bluuebunny/crossref_metadata_2025 huggingface dataset:
A Female Psoriatic Arthritis Patient Involving the TMJ
Authors: Falisi Giovanni , Gatto Roberto , Di Paolo Carlo , De Biase Alberto , Franceschini Carlo , Monaco Annalisa , Rastelli Sofia , Botticelli Gianluca
Published: February 2021

Psoriatic arthritis (PsA) is an inflammatory chronic arthritis associated with psoriasis. Currently, data about gender differences in clinical manifestation and therapeutic outcomes of PsA are limited. Frequently, women manifest a peripheral disease while men have an axial localization. Moreover, women display higher disease activity and physical activity limitations, if compared to men. Although the involvement of the temporomandibular joint (TMJ) is quite rare, it can seriously impact the quality of life. The morpho-functional peculiarities of TMJ require a multidisciplinary approach to perform a correct diagnosis and a successful treatment. Here, we report a case of a woman affected by PsA involving TMJ treated by combining pharmacological therapy and an occlusal splint. The coordination between different specialties led to a complete remission of clinical symptoms and a regression of lesions.
Output Feedback NCS of DoS Attacks Triggered by Double-Ended Events
Authors: Feng Xinzhi , Yang Yang , Qi Xiaozhong , Xu Chunming , Ji Ze
Published: February 2021

In recent years, the research of the network control system under the event triggering mechanism subjected to network attacks has attracted foreign and domestic scholars’ wide attention. Among all kinds of network attacks, denial-of-service (DoS) attack is considered the most likely to impact the performance of NCS significantly. The existing results on event triggering do not assess the occurrence of DoS attacks and controller changes, which will reduce the control performance of the addressed system. Aiming at the network control system attacked by DoS, this paper combines double-ended elastic event trigger control, DoS attack, and quantitative feedback control to study the stability of NCS with quantitative feedback of DoS attack triggered by a double-ended elastic event. Simulation examples show that this method can meet the requirements of control performance and counteract the known periodic DoS attacks, which save limited resources and improve the system’s antijamming ability.
Development of a New Nanocarrier for Dietary Garcinol: Characterization and In Vitro Efficacy Evaluation Using Breast Cancer Stem Cells Grown in Hypoxia
Authors: Hulangamuwa Amal Charindra , Ediriweera Meran Keshawa , Rajagopalan Umapriyatharshini , Karunaratne Desiree Nedra , Tennekoon Kamani Hemamala , Samarakoon Sameera Ranganath
Published: February 2021

Garcinol (GA), a polyisoprenylated benzophenone derivative, is one of the major phytochemicals found in a number of fruits of Garcinia. This study aimed to develop a new nanodelivery system comprising GA, hyaluronic acid (HA), and poly(lactic-co-glycolic acid) (PLGA) to actively target breast cancer stem cells (bCSCs) grown under hypoxic conditions. HA has been reported to show higher affinity for the cluster-determinant 44 receptor (CD44), while PLGA is an FDA-approved biodegradable polymer used in clinical applications. Nanoparticles (NPs) were prepared by emulsion solvent diffusion technique using DMAB as the emulsifier. Following preparation, particle size, surface charge, and polydispersity index of NPs were characterized. Antiproliferative effects of NPs were assessed by the WST-1 cell proliferation assay. Apoptotic effects of NPs were evaluated by the caspase-3/7 assay. Effects of prepared NPs on the expression of genes related to hypoxia-inducing factors (HIF-1α and HIF-2α) and notch ligands (DLL1 and Jagged1) were evaluated using real-time PCR. HA-coated garcinol-loaded NPs (HA-GA-NPs) showed greater antiproliferative effects in bCSCs grown under hypoxia. Moreover, HA-GA-NPs showed an improved cellular uptake via receptor-mediated endocytosis compared to non-HA-coated GA-NPs. Exposure to GA-HA-NPs resulted in a significant downregulation in hypoxia-inducing factors and notch pathway-related genes. Activation of caspase-3/7 confirmed the HA-GA-NPs can induce apoptosis in bCSCs. Overall findings of the study confirm that HA-GA-NPs can be considered as an effective nanodelivery system to target bCSCs grown under the hypoxic microenvironment.
The Prevalence and Risk Factors of Hypertension among the Urban Population in Southeast Asian Countries: A Systematic Review and Meta-Analysis
Authors: Mohammed Nawi Azmawati , Mohammad Zulkefley , Jetly Kavita , Abd Razak Mohamad Aznuddin , Ramli Nur Suhada , Wan Ibadullah Wan Abdul Hannan , Ahmad Norfazilah
Published: February 2021

The trend of global prevalence for hypertension has been dramatically increasing for the past two decades in Southeast Asian countries. A systematic review aiming to assess the prevalence of hypertension and its risk factors among the urban population in Southeast Asian countries was conducted. We performed database searches of PubMed and Web of Science and performed meta-analysis to determine the pooled prevalence estimate. The overall pooled prevalence estimate of hypertension for Southeast Asian urban population was 33.82%. Among this, 33.98% of hypertension was reported in the community and 32.45% among adolescents in school. The common risk factors that we found were male, ethnicity, education and socioeconomic level, body mass index, waist circumference, smoking, and dyslipidaemia. The review indicates an urgent need for primary and secondary prevention activities. Therefore, a multisectoral and intersectoral approach and collaboration should be undertaken to improve the overall health outcomes of all populations in all Southeast Asian countries.
A Deep-Learning Model with Learnable Group Convolution and Deep Supervision for Brain Tumor Segmentation
Authors: Liu Hengxin , Li Qiang , Wang I-Chi
Published: February 2021

The segmentation of brain tumors in medical images is a crucial step of clinical treatment. Manual segmentation is time consuming and labor intensive, and existing automatic segmentation methods suffer from issues such as numerous parameters and low precision. To resolve these issues, this study proposes a learnable group convolution-based segmentation method that replaces convolution in the feature extraction stage with learnable group convolution, thereby reducing the number of convolutional network parameters and enhancing communication between convolution groups. To improve utilization of the feature maps, we added a skip connection structure between learnable group convolution modules, which increased segmentation precision. We used deep supervision to combine output images in the network output stage to reduce overfitting and enhance the recognition capabilities of the network. We tested the proposed algorithm model using the open BraTS 2018 dataset. The experiment results revealed that the proposed model is superior to 3D U-Net and DMFNet and has better segmentation results for tumor cores than No New-Net and NVDLMED, the winning methods in the BraTS 2018 challenge. The segmentation precision of the proposed method with regard to whole tumors, enhancing tumors, and tumor cores was 90.25%, 80.36%, and 86.20%. Furthermore, the proposed method uses fewer parameters and a less complex model.
Mechanical and Mesoscale Analyses of Cement Stabilized Macadam Prepared by Vibratory and Nonvibratory Mixing Techniques
Authors: Wang Jijing , Tan Zhihua
Published: February 2021

The objective of this study is to analyze the effects of mixing techniques on the mechanical behavior and meso‐structure of cement‐treated aggregate. Different specimens were prepared by vibratory and nonvibratory mixing techniques. X‐ray CT scans were performed to illustrate the distribution of cement mortar on aggregate. The strength, modulus, and fatigue tests under different stress states were tested to reveal the impacts of mixing techniques. Then, the relationships between strengths and loading rates and that between moduli and stress levels were established. Hereafter, the S‐N fatigue equation that modified with stress ratio related to loading rates was used to describe the fatigue performance. The results indicate that the cement mortar of specimens prepared by vibratory mixing was well‐distributed on aggregates. The strength, modulus, and fatigue life of the specimens prepared by vibratory mixing were higher under the test condition threshold. Moreover, the growth rate of strength and modulus with loading for specimens prepared by vibratory mixing was slightly larger than that for specimens prepared by nonvibratory mixing. Compared with the cement‐treated aggregates specimens prepared by nonvibratory mixing, the fatigue life of cement‐treated aggregates specimens prepared by vibratory mixing had more stable stress sensitivity.
A Fuzzy-Decomposition Grey Modeling Procedure for Management Decision Analysis
Authors: Guo Jianhong , Chang Che-Jung , Huang Yingyi , Yu Kun-Peng
Published: February 2021

To cope with the increasingly fierce market competition environment, enterprises need to quickly respond to business issues and maintain business advantages, which require timely and correct decisions. In this context, the general mathematical modeling method may cause overfitting phenomenon when using small data sets, so it is difficult to ensure good analysis performance. Therefore, it is significant for enterprises to use limited samples to analyze and forecast. Over the past few decades, the grey model and its extensions have been shown to be effective tools for processing small data sets. To further enforce the effectiveness of data uncertainty processing, a fuzzy-decomposition modeling procedure for grey models is developed. Specifically, Latent Information (LI) function is employed to decompose the initial series into three subseries; next, the three subseries are used to build three grey models and create the estimated values of the three subseries; finally, the weighted average method is applying to combine the estimated values of the three subseries into a single final predicted value. After the actual test on the monthly demand data of the thin-film transistor liquid crystal display panels, the proposed fuzzy-decomposition modeling procedure can result in good prediction outcomes and is thus an appropriate decision analysis tool for managers.
Expression and Gene Regulation Network of Metabolic Enzyme Phosphoglycerate Mutase Enzyme 1 in Breast Cancer Based on Data Mining
Authors: Wang Yongxuan , Xiong Xifeng , Hua Xing , Liu Wei
Published: February 2021

The metabolic enzyme phosphoglycerate mutase enzyme 1 (PGAM1) is a key enzyme in the glycolysis pathway, and glycolysis is closely related to cancer progression, suggesting that PGAM1 may have important functions in breast cancer. We used sequencing data from the Oncomine database and UALCAN database to analyze the expression of PGAM1 and its influence on the clinicopathological characteristics of breast cancer. LinkedOmics was used to identify genes related to PGAM1 expression, kinases, miRNAs, and transcription factors that were significantly related to PGAM1 through GSEA. cBioPortal was used to identify the alternation frequency and form of PGAM1 in breast cancer. The expression level of PGAM1 in breast cancer was significantly higher than that in normal tissues. Moreover, the expression level of PGAM1 is closely related to the molecular subtype and TP53 mutation status. The expression level of PGAM1 in HER2‐positive and triple‐negative tumors was significantly higher than that of luminal type. The expression level of PGAM1 in TP53‐mutant tumors was higher than that in non‐TP53‐mutant tumors. In addition, the overall survival of patients with high PGAM1 expression was significantly worse than that of patients with low expression (P = 0.0077). Through GSEA analysis, we found multiple kinases, miRNAs, and transcription factors significantly related to PFKFB4. cBioPortal analysis showed that the mutation rate of PGAM1 in breast cancer was relatively low (4%), and the main form of mutation was high mRNA expression. This study suggests that PGAM1 is a potential diagnostic and prognostic marker in breast cancer. Through data mining, we revealed the potential regulatory network information of PGAM1, laying a foundation for further research on the role of PGAM1 in breast cancer.
RXRα Blocks Nerve Regeneration after Spinal Cord Injury by Targeting p66shc
Authors: Yu Pei , Yang Kai , Jiang Min
Published: February 2021

Nerve regeneration after spinal cord injury is regulated by many factors. Studies have found that the expression of retinoid X receptor α (RXRα) does not change significantly after spinal cord injury but that the distribution of RXRα in cells changes significantly. In undamaged tissues, RXRα is distributed in motor neurons and the cytoplasm of glial cells. RXRα migrates to the nucleus of surviving neurons after injury, indicating that RXRα is involved in the regulation of gene expression after spinal cord injury. p66shc is an important protein that regulates cell senescence and oxidative stress. It can induce the apoptosis and necrosis of many cell types, promoting body aging. The absence of p66shc enhances the resistance of cells to reactive oxygen species (ROS) and thus prolongs life. It has been found that p66shc deletion can promote hippocampal neurogenesis and play a neuroprotective role in mice with multiple sclerosis. To verify the function of RXRα after spinal cord injury, we established a rat T9 spinal cord transection model. After RXRα agonist or antagonist administration, we found that RXRα agonists inhibited nerve regeneration after spinal cord injury, while RXRα antagonists promoted the regeneration of injured neurites and the recovery of motor function in rats. The results showed that RXRα played an impeding role in repair after spinal cord injury. Immunofluorescence staining showed that p66shc expression was upregulated in neurons after spinal cord injury (in vivo and in vitro) and colocalized with RXRα. RXRα overexpression in cultured neurons promoted the expression of p66shc, while RXRα interference inhibited the expression of p66shc. Using a luciferase assay, we found that RXRα could bind to the promoter region of p66shc and regulate the expression of p66shc, thereby regulating nerve regeneration after spinal cord injury. The above results showed that RXRα inhibited nerve regeneration after spinal cord injury by promoting p66shc expression, and interference with RXRα or p66shc promoted functional recovery after spinal cord injury.
Associating Multivariate Traits with Genetic Variants Using Collapsing and Kernel Methods with Pedigree- or Population-Based Studies
Authors: Chien Li-Chu
Published: February 2021

In genetic association analysis, several relevant phenotypes or multivariate traits with different types of components are usually collected to study complex or multifactorial diseases. Over the past few years, jointly testing for association between multivariate traits and multiple genetic variants has become more popular because it can increase statistical power to identify causal genes in pedigree- or population-based studies. However, most of the existing methods mainly focus on testing genetic variants associated with multiple continuous phenotypes. In this investigation, we develop a framework for identifying the pleiotropic effects of genetic variants on multivariate traits by using collapsing and kernel methods with pedigree- or population-structured data. The proposed framework is applicable to the burden test, the kernel test, and the omnibus test for autosomes and the X chromosome. The proposed multivariate trait association methods can accommodate continuous phenotypes or binary phenotypes and further can adjust for covariates. Simulation studies show that the performance of our methods is satisfactory with respect to the empirical type I error rates and power rates in comparison with the existing methods.
From Diagnosis to Management; Mucocele of Stump Appendicitis, Extremely Rare Finding in an Uncommon Surgical Disease: Literature Review
Authors: Ali Syed Muhammad , Al-Tarakji Mohannad , Shahid Fakhar , Qabani Amjad Salah , Shah Amjad Ali , Ahmed Khalid , Khan Muhammad Burhan , Inamullah
Published: February 2021

Mucocele of the appendix is the accumulation of mucoid material in the appendiceal lumen. Although the terminology is imprecise, as it does not differentiate between the benign and malignant nature of the condition, preoperative recognition is imperative as spillage of the mucus during surgical handling can result in grave complications like pseudomyxoma peritonei. Mucocele developing in a stump of the appendix, i.e., a remnant of appendiceal tissue after surgical removal of an inflamed organ, is an extremely uncommon phenomenon, as not many cases are reported in the literature. In this review, all cases reported in English literature are discussed.
Reducing Compressibility of the Expansive Soil by Microbiological‐Induced Calcium Carbonate Precipitation
Authors: Li Xiaobing , Zhang Chunshun , Xiao Hongbin , Jiang Weichang , Qian Junfeng , Li Zixiang
Published: February 2021

Most of the research studies on the improvement of expansive soils are focused on reducing their expansive properties; however, there are few studies on the impact of the soil compressibility after the improvement. In this paper, through indoor high‐pressure consolidation tests, the recent microbial‐induced calcium carbonate precipitation (MICP) technology is studied to improve the compression characteristics of the expansive soil. The significant effect of different microbial concentrations (achieved by different number of treatments) on the compression deformation is revealed with the hyperbolic function that involves two parameters with clear physical meanings. In particular, after 6 times of treatment with the microbial solution, the compression characteristics of the expansive soil reach the best improvement effect; continuing to increase the number of microbial treatments is, otherwise, not conducive to improving the soil compression performance. Also, a dramatical increase of the structural strength of the microbial‐treated expansive soil is presented and investigated. Moreover, we performed a scanning electron microscope (SEM) experiment and confirmed the existence of crystals due to mineralization. This study shows that MICP is an effective and environmentally friendly means of reducing the compressibility of the expansive soil.
Effect of Fermentation with Two Molds on Characteristics of Chicken Meat
Authors: Guo Liping , Li Yan , Ding Shengchao , Wang Baowei , Zhu Yinglian , Pang Bin , Huang Ming , Ho Harvey , Yu Jiying , Sun Jingxin
Published: February 2021

In the present study, we investigated the characteristics of chicken meat fermented with Penicillium nalgiovense and Penicillium chrysogenum. Hardness and springiness gradually decreased, while gumminess gradually increased during fermentation. Fermentation with P. chrysogenum led to higher hardness and lower gumminess than fermentation with P. nalgiovense. Fermentation with two molds resulted in similar microstructure, such as granule formation and fractured myofibril. The highest percentage of secondary structure was ɑ-helix, and tyrosine residues were buried after fermentation. P. nalgiovense-fermented samples contained more bound water, lower relative content of alkanes, and higher relative content of aldehydes than P. chrysogenum-fermented samples.
Application of Plane Homography for Vehicle Speed Calculations in Traffic Accident Investigations
Authors: Chen Qiang , Xu Hong-Guo , Liu Xiao-Feng , Guan Zhi-Wei
Published: February 2021

The analysis of vehicle speeds at the moment of traffic accidents is becoming increasingly important. To solve difficult calculations arising from video analysis when the shooting direction of the camera is the same as the driving direction of the vehicles, an improved plane homography method is proposed. This method is based on detecting the frame rate of and extracting all of the key image frames from a surveillance video. Next, a normalizing approach for the control points is proposed to reduce the ill-conditions of matrix calculations when the perspective image is rectified to an orthographic image. The information in the rectified image is then measured and recorded by extracting the mark point information. Finally, the corresponding curve of time and speed for the examined vehicle is created, which can be used to analyze the average braking deceleration of the accident-causing vehicle. This method can directly determine the speed of a vehicle using videos of a traffic accident without any reference to the dimensions of the vehicle itself. Considering an actual traffic accident as an example, the driving trajectories and velocity curves for two vehicles are obtained using this method. The proposed method can effectively overcome the shortcomings of the commonly used speed recognition methods and it is easy to utilize.
Abdominal Tuberculosis Complicated by Intestinal Perforation
Authors: Sala Michiel L. , Verhage Samuel M. , Zijta Frank
Published: February 2021

Although relatively rare, there is an increasing incidence of abdominal tuberculosis (TB) in the developed countries, with the peritoneum being the most common site of involvement. Manifestation of abdominal TB should be considered in patients with relevant clinical symptoms and risk factors, including a history of prior TB infection and residence in or travel to an area where tuberculosis is endemic. We report a case of intestinal tuberculosis with a complicated disease course after the completion of treatment. Persisting abdominal symptoms during or after treatment should raise suspicion of subclinical intestinal obstruction. Early clinical recognition and surgical treatment may avoid poor outcome due to intestinal perforation.
Crosstalk between Macrophages, T Cells, and Iron Metabolism in Tumor Microenvironment
Authors: Shen Lesang , Zhou Yunxiang , He Haifei , Chen Wuzhen , Lenahan Cameron , Li Xiaoyi , Deng Yongchuan , Shao Anwen , Huang Jian
Published: February 2021

Leukocytes, including macrophages and T cells, represent key players in the human immune system, which plays a considerable role in the development and progression of tumors by immune surveillance or immune escape. Boosting the recruitment of leukocytes into the tumor microenvironment and promoting their antitumor responses have been hot areas of research in recent years. Although immunotherapy has manifested a certain level of success in some malignancies, the overall effectiveness is far from satisfactory. Iron is an essential trace element required in multiple, normal cellular processes, such as DNA synthesis and repair, cellular respiration, metabolism, and signaling, while dysregulated iron metabolism has been declared one of the metabolic hallmarks of malignant cancer cells. Furthermore, iron is implicated in the modulation of innate and adaptive immune responses, and elucidating the targeted regulation of iron metabolism may have the potential to benefit antitumor immunity and cancer treatment. In the present review, we briefly summarize the roles of leukocytes and iron metabolism in tumorigenesis, as well as their crosstalk in the tumor microenvironment. The combination of immunotherapy with targeted regulation of iron and iron‐dependent regulated cell death (ferroptosis) may be a focus of future research.
Faidherbia albida (Delile) Tree Dieback Effects on Crop Production in the Parkland Agroforests of Southwestern Niger
Authors: Tougiani Abasse , Massaoudou Moussa , Haougui Adamou , Laouali Amadou , Weber John C.
Published: February 2021

Faidherbiaalbida is an agroforestry tree species playing important agroecological and socioeconomic roles in arid and semiarid zones in Africa. For many years, anthropogenic and abiotic stresses were considered as the main threats for the species in West African parkland agroforests. Considerable dieback has recently occurred in F. albida trees of parkland agroforests in central southwestern Niger, and the causes are unknown. The objectives of this study are to (i) investigate the magnitude of dieback of F. albida trees and (ii) assess local community perceptions of the effects of F. albida dieback on crop production. The health status and phenology of 213 F. albida trees were observed in the area where the dieback is occurring. Similarly, a sample of 144 people, 86% of which were farmers, was surveyed. Dieback incidence of F. albida trees was 19%, with mortality of 6%. Large-diameter trees had greater dieback than small-diameter trees. The most affected parts of the tree were the branches at 54% and the trunks at 39%. The populations noted a 33–55% reduction in the yields of major crops. This dieback of F. albida trees poses a serious threat to the survival of rural communities. Further studies can be conducted to identify the cause or cause of the dieback to guide the suitable agroforestry parkland management strategies.
Data-Driven Computational Modeling Identifies Determinants of Glioblastoma Response to SHP2 Inhibition
Authors: Day Evan K. , Zhong Qing , Purow Benjamin , Lazzara Matthew J.
Published: February 2021

Oncogenic protein tyrosine phosphatases have long been viewed as drug targets of interest, and recently developed allosteric inhibitors of SH2 domain–containing phosphatase-2 (SHP2) have entered clinical trials. However, the ability of phosphatases to regulate many targets directly or indirectly and to both promote and antagonize oncogenic signaling may make the efficacy of phosphatase inhibition challenging to predict. Here we explore the consequences of antagonizing SHP2 in glioblastoma, a recalcitrant cancer where SHP2 has been proposed as a useful drug target. Measuring protein phosphorylation and expression in glioblastoma cells across 40 signaling pathway nodes in response to different drugs and for different oxygen tensions revealed that SHP2 antagonism has network-level, context-dependent signaling consequences that affect cell phenotypes (e.g., cell death) in unanticipated ways. To map specific signaling consequences of SHP2 antagonism to phenotypes of interest, a data-driven computational model was constructed based on the paired signaling and phenotype data. Model predictions aided in identifying three signaling processes with implications for treating glioblastoma with SHP2 inhibitors. These included PTEN-dependent DNA damage repair in response to SHP2 inhibition, AKT-mediated bypass resistance in response to chronic SHP2 inhibition, and SHP2 control of hypoxia-inducible factor expression through multiple MAPKs. Model-generated hypotheses were validated in multiple glioblastoma cell lines, in mouse tumor xenografts, and through analysis of The Cancer Genome Atlas data. Collectively, these results suggest that in glioblastoma, SHP2 inhibitors antagonize some signaling processes more effectively than existing kinase inhibitors but can also limit the efficacy of other drugs when used in combination.

Significance:

These findings demonstrate that allosteric SHP2 inhibitors have multivariate and context-dependent effects in glioblastoma that may make them useful components of some combination therapies, but not others.
Inflammation and Apolipoproteins Are Potential Biomarkers for Stratification of Cutaneous Melanoma Patients for Immunotherapy and Targeted Therapy
Authors: Karlsson Max J. , Costa Svedman Fernanda , Tebani Abdellah , Kotol David , Höiom Veronica , Fagerberg Linn , Edfors Fredrik , Uhlén Mathias , Egyhazi Brage Suzanne , Maddalo Gianluca
Published: February 2021

Malignant cutaneous melanoma is one of the most common cancers in young adults. During the last decade, targeted and immunotherapies have significantly increased the overall survival of patients with malignant cutaneous melanoma. Nevertheless, disease progression is common, and a lack of predictive biomarkers of patient response to therapy hinders individualized treatment strategies. To address this issue, we performed a longitudinal study using an unbiased proteomics approach to identify and quantify proteins in plasma both before and during treatment from 109 patients treated with either targeted or immunotherapy. Linear modeling and machine learning approaches identified 43 potential prognostic and predictive biomarkers. A reverse correlation between apolipoproteins and proteins related to inflammation was observed. In the immunotherapy group, patients with low pretreatment expression of apolipoproteins and high expression of inflammation markers had shorter progression-free survival. Similarly, increased expression of LDHB during treatment elicited a significant impact on response to immunotherapy. Overall, we identified potential common and treatment-specific biomarkers in malignant cutaneous melanoma, paving the way for clinical use of these biomarkers following validation on a larger cohort.

Significance:

This study identifies a potential biomarker panel that could improve the selection of therapy for patients with cutaneous melanoma.
PINK1-Mediated Inhibition of EGFR Dimerization and Activation Impedes EGFR-Driven Lung Tumorigenesis
Authors: Lin Emily Pei-Ying , Huang Bo-Tsang , Lai Wei-Yun , Tseng Yi-Ting , Yang Shuenn-Chen , Kuo Hao-Cheng , Yang Pan-Chyr
Published: February 2021

EGFR is established as a driver of lung cancer, yet the regulatory machinery underlying its oncogenic activity is not fully understood. PTEN-induced kinase 1 (PINK1) kinase is a key player in mitochondrial quality control, although its role in lung cancer and EGFR regulation is unclear. In this study, we show that PINK1 physically directly interacts with EGFR via the PINK1 C-terminal domain (PINK1-CTD) and the EGFR tyrosine kinase domain. This interaction constituted an endogenous steric hindrance to receptor dimerization and inhibited EGFR-mediated lung carcinogenesis. Depletion of PINK1 from lung cancer cells promoted EGFR dimerization, receptor activation, EGFR downstream signaling, and tumor growth. In contrast, overexpression of PINK1 or PINK1-CTD suppressed EGFR dimerization, activation, downstream signaling, and tumor growth. These findings identify key elements in the EGFR regulatory cascade and illustrate a new direction for the development of anti-EGFR therapeutics, suggesting translational potential of the PINK1-CTD in lung cancer.

Significance:

This study identifies PINK1 as a critical tumor suppressor that impedes EGFR dimerization and highlights PINK1-CTD as a potential therapeutic agent in EGFR-driven lung cancer.
PLEKHA4 Promotes Wnt/β-Catenin Signaling–Mediated G1–S Transition and Proliferation in Melanoma
Authors: Shami Shah Adnan , Cao Xiaofu , White Andrew C. , Baskin Jeremy M.
Published: February 2021

Despite recent promising advances in targeted therapies and immunotherapies, patients with melanoma incur substantial mortality. In particular, inhibitors targeting BRAF-mutant melanoma can lead to resistance, and no targeted therapies exist for NRAS-mutant melanoma, motivating the search for additional therapeutic targets and vulnerable pathways. Here we identify a regulator of Wnt/β-catenin signaling, PLEKHA4, as a factor required for melanoma proliferation and survival. PLEKHA4 knockdown in vitro decreased Dishevelled levels, attenuated Wnt/β-catenin signaling, and blocked progression through the G1–S cell-cycle transition. In mouse xenograft and allograft models, inducible PLEKHA4 knockdown attenuated tumor growth in BRAF- and NRAS-mutant melanomas and exhibited an additive effect with the clinically used inhibitor encorafenib in a BRAF-mutant model. As an E3 ubiquitin ligase regulator with both lipid- and protein-binding partners, PLEKHA4 presents several opportunities for targeting with small molecules. Our work identifies PLEKHA4 as a promising drug target for melanoma and clarifies a controversial role for Wnt/β-catenin signaling in the control of melanoma proliferation.

Significance:

This study establishes that melanoma cell proliferation requires the protein PLEKHA4 to promote pathologic Wnt signaling for proliferation, highlighting PLEKHA4 inhibition as a new avenue for the development of targeted therapies.
Rapid Depletion of Intratumoral Regulatory T Cells Induces Synchronized CD8 T- and NK-cell Activation and IFNγ-Dependent Tumor Vessel Regression
Authors: Kurebayashi Yutaka , Olkowski Colleen P. , Lane Kelly C. , Vasalatiy Olga V. , Xu Biying C. , Okada Ryuhei , Furusawa Aki , Choyke Peter L. , Kobayashi Hisataka , Sato Noriko
Published: February 2021

Regulatory T cells (Tregs) are known to inhibit antitumor immunity, yet the specific mechanism by which intratumoral Tregs promote tumor growth remains unclear. To better understand the roles of intratumoral Tregs, we selectively depleted tumor-infiltrating Tregs using anti-CD25-F(ab′)2 near-infrared photoimmunotherapy. Depletion of tumor-infiltrating Tregs induced transient but synchronized IFNγ expression in CD8 T and natural killer (NK) cells. Despite the small fraction of CD8 T and NK cells contained within examined tumors, IFNγ produced by these CD8 T and NK cells led to efficient and rapid tumor vessel regression, intratumoral ischemia, and tumor necrosis/apoptosis and growth suppression. IFNγ receptor expression on vascular endothelial cells was required for these effects. Similar findings were observed in the early phase of systemic Treg depletion in tumor-bearing Foxp3DTR mice; combination with IL15 therapy further inhibited tumor growth and achieved increased complete regression. These results indicate the pivotal roles of intratumoral Tregs in maintaining tumor vessels and tumor growth by suppressing CD8 T and NK cells from producing IFNγ, providing insight into the mechanism of Treg-targeting therapies.

Significance:

Intratumoral Treg depletion induces synchronized intratumoral CD8 T- and NK-cell activation, IFNγ-dependent tumor vessel regression, and ischemic tumor necrosis/apoptosis, indicating the roles of intratumoral Tregs to support the tumor vasculature.
YAP and β-Catenin Cooperate to Drive Oncogenesis in Basal Breast Cancer
Authors: Quinn Hazel M. , Vogel Regina , Popp Oliver , Mertins Philipp , Lan Linxiang , Messerschmidt Clemens , Landshammer Alexandro , Lisek Kamil , Château-Joubert Sophie , Marangoni Elisabetta , Koren Elle , Fuchs Yaron , Birchmeier Walter
Published: February 2021

Targeting cancer stem cells (CSC) can serve as an effective approach toward limiting resistance to therapies. While basal-like (triple-negative) breast cancers encompass cells with CSC features, rational therapies remain poorly established. We show here that the receptor tyrosine kinase Met promotes YAP activity in basal-like breast cancer and find enhanced YAP activity within the CSC population. Interfering with YAP activity delayed basal-like cancer formation, prevented luminal to basal transdifferentiation, and reduced CSC. YAP knockout mammary glands revealed a decrease in β-catenin target genes, suggesting that YAP is required for nuclear β-catenin activity. Mechanistically, nuclear YAP interacted with β-catenin and TEAD4 at gene regulatory elements. Proteomic patient data revealed an upregulation of the YAP signature in basal-like breast cancers. Our findings demonstrate that in basal-like breast cancers, β-catenin activity is dependent on YAP signaling and controls the CSC program. These findings suggest that targeting the YAP/TEAD4/β-catenin complex offers a potential therapeutic strategy for eradicating CSCs in basal-like breast cancers.

Significance:

These findings show that YAP cooperates with β-catenin in basal-like breast cancer to regulate CSCs and that targeting this interaction may be a novel CSC therapy for patients with basal-like breast cancer.
Silencing of SmgGDS, a Novel mTORC1 Inducer That Binds to RHEBs, Inhibits Malignant Mesothelioma Cell Proliferation
Authors: Sato Tatsuhiro , Mukai Satomi , Ikeda Haruna , Mishiro-Sato Emi , Akao Ken , Kobayashi Toshiyuki , Hino Okio , Shimono Wataru , Shibagaki Yoshio , Hattori Seisuke , Sekido Yoshitaka
Published: February 2021

Malignant mesothelioma (MM) is an aggressive tumor that typically develops after a long latency following asbestos exposure. Although mechanistic target of rapamycin complex 1 (mTORC1) activation enhances MM cell growth, the mTORC1 inhibitor everolimus has shown limited efficacy in clinical trials of MM patients. We explored the mechanism underlying mTORC1 activation in MM cells and its effects on cell proliferation and progression. Analysis of the expression profiles of 87 MMs from The Cancer Genome Atlas revealed that 40 samples (46%) displayed altered expression of RPTOR (mTORC1 component) and genes immediately upstream that activate mTORC1. Among them, we focused on RHEB and RHEBL1, which encode direct activators of mTORC1. Exogenous RHEBL1 expression enhanced MM cell growth, indicating that RHEB–mTORC1 signaling acts as a pro-oncogenic cascade. We investigated molecules that directly activate RHEBs, identifying SmgGDS as a novel RHEB-binding protein. SmgGDS knockdown reduced mTORC1 activation and inhibited the proliferation of MM cells with mTORC1 activation. Interestingly, SmgGDS displayed high binding affinity with inactive GDP-bound RHEBL1, and its knockdown reduced cytosolic RHEBL1 without affecting its activation. These findings suggest that SmgGDS retains GDP-bound RHEBs in the cytosol, whereas GTP-bound RHEBs are localized on intracellular membranes to promote mTORC1 activation. We revealed a novel role for SmgGDS in the RHEB–mTORC1 pathway and its potential as a therapeutic target in MM with aberrant mTORC1 activation.

Implications:

Our data showing that SmgGDS regulates RHEB localization to activate mTORC1 indicate that SmgGDS can be used as a new therapeutic target for MM exhibiting mTORC1 activation.
Antiglaucoma Potential of β-Glucogallin Is Mediated by Modulating Mitochondrial Responses in Experimentally Induced Glaucoma
Authors: Cao Tingting , Wang Jun , Wu Yuanyuan , Wang Lianfeng , Zhang Huiqin
Published: February 2021

Background: The use of phytochemicals for the treatment of various bodily ailments has been in practice since ancient days. Even though in practice, scientific studies on the protective effect of β-glucogallin (BG) against glaucoma is limited. Objectives: In the present study, the in vitro glaucoma model (hydrostatic pressure) using PC12 neuronal cells exposed to BG were used to elucidate its protective effects. Method: The cultured cells were analyzed for the mitochondrial responses, oxidant-antioxidant status, and expression of caveolin-1, ANGPTL7, the glaucoma markers, and cytokines. Results: We demonstrated a significant increase in the expression of glial fibrillary acidic protein, ANGPTL7, with altered mitochondrial enzymes in glaucoma cells compared to the control. Moreover, cells predisposed to hydrostatic pressure demonstrated an increase in oxidative stress with augmented (p < 0.01) inflammatory cytokines such as IL-2, CXCR4, IL-6, IL-8, MCP-1, and TNF-α. On the other hand, cells pretreated with BG attenuated the reactive oxygen species levels with improved antioxidant enzymes. Simultaneously, the levels of inflammatory cytokines and ANGPTL7 proteins were found attenuated with restored mitochondrial responses in BG pretreated cells. Conclusion: Thus, the results of the present study demonstrate that the use of BG on retinal cells against relieving the intraocular pressure may be a promising therapeutic for controlling the disease progression.
Analysis of the cattle trade network in the state of Mato Grosso, Brazil
Authors: Negreiros Rísia Lopes , Grisi-Filho José Henrique Hildebrand , Dias Ricardo Augusto , Ferreira Fernando , Ferreira Neto José Soares , Ossada Raul , Amaku Marcos
Published: February 2021

We characterized the network of cattle movements in Mato Grosso, Brazil—a state responsible for a significant amount of Brazilian beef exports. In this analysis, we were particularly interested in the importance of slaughterhouses in the network of cattle movements, in the characteristics of the trade for different purposes (especially for reproduction, fattening, and slaughter), and about the importance of the main traders. We found that the median distance of all movements was 79.0 km, with an interquartile range between 37.2 and 163.2 km, which suggests a relatively short-range trade pattern; roughly 20% of the premises purchasing more animals were responsible for 95% of the animals purchased and 20% of the premises selling more animals were responsible for 86% of the animals sold, indicating the importance of the cattle trade hubs. Fitting the degree distribution using a power-law distribution, we obtained a scaling parameter of 2.59, indicating that the cattle movement network of Mato Grosso is less dense than other observed cattle movement networks. The networks for fattening, reproduction, and slaughtering only comprised 73%, 56%, and 25% of all nodes and 52%, 30%, and 17% of all edges, respectively; and slaughterhouses had the highest in-degrees and total degrees, followed by markets and farms, playing the role of main cattle trade hubs. Therefore, slaughterhouses are potentially useful as surveillance points to detect cases, and controlling important trader premises may optimize the use of resources for controlling diseases.
Pontos de escuta e diegese múltipla da chanson no cinema
Authors: Vidigal Leonardo Alvares
Published: February 2021

A chanson é um gênero de música popular ouvido no cinema produzido na França. Por meio de uma integração entre a análise microtextual (na relação sincrônica entre som e imagem), macrotextual (no interior da cena), microcontextual (no conjunto do filme) e macrocontextual (no momento histórico da sociedade em que se insere), serão abordadas três películas. O objetivo é demonstrar como as chansons operam, não apenas na sinergia entre a indústria fonográfica e cinematográfica, mas também narrativamente, exprimindo emoções das personagens, catalisando falas e ações nos filmes, além de explicitar as diferentes formas de manipulação do ponto de escuta e dos regimes da diegese.
Apresentação
Authors: Morettin Eduardo Victorio
Published: February 2021

Apresentação da edição 55
Impact of Cardiovascular Hemodynamics on Cognitive Aging
Authors: Moore Elizabeth E. , Jefferson Angela L.
Published: February 2021

It is well known that cardiovascular disease and related vascular risk factors are associated with cognitive decline and worse brain health outcomes among aging adults. Recently, subtle age-related changes in cardiac hemodynamics have been proposed as an emerging risk factor for abnormal brain aging, even in the absence of cardiovascular disease. Changes in cardiac function, vital for determining the total amount of blood available for perfusing the body, and arterial stiffness, important for regulating blood flow delivery, have been associated with compromised brain structure and function among older adults. Such alterations in cardiac output and arterial stiffening may directly affect brain health through blood-brain barrier breakdown or oligemia, or may interact with Alzheimer disease and concomitant pathologies common in aging adults to accelerate cognitive decline. This review examines how age-related alterations in cardiovascular integrity contribute to abnormal brain aging, emphasizing that changes in systemic hemodynamics may compromise brain health before or concurrently with the development of neurodegenerative processes that are common in aging.
Novel Lesional Transcriptional Signature Separates Atherosclerosis With and Without Diabetes in Yorkshire Swine and Humans
Authors: Haemmig Stefan , Hashemi Gheinani Ali , Zaromytidou Marina , Siasos Gerasimos , Coskun Ahmet Umit , Cormier Michelle A. , Gross David A. , Wara A.K.M. Khyrul , Antoniadis Antonios P. , Sun Xinghui , Sukhova Galina K. , Welt Fred G.P. , Andreou Ioannis , Whatling Carl , Gan Li-Ming , Wikström Johannes , Edelman Elazer R. , Libby Peter , Stone Peter H. , Feinberg Mark W.
Published: February 2021

Objective:

Accelerated atherosclerosis in diabetes constitutes an ongoing challenge despite optimal medical therapies. This study aimed to identify evolutionarily conserved lesion-based regulatory signaling networks in diabetic versus nondiabetic conditions during the development of atherosclerosis in an initial translational effort to provide insights for targets.

Approach and Results:

Serial 3-mm coronary artery segments of hypercholesterolemic Yorkshire swine and diabetic-hypercholesterolemic swine were characterized as mild, moderate, or severe phenotypic manifestations of coronary atherosclerosis based on histopathologic examination. Lesional RNA sequencing was performed (n=3–8 lesions per group) corresponding to increasing phenotypic severity. Differentially expressed genes, transcription factors, upstream regulators, and hubs were validated using the NanoString technology and a human atherosclerotic specimen cohort.

Despite similar stage histopathologic characterization of lesions, genome-wide transcriptomics revealed gene sets and nodal signaling pathways uniquely expressed in diabetic lesions including signaling pathways for Th17, IL (interleukin)-17F, TWEAK (TNF [tumor necrosis factor]-related weak inducer of apoptosis), CD27, and PI3K/Akt. In contrast, pathways of nondiabetic lesions involved TREM-1 and Th1 and Th2 responses during the initiation stage, whereas networks for mitochondrial dysfunction, oxidative phosphorylation, and lipid metabolism emerged with progression. RNA sequencing data were validated in a human atherosclerosis specimen cohort using machine learning algorithms.
F8
,
MAPKAPK3
, and
ITGB1
emerged as powerful genes for clustering diabetic versus nondiabetic lesions and for separating different degrees of atherosclerosis progression.

Conclusions:

This study identifies evolutionarily conserved gene signatures and signaling pathways in a stage-specific manner that successfully distinguishes diabetes- and non–diabetes-associated atherosclerosis. These findings establish new molecular insights and therapeutic opportunities to address accelerated atherosclerotic lesion formation in diabetes.
Mast Cells Are the Trigger of Small Vessel Disease and Diastolic Dysfunction in Diabetic Obese Mice
Authors: Guimbal Sarah , Cornuault Lauriane , Rouault Paul , Hollier Pierre-Louis , Chapouly Candice , Bats Marie-Lise , Imbault Julien , Gadeau Alain-Pierre , Couffinhal Thierry , Renault Marie-Ange
Published: February 2021

Objective:

Heart failure with preserved ejection fraction is a major health care issue which has been difficult to manage to date, due to its complex and not well understood pathophysiology. Specifically, if a wealth of literature focuses on heart failure with preserved ejection fraction cardiac component, very little information can be found on its vascular component. Our goal is to unravel the critical role of cardiac small vessel disease in the pathophysiology of diastolic dysfunction.

Approach and Results:

To do so, we used leptin receptor deficient (Lepr
db/db
) female mice, a recognized model of diastolic dysfunction. In these mice, the increased end-diastolic pressure signing diastolic dysfunction is associated with vascular leakage, endothelial cell activation, and leucocyte infiltration. Strikingly, a RNA sequencing analysis of the cardiac vascular fraction of both Lepr
db/db
and control mice confirmed endothelial dysfunction and systemic inflammation, but above all, revealed a strong increase in several mast cell markers (notably FceR1a [high affinity immunoglobulin epsilon receptor subunit α], tryptase, and chymase). We then confirmed this accumulation of activated mast cells in the heart of Lepr
db/db
mice via histology. Importantly, we found that both mast cell degranulation inhibition and specific histamine blockade reduced vascular leakage, leucocyte infiltration, and subsequently end-diastolic pressure in Lepr
db/db
mice. This demonstrated, for the first time, that mast cells, via histamine release, participate in the development of cardiac small vessel disease leading to diastolic dysfunction.

Conclusions:

Cardiac small vessel disease is a key mechanism of heart failure with preserved ejection fraction pathophysiology that can be targeted to prevent the occurrence of diastolic dysfunction, by using both mast cell stabilizers and antihistaminic drugs.