bluuebunny/crossref_metadata_2025 huggingface dataset:
Detect Insider Attacks in Industrial Cyber-physical Systems Using Multi-physical Features-based Fingerprinting
Authors: Hong Zhen , Lu Lingling , Zheng Dehua , Suo Jiahui , Sun Peng , Beyah Raheem , Wen Zhenyu
Published: February 2023

ICPS software and hardware suffer from low update frequency, making it easier for insiders to bypass external defenses and launch concealed destructive attacks. To address these concerns, we design a device fingerprinting method based on multi-physical features, augmenting current intrusion detection techniques in the ICPS environment. In this article, we use the sorting system as an example, demonstrating that the proposed device fingerprinting technology has generality in the intrusion detection of ICPS control flow. Specifically, we first formalize the physical model of the sorting system to analyze the critical device features. Then, we extract these physical features from the sensor data collected in a physical testbed. Utilizing featurized data, we train a classifier that generates fingerprints in real-time in the production environment. Moreover, we develop a differential detection model based on device fingerprints to discover stealthy insider attacks efficiently. We evaluate the proposed method in a real-world testbed. Experiment results show that the detecting performance of classifiers approaches 100% when the the number of component types is small.
Welcome to AI matters 8(4)
Authors: Karpatne Anuj , Yao Ziyu
Published: February 2023

Welcome to the last issue of this year's AI Matters Newsletter. We will open this issue by a conference report by Louise Dennis. Dilini Samarasinghe will then summarize the upcoming events in the last month of 2022 and early months of 2023. We wish everyone a joyful end of year, and look forward to your continuing involvement in 2023!
Neural Architecture Search for GNN-Based Graph Classification
Authors: Wei Lanning , Zhao Huan , He Zhiqiang , Yao Quanming
Published: February 2023

Graph classification is an important problem with applications across many domains, for which graph neural networks (GNNs) have been state-of-the-art (SOTA) methods. In the literature, to adopt GNNs for the graph classification task, there are two groups of methods: global pooling and hierarchical pooling. The global pooling methods obtain the graph representation vectors by globally pooling all of the node embeddings together at the end of several GNN layers, whereas the hierarchical pooling methods provide one extra pooling operation between the GNN layers to extract hierarchical information and improve the graph representations. Both global and hierarchical pooling methods are effective in different scenarios. Due to highly diverse applications, it is challenging to design data-specific pooling methods with human expertise. To address this problem, we propose PAS (Pooling Architecture Search) to design adaptive pooling architectures by using the neural architecture search (NAS). To enable the search space design, we propose a unified pooling framework consisting of four modules: Aggregation, Pooling, Readout, and Merge. Two variants, PAS-G and PAS-NE, are provided to design the pooling operations in different scales. A set of candidate operations is designed in the search space using this framework. Then, existing human-designed pooling methods, including global and hierarchical ones, can be incorporated. To enable efficient search, a coarsening strategy is developed to continuously relax the search space, and then a differentiable search method can be adopted.

We conduct extensive experiments on six real-world datasets, including the large-scale datasets MR and ogbg-molhiv. Experimental results in this article demonstrate the effectiveness and efficiency of the proposed PAS in designing the pooling architectures for graph classification. The Top-1 performance on two Open Graph Benchmark (OGB) datasets

1

further indicates the utility of PAS when facing diverse realistic data. The implementation of PAS is available at: https://github.com/AutoML-Research/PAS.
T-cadherin is a novel regulator of pericyte function during angiogenesis
Authors: Dasen Boris , Pigeot Sebastien , Born Gordian Manfred , Verrier Sophie , Rivero Olga , Dittrich Petra S. , Martin Ivan , Filippova Maria
Published: February 2023

Pericytes are mural cells that play an important role in regulation of angiogenesis and endothelial function. Cadherins are a superfamily of adhesion molecules mediating Ca2+-dependent homophilic cell-cell interactions that control morphogenesis and tissue remodeling. To date, classical N-cadherin is the only cadherin described on pericytes. Here, we demonstrate that pericytes also express T-cadherin (H-cadherin, CDH13), an atypical glycosyl-phosphatidylinositol (GPI)-anchored member of the superfamily that has previously been implicated in regulation of neurite guidance, endothelial angiogenic behavior, and smooth muscle cell differentiation and progression of cardiovascular disease. The aim of the study was to investigate T-cadherin function in pericytes. Expression of T-cadherin in pericytes from different tissues was performed by immunofluorescence analysis. Using lentivirus-mediated gain-of-function and loss-of-function in cultured human pericytes, we demonstrate that T-cadherin regulates pericyte proliferation, migration, invasion, and interactions with endothelial cells during angiogenesis in vitro and in vivo. T-cadherin effects are associated with the reorganization of the cytoskeleton, modulation of cyclin D1, α-smooth muscle actin (αSMA), integrin β3, metalloprotease MMP1, and collagen expression levels, and involve Akt/GSK3β and ROCK intracellular signaling pathways. We also report the development of a novel multiwell 3-D microchannel slide for easy analysis of sprouting angiogenesis from a bioengineered microvessel in vitro. In conclusion, our data identify T-cadherin as a novel regulator of pericyte function and support that it is required for pericyte proliferation and invasion during active phase of angiogenesis, while T-cadherin loss shifts pericytes toward the myofibroblast state rendering them unable to control endothelial angiogenic behavior.
Sympathetic transduction to blood pressure during euglycemic-hyperinsulinemia in young healthy adults: role of burst amplitude
Authors: Young Benjamin E. , Padilla Jaume , Shoemaker J. Kevin , Curry Timothy B. , Fadel Paul J. , Limberg Jacqueline K.
Published: February 2023

Insulin acts centrally to stimulate sympathetic vasoconstrictor outflow to skeletal muscle and peripherally to promote vasodilation. Given these divergent actions, the “net effect” of insulin on the transduction of muscle sympathetic nerve activity (MSNA) into vasoconstriction and thus, blood pressure (BP) remains unclear. We hypothesized that sympathetic transduction to BP would be attenuated during hyperinsulinemia compared with baseline. In 22 young healthy adults, MSNA (microneurography), and beat-to-beat BP (Finometer or arterial catheter) were continuously recorded, and signal-averaging was performed to quantify the mean arterial pressure (MAP) and total vascular conductance (TVC; Modelflow) responses following spontaneous bursts of MSNA at baseline and during a euglycemic-hyperinsulinemic clamp. Hyperinsulinemia significantly increased MSNA burst frequency and mean burst amplitude (baseline: 46 ± 6 au; insulin: 65 ± 16 au, P < 0.001) but did not alter MAP. The peak MAP (baseline: 3.2 ± 1.5 mmHg; insulin: 3.0 ± 1.9 mmHg, P = 0.67) and nadir TVC ( P = 0.45) responses following all MSNA bursts were not different between conditions indicating preserved sympathetic transduction. However, when MSNA bursts were segregated into quartiles based on their amplitudes at baseline and compared with similar amplitude bursts during hyperinsulinemia, the peak MAP and TVC responses were blunted (e.g., largest burst quartile: MAP, baseline: Δ4.4 ± 1.7 mmHg; hyperinsulinemia: Δ3.0 ± 0.8 mmHg, P = 0.02). Notably, ∼15% of bursts during hyperinsulinemia exceeded the size of any burst at baseline, yet the MAP/TVC responses to these larger bursts (MAP, Δ4.9 ± 1.4 mmHg) did not differ from the largest baseline bursts ( P = 0.47). These findings indicate that increases in MSNA burst amplitude contribute to the overall maintenance of sympathetic transduction during hyperinsulinemia.
Influence of Microstructural Characteristics on Wear and Corrosion Behaviour of Si3N4-Reinforced Al2219 Composites
Authors: Manjunatha C. J. , Prasad C. Durga , Hanumanthappa Harish , Kannan A. Rajesh , Mohan Dhanesh G. , Shanmugam Bharath Kumar , Venkategowda C.
Published: February 2023

The fabrication of the Al2219 + Si3N4 composites was done by means of stir casting process. The specimen was subjected to microstructural studies. The density of Si3N4 employed in the fabrication of the composites has been evaluated. Generally, the density of the composites increases as the weight percent of Si3N4 increases. TGA and DTA were performed at temperatures ranging from 30°C to 800°C, with some mass loss noted as well as the thermal stability of an AA2219 matrix improved. Under various parameters of applied load, operating duration, and speed, the wear behaviour of the produced aluminium matrix composite (AMC) was examined. Corrosion behaviour was examined using potentiodynamic polarization curve data, and it was discovered that the rate of corrosion decreases with increasing Si3N4 content, adding to the AA2219 matrix. The research work is intended to produce a totally new composite material with various compositions of reinforcement and to investigate their mechanical properties and a result of simulation.
Building English Audio-Visual and Oral Mobile Teaching System Based on Virtual Augmented Reality Technology
Authors: Xinzhen Deng , Zhifen Ren
Published: February 2023

Aiming at the problem that the current English textbooks still provide video materials in the form of CD-ROMs, which affects the learning effect, a research method of English audio-visual mobile teaching system based on virtual and augmented reality technology is proposed. The system first builds a recognition map database and stores it in the cloud and names the corresponding video files according to the name of the recognition map, then uses Unity3D to design and render the scene, design the virtual video playback button of the ImageTarget object, and write script code to realize the recognition map database and its corresponding video, access, and finally, generate a user-friendly mobile application. Users only need to point the lens at the book illustration to present the visual effect of superposition of virtual and real and realize the playback of English teaching videos on mobile devices. The results show that compared with the original image grayscale distribution map, the pixels near the 0 value of the pixel distribution map after twice filtering are significantly reduced, which reduces the hole noise of the image, and the original image and the image after twice filtering are not 0. The peak value of the pixel is close, maintaining the detailed characteristics of the image. The application of augmented reality technology to English video teaching enables users to enjoy novel learning methods and an interactive experience combining virtual and real.
Using GQIM Model and Gompertz Model to Measure, Analyze, and Optimize the Whole Process of Software Project
Authors: Zhao Li , Wu Yongchun , Wang Xiujuan , Zhu Meihong
Published: February 2023

This paper proposes a novel concept of using defect management technology to measure, predict, and optimize the management of the entire software project cycle. It first utilizes the software defect measurement GQIM model and prediction Gompertz model to track and quantify the defects of the entire project cycle. Then, the specific optimization strategy is proposed to manage the core processes of the project management, including project scope management, project time management, project quality management, project human resource management, project communication management, and project risk management. This study solves the quantification problems that are common in the current software project management process, such as complex testing procedures, high defect repair costs, and high communication costs. Furthermore, it contributes to promote the overall level of project management in the software industry. Taking the SDLM’s electronic banking software project management as an example, the various management quality indicators before and after the optimization of the project management process strongly indicate that using software defect management technology to optimize the software project management process is feasible and effective.
Effect of Several Naja atra Antivenom Injection Methods on the Rabbit Model of Naja naja atra Bite Poisoning
Authors: Yang Jie , Li Jin-Cheng , Huang Zhou , Huang Dong-Ling , Wang Fan , Wei Wan-Xia , Nong Ji-Fei , Yang Feng , Lu Xue-Ling , Zhu Jun-Rong , Wang Wei
Published: February 2023

Snakebite is a global public health concern, which often occurs in tropical and subtropical underdeveloped areas, but it is often neglected. In the southern China, Naja naja atra (Chinese cobra) is a common venomous snake that causes swelling and necrosis of local tissues, even amputation and death. Currently, the main therapy is the administration of Naja atra antivenom, which greatly reduces mortality. However, the antivenom is not particularly effective in the improvement of local tissue necrosis. Clinically, antivenom is mainly administered intravenously. We speculated that the method of injection influences the efficacy of antivenom. In this study, the rabbit model was used to explore the effects of different antivenom injection methods on systemic and local poisoning symptoms. If topical injection of antivenom contributes to ameliorate tissue necrosis, then we need to reconsider the use of Naja atra antivenom.
Energy-Efficient DNN Partitioning and Offloading for Task Completion Rate Maximization in Multiuser Edge Intelligence
Authors: Tian Xianzhong , Xu Pengcheng , Gu Hui , Meng Huixiao
Published: February 2023

Deep Neural Network (DNN) has become an essential technology for edge intelligence. Due to significant resource and energy requirements for large-scale DNNs’ inference, executing them directly on energy-constrained Internet of Things (IoT) devices is impractical. DNN partitioning provides a feasible solution for this problem by offloading some DNN layers to execute on the edge server. However, the resources of edge servers are also typically limited. An energy-constrained and resource-constrained optimization problem is generated in such a realistic environment. Motivated by this, we investigate an optimization problem of DNN partitioning and offloading in a multiuser resource-constrained environment, which is considered an intractable Mixed-Integer Nonlinear Problem (MINLP). We decompose the problem into two subproblems and propose an Energy-Efficient DNN Partitioning and Offloading (EEDPO) strategy to solve it in polynomial time based on the minimum cut/maximum flow theorem and dynamic programming. Finally, we test the impact of energy constraint, DNN type, and device number on the performance of EEDPO. Simulation results on realistic DNN models demonstrate that the proposed strategy can significantly improve the DNN inference task completion rate compared to other methods.
[Retracted] Optimization of College Teachers’ Performance Management Using Artificial Intelligence Technology
Authors: Liu Yi , Fang Yu
Published: February 2023

This work aims to adapt to the coming of a knowledge economy society and promote the improvement of China’s higher education system. It is necessary to establish a new management mechanism of college teachers’ performance evaluation to strengthen the quality of college teachers and improve the level of education and scientific research. Performance appraisal can be used to monitor the teaching staff scientifically and effectively to continuously improve and develop the college teacher system in China. This work first investigates the characteristics of performance evaluation of worldwide colleges, analyzes the development status of performance evaluation, and constructs a new performance evaluation index system through data and interviews. Then, based on the radial basis function neural network in artificial intelligence technology, a fine evaluation model of Chinese college teachers’ performance is established. Network training is adopted to analyze the previous performance evaluation to ensure that the final weight is obtained to minimize the sum of previous evaluation errors. Then, the index data of 61 teachers’ educational performance evaluation of X college from 2016 to 2021 are used for analysis and verification. The experimental results show that only 9.9% of the teachers in X college have excellent performance evaluation results, 29.5% of the teachers have medium evaluation results, and the statistical excellent rate is only 26.3%. Finally, the corresponding improvement suggestions and countermeasures are given for the low excellent rate of colleges.
Entropy Generation and Exergy Assessment of Methane–Nitrous Oxide Diffusion Flames in a Triple-Port Burner
Authors: Chou Dean , Tsai Wen-Yuan , Emami Mohsen Davazdah , Li Yueh-Heng
Published: February 2023

A triple-port burner was used in this study, and a numerical simulation was employed to investigate the entropy generation rate of CH4–N2O diffusion flames at the

R

ratio
=
1

. Here,

R

ratio refers to the ratio of the oxidizer flow velocity to the fuel flow velocity. In order to scrutinize the decomposition effect of N2O on entropy generation, an oxygen-enriched gas with the same nitrogen to oxygen ratio as N2O (N-to-

O
=
2

) was used in CH4–N2–O2 diffusion flames. Besides, because the N2O could decompose into the oxygen-enriched gas, the oxygen-enriched effect was also studied by the CH4–air diffusion flames that were conducted in this research. The entropy generation rate comprises of three items in this study, including heat conduction, mass diffusion, and chemical reaction. As a result, the different reaction pathways would take part in the major reaction pathway in CH4–N2O diffusion flames, causing more entropy generation rate being produced through the more intense reactions in CH4–N2O diffusion flames. The irreversibility in CH4–air diffusion flames are dominated through heat conduction and chemical reaction, which is an identical result in CH4–N2–O2 diffusion flames. However, in CH4–N2O diffusion flames, chemical reactions dominated the irreversibility because of the more intense reaction caused by the thermal effect of N2O decomposition. As a result, the decomposition effect of N2O influences the availability of CH4–N2O diffusion flames.
DIT: A Dynamic Bandwidth Isolated Transmission System for Large-Scale Inter-DC Wireless Communication Network
Authors: Zhang Shiyan , Zhang Yuchao , Wang Ran , Gong Xiangyang , Xiong Yongping
Published: February 2023

Large companies are increasingly providing their services over interdomain data centers. Such large-scale wireless communication networks carry various applications, including both online time-sensitive services and offline bandwidth-sensitive services. These applications share the same physical links but have different bandwidth requirements at different time, making the coscheduling problem a key challenge in improving the overall network utility. Most existing commercial systems reserve peak value bandwidth for online time-sensitive services to ensure the quality of service and use the leftover bandwidth to transmit offline data in a best-effort manner. Such systems cannot obtain high link utilizations because of the nonstationarity of online traffic. To solve this problem, we present a dynamic isolated transmission (DIT) system in this paper, where a sliding-

k

algorithm is designed to predict online traffic, and a bottleneck bypass routing scheme is proposed to schedule the mixed traffic in a shared inter-DC wireless communication network. We conduct a series of experiments in an experimental inter-DC wireless communication network to analyze for efficient network operation of the DIT and compare its performance with typical existing fix-bandwidth-based solutions including Microsoft’s SWAN. The results show that DIT outperforms existing solutions, improving the interdomain link utilization by 18% and the intradomain link utilization by 65%.
Mechanism of Jiawei Zhengqi Powder in the Treatment of Ulcerative Colitis Based on Network Pharmacology and Molecular Docking
Authors: Zhao Chao , Zhi ChenYang , Zhou JianHua
Published: February 2023

Objective. Ulcerative colitis is an intestinal condition that severely affects the life quality of a patient. Jiawei Zhengqi powder (JWZQS) has some therapeutic benefits for ulcerative colitis. The current study investigated the therapeutic mechanism of JWZQS for ulcerative colitis using a network pharmacology analytical approach. Methods. In this study, network pharmacology was used to investigate the potential mechanism of JWZQS in treating ulcerative colitis. The common targets between the two were identified, and a network map was created with the Cytoscape software. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses of JWZQS was performed using the Metascape database. Protein‐protein interaction networks (PPI) was created to screen core targets and main components, and molecular docking was conducted between the main components and core targets. The expression levels of IL‐1β, IL‐6, and TNF‐α were detected in animal experiments. Their effect on the NF‐κB signaling pathway and the protective mechanism of JWZQS on the colon by tight junction protein were investigated. Results. There were 2127 potential ulcerative colitis targets and 35 components identified, including 201 non‐reproducible targets and 123 targets shared by drugs and diseases. Following the analysis, we discovered 13 significant active components and 10 core targets. The first 5 active ingredients and their corresponding targets were molecularly docked, and the results showed a high level of affinity. GO analysis showed that JWZQS participate in multiple biological processes to treat UC. KEGG analysis showed that JWZQS may be involved in regulating multiple pathways, and the NF‐κB signaling pathway was selected for analysis and verification. JWZQS has been shown in animal studies to effectively inhibit the NF‐κB pathway; reduce the expression of IL‐1β, TNF‐α, and IL‐6 in colon tissue; and increase the expression of ZO‐1, Occludin, and Claudin‐1. Conclusion. The network pharmacological study provides preliminary evidence that JWZQS can treat UC through multiple components and targets. JWZQS has been shown in animal studies to effectively reduce the expression levels of IL‐1β, TNF‐α, and IL‐6, inhibit the phosphorylation of the NF‐κB pathway, and alleviate colon injury. JWZQS can be used in clinical, but the precise mechanism of UC treatment requires further investigation.
LncRNA PANTR1 is Associated with Poor Prognostic and Suppresses Apoptosis in Glioma
Authors: Shi Fei , Hu Jie , Zheng Ping , Lv Yisong , Liu Hongyu , Zhang Guiyun , Jiang Hongyu
Published: February 2023

Glioma is the most common tumor in the central nervous system. High-grade gliomas confer a poor prognosis, being a serious health and economic burden. Current literature suggests the important role of long noncoding RNA (lncRNA) in mammals, especially in tumorigenesis of various tumors. The functions of lncRNA POU3F3 adjacent noncoding transcript 1 (PANTR1) have been investigated in hepatocellular carcinoma but remain yet unclear in gliomas. We evaluated the role of PANTR1 in glioma cells using published data from The Cancer Genome Atlas (TCGA), then validated it by ex vivo experiments. To investigate the potential cellular mechanism of different levels of PANTR1 expression in glioma cells, we used siRNA-mediated knockdown in low-grade (grade II) cell lines and GBM (grade IV) cell lines (SW1088 and SHG44, respectively). On the molecular level, low expression of PANTR1 caused significantly reduced glioma cell viability and enhanced cell death. Moreover, we identified the importance of PANTR1 expression for cell migration in both cell lines, a critical foundation for invasiveness in recurrent gliomas. In conclusion, this study provides the first evidence that PANTR1 has a relevant role in human glioma by influencing cell viability and cell death.
A Multimodal Network Security Framework for Healthcare Based on Deep Learning
Authors: Chen Qiang Qiang , Li Jian Ping , Haq Amin ul , Agbley Bless Lord Y. , Hussain Arif , Khan Inayat , Khan Riaz Ullah , Khan Jalaluddin , Ali Ijaz
Published: February 2023

As the network is closely related to people’s daily life, network security has become an important factor affecting the physical and mental health of human beings. Network flow classification is the foundation of network security. It is the basis for providing various network services such as network security maintenance, network monitoring, and network quality of service (QoS). Therefore, this field has always been a hot spot of academic and industrial research. Existing studies have shown that through appropriate data preprocessing techniques, machine learning methods can be used to classify network flows, most of which, however, are based on manually and expert‐originated feature sets; it is a time‐consuming and laborious work. Moreover, only features extracted by a single model can be used in classification tasks, which can easily make the model inefficient and prone to overfitting. In order to solve the abovementioned problems, this study proposes a multimodal automatic analysis framework based on spatial and sequential features. The framework is completely based on the deep learning method and realizes automatic extraction of two types of features, which is very suitable for processing large‐flow information; this improves the efficiency of network flow classification. There are two types of frameworks based on pretraining and joint‐training, respectively, with analyzing the advantages and disadvantages of them in practice. In terms of evaluation, compared with the previous methods, the experimental results show that the framework has good performance in both accuracy and stability.
Influence of Recycled Glass on Strength Development of Alkali-Activated High-Calcium Fly Ash Mortar
Authors: Damrongwiriyanupap Nattapong , Wongchairattana Sangsan , Phoo-Ngernkham Tanakorn , Petcherdchoo Aruz , Limkatanyu Suchart , Chindaprasirt Prinya
Published: February 2023

This article presents the development of green and sustainable mortars using alkali-activated high-calcium fly ash (AAFA) and recycled glass (RG) as part of the fine aggregate. RG was used to replace river sand at dosages of 0%, 25%, 50%, 75%, and 100% by weight. Sodium hydroxide (SH) and sodium silicate (SS) solutions were used as liquid alkaline activators in all mixtures. The AAFA samples were prepared with different liquid-to-binder ratios of 0.6 and 0.7, and the ratio of SS-to-SH was fixed at 2.0. Compressive and flexural strengths were determined at the ages of 7, 28, and 60 days. Test results showed that the compressive and flexural strengths of AAFA mortars declined as RG replacement increased; nevertheless, they increased with curing time. The high Na2O concentration derived from RG and the weak interfacial transition zone of RG are reasons for the decrease in strength development. The optimum percentage replacement of fine aggregates with RG was found at 25%. The 28-day compressive strength of AAFA with 25% RG was 32.5 MPa for L/B ratios of 0.6 and 29.5 MPa for L/B ratios of 0.7, which resulted in a strength index higher than 75% while releasing low CO2.
Tumor and Stromal Cell Targeting with Nintedanib and Alpelisib Overcomes Intrinsic Bladder Cancer Resistance
Authors: Marqués Miriam , Corral Sonia , Sánchez-Díaz María , del Pozo Natalia , Martínez de Villarreal Jaime , Schweifer Norbert , Zagorac Ivana , Hilberg Frank , Real Francisco X.
Published: February 2023

Bladder cancer is a highly prevalent tumor, requiring the urgent development of novel therapies, especially for locally advanced and metastatic disease. Nintedanib is a potent antifibrotic angio-kinase inhibitor, which has shown clinical efficacy in combination with chemotherapy in patients with locally advanced muscle-invasive bladder cancer. Nintedanib inhibits fibroblast growth factor receptors (FGFRs), validated targets in patients with bladder cancer harboring FGFR3/2 genetic alterations. Here, we aimed at studying its mechanisms of action to understand therapy resistance, identify markers predictive of response, and improve the design of future clinical trials. We have used a panel of genetically well-characterized human bladder cancer cells to identify the molecular and transcriptomic changes induced upon treatment with nintedanib, in vitro and in vivo, at the tumor and stroma cell levels. We showed that bladder cancer cells display an intrinsic resistance to nintedanib treatment in vitro, independently of their FGFR3 status. However, nintedanib has higher antitumor activity on mouse xenografts. We have identified PI3K activation as a resistance mechanism against nintedanib in bladder cancer and evidenced that the combination of nintedanib with the PI3K inhibitor alpelisib has synergistic antitumor activity. Treatment with this combination is associated with cell-cycle inhibition at the tumoral and stromal levels and potent nontumor cell autonomous effects on α-smooth muscle actin—positive tumor infiltrating cells and tumor vasculature. The combination of nintedanib with PI3K inhibitors not only reversed bladder cancer resistance to nintedanib but also enhanced its antiangiogenic effects.
ADAM Metallopeptidase Domain 12 Facilitates Colorectal Cancer Progression by Inhibiting Hippo Signaling Pathway Activity
Authors: Wang XiaoPeng , Zhu Mo , Zuo Hao , Hou Guowei , Xie Rui
Published: February 2023

This work focused on investigating the effect of A Disintegrin And Metalloproteases 12 (ADAM12) on colorectal cancer development. ADAM12 levels within colorectal cancer samples were analyzed by using The Cancer Genome Atlas (TCGA) database. Then, altogether 55 patients with colorectal cancer were enrolled to detect ADAM12 expression. ADAM12 overexpression or knockdown was transfected into colorectal cancer cells. Thereafter, this work examined colorectal cancer cell viability through Cell Counting Kit-8 (CCK-8) and cell clone forming assays. Meanwhile, nude mice were utilized for in vivo analysis. Transwell assays were conducted for detecting migration and invasion of colorectal cancer cells. In addition, mRN and protein expression was analyzed through qRT-PCR, Western blotting (WB) together with IHC staining. As a result, ADAM12 and YAP1 expression increased among colorectal cancer cases, and it indicated the dismal prognostic outcome of patients. Furthermore, ADAM12 promoted colorectal cancer cell growth, migration, invasion along with in vivo growth. ADAM12 suppressed p-MST1/MST1, p-LATS1/LATS1 together with p-YAP1 protein levels within colorectal cancer cells. ADAM12 increased YAP1 and TAZ protein levels as well as CTGF, Cyr61, and Birc5 mRNA expression in colorectal cancer cells. YAP1 inhibitor administration counteracted ADAM12’s function in promoting colorectal cancer cell growth, migration, invasion, and increasing CTGF, Cyr61, and Birc5 expression.

Implications:

Our study indicates that ADAM12 facilitates colorectal cancer progression through suppressing Hippo pathway activity, and that ADAM12 is the candidate therapeutic target and prognostic biomarker for patients with colorectal cancer.
S100A8/S100A9 Promote Progression of Multiple Myeloma via Expansion of Megakaryocytes
Authors: Lin Cindy , Garcia-Gerique Laura , Bonner Erin E. , Mastio Jerome , Rosenwasser Matthew , Cruz Zachary , Lawler Michael , Bernabei Luca , Muthumani Kar , Liu Qin , Poncz Mortimer , Vogl Thomas , Törngren Marie , Eriksson Helena , Vogl Dan T. , Gabrilovich Dmitry I. , Nefedova Yulia
Published: February 2023

Multiple myeloma is characterized by clonal proliferation of plasma cells that accumulate preferentially in the bone marrow (BM). The tumor microenvironment is one of the leading factors that promote tumor progression. Neutrophils and monocytes are a major part of the BM tumor microenvironment, but the mechanism of their contribution to multiple myeloma progression remains unclear. Here, we describe a novel mechanism by which S100A8/S100A9 proteins produced by BM neutrophils and monocytes promote the expansion of megakaryocytes supporting multiple myeloma progression. S100A8/S100A9 alone was not sufficient to drive megakaryopoiesis but markedly enhanced the effect of thrombopoietin, an effect that was mediated by Toll-like receptor 4 and activation of the STAT5 transcription factor. Targeting S100A9 with tasquinimod as a single agent and in combination with lenalidomide and with proteasome inhibitors has potent antimyeloma effect that is at least partly independent of the adaptive immune system. This newly identified axis of signaling involving myeloid cells and megakaryocytes may provide a new avenue for therapeutic targeting in multiple myeloma.

Significance:

We identified a novel mechanism by which myeloid cells promote myeloma progression independently of the adaptive immune system. Specifically, we discovered a novel role of S100A8/S100A9, the most abundant proteins produced by neutrophils and monocytes, in regulation of myeloma progression via promotion of the megakaryocyte expansion and angiogenesis. Tasquinimod, an inhibitor of S100A9, has potent antimyeloma effects as a single agent and in combination with lenalidomide and with proteasome inhibitors.
Changes in Lower Urinary Tract Symptoms in Benign Prostatic Hyperplasia Patients Affected by Covid-19
Authors: Ivanov Atanas , Antonov Petar , Hristova-Atanasova Eleonora , Uchikov Petar
Published: February 2023

Introduction: Benign prostatic hyperplasia (BPH) is a histological diagnosis characterized by an increase in the number of epithelial and stromal cells in the transitional zone of the prostate gland. The clinical manifestation of BPH is associated with the appearance of so-called lower urinary tract symptoms (LUTS) which can also be a consequence of other conditions not related to the prostate. Covid-19, also known as severe acute respiratory syndrome coronavirus 2 was discovered as a disease in late 2019 in the city of Wuhan, China. Materials and Methods: A case-control study was conducted between September 2021 and May 2022. Information was initially collected on 60 patients followed up and treated conservatively for BPH in two outpatient practices and recovered from Covid-19. After processing the received information, 27 patients were excluded from the study and 33 patients remained for observation The assessment of patients is carried out through an internationally validated questionnaire – international prostate symptom score (IPPS), prostate specific antigen, digital rectal examination (DRЕ), and ultrasound diagnostics of the prostate gland with consideration of its volume and the amount of residual urine. Results: Our data show a strong correlation between the changes in LUTS in patients with BPH and Covid-19 infection. Conclusion: Although almost 3 years have passed since the beginning of this pandemic, there are still many unanswered questions surrounding this disease. We believe that with our experience we will enrich the information about the relationship between Covid-19 and LUTS, and the results obtained by us can serve as a basis for future large-scale and more in-depth studies on the subject.
The G-Protein-Coupled Formyl Peptide Receptor 2 Promotes Endothelial-Mesenchymal Transition in Diabetic Retinopathy
Authors: Lou Xueying , Liu Shuang , Shi Jian , Chen Hongliang , Wang Zichen , Le Yingying , Chen Hui , Zhu Rongrong , Yu Ying
Published: February 2023

Introduction: In proliferative diabetic retinopathy (PDR), retinal neovascularization is the essential pathogenic process that is linked to endothelial-to-mesenchymal transition (EndoMT) induced by high glucose (HG). This pathophysiological process may be regulated by a G-protein-coupled chemoattractant receptor FPR2 (mouse Fpr2), involved in inflammatory cell migration and proliferation. In the current study, we investigated the role of Fpr2 in regulating EndoMT and the underlying mechanisms during diabetic retinopathy progression. Methods: FPR2 agonist or inhibitor was added to human microvascular endothelial cells (HMECs) exposed to normal glucose or HG. Morphologic, phenotypic, and functional changes of HMECs as well as the formation of microvasculature related to EndoMT were assessed. EndoMT biomarkers were detected in the retinal tissues of diabetic mice and fibrovascular epiretinal membranes (FVMs) from patients with PDR. Results: HG upregulated FPR2 in HMECs, which triggered morphological changes, and the cells acquired mesenchymal phenotype, with enhanced cell migration, viability, and angiogenic process shown by tube formation and aortic ring sprouting. Inhibition of FPR2 attenuated HG-induced EndoMT and endothelial cell migration to form vessel-like tube structures. RNA sequence and protein analysis further revealed that inhibition of FPR2 decreased the expression of genes associated with EndoMT. ERK1/2 and P38 signaling pathway was activated in HMECs, promoting neovascularization in HG-induced EndoMT of HMECs. In vivo, increased expression of mesenchymal markers was detected in the retina of diabetic mice and FVMs from patients with PDR. FPR2 deficiency was associated with diminished EndoMT-related phenotypic changes in the retina of diabetic mice. Conclusions: FPR2 is actively involved in the progression of EndoMT that may contribute to the pathogenesis of PDR. Thus, FPR2 may be a potential therapeutic target for PDR.
Incidence, Prevalence, Hospitalization Rates, and Treatment Patterns in Myasthenia Gravis: A 10-Year Real-World Data Analysis of German Claims Data
Authors: Wartmann Hannes , Hoffmann Sarah , Ruck Tobias , Nelke Christopher , Deiters Barthold , Volmer Timm
Published: February 2023

Background: Myasthenia gravis (MG) is a rare chronic autoimmune disease caused by autoantibodies directed against postsynaptic antigens of the neuromuscular junction. Over the last decades, increasing incidence and prevalence rates have been reported. Epidemiological data on prevalence and incidence in Germany are lacking. Furthermore, the MG treatment landscape is rapidly changing due to the continued approval of novel monoclonal antibodies. Method: This is a retrospective study assessing incidence, prevalence, and hospitalization rates of MG as well as treatment patterns in Germany over 10 years based on medical claims data covering 6.1 million insured persons. Results: Between 2011 and 2020, the prevalence rate of MG increased from 15.7 to 28.2 per 100,000 person-years. The age-adjusted incidence rate was 2.8 per 100,000 person-years within the study period (95% confidence interval, 2.43–3.22) and decreased dramatically in 2020, the year of the COVID-19 pandemic. Similarly, the hospitalization rate fluctuated within the study period but reached an overall low of 8.3% in 2020 (mean hospitalization rate 11.5%). Treatment patterns showed that most MG patients are treated with base therapy. However, crisis intervention is necessary for 2–5% of MG patients, and therapeutic monoclonal antibodies, including rituximab and eculizumab, are increasingly used. Conclusion: This is the first study on MG prevalence and incidence rates in Germany. Data show an increase in prevalence by 1.8-fold over 10 years. Decreasing incidence and hospitalization rates in 2020 hint at the impact of the COVID-19 pandemic. Treatment patterns in MG are changing with the advent of therapeutic monoclonal antibodies in this indication.
Impact of Dapagliflozin Treatment on Serum Sodium Concentrations in Acute Heart Failure
Authors: Charaya Kristina , Shchekochikhin Dmitry , Agadzhanyan Anna , Vashkevich Maria , Chashkina Maria , Kulikov Valeri , Andreev Denis
Published: February 2023

Introduction: The dynamics of serum sodium are important in acute heart failure (AHF), and hyponatremia is associated with a poor prognosis. The effect of sodium-glucose cotransporter type 2 inhibitors (SGLT2i) on serum sodium concentrations in AHF is unknown. Methods: In a single-centre, controlled, randomized study, patients were prescribed dapagliflozin in addition to standard treatment during the first 24 h of hospitalization versus standard treatments. The pre-specified outcome was an absolute change in plasma sodium concentrations between randomization (first 24 h after admission) and discharge. The secondary outcomes were an absolute change in serum sodium concentrations within 48 h of randomization and the persistence of hyponatremia. Results: The sample comprised 285 patients (53% males; average age 73.26 ± 13 years); 140 of these were randomized to the dapagliflozin group. The average ejection fraction was 46 ± 14%; 155 patients (54%) had ischaemic heart failure; and 35% had diabetes mellitus. Median N-terminal pro b-type natriuretic peptide was 4,225 [2,120; 9,105] pg/mL. The average estimated glomerular filtration rate was 53.9 ± 17.2 mL/min. Hospital mortality was 6.7%. At randomization, serum sodium concentrations were 139.8 ± 4.32 mmol/L in the dapagliflozin group versus 140.85 ± 4.04 mmol/L in the control group; p = 0.048. 48 h later, there was an increase in serum sodium in the dapagliflozin group (2 [−2; 4] mmol/L), as compared to the control group (−1 [−3.75; 2]); p < 0.001. This was accompanied by equilibration of the sodium levels between the groups (141.08 ± 4.08 mmol/L in the dapagliflozin group vs. 140.05 ± 4.82 mmol/L in the control group; p = 0.096). At the time of discharge, there was no difference in serum sodium concentrations (140.98 ± 4.77 mmol/L vs. 139.86 ± 4.45 mmol/L; p = 0.082). The increase in serum sodium concentrations during the period of observation [randomization; discharge] was small but statistically significant in the dapagliflozin group (1 [−3; 3.75] mmol/L vs. −2 [−4.5; 2] mmol/L; p = 0.015). Of 36 patients (21 in the dapagliflozin group and 15 in the control group) with baseline hyponatraemia, this persisted in 6 (16.6%) in the dapagliflozin group and in 11 (73.3%) in the control group (p = 0.008). Conclusion: The use of dapagliflozin in AHF is associated with a tendency to the increase in serum sodium concentrations and lesser persistence of hyponatremia. This effect occurred within the first 48 h and persisted until discharge. The impact of dapagliflozin on serum sodium was more pronounced in patients with hyponatremia at randomization.
Management of Idiopathic Granulomatous Mastitis: A Single Institution Experience
Authors: Esmaeil Nawzad Khaleil , Salih Abdulwahid M. , Pshtiwan Lana R.A. , Muhialdeen Aso S. , Abdullah Ari M. , Hama Jihad Ibrahim , Hammood Zuhair D. , Kakamad Fahmi H. , Tahir Soran H. , Abdalla Berun A. , Salih Karzan M. , Mohammed Shvan H.
Published: February 2023

Introduction: There are multiple management modalities for idiopathic granulomatous mastitis, but the treatment of choice is still under debate. This study aims to evaluate the diagnosis and outcomes of different management modalities in patients with idiopathic granulomatous mastitis and to identify the risk factors associated with recurrence. Method: This is a single-group cohort study that included those patients who had idiopathic granulomatous mastitis. Ultrasonography was conducted for all of the cases using LOGIQ E9 with an ML6-15 transducer (5–15 MHz). A core needle biopsy was conducted to take samples from the cases for histopathological examination. The patients were put on steroid therapy. Whenever the cases did not respond to the steroid therapy, treatment with a combination of low-dose steroids and methotrexate was started. In the lack of response to conservative treatments, surgical interventions were started. Results: Sixty-three cases with a confirmed histopathological diagnosis of granulomatous mastitis were included. The mean age of patients was 35.7 years. The history of more than one childbirth was positive in a large portion of the cases (82.5%). The lesion side was unilateral in 58.7% of the cases. A large proportion of the lesions were classified as BIRADS category 2. The best treatment outcome was yielded by a combination of low-dose steroids and incision and drainage. The factors of age, lesion area (cm2), skin thickening, and white blood cell count enhanced the chance of recurrence. Conclusion: Incision and drainage in combination with a low dose of steroids can give an acceptable outcome with a low rate of recurrence.
Characteristics of Patients Presenting at a University Outpatient Department for Complementary and Integrative Medicine
Authors: Rotter Gabriele , Binting Sylvia , Teut Michael , Ortiz Miriam , Willich Stefan N. , Brinkhaus Benno
Published: February 2023

Background: Complementary and integrative medicine (CIM) is increasingly provided at university outpatient departments (OPDs) in Germany, but its scientific evaluation is sparse. Therefore, we aimed to investigate and evaluate feasibility, patients’ characteristics and complaints at a university’s CIM-OPD. Methods: A prospective evaluation included new patients without age restriction. At baseline, and after 6 and 12 months, patients filled out paper questionnaires. Patients rated their mean subjectively perceived severity of the main complaint within the last 7 days on a numerical rating scale (NRS) from 0 = no complaints to 10 = maximum complaints, their perceived resilience capacity in everyday life within the last 7 days (0 = not resilient to 10 = very resilient), and their contentment with the treatment (0 = not content to 10 = very content). Diagnoses were provided by physicians and coded according to the International Statistical Classification of Diseases and Related Health Problems, 10th revision. All data were analyzed descriptively. Results: During two years, 536 new patients {72.6% response, age (mean ± standard deviation [SD] and range) 49.6 ± 15.8 and 1–86 years, 75.7% female} chose to participate. The most frequent diagnosis groups were neoplasms (C00-C97, n = 143, 18.6%) and musculoskeletal diseases (M00-M99, n = 137, 17.9%). In n = 165 patients (30.8%), more than one diagnosis was provided. In a subgroup of 187 patients, who returned the questionnaire after 6 months, we compared baseline to 6-month values: severity of main complaint (mean ± SD) 5.2 ± 2.6 changed to 3.9 ± 2.6; resilience capacity 5.1 ± 2.6 to 5.6 ± 2.4. After 6 months, respondents rated their contentment with the treatment with (mean ± SD) 7.7 ± 2.6. Data after 12 months (n = 113) are comparable to data after 6 months. Conclusion: Patients of our CIM-OPD had a broad age range, were predominantly female, and suffered mostly from oncologic-related complaints and musculoskeletal diseases. In the responding subgroup after 6 months, patients were content with the treatment. These results should be verified by further prospective evaluations.