bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimum Conditions and LC-ESI-MS Analysis of Phenolic Rich Extract from Eucalyptus marginata L. under Maceration and Ultrasound-Assisted Extraction Methods Using Response Surface Methodology
Authors: Hasni Soumaya , Rigane Ghayth , Ghazghazi Hanene , Riguene Hajer , Bouallegue Amir , Khedher Olfa , Oueslati Moufida A. , Ben Salem Ridha
Published: November 2021

Eucalyptus marginata L. has a significant value in traditional medicine and recently has been shown to possess many pharmacological properties in vitro. The main goal of the present study was to optimize the extraction parameters of phenolic compounds from Eucalyptus marginata L. leaves using the extraction technique assisted by ultrasound in comparison with maceration using response surface methodology as a predicted tool. Therefore, total phenolic and flavonoid contents have been optimized, taking into account four variables: extraction time, temperature, liquid-to-solid ratio, and ethanol concentration. The optimum ultrasound-assisted extraction method for total phenolic and total flavonoid contents was obtained by ensuring the following parameters: t = 49.9 min, T = 74.9°C, liquid-to-solid ratio = 39.5 ml/g, and ethanol = 58.48%. The optimum extract has been subjected to LC-ESI-MS analysis. This technique allowed us to identify ten phenolic compounds: four phenolic acids mainly gallic acid (27.77 ± 0.06 µg/g DW) and protocatechuic acid (37.66 ± 0.04 µg/g DW) and six flavonoid compounds such as quercetrin (150.78 ± 0.02 µg/g DW) and hyperoside (39.19 ± 0.03 µg/g DW). These green and efficient procedures should be a promising option to guide industrial design for the production of phenolic-rich plant extracts.
Application Value of a Deep Convolutional Neural Network Model for Cytological Assessment of Thyroid Nodules
Authors: Ren Ying , He Yu , Cong Linghua
Published: November 2021

Objective. To investigate the application value of a deep convolutional neural network (CNN) model for cytological assessment of thyroid nodules. Methods. 117 patients with thyroid nodules who underwent thyroid cytology examination in the Affiliated People’s Hospital of Ningbo University between January 2017 and December 2019 were included in this study. 100 papillary thyroid cancer samples and 100 nonmalignant samples were collected respectively. The sample images were translated vertically and horizontally. Thus, 900 images were separately created in the vertical and horizontal directions. The sample images were randomly divided into training samples (n = 1260) and test samples (n = 540) at the ratio of 7 : 3 per the training sample to test sample. According to the training samples, the pretrained deep convolutional neural network architecture Resnet50 was trained and fine-tuned. A convolutional neural network-based computer-aided detection (CNN-CAD) system was constructed to perform full-length scan of the test sample slices. The ability of CNN-CAD to screen malignant tumors was analyzed using the threshold setting method. Eighty pathological images were collected from patients who received treatment between January 2020 and May 2020 and used to verify the value of CNN in the screening of malignant thyroid nodules as verification set. Results. With the number of iterations increasing, the training and verification loss of CNN model gradually decreased and tended to be stable, and the training and verification accuracy of CNN model gradually increased and tended to be stable. The average loss rate of training samples determined by the CNN model was (22.35 ± 0.62) %, and the average loss rate of test samples determined by the CNN model was (26.41 ± 3.37) %. The average accuracy rate of training samples determined by the CNN model was (91.04 ± 2.11) %, and the average accuracy rate of test samples determined by the CNN model was (91.26 ± 1.02)%. Conclusion. A CNN model exhibits a high value in the cytological diagnosis of thyroid diseases which can be used for the cytological diagnosis of malignant thyroid tumor in the clinic.
Aloe-Emodin-Mediated Photodynamic Therapy Induces Apoptosis in Basal Cell Carcinoma Cells via Activation of ERK/JNK Signaling Pathway
Authors: Odhiambo Woodvine Otieno , Geng Songmei , Wang Xiaopeng , Chen Xiaodong , Qin Mengting , Yuan Meng , Wang Yang , Riaz Farooq , Liu Chengcheng , Ji Yanhong
Published: November 2021

Basal cell carcinoma (BCC) is the most prevalent epidermal cancerous neoplasm. Previous studies have reported the noninvasive, cost-effective, and localized photodynamic therapy (PDT) approach to BCC treatment. This study investigated the photodynamic effects of aloe-emodin (AE), a natural anthraquinone photosensitizer (PS), on proliferation and apoptosis of BCC TE 354.T cell line. To evaluate the effects of AE-mediated PDT, we used various concentrations of AE (0, 2.5, 5, and 10 μM) and white light energy (0, 12, 24, and 36 J/cm2). CCK-8 assay was used to analyse cell viability following AE-mediated PDT. The cell death rate and reactive oxygen species (ROS) were assessed by flow cytometry. Western blotting was used to determine the effects of AE-mediated PDT on the apoptotic proteins, Akt, and MAPK pathways. AE-mediated PDT inhibited tumorigenic cell proliferation, consequently enhancing apoptosis in AE and PDT concentration and dose-dependent manner, respectively. Significantly increased TE 354.T cell apoptosis and intracellular ROS production were both observed after AE-mediated PDT. Following the AE-mediated PDT, cytochrome and antitumor p53 were elevated; however expression of Bcl-2 was significantly decreased. Significant caspase 3 elevation post-AE-mediated PDT suggested intrinsically driven apoptosis. Additionally, AE-mediated PDT significantly suppressed NF-κB, Akt, and ERK pathways while JNK expression was significantly increased. AE-mediated PDT induced TE 354.T cell apoptosis through the intracellular generation of ROS. Akt, ERK, and JNK all play various roles in ensuring successful TE 354.T tumor cell apoptosis.
Effect of Traditional Chinese Medicine Combined with Bladder Perfusion with Hydroxycamptothecin on Color Ultrasound and Clinical Efficacy in Patients with Bladder Cancer Surgery
Authors: Zhou Shisheng , Fan Xia , Du Xiaojie , Liu Shuang , Sun Hongmei , Zhang Yan
Published: November 2021

Objective. To observe the clinical effect of Xiaozheng Decoction combined with bladder perfusion with hydroxycamptothecin in the treatment of bladder cancer. Methods. A total of 92 bladder cancer patients admitted to our hospital from January to December 2018 were selected and divided into an observation group and a control group according to the random number table method, with 46 cases in each group. The observation group was given Xiaozheng Decoction combined with bladder perfusion with hydroxycamptothecin, and the control group was given hydroxycamptothecin. The levels of serum-related factors (intercellular adhesion molecule-1 (ICAM-1), E-cadherin, cell adhesion molecules (CAM), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF)), white blood cell (WBC) level, immune function indexes, short-term total response rate, and incidence of adverse reactions were compared between the two groups before and after treatment. Results. After 2 years of postoperative treatment, the levels of ICAM-1, E-cadherin, CAM-1, FGF, and VEGF (a, b, c) in both groups were improved compared with those before treatment and the observation group was better than the control group

p
<
0.01

. The number of WBCs was significantly higher than in the control group after Traditional Chinese Medicine (TCM) treatment. The observation group was better than the control group in increasing CD3+ and CD4+ levels and decreasing CD8+ level

p
<
0.05

, indicating that this prescription could improve the immune function of patients. The recurrence rate in the observation group was 6.52% after 2 years of treatment, lower than 17.39% in the control group. Color ultrasound parameters showed that there were no statistically significant differences in arrive time (AT) and time to peak (TTP) between patients with and without recurrence and peak intensity (PI) and washout time (WT) were higher in patients with recurrence than in patients without recurrence

p
<
0.01

. The incidence of adverse reactions was significantly lower than that of the control group

p
<
0.01

. Conclusion. The clinical effect of Xiaozheng Decoction combined with hydroxycamptothecin on the treatment of bladder cancer was clear and superior to that of hydroxycamptothecin, which could effectively improve the serological indicators of patients with a low incidence of adverse reactions and prolong the survival cycle of patients. Therefore, it is worthy of promotion and application.
Crosslinking, Mechanical Properties, and Antimicrobial Activity of Photocurable Diacrylate Urethane/ZnO-Ag Nanocomposite Coating
Authors: Do Truc Vy , Ha Minh Nguyet , Nguyen Tuan Anh , Ha Hoang Thu , Nguyen Thien Vuong
Published: November 2021

In this article, ZnO-Ag nanohybrids were chemically synthesized in the aqueous medium by reducing silver nitrate with sodium borohydride NaBH4. These nanohybrids were then homogeneously dispersed into the diacrylate urethane/1,6-hexanediol diacrylate resin system at a content of 2 wt%. The structural morphology, mechanical resistances, and crosslinking of the as-prepared nanocomposite coating (nanocoating) were evaluated. The antimicrobial characteristic was tested by keeping track of the lag-log growth phase of E. coli bacteria in the coating existence among cell cultures. The obtained data indicated that the nanohybrids added into the UV curing diacrylate urethane matrices had significantly increased the abrasion resistance, relative hardness, and conversion of the acrylate groups of the nanocoating. In addition, the antibacterial test revealed that the nanocoating had good antibacterial property against E. coli, whereas for the pure coating (without ZnO-Ag nanoparticles), there was no antibacterial activity observed.
Industrial Internet Federated Learning Driven by IoT Equipment ID and Blockchain
Authors: Zhang Xu , Hou Haibo , Fang Zhao , Wang Zhiqian
Published: November 2021

With the development of Internet of Things (IoT), 5G, and industrial technology, Industrial Internet has become an emerging research field. Due to the industrial specialty, higher requirements are put forward for time delay, safety, and stability of the identification analysis service. The traditional domain name system (DNS) cannot meet the requirements of industrial Internet because of the single form of identification subject and weak awareness of security protection. As a solution, this work applies blockchain and federated learning (FL) to the industrial Internet identification. Blockchain is a decentralized infrastructure widely used in digital encrypted currencies such as Bitcoin, which can make secure data storage and access possible. Federated learning protects terminal personal data privacy and can carry out efficient machine learning among multiple participants. The numerical results justify that our proposed federated learning and blockchain combination lays a strong foundation for the development of future industrial Internet.
Decision-Making Optimization of Mine Gas Monitoring Based on Gauss Process Regression and Interval Number Correlation Analysis
Authors: Dong Dingwen
Published: November 2021

For the subjective limitation of gas sensor calibration in coal mines, a decision-making method for gas sensor calibration under monitoring failure was studied based on the Gauss process regression (GPR) and the correlation analysis of interval numbers. Based on the correlation characteristics of gas monitoring data of each monitoring point in the work face area in coal mine, the initial confidence interval of gas concentration in monitoring failure period was obtained by GPR, and then the confidence interval was further optimized by the correlation analysis of interval numbers. According to the correlation characteristics of monitoring data of each monitoring point, its similarity of dynamic variation tendency was measured by using Euclidean distance of interval numbers, and the optimal confidence interval was determined by calculating the correlation degree of interval numbers. The case study shows that making full use of the effective monitoring information of multiple monitoring points ensures the reliability of the initial confidence interval; the dynamic adjustment of model parameters in correlation analysis of interval number avoids the subjectivity defect of similar methods and further obtains the consistency between interval numbers’ reliability and correlation degree, which can ensure the effectiveness of the application of this method.
Influence of MRI on Diagnostic Efficacy and Satisfaction of Patients with Alzheimer’s Disease
Authors: Dong Zheng , Yang Xinyu , Chang Liming , Song Xin , Li Xiangchun , Wang Jiantao , Li Juntao
Published: November 2021

Objective. To inquire into the influence of magnetic resonance imaging (MRI) on the diagnostic efficacy and satisfaction of patients with Alzheimer’s disease (AD). Methods. This study included 42 healthy people (control group) and 66 patients with AD (AD group). The hippocampus volume, temporal sulcus spacing, left-right brain diameter, brain lobe volume, hippocampal height, temporal horn width, lateral fissure width, and degree of leukoaraiosis were all measured using an MRI scan. After diagnosis, the satisfaction of patients in both arms was investigated and the satisfaction degree was recorded. Results. Compared with the control group, the left and right hippocampal volumes and hippocampal height of AD patients were smaller, while the temporal sulcus spacing, temporal horn width, lateral fissure width, and left-right brain diameter were remarkably higher. A statistical difference was present in the degree of leukoaraiosis between the two arms. The frontal and temporal lobe volumes of AD patients were notably lower while the volumes of parietal and occipital lobes were similar, versus the control group. The total satisfaction was 83.33% in the control group and 86.36% in the AD group, with no statistical difference between the two arms. Conclusions. MRI can effectively mine the brain information of AD patients with a high patient satisfaction, which has potential value in clinical application.
Numerical Investigation of Chemical Schnakenberg Mathematical Model
Authors: Khan Faiz Muhammad , Ali Amjad , Hamadneh Nawaf , Abdullah  , Alam Md Nur
Published: November 2021

Schnakenberg model is known as one of the influential model used in several biological processes. The proposed model is an autocatalytic reaction in nature that arises in various biological models. In such kind of reactions, the rate of reaction speeds up as the reaction proceeds. It is because when a product itself acts as a catalyst. In fact, model endows fractional derivatives that got great advancement in the investigation of mathematical modeling with memory effect. Therefore, in the present paper, the authors develop a scheme for the solution of fractional order Schnakenberg model. The proposed model describes an auto chemical reaction with possible oscillatory behavior which may have several applications in biological and biochemical processes. In this work, the authors generalized the concept of integer order Schnakenberg model to fractional order Schnakenberg model. We provided the approximate solution for the underlying generalized nonlinear Schnakenberg model in the sense of Caputo differential operator via Laplace Adomian decomposition method (LADM). Furthermore, we established the general scheme for the considered model in the form of infinite series by the aforementioned technique. The consequent results obtained by the proposed technique ensure that LADM is an effective and accurate techniques to handle nonlinear partial differential equations as compared to the other available numerical techniques. Finally, the obtained numerical solution is visualized graphically by MATLAB to describe the dynamics of desired solution.
Nrf3 Promotes 5-FU Resistance in Colorectal Cancer Cells via the NF-κB/BCL-2 Signaling Pathway In Vitro and In Vivo
Authors: Cai Bi-Qing , Chen Wan-Meng , Zhao Jia , Hou Wei , Tang Jian-Cai
Published: November 2021

Increasing evidence indicates that nuclear factor, erythroid 2-like 3 (Nrf3) is connected with tumorigenesis. However, the relationship between Nrf3 and tumor drug resistance remains elusive. In this study, we investigated the effect and mechanism of action by which Nrf3 regulated the sensitivity of colon cancer cells to 5-fluorouracil (5-FU). We found Nrf3 was significantly increased in colon cancer tissues. Furthermore, we observed that Nrf3 knockdown and overexpression can significantly affect the sensitivity of colon cancer cells to 5-FU in vitro and in vivo. Moreover, Nrf3 promoted the expression of RELA, P-RELA, and BCL-2. Inhibition of NF-κB partly reversed the effects of Nrf3 overexpression, resulting in the resistance of colon cancer cells to 5-FU. Overall, the study revealed that Nrf3 was connected to the sensitivity of colon cancer cells to 5-FU, and its possible mechanism was related to the NF-κB signaling pathway, which provided a new target for overcoming the resistance of colon cancer cells to 5-FU.
A Distributed Security SDN Cluster Architecture for Smart Grid Based on Blockchain Technology
Authors: Xiong Ao , Tian Hongkang , He Wenchen , Zhang Jie , Meng Huiping , Guo Shaoyong , Wang Xinyan , Wu Xinyi , Kadoch Michel
Published: November 2021

This paper proposes a smart grid distributed security architecture based on blockchain technology and SDN cluster structure, referred to as ClusterBlock model, which combines the advantages of two emerging technologies, blockchain and SDN. The blockchain technology allows for distributed peer-to-peer networks, where the network can ensure the trusted interaction of untrusted nodes in the network. At the same time, this article adopts the design of an SDN controller distributed cluster to avoid single point of failure and balance the load between equipment and the controller. A cluster head was selected in each SDN cluster, and it was used as a blockchain node to construct an SDN cluster head blockchain. By combining blockchain technology, the security and privacy of the SDN communication network can be enhanced. At the same time, this paper designs a distributed control strategy and network attack detection algorithm based on blockchain consensus and introduces the Jaccard similarity coefficient to detect the network attacks. Finally, this paper evaluates the ClusterBlock model and the existing model based on the OpenFlow protocol through simulation experiments and compares the security performance. The evaluation results show that the ClusterBlock model has more stable bandwidth and stronger security performance in the face of DDoS attacks of the same scale.
Development Strategy of Internet Interactive Video under the Background of 5G Converged Media and Wireless Communication
Authors: Miao Ruomu , Li Juan , Gao Jiayin
Published: November 2021

At this stage, the promotion of 5G network has a positive basic value for the development of Internet interactive video. With the arrival of 5G era and the vigorous development of wireless communication technology, the trend of media convergence is more and more intense. The innovation of emerging technology and communication mode provides a strong support for the development of interactive video. With 5G technology as the background, Internet interactive video ushered in a blowout period of development. In recent years, video websites at home and abroad have launched interactive videos with their own characteristics. So, the imagination of integrated media evolved into the reality gradually. However, the excessively fast development speed concealed many existing shortcomings. There are still many constraints and deficiencies in the deep integration of each link of Internet interactive video. This paper discusses the development status of Internet interactive video and deeply analyzes the development characteristics of interactive video. In view of the existing problems, this paper puts forward development suggestions from the aspects of creating high‐quality content and building “interactive video +” to help the better development of Internet interactive video.
A Method of Using Data Mining and Edge Computing to Calculate the Standing Efficiency of Basketball Games
Authors: Wang Zhe , Liu Yuzhong
Published: November 2021

The continuous improvement of basketball tactics has high requirements for athletes’ position selection. This article proposes an intelligent method for basketball position selection. Massive basketball game data will provide people with richer content. Analyzing massive basketball game data can provide a new method for position efficiency calculation. To solve this problem, we can combine edge computing and data mining technology classification technology to build a basketball game position efficiency calculation model. First of all, we build a basketball game position efficiency calculation architecture through edge computing technology. Secondly, we use random forest algorithm and fuzzy neural network algorithm to analyze relevant basketball game information. The experimental simulation test results verify the superior performance of the basketball game position efficiency calculation model established in this paper. This model can provide help to improve the information level of basketball games.
Bisdemethoxycurcumin Protects Small Intestine from Lipopolysaccharide‐Induced Mitochondrial Dysfunction via Activating Mitochondrial Antioxidant Systems and Mitochondrial Biogenesis in Broiler Chickens
Authors: Zhang Jingfei , Yang Yuxiang , Han Hongli , Zhang Lili , Wang Tian
Published: November 2021

Bisdemethoxycurcumin is one of the three curcuminoids of turmeric and exhibits good antioxidant activity in animal models. This study is aimed at investigating the effect of bisdemethoxycurcumin on small intestinal mitochondrial dysfunction in lipopolysaccharide‐ (LPS‐) treated broilers, especially on the mitochondrial thioredoxin 2 system and mitochondrial biogenesis. A total of 320 broiler chickens were randomly assigned into four experimental diets using a 2 × 2 factorial arrangement with diet (0 and 150 mg/kg bisdemethoxycurcumin supplementation) and stress (saline or LPS challenge) for 20 days. Broilers received a dose of LPS (1 mg/kg body weight) or sterile saline intraperitoneally on days 16, 18, and 20 of the trial. Bisdemethoxycurcumin mitigated the mitochondrial dysfunction of jejunum and ileum induced by LPS, as evident by the reduced reactive oxygen species levels and the increased mitochondrial membrane potential. Bisdemethoxycurcumin partially reversed the decrease in the mitochondrial DNA copy number and the depletion of ATP levels. Bisdemethoxycurcumin activated the mitochondrial antioxidant response, including the prevention of lipid peroxidation, enhancement of manganese superoxide dismutase activity, and the upregulation of the mitochondrial glutaredoxin 5 and thioredoxin 2 system. The enhanced mitochondrial respiratory complex activities in jejunum and ileum were also attributed to bisdemethoxycurcumin treatment. In addition, bisdemethoxycurcumin induced mitochondrial biogenesis via transcriptional regulation of proliferator‐activated receptor‐gamma coactivator‐1alpha pathway. In conclusion, our results demonstrated the potential of bisdemethoxycurcumin to attenuate small intestinal mitochondrial dysfunction, which might be mediated via activating the mitochondrial antioxidant system and mitochondrial biogenesis in LPS‐treated broilers.
Experimental Research on the Similarity of Rime Icing on a Cylinder Rotating around Its Horizontal Axis
Authors: Shi Lei , Li Yan , Guo Wenfeng , Sun Ce
Published: November 2021

Ice accumulation on the blade of a wind turbine surface seriously threatens the operational safety of the turbine; therefore, the research on this problem is very important. In this paper, a new similarity criterion of icing shape for a rotational model was proposed based on the similarity criterion for translational motion models in the aviation field, and experimental studies on the similarity of the rotational model icing were carried out. To validate the similarity criterion, icing wind tunnel tests were carried out with aluminum cylinders with diameters of 40 mm and 20 mm. Key parameters for the experiment, such as wind speed, temperature, liquid water content, medium volume diameter, and test time, were selected based on the criterion. All the icing tests were carried out in a new self-designed icing wind tunnel test system based on natural low-temperature conditions. The icing shapes observed in the tests were confirmed after many repetitions. To quantitatively analyze the similarity between different sizes of ice shapes, a dimensionless method for evaluating the similarity of ice shapes of different sizes was defined based on the typical characteristics of ice shapes. The research results show that the similarity score between two sizes of ice shapes under different test conditions is 81%~90%. The accuracy and applicability of the icing shape similarity criterion were thus validated. The research results in this paper lay a theoretical and experimental foundation for exploring the icing shape similarity of a rotating model.
FGFR3 Destabilizes PD-L1 via NEDD4 to Control T-cell–Mediated Bladder Cancer Immune Surveillance
Authors: Jing Weiqiang , Wang Ganyu , Cui Zhiwei , Xiong Gaozhong , Jiang Xin , Li Yue , Li Wushan , Han Bo , Chen Shouzhen , Shi Benkang
Published: November 2021

Fibroblast growth factor receptor 3 (FGFR3) is frequently activated by mutation or overexpression, and it is a validated therapeutic target in urothelial carcinoma (UC) of the bladder. However, the role and detailed molecular mechanism of FGFR3 in the immune microenvironment of bladder cancer remain largely unknown. Here, we demonstrate that inhibition of FGFR3 in FGFR3-activated bladder cancer elevates PD-L1 protein levels by affecting its ubiquitination, thereby inhibiting the antitumor activity of CD8+ T cells. Tissue microarray analysis in human UC showed an inverse correlation between FGFR3 and PD-L1. Furthermore, NEDD4, an E3 ubiquitin ligase of the NEDD4 family of proteins, was phosphorylated by FGFR3 activation and served as a regulator of PD-L1 ubiquitination. Mechanistically, NEDD4 interacted with PD-L1 and catalyzed Lys48 (K48)-linked polyubiquitination of PD-L1. In mice bearing NEDD4 knockout bladder cancer, CD8+ T-cell infiltration and antitumor activity were significantly inhibited due to PD-L1 upregulation in bladder cancer cells. Furthermore, multiple FGFR3-activated tumor-bearing mouse models suggested that attenuated CD8+ T-cell–mediated antitumor efficacy following FGFR3-targeted therapy could be rescued by a combination with anti-PD-1 immunotherapy, which leads to effective tumor suppression. This study establishes a key molecular link between targeted therapy and immune surveillance and identifies NEDD4 as a crucial E3 ubiquitin ligase that targets PD-L1 for degradation in FGFR3-activated bladder cancer. These findings may potentially be exploited for combination therapies in UC of the bladder and possibly other malignancies with activated FGFR3.

Significance:

NEDD4 links two important molecules associated with targeted therapy and immune surveillance, providing mechanistic rationale and preclinical support for immuno-targeted combination therapy for FGFR3-activated bladder cancer.
MALT1 Is a Targetable Driver of Epithelial-to-Mesenchymal Transition in Claudin-Low, Triple-Negative Breast Cancer
Authors: Lee Jia-Ying Lloyd , Ekambaram Prasanna , Carleton Neil M. , Hu Dong , Klei Linda R. , Cai Zongyou , Myers Max I. , Hubel Nathaniel E. , Covic Lidija , Agnihotri Sameer , Krappmann Daniel , Bornancin Frédéric , Lee Adrian V. , Oesterreich Steffi , McAllister-Lucas Linda M. , Lucas Peter C.
Published: November 2021

MALT1 is the effector protein of the CARMA/Bcl10/MALT1 (CBM) signalosome, a multiprotein complex that drives pro-inflammatory signaling pathways downstream of a diverse set of receptors. Although CBM activity is best known for its role in immune cells, emerging evidence suggests that it plays a key role in the pathogenesis of solid tumors, where it can be activated by selected G protein–coupled receptors (GPCR). Here, we demonstrated that overexpression of GPCRs implicated in breast cancer pathogenesis, specifically the receptors for Angiotensin II and thrombin (AT1R and PAR1), drove a strong epithelial-to-mesenchymal transition (EMT) program in breast cancer cells that is characteristic of claudin-low, triple-negative breast cancer (TNBC). In concert, MALT1 was activated in these cells and contributed to the dramatic EMT phenotypic changes through regulation of master EMT transcription factors including Snail and ZEB1. Importantly, blocking MALT1 signaling, through either siRNA-mediated depletion of MALT1 protein or pharmacologic inhibition of its activity, was effective at partially reversing the molecular and phenotypic indicators of EMT. Treatment of mice with mepazine, a pharmacologic MALT1 inhibitor, reduced growth of PAR1+, MDA-MB-231 xenografts and had an even more dramatic effect in reducing the burden of metastatic disease. These findings highlight MALT1 as an attractive therapeutic target for claudin-low TNBCs harboring overexpression of one or more selected GPCRs.

Implications:

This study nominates a GPCR/MALT1 signaling axis as a pathway that can be pharmaceutically targeted to abrogate EMT and metastatic progression in TNBC, an aggressive form of breast cancer that currently lacks targeted therapies.
Intentional Modulation of Ibrutinib Pharmacokinetics through CYP3A Inhibition
Authors: Eisenmann Eric D. , Fu Qiang , Muhowski Elizabeth M. , Jin Yan , Uddin Muhammad Erfan , Garrison Dominique A. , Weber Robert H. , Woyach Jennifer A. , Byrd John C. , Sparreboom Alex , Baker Sharyn D.
Published: November 2021

Ibrutinib (Imbruvica; PCI-32765) is an orally administered inhibitor of Bruton's tyrosine kinase that has transformed the treatment of B-cell malignancies. However, ibrutinib has very low oral bioavailability that contributes to significant variability in systemic exposure between patients, and this has the potential to affect both efficacy and toxicity. We hypothesized that the oral bioavailability of ibrutinib is limited by CYP3A isoform–mediated metabolism, and that this pathway can be inhibited to improve the pharmacokinetic properties of ibrutinib. Pharmacokinetic studies were performed in wild-type mice and mice genetically engineered to lack all CYP3A isoforms (CYP3A−/−) that received ibrutinib alone or in combination with CYP3A inhibitors cobicistat or ketoconazole. Computational modeling was performed to derive doses of ibrutinib that, when given after a CYP3A inhibitor, results in therapeutically relevant drug levels. Deficiency of CYP3A in mice was associated with an approximately 10-fold increase in the AUC of ibrutinib. This result could be phenocopied by administration of cobicistat before ibrutinib in wild-type mice, but cobicistat did not influence levels of ibrutinib in CYP3A−/− mice. Population pharmacokinetic and prospectively validated physiologically based pharmacokinetic models established preclinical and clinical doses of ibrutinib that could be given safely in combination with cobicistat without negatively affecting antileukemic properties. These findings signify a dominant role for CYP3A-mediated metabolism in the elimination of ibrutinib, and suggest a role for pharmacologic inhibitors of this pathway to intentionally modulate the plasma levels and improve the therapeutic use of this clinically important agent.

Significance:

Ibrutinib has limited oral bioavailability, which contributes to significant interindividual pharmacokinetic variability. Using engineered mouse models, we here report a causal relationship between CYP3A-mediated metabolism and ibrutinib's bioavailability and drug–drug interaction with cobicistat. These results offer a mechanistic basis for reported pharmacokinetic interactions with ibrutinib, and in conjunction with a newly developed computational model, allow for the rational design of clinical trials aimed at improving the therapeutic use of ibrutinib.
Comparison of Diagnostic Rates and Concordance with Subsequent Surgical Resections between Conventional Smear and ThinPrep Preparations versus ThinPrep Only in Thyroid Fine Needle Aspiration (T-FNA) Specimens
Authors: Rufail Miguel , Jing Xin , Smola Brian , Heider Amer , Cantley Richard , Pang Judy C. , Lew Madelyn
Published: November 2021

Background: Thyroid fine needle aspiration (T-FNA) is a mainstay in management of thyroid nodules. However, the preparation of T-FNA specimens varies across institutions. Prior studies have compared diagnostic rates between different specimen preparations of T-FNA specimens and their associated advantages and disadvantages. However, few have compared the rates of all diagnostic categories of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) between liquid-based preparations (LBPs) and a combination of LBP and conventional smear (CS) preparations. Our study compares TBSRTC diagnostic rates between these 2 cohorts and correlates cytologic diagnoses with subsequent thyroid resections to evaluate rates of neoplasia (RON) and malignancy (ROM). Methods: 584 consecutive thyroid FNA specimens were collected and stratified by preparation type (ThinPrep [TP] vs. CS & TP). Diagnostic rates for each TBSRTC diagnostic category were calculated. The institution’s electronic medical records database was searched for histologic diagnoses of previously sampled thyroid nodules to evaluate the RON and ROM. Results: Of 584 thyroid FNA specimens, 73 (12.5%) and 511 (87.5%) were evaluated by TP only and CS & TP, respectively, reflecting the predominance of rapid on-site evaluation (ROSE) with CS for T-FNAs at our institution. Of the TP only and CS & TP cohorts, 29 (39.7%) and 98 (19.2%) had subsequent resections, respectively. The frequency of non-diagnostic cases was lower in the CS & TP cohort (12.7% vs. 26%). While the diagnostic rate of follicular lesion of undetermined significance was similar for both cohorts, SFN categorization was only utilized in the CS & TP cohort (1.5% vs. 0%). Although RON and ROM were similar between cohorts in many of the TBSRTC categories, there was a higher RON associated with non-diagnostic specimens in the TP only cohort when the denominator included all non-diagnostic cases. Conclusion: The combination of CS and LBP may potentially decrease the non-diagnostic rate of T-FNA specimens as well as the number of passes required for diagnosis, particularly with ROSE. Evaluation of morphologic features highlighted in conventional smears may facilitate diagnostic categorization in the “suspicious for follicular neoplasm” category.
SARS-CoV-2 vaccines–induced thrombotic thrombocytopenia: should we consider immuno-hypersensitivity?
Authors: Reuben Rine Christopher , Adogo Lillian Yami
Published: November 2021

The coronavirus disease 2019 (COVID-19) pandemic is significantly causing unprecedented clinical, socioeconomic, and public health challenges globally. The successful global administration of effective, safe and sustainable vaccine(s) is widely believed to be crucial in mitigating as well as preventing COVID-19. However, the rising cases of severe adverse events following immunization (AEFI) with COVID-19 vaccines including thrombosis, thrombocytopenia, and in some instances, death have created serious global concerns and could enormously contribute to vaccine hesitancy. Although the complete underlying pathophysiology and immunopathology of the COVID-19 vaccines related to AEFI, including thrombosis and/or anaphylaxis, are yet to be determined, exploring possible immuno-hypersensitivity could be crucial in the mechanisms associated with these reactions, thereby mitigating their occurrences as well as restoring confidence in vaccine administration for a COVID-19 free world.
Large Diameter Advanta V12 Covered Stent Trial for Coarctation of the Aorta: COARC Study
Authors: Bruckheimer Elchanan , Birk Einat , Benson Lee , Butera Gianfranco , Martin Robin , Roberts Philip A. , Schneider Martin B.E. , Schubert Stephan , Sievert Horst , Pedra Carlos C.A.
Published: November 2021

Background:

Covered stent implantation for treatment of coarctation of the aorta (CoA) is effective and can prevent aortic wall injury. Prospective studies with long-term follow-up, including imaging, are lacking. We report the acute and long-term outcomes for use of the Large Diameter Advanta V12 covered stent for treatment of native and recurrent CoA.

Methods:

A prospective, multicenter, nonrandomized study was performed including 70 patients (43 male), median age 17 years, median weight 57.4 kg with CoA who underwent implantation of the Large Diameter Advanta V12 covered stent. Annual follow-up for 5 years included Doppler echocardiography to calculate diastolic velocity: systolic velocity ratio.

Results:

CoA diameter increased from 5.6±3.6 to 14.9±3.9 mm (
P
<0.0001) and the pressure gradient decreased from 35.8±16.2 to 5.6±7.9 mm Hg (
P
<0.0001). Preimplantation diastolic velocity:systolic velocity of 0.6±0.16 dropped to 0.34±0.13 (
P
<0.0001) and was maintained at 5 years. Computed tomography angiograms at 12 months postimplantation demonstrated the stent:transverse arch diameter to be similar, 0.91±0.09 to postprocedure 0.86±0.14. Major adverse vascular events at 30 days and 12 months were 1.4% and 4.3%, respectively. Significant adverse events included three patients who required stent implantation to treat infolding. There were no mortalities.

Conclusions:

The Large Diameter Advanta V12 covered stent is safe and effective for the treatment of CoA with an immediate and sustained reduction of the pressure gradient over 12 months and 5 years as assessed by preimplantation and postimplantation Doppler echocardiography and 12-month computed tomography angiography.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00978952. URL:
http://www.anzctr.org.au
; Unique identifier: ACTRN12612000013864.
A regression framework for brain network distance metrics
Authors: Tomlinson Chal E. , Laurienti Paul J. , Lyday Robert G. , Simpson Sean L.
Published: November 2021

Analyzing brain networks has long been a prominent research topic in neuroimaging. However, statistical methods to detect differences between these networks and relate them to phenotypic traits are still sorely needed. Our previous work developed a novel permutation testing framework to detect differences between two groups. Here we advance that work to allow both assessing differences by continuous phenotypes and controlling for confounding variables. To achieve this, we propose an innovative regression framework to relate distances (or similarities) between brain network features to functions of absolute differences in continuous covariates and indicators of difference for categorical variables. We explore several similarity metrics for comparing distances (or similarities) between connection matrices, and adapt several standard methods for estimation and inference within our framework: standard F test, F test with individual level effects (ILE), feasible generalized least squares (FGLS), and permutation. Via simulation studies, we assess all approaches for estimation and inference while comparing them with existing multivariate distance matrix regression (MDMR) methods. We then illustrate the utility of our framework by analyzing the relationship between fluid intelligence and brain network distances in Human Connectome Project (HCP) data.
Minority Actorness Through a Non-Europeanised Policy Area
Authors: Huseyinoglu Ali , Hoch Tamara
Published: November 2021

By bringing together the literatures on Europeanisation and minority studies, this article illustrates the centrality of actors representing national minorities as a key to understand Europeanisation of minority politics today. Minority politics is becoming Europeanised indeed, however, not in the ways commonly expected. And although the EU repeatedly fails to develop a clear minority policy, an actor-centred approach adopted in this study helps to reveal how minority actors extend their political strategies to the European level through different channels and how they exploit various opportunities stemming from European-level politics. Jacquot and Woll’s concept of ‘usages of Europe’ not only enables us to trace how actors multiply channels and arenas of participation, but it also helps to spot the emergence of tactics of experimentation with European-level norms and rules, contributing to an acquisition of new roles among minority actors and supporting an actorness formation among those active. As the actors engage in criticising EU institutions, they develop tactics of responsibilising which in turn affects their minority agendas and the actors themselves. In this respect, this study contributes to developing the weakly studied literature about minority agency and Europeanisation.
The Worse than Nothing Account of Harm and the Preemption Problem
Authors: Immerman Daniel
Published: November 2021

Because harm is an important notion in ethics, it’s worth investigating what it amounts to. The counterfactual comparative account of harm, commonly thought to be the most promising account of harm, analyzes harm by comparing what actually happened with what would have happened in some counterfactual situation. But it faces the preemption problem, a problem so serious that it has driven some to suggest we abandon the counterfactual comparative account and maybe even abandon the notion of harm altogether. This paper defends a version of the counterfactual comparative account that solves the preemption problem, a version called the “worse than nothing account.” It says that you harm someone just in case you leave them worse off than if you’d done nothing at all.
Consenting Under Third-Party Coercion
Authors: Kiener Maximilian
Published: November 2021

This paper focuses on consent and third-party coercion, viz. cases in which a person consents to another person performing a certain act because a third party coerced her into doing so. I argue that, in these cases, the validity of consent depends on the behavior of the recipient of consent rather than the third party’s coercion taken separately, and I will specify the conditions under which consent is invalid. My view, which is a novel version of what I call a Recipient-Focus-View, holds that coercion invalidates consent only if consent was ‘obtained by’ coercion, but not if consent was ‘merely motivated by’ coercion. I explain and support my view on the basis that it best reconciles an unnoticed tension between two fundamental principles in the debate on consent (which I call the Coercion Principle and the Permissibility Principle) and that it can deal with cases that undermine other Recipient-Focus-Views.
Koorchaloma oryzae sp. nov. (Stachybotryaceae, Sordariomycetes), from Oryza sativa (Poaceae) in northern Thailand
Authors: TIAN XINGGUO , KARUNARATHNA SAMANTHA C. , MAPOOK AUSANA , XU JIANCHU , BAO DANFENG , PROMPUTTHA ITTHAYAKORN , TIBPROMMA SAOWALUCK
Published: November 2021

A new species of Koorchaloma is described based on morphology and multigene phylogenetic analyses of ITS, LSU and RPB2. Phylogenetic analyses showed our strain clusters with K. europaea with moderate statistical support. Koorchaloma oryzae sp. nov. is morphologically similar to K. europaea, but it can be distinguished by the conidiophores and conidia, while ITS pairwise nucleotide comparison of these two species also revealed differences. Koorchaloma oryzae is compared with all known Koorchaloma species, and a key to Koorchaloma species is provided. Genealogical concordance phylogenetic species recognition analysis (PHI test) results of the new species and closely related species are also given.
New nomenclatural and taxonomic adjustments in Dracaena (Asparagaceae)
Authors: TAKAWIRA-NYENYA RATIDZAYI , THIEDE JOACHIM , MUCINA LADISLAV
Published: November 2021

Recent molecular phylogenetic studies showed that the genus Sansevieria (excluding S. sambiranensis) forms a monophyletic clade nested within the paraphyletic genus Dracaena. Consequently, the genus Sansevieria was sunk into the genus Dracaena and new combinations were published to accommodate the transfer of taxa from Sansevieria into Dracaena. Since the inclusion of Sansevieria into Dracaena, new taxa have been published in Sansevieria. This paper presents fourteen name changes including twelve new combinations in Dracaena and two rank adjustments, one new synonym, and one lectotypification aiming at further standardisation of the taxonomy of Dracaena.
Comparing Frontal Structures of Extratropical Cyclones in the Northwestern Pacific and Northwestern Atlantic Storm Tracks
Authors: Tochimoto Eigo , Niino Hiroshi
Published: November 2021

The frontal structures of extratropical cyclones developing in the northwestern Pacific storm track are relatively poorly understood compared with those in Europe and the Atlantic Ocean, for which representative conceptual models have been developed. In this paper, the structures of cyclones and their associated fronts in the northwestern Pacific (NP), as well as in the Okhotsk Sea and Sea of Japan (OJ), are examined at their developing and mature stages using Japanese 55-year Reanalysis dataset. Furthermore, the frontal structures in the NP are compared with those in the northwestern Atlantic (NA). At the time of maximum deepening rate, cyclones in the NP are accompanied by strong warm and cold fronts, whereas cyclones in the OJ are more frequently accompanied by cold fronts than by warm fronts and tend to have stronger cold fronts than warm fronts. The weaker warm fronts than cold fronts to the east and northeast of cyclones in the OJ is likely due to the cyclones developing to the north and away from the region where the horizontal gradient of environmental potential temperature is strong. A comparison between mature cyclones in the NP and NA shows that the warm fronts in the NA tend to extend northeastward, whereas those in the NP extend more southeastward. These differences in warm fronts between NP and NA are suggested to be due to the difference in the horizontal structures of the warm currents between NP and NA.
Book review: Melissa Macauley, Distant Shores: Colonial Encounters on China’s Maritime Frontier
Authors: Thampi Madhavi
Published: November 2021

Melissa Macauley, Distant Shores: Colonial Encounters on China’s Maritime Frontier (Princeton, NJ: Princeton University Press, 2021), pp. 378, $39.95. ISBN: 9780691213484.
Continuity of care for drug users in prison and beyond: A qualitative insight
Authors: Stöver Heino , Jamin Daniela , Jauffret-Roustide Marie , Michel Laurent , Mendes Vânia , Vanderplasschen Wouter
Published: November 2021

Social work in prisons is linked to specific tasks regarding the care for the people who are incarcerated. A multi-country qualitative study was set up to explore drug users’ and professionals’ perceptions of continuity of care in prison and beyond. It has been pointed out that continuity of care is associated with different barriers, especially regarding social work. Nevertheless, good practice examples do exist and could be implemented by social workers. Social workers and opioid users face challenges in the context of imprisonment, so different measures need to be implemented to support opioid users and for social workers to support them.