcia and Curiel, p. 1841.

This article is highlighted in the In This Issue feature, p. 1825