bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of Capital Structure on the Performance of Chinese E‐Commerce Industry Companies (2013–2019 Panel Data)
Authors: Zhang Meng-Yao , Lin Li-Wei , Chen Huei-Ping , Zhao Xuan-Ze
Published: July 2022

This research examined how to estimate performance in China’s e‐commerce industry, by taking 2013–2019 e‐commerce listed companies as the research samples and using an empirical research method to study the relationship between capital structure and firm performance. The empirical results show that the debt‐to‐asset ratio and the long‐term interest‐bearing debt ratio have a negative impact on firm performance, but the impact of the long‐term interest‐bearing debt ratio is not significant. Moreover, the short‐term interest‐bearing debt ratio and the total asset turnover ratio have a positive impact on firm performance, while the impacts of the current assets ratio and intangible assets ratio on firm performance are not significant. The following suggestions are drawn from the results in order of importance. (1) Enterprises should maintain a reasonable debt‐to‐assets ratio and a stable capital structure and appropriately increase the proportion of short‐term liabilities. (2) Firms should moderately invest to expand their scale and improve their profitability, so as to increase retained earnings and develop internal financing channels.
Coupled Thermal Stress Analysis of Volvo Truck Disc Brake
Authors: Bena Welteji , Sirata Goftila
Published: July 2022

This paper deals with the coupled thermal structural analysis developed in Volvo heavy truck disc brake as a function of disc thickness and braking time. A ventilated type of disc brake was employed by having vents (holes) on its surface, which needs a cooling system. When the brake pedal is applied, the friction between the disc and pad tremendously increases due to the heat generated in this system. This heat was partitioned into two contacting bodies (disc rotor and pad). Both analytical and numerical approaches were used to carry out the analysis. Analytically, the transient temperature obtained by the partial solution approach and the stress field were evaluated by the elastic von Mises criterion. In the numerical approach, temperature and stress response were analyzed by the explicit standard ABAQUS. From both results, high thermal gradient and von Mises stress distribution were observed at the sharp edges of the disc, which causes a decrement in braking efficiency and an overall drop in braking performance.
Study on Nursing Effect of Psychological Intervention on Uremic Hemodialysis Patients
Authors: Chen Yan , Ding Jie , Li Chunqing , Wu Ting , Li Qingya , Chen Rujing , Zhou Jingfen
Published: July 2022

Aim. Patients in the hemodialysis stage are prone to psychological pressure of depression and anxiety and have resistance, which affects the clinical treatment effect. Effective psychological intervention plays a very important role in improving patients’ psychological pressure and patients’ compliance. The aim of this study is to explore the nursing effect of psychological intervention on uremic hemodialysis patients. Methods. There were 126 uremic hemodialysis patients admitted to the hospital from August 2020 to December 2021. The patients were randomly divided into the routine nursing care group (

n
=
63

) and psychological intervention group (

n
=
63

). The routine nursing care group received routine nursing care for uremia hemodialysis patients. The psychological intervention group implemented psychological intervention on uremia hemodialysis patients. The methods of psychological intervention mainly include establishing a good nurse-patient relationship, popularizing hemodialysis knowledge, timely psychological counseling for patients, and organizing patient communication meetings. The treatment compliance, Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS) of the two groups were compared before and after nursing. SF-36 scale was used to evaluate the quality of life of patients. The incidence of complications and nursing satisfaction were compared between the two groups. Results. The treatment compliance rate and nursing satisfaction of hemodialysis uremic patients in the psychological intervention group were significantly higher than the routine nursing care group. The SAS and SDS of hemodialysis uremia patients in the psychological intervention group were significantly lower than the routine nursing care group after psychological intervention, and SF-36 scale was significantly higher than the routine nursing group. The main complications of uremic hemodialysis patients are hypotension, hyperkalemia, internal fistula occlusion, and infection. Compared with the routine nursing care group, the incidence of complications in the psychological intervention group was significantly reduced. Conclusion. The implementation of psychological nursing intervention for uremic hemodialysis patients have a very significant effect on reducing the incidence of complications and improving anxiety, depression, treatment compliance, and the quality of life and the nursing satisfaction.
LncRNA ZNF674-AS1 Hinders Proliferation and Invasion of Hepatic Carcinoma Cells through the Glycolysis Pathway
Authors: Li Dongliang , Xie Yan , Sun Jisan , Zhang Li , Jiang Wentao
Published: July 2022

Purpose. Long noncoding RNAs (lncRNAs) play important roles in regulating various functions of cells at the levels of transcription and posttranscription. Extensive investigations have illustrated that lncRNAs are critical in the glucose metabolism of tumor cells, but their mechanisms of action need to be further explored. This study evaluates the role of lncRNA ZNF674-AS1 on the apoptosis and proliferation of human hepatic carcinoma cells in vitro through the glucose metabolism and its related mechanisms. Methods. Real-time quantitative PCR was employed for detecting the level of expressions for lncRNA ZNF674-AS1 in liver cancer tissues (25 cases), paracancerous tissues, and liver cancer cell lines. The lncRNA ZNF674-AS1 high expression cell strain was constructed by the lentiviral overexpression vector. CCK-8, plate colony formation, transwell assay, lactate production, glucose consumption, and ATP levels were used to detect the change of cell proliferation, colony formation, migration, and invasion, as well as glycolytic capability. Western blot was carried out to detect the expression of HK2, PFKL, PKM2, GLUT1, and PKM1, which are the key proteins of glycolysis in cells. Result. The lncRNA ZNF674-AS1 was undesirably expressed in liver cancer cell lines and tissues. Cell function assessments showed that compared with the blank control group (vector), overexpression of lncRNA ZNF674-AS1 could substantially hinder the proliferation, colony formation, migration, and invasion capability of liver cancer cells. Furthermore, overexpression of lncRNA ZNF674-AS1 could inhibit cell glycolysis (inhibit glucose consumption and reduce intracellular lactate and ATP levels) by inhibiting the expression of key proteins (such as PFKL, HK2, PKM2, and GLUT1) in the process of glycolysis. Conclusion. As a tumor repressor gene, lncRNA ZNF674-AS1 inhibits the expression of key proteins in glycolysis to inhibit glycolysis level, thereby inhibiting cell migration and proliferation. Therefore, lncRNA ZNF674-AS1 could be a potent therapeutic target or a novel diagnostic molecule for patients suffering from liver cancer.
Antimicrobial and Mechanical Properties of Orthodontic Acrylic Resin Containing Zinc Oxide and Titanium Dioxide Nanoparticles Supported on 4A Zeolite
Authors: Esmaeilzadeh Mahdiyeh , Divband Baharak , Ranjkesh Bahram , Pournaghi Azar Fatemeh , Yeganeh Sefidan Fatemeh , Kachoei Mojgan , Karimzadeh Behnaz
Published: July 2022

Polymethyl methacrylate (PMMA) is widely used to manufacture removable orthodontic appliances. However, since the porous structure, cold-curing acrylic resins are susceptible to bacterial adhesion and colonization. The aim of this study was to investigate the antibacterial and mechanical properties of a cold-curing PMMA resin containing ZnO and TiO2 nanoparticles supported on the 4A zeolite. ZnO and TiO2 nanoparticles supported on the 4A zeolite were synthesized. Nanoparticles were added in three compositions as ZnO/4A, TiO2/4A, and ZnO/TiO2/4A at 2wt% and 4wt% concentrations to cold-curing acrylic resin powder (SR Triplex® Cold Ivoclar Vivadent AG, FL-9494 Schaan/Liechtenstein). X-ray diffraction (XRD), Field Emission Scanning Electron Microscopy (FE-SEM), energy dispersive X-ray (EDX), transmission electron microscopy (TEM), and dynamic light scattering (DLS) were performed to investigate the nanocomposite characteristics. A direct test method was used to assess the antibacterial properties against Streptococcus mutans, Klebsiella pneumoniae, and Escherichia coli. The surface roughness of acrylic samples was measured with a profilometer. Flexural strength was evaluated by a three-point bending test, and one-way ANOVA and Tukey’s post hoc tests were used for statistical evaluation of the data. A

p

value of less than 0.05 was considered statistically significant. XRD confirmed the accurate crystalline structure of synthesized nanoparticles; FE-SEM images showed nanoparticle dispersion within polymerized acryl. The addition of 2 and 4 wt% of ZnO/4A, TiO2/4A, and ZnO/TiO2/4A caused colony reduction in all types of tested microorganisms more than 99% and 100%, respectively. The mean flexural strengths of acrylic specimens containing 2wt% and 4wt% of synthesized nanoparticles were significantly lower than those of the resin without nanoparticles. Fabricated samples showed favorable antibacterial properties but decreased flexural strength.
Effect Analysis of In-Hospital Transfer Care Based on STABLE Technology in Critically Ill Newborns
Authors: Fang Li , Pei Jiaoru , Jiang Siqiong
Published: July 2022

Purpose. Analysis of the effectiveness of in-hospital transfer care based on the STABLE (sugar and safe care, temperature, airway, blood pressure, lab work, emotional support) technique in critically ill neonates. Methods. Retrospective analysis of the case data of 180 critically ill neonates transferred to the NICU (neonatal intensive care unit) via the delivery room (operating room) in our hospital from April 2020 to December 2021. Of which, 88 newborns from April 2020 to February 2021 were resuscitated by conventional resuscitation and then transferred to the NICU by the nurses in the delivery room (operating room) through the green channel, and they were recorded as the control group; and 92 newborns from March to December 2021 were transferred to the NICU by the NICU transfer nurses who arrived at the delivery room (operating room) earlier and used the in-hospital transfer care based on STABLE technology, and they were recorded as the intervention group. The indicators to be assessed were the execution pass rate in the simulated assessment of the transfer emergency procedure for both groups of transporters, execution times of the various subprocesses during the transfer procedure for both groups of transporters, accidents in transit, and blood glucose, blood pressure, body temperature, respiration, blood gas indicators, and family satisfaction of children in both groups after transfer. Results. The total execution pass rate for transporters was higher in the intervention group than in the control group (

P
<
0.05

). The execution times of the various subprocesses during the transfer procedure of transporters were shorter in the intervention group than in the control group (

P
<
0.05

). The incidence of accidents in transit was lower in the intervention group than in the control group (

P
<
0.05

). After transfer, the blood glucose, blood pressure, body temperature, respiratory, and blood gas indicators of the children in the intervention group were all more stable than those in the control group (

P
<
0.05

). The satisfaction of the families of the children in the intervention group was higher than that of the control group (

P
<
0.05

). Conclusion. The implementation of transfer care based on STABLE technology for newborns in urgent need of in-hospital transfer can effectively improve the comprehensive quality and emergency response ability of transfer nurses and shorten the in-hospital transfer time, and the incidence of adverse reactions during the transfer of children is less, the vital signs are stable, and the satisfaction of family members is high, which is of promotion value.
BSC-Based Performance Evaluation Model for Securities Industry and Its Application
Authors: Yuan Ling , Sun Shan-Hui , Cai Zheng-Qun
Published: July 2022

In the study on China’s securities industry, the securities industry is divided into four types: investment in securities, securities brokerage, securities consulting, and securities underwriting and asset management. In this paper, a performance evaluation index system for the securities industry is established by using the balanced scorecard method. Based on the analytic hierarchy process, entropy weight method, and improved entropy weight method, we propose the traditional integrated weighting method and improved integrated weighting method, thus arriving at four different index weight systems. Finally, we work out the comprehensive scores of four types of securities companies under the four index weight systems, analyze the actual situation of China’s securities industry by comparing the scores and rankings of securities companies under the four index weight systems, and then put forward specific suggestions.
Clinical Value of Vitamin D, Trace Elements, Glucose, and Lipid Metabolism in Diagnosis and Severity Evaluation of Psoriasis
Authors: Huang Da , Su Liangbao , Zhuang Lihua , Wu Jie , Zhuang Jihua
Published: July 2022

Objective. The levels of vitamin D, trace elements, and glucose and lipid metabolism in psoriasis were evaluated, and their value in disease diagnosis and severity evaluation was explored. Methods. In this study, the serum trace elements, blood glucose, and blood lipid indexes of 360 patients with psoriasis and 500 healthy subjects were compared and analyzed. Results. The results of 25-(OH) D3, Cu/Zn, and HDL-C in patients with psoriasis were significantly different from those in the control group. With the aggravation of the disease, Psoriasis Area and Severity Index (PASI) was positively correlated with 25-(OH) D3 and HDL-C and negatively correlated with Cu/Zn. The AUC of the three indexes for the diagnosis of psoriasis was 0.899, 0.675, and 0.848, respectively. Conclusion. There are metabolic abnormalities of 25-(OH) D3, Cu/Zn, and HDL-C in patients with psoriasis, and paying attention to these indicators is conducive to the diagnosis of disease.
Distributed Antenna-and-Relay Selection Schemes for MIMO Cooperative Relay Network
Authors: Zhang Yang , Wang Wei , Zhao Xiangmo , Hou Jun
Published: July 2022

Relay selection, antenna selection, and link selection are three potent means to enrich network capacity in MIMO relaying networks. To reduce feedback overhead, in this paper, three distributed antenna-and-relay selection schemes are proposed for AF multiple-relay network, which is equipped with multiple antennas at nodes. Closed-form formulations of system outage probability are derived for these schemes, as well as the lower bounds and upper bounds. Furthermore, the approximate expressions of outage probability at high SNR regime are also derived, showing that the proposed optimal strategy can achieve full diversity order. In addition, link selection scheme can improve spectral efficiency since it saves one time slot when direct link is selected.
Nitrogen Inversion Model in a Wetland Environment Based on the Canopy Reflectance of Emergent Plants
Authors: Wu Dongli , Zhao Dongliang , Zhu Yongchao , Shen Chao , Xue Hongxi
Published: July 2022

Reuse of reclaimed water in constructed wetlands is a promising way to conserve water resources and improve water quality, and it is playing a very important role in wetland restoration and reconstruction. This study utilized reflectance spectra of wetland vegetation to estimate nitrogen content in water in the Beijing Bai River constructed wetland, a typically constructed wetland that uses reclaimed water. Canopy reflectance spectra of two dominant plants in the wetland, including reed and cattail, were acquired using a spectrometer (350–2500 nm). Simultaneously, water samples were collected to measure water quality. To establish the appreciate relationship between total nitrogen content (TN) and reflectance spectra, both simple and multiple regression models, including simple ration spectral index (SR), normalized difference spectral index (ND), stepwise multiple linear regression (SMLR) model, and partial least squares regression (PLSR), were adopted in this study. The results showed that (1) compared with simple regression models (SR and ND), multiple regressions models (SMLR and PLSR) could provide a more accurate estimation of TN concentration in the wetland environment. Among these models, the PLSR model had the highest accuracy and was proven to be the most useful tool to reveal the relationship between the spectral reflectance of wetland plants and the total nitrogen consistency of wetland at the canopy scale. (2) The inversion effect of TN concentration in water is slightly better than that of wetland vegetation, and the reflection spectrum of the reed can predict TN concentration more accurately than that of cattail. The finding not only provides solid evidence for the potential application of remote sensing to detect water eutrophication but also enhances our understanding of the monitoring and management of water quality in urban wetlands using recycled water.
Customizable Encryption Algorithms to Manage Data Assets Based on Blockchain Technology in Smart City
Authors: Al-Dhlan Kawther A. , Alreshidi Hamad A. , Pervez Shahbaz , Paraveen Zahida , Zeki Akram M. , Sid Ahmed Nada M. O. , Alshammari Eid J. , Lingamuthu Velmurugan
Published: July 2022

The adoption of blockchain technology can provide data asset management’s high security, privacy, and traceability. After a comprehensive investigation of the present blockchain-based data asset management mechanism, it was determined that it is only relevant to a portion of the blockchain system design. To address this issue, a new model of data asset management based on blockchain technology is being developed, which incorporates applications at all levels of the blockchain system. This model implements a network layer node authority control mechanism, a consensus layer consensus mechanism with customizable attributes, improved data query efficiency at the data layer by optimizing the structure and building indexes, intelligent data management, and smart contract layer management. Furthermore, at the transaction layer, sharing information encryption using customizable encryption algorithms is introduced. The experimental results reveal that, when compared to the traditional paradigm, the new blockchain-based data asset management strategy enhances the efficiency of on-chain data queries by 2.33 times.
Medical Image Classification Using Transfer Learning and Chaos Game Optimization on the Internet of Medical Things
Authors: Mabrouk Alhassan , Dahou Abdelghani , Elaziz Mohamed Abd , Díaz Redondo Rebeca P. , Kayed Mohammed
Published: July 2022

The Internet of Medical Things (IoMT) has dramatically benefited medical professionals that patients and physicians can access from all regions. Although the automatic detection and prediction of diseases such as melanoma and leukemia is still being investigated and studied in IoMT, existing approaches are not able to achieve a high degree of efficiency. Thus, with a new approach that provides better results, patients would access the adequate treatments earlier and the death rate would be reduced. Therefore, this paper introduces an IoMT proposal for medical images’ classification that may be used anywhere, i.e., it is an ubiquitous approach. It was designed in two stages: first, we employ a transfer learning (TL)-based method for feature extraction, which is carried out using MobileNetV3; second, we use the chaos game optimization (CGO) for feature selection, with the aim of excluding unnecessary features and improving the performance, which is key in IoMT. Our methodology was evaluated using ISIC-2016, PH2, and Blood-Cell datasets. The experimental results indicated that the proposed approach obtained an accuracy of 88.39% on ISIC-2016, 97.52% on PH2, and 88.79% on Blood-cell datsets. Moreover, our approach had successful performances for the metrics employed compared to other existing methods.
Design of Two-Regional Flexible-Route Bus Systems considering Interregional Demands
Authors: Wang Siqing , Wang Jian , Song Lang , Niu Zhipeng , Hu Xiaowei
Published: July 2022

The flexible-route bus system is a type of dynamic public transit service. Routes and timetables are not fixed during the operation process, and driving routes are planned according to passengers’ reservation needs. This study develops a model that considers inter-regional travel demands. The optimal network layout is determined by minimizing an objective function that comprises operator and user costs. Then, two cases with and without loop-line buses are analyzed. In the case of the joint optimal solution, the parameter values of region side width, region angle, and cost components are compared. Results indicate that regional flexible transit is suitable for operation in areas with low demand density. Within certain ranges, increases in vehicle capacity and in the number of circle layers result in additional average total costs. Furthermore, adopting a mode with a loop is better when numerous inter-regional demands exist. The findings derived from numerical and sensitivity analyses can be used as planning guides for designing flexible-route bus systems.
Deep Image Watermarking to JPEG Compression Based on Mixed-Frequency Channel Attention
Authors: Tan Jun , Hu Yinan , Shi Ziming , Wang Bin
Published: July 2022

Deep blind watermarking algorithms based on an end-to-end encoder-decoder architecture have recently been extensively studied as an important technology for protecting copyright. However, none of the existing algorithms can fully utilize the channel features of the image to improve the robustness against JPEG compression while obtaining high visual quality. Therefore, we propose firstly a mixed-frequency channel attention method in the encoder, which utilizes different frequency components of the 2D-DCT domain as weight coefficients during channel squeezing and excitation. Its essence is to suppress the useless feature maps and enhance the feature maps suitable for watermarking embedding by introducing frequency analysis in the channel dimension. The experimental results indicate that the PSNR of our method reaches over 38 and the BER is less than 0.01% under the JPEG compression with quality factor

Q
=
50

. Besides, the proposed framework also obtains excellent robustness for a variety of common distortions, including Gaussian filter, crop, crop out, and drop out.
Genetic Risk of Second Primary Cancer in Breast Cancer Survivors: The Multiethnic Cohort Study
Authors: Chen Fei , Park Sungshim L. , Wilkens Lynne R. , Wan Peggy , Hart Steven N. , Hu Chunling , Yadav Siddhartha , Couch Fergus J. , Conti David V. , de Smith Adam J. , Haiman Christopher A.
Published: July 2022

Women who have had breast cancer in the past are at increased risk of developing a second primary cancer (SPC), including second primary breast cancer (SPBC) or a second primary non-breast cancer (SPNBC). In the Multiethnic Cohort (MEC) Study, we conducted a prospective cohort analysis in 3,223 female breast cancer survivors from five racial/ethnic populations (White, African American, Japanese American, Latino, and Native Hawaiian) to assess the association of rare pathogenic variants (PV) in 37 known cancer predisposition genes with risk of SPC. A total of 719 (22.3%) women developed SPC, of which, 323 (10.0%) were SPBC. Germline PVs in BRCA1 (HR, 2.28; 95% CI, 1.11–4.65) and ERCC2 (HR, 3.51; 95% CI, 1.29–9.54) were significantly enriched in women with SPC. In the subtype analysis for SPBC, a significant association of ERCC2 PVs (HR, 5.09; 95% CI, 1.58–16.4) and a suggestive association of BRCA2 PVs (HR, 2.24; 95% CI, 0.91–5.55) were observed. There was also a higher risk of SPNBC in carriers of BRCA1 PVs (HR, 2.98; 95% CI, 1.21–7.36). These results provide evidence that germline PVs in BRCA1, BRCA2, and ERCC2 contribute to the development of SPC in breast cancer survivors. These findings also suggest that compromised DNA repair mechanisms could be a predisposition factor for SPC in patients with breast cancer, supporting the need for closer monitoring of SPC in women carrying PVs in these genes.

Significance:

This multiethnic study links germline pathogenic variants in BRCA1, BRCA2, and ERCC2 to the development of second primary cancer in breast cancer survivors, providing biological insights and biomarkers to guide patient monitoring.
Comprehensive Serum Proteome Profiling of Cytokine Release Syndrome and Immune Effector Cell–Associated Neurotoxicity Syndrome Patients with B-Cell ALL Receiving CAR T19
Authors: Diorio Caroline , Shraim Rawan , Myers Regina , Behrens Edward M. , Canna Scott , Bassiri Hamid , Aplenc Richard , Burudpakdee Chakkapong , Chen Fang , DiNofia Amanda M. , Gill Saar , Gonzalez Vanessa , Lambert Michele P. , Leahy Allison Barz , Levine Bruce L. , Lindell Robert B. , Maude Shannon L. , Melenhorst J. Joseph , Newman Haley , Perazzelli Jessica , Seif Alix E. , Lacey Simon F. , June Carl H. , Barrett David M. , Grupp Stephan A. , Teachey David T.
Published: July 2022

Purpose:

To study the biology and identify markers of severe cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) in children after chimeric antigen receptor T-cell (CAR T) treatment.

Experimental Design:

We used comprehensive proteomic profiling to measure over 1,400 serum proteins at multiple serial timepoints in a cohort of patients with B-cell acute lymphoblastic leukemia treated with the CD19-targeted CAR T CTL019 on two clinical trials.

Results:

We identified fms-like tyrosine kinase 3 (FLT3) and mast cell immunoglobulin-like receptor 1 (MILR1) as preinfusion predictive biomarkers of severe CRS. We demonstrated that CRS is an IFNγ-driven process with a protein signature overlapping with hemophagocytic lymphohistiocytosis (HLH). We identified IL18 as a potentially targetable cytokine associated with the development of ICANS.

Conclusions:

We identified preinfusion biomarkers that can be used to predict severe CRS with a sensitivity, specificity, and accuracy superior to the current gold standard of disease burden. We demonstrated the fundamental role of the IFNγ pathway in driving CRS, suggesting CRS and carHLH are overlapping rather than distinct phenomena, an observation with important treatment implications. We identified IL18 as a possible targetable cytokine in ICANS, providing rationale for IL18 blocking therapies to be translated into clinical trials in ICANS.
Anticancer Activity of the Combination of Cabozantinib and Temozolomide in Uterine Sarcoma
Authors: Noh Joseph J. , Cho Young-Jae , Ryu Ji-Yoon , Choi Jung-Joo , Hwang Jae Ryoung , Choi Ju-Yeon , Lee Jeong-Won
Published: July 2022

Purpose:

To evaluate the anticancer effects of cabozantinib, temozolomide, and their combination in uterine sarcoma cell lines and mouse xenograft models.

Experimental Design:

Human uterine sarcoma cell lines (SK-LMS-1, SK-UT-1, MES-SA, and SKN) were used to evaluate the anticancer activity of cabozantinib, temozolomide, and their combination. The optimal dose of each drug was determined by MTT assay. Cell proliferation and apoptosis were assessed 48 and 72 hours after the drug treatments. The tumor weights were measured in an SK-LMS-1 xenograft mouse model and a patient-derived xenograft (PDX) model of leiomyosarcoma treated with cabozantinib, temozolomide, or both.

Results:

Given individually, cabozantinib and temozolomide each significantly decreased the growth and viability of cells. This inhibitory effect was more pronounced when cabozantinib (0.50 μmol/L) and temozolomide (0.25 or 0.50 mmol/L) were co-administered (P < 0.05). The combination of the drugs also significantly increased apoptosis in all cells. Moreover, this effect was consistently observed in patient-derived leiomyosarcoma cells. In vivo studies with SK-LMS-1 cell xenografts and the PDX model with leiomyosarcoma demonstrated that combined treatment with cabozantinib (5 mg/kg/d, per os administration) and temozolomide (5 mg/kg/d, per os administration) synergistically decreased tumor growth (both P < 0.05).

Conclusions:

The addition of cabozantinib to temozolomide offers synergistic anticancer effects in uterine sarcoma cell lines and xenograft mouse models, including PDX. These results warrant further investigation in a clinical trial.
GITR Antibodies in Cancer: Not Ready for Prime Time
Authors: Hernandez-Guerrero Tatiana , Moreno Victor
Published: July 2022

Glucocorticoid-induced TNF receptor (TNFR)-related protein (GITR) agonistic antibodies are expected to increase the antitumor response mainly by reducing the effect of Foxp3+ T-regulatory cells. TRX-518 is a novel GITR agonist that has shown good pharmacodynamic activity by depleting regulatory T cells (Tregs) in preclinical models, with limited clinical activity demonstrated in patients with advanced solid tumors.

See related article by Davar et al., p. 3990
EPAC Regulates Melanoma Growth by Stimulating mTORC1 Signaling and Loss of EPAC Signaling Dependence Correlates with Melanoma Progression
Authors: Krishnan Aishwarya , Bhasker Aishwarya I. , Singh Mithalesh K. , Rodriguez Carlos. I. , Pérez Edgardo Castro , Altameemi Sarah , Lares Marcos , Khan Hamidullah , Ndiaye Mary , Ahmad Nihal , Schieke Stefan M. , Setaluri Vijayasaradhi
Published: July 2022

Exchange proteins directly activated by cAMP (EPAC) belong to a family of RAP guanine nucleotide exchange factors (RAPGEF). EPAC1/2 (RAPGEF3/4) activates RAP1 and the alternative cAMP signaling pathway. We previously showed that the differential growth response of primary and metastatic melanoma cells to cAMP is mediated by EPAC. However, the mechanisms responsible for this differential response to EPAC signaling are not understood. In this study, we show that pharmacologic inhibition or siRNA-mediated knockdown of EPAC selectively inhibits the growth and survival of primary melanoma cells by downregulation of cell-cycle proteins and inhibiting the cell-cycle progression independent of ERK1/2 phosphorylation. EPAC inhibition results in upregulation of AKT phosphorylation but a downregulation of mTORC1 activity and its downstream effectors. We also show that EPAC regulates both glycolysis and oxidative phosphorylation, and production of mitochondrial reactive oxygen species, preferentially in primary melanoma cells. Employing a series of genetically matched primary and lymph node metastatic (LNM) melanoma cells, and distant organ metastatic melanoma cells, we show that the LNM and metastatic melanoma cells become progressively less responsive and refractory to EPAC inhibition suggesting loss of dependency on EPAC signaling correlates with melanoma progression. Analysis of The Cancer Genome Atlas dataset showed that lower RAPGEF3, RAPGEF4 mRNA expression in primary tumor is a predictor of better disease-free survival of patients diagnosed with primary melanoma suggesting that EPAC signaling facilitates tumor progression and EPAC is a useful prognostic marker. These data highlight EPAC signaling as a potential target for prevention of melanoma progression.

Implications:

This study establishes loss of dependency on EPAC-mTORC1 signaling as hallmark of primary melanoma evolution and targeting this escape mechanism is a promising strategy for metastatic melanoma.
Suppressed Cellular Senescence Mediated by T-box3 in Aged Gastric Epithelial Cells may Contribute to Aging-related Carcinogenesis
Authors: Takeuchi Akio , Asano Naoki , Imatani Akira , Saito Masashi , Jin Xiaoyi , Saito Masahiro , Kanno Takeshi , Hatta Waku , Uno Kaname , Koike Tomoyuki , Masamune Atsushi
Published: July 2022

Aging is a risk factor for cancers in various organs. Recent advances in the organoid culturing system have made it viable to investigate the influence of aging utilizing these mini organs. In this study, we aimed to examine the implications of aging for gastric carcinogenesis. Gastric organoids established from aged mice grew larger, proliferated vigorously, and survived longer than that from young mice. Because Wnt/β-catenin signaling was intensified in the aged organoids and because removal of Wnt-related factors diminished their proliferation, we investigated for Wnt target gene that contributed to enhanced proliferation and discovered that the aged organoids expressed the transcription factor T-box3 (Tbx3), which has been reported to suppress cellular senescence. Indeed, cellular senescence was suppressed in the aged organoids, and this resulted from enhanced G2–M transition. As for the mechanism involved in the intensified Wnt/β-catenin signaling, we identified that Dickkopf3 (Dkk3) expression was reduced in the aged organoids due to methylation of the Dkk3 gene. Finally, the expression of TBX3 was enhanced in human atrophic gastritis and even more enhanced in human gastric cancers. In addition, its expression correlated positively with patients’ age. These results indicated that the emergence of antisenescent property in aged gastric organoids due to enhanced Tbx3 expression led to accelerated cellular proliferation and organoid formation. Because the enhanced Tbx3 expression seen in aged gastric organoids was also observed in human gastric cancer tissues, this Dkk3-Wnt-Tbx3 pathway may be involved in aging-related gastric carcinogenesis.

Significance:

This work provides an insight into the mechanism involved in aging-related gastric carcinogenesis through studies utilizing organoids established from young and aged murine stomachs.
DHX37 and 46,XY DSD: A New Ribosomopathy?
Authors: McElreavey Kenneth , Pailhoux Eric , Bashamboo Anu
Published: July 2022

Recently, a series of recurrent missense variants in the RNA-helicase DHX37 have been reported associated with either 46,XY gonadal dysgenesis, 46,XY testicular regression syndrome (TRS), or anorchia. All affected children have non-syndromic forms of disorders/differences of sex development (DSD). These variants, which involve highly conserved amino acids within known functional domains of the protein, are predicted by in silico tools to have a deleterious effect on helicase function. DHX37 is required for ribosome biogenesis in eukaryotes, and how these variants cause DSD is unclear. The relationship between DHX37 and human congenital disorders is complex as compound heterozygous as well as de novo heterozygous missense variants in DHX37 are also associated with a complex congenital developmental syndrome (NEDBAVC, neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies; OMIM 618731), consisting of microcephaly, global developmental delay, seizures, facial dysmorphia, and kidney and cardiac anomalies. Here, we will give a brief overview of ribosome biogenesis and the role of DHX37 in this process. We will discuss variants in DHX37, their contribution to human disease in the general context of human ribosomopathies, and the possible disease mechanisms that may be involved.
Smartphone-Based Gait Cadence to Identify Older Adults with Decreased Functional Capacity
Authors: Rubin Daniel S. , Ranjeva Sylvia L. , Urbanek Jacek K. , Karas Marta , Madariaga Maria Lucia L. , Huisingh-Scheetz Megan
Published: July 2022

Background: Functional capacity assessment is a critical step in the preoperative evaluation to identify patients at increased risk of cardiac complications and disability after major noncardiac surgery. Smartphones offer the potential to objectively measure functional capacity but are limited by inaccuracy in patients with poor functional capacity. Open-source methods exist to analyze accelerometer data to estimate gait cadence (steps/min), which is directly associated with activity intensity. Here, we used an updated Step Test smartphone application with an open-source method to analyze accelerometer data to estimate gait cadence and functional capacity in older adults. Methods: We performed a prospective observational cohort study within the Frailty, Activity, Body Composition and Energy Expenditure in Aging study at the University of Chicago. Participants completed the Duke Activity Status Index (DASI) and performed an in-clinic 6-min walk test (6MWT) while using the Step Test application on a study smartphone. Gait cadence was measured from the raw accelerometer data using an adaptive empirical pattern transformation method, which has been previously validated. A 6MWT distance of 370 m was used as an objective threshold to identify patients at high risk. We performed multivariable logistic regression to predict walking distance using a priori explanatory variables. Results: Sixty patients were enrolled in the study. Thirty-seven patients completed the protocol and were included in the final data analysis. The median (IQR) age of the overall cohort was 71 (69–74) years, with a body mass index of 31 (27–32). There were no differences in any clinical characteristics or functional measures between participants that were able to walk 370 m during the 6MWT and those that could not walk that distance. Median (IQR) gait cadence for the entire cohort was 110 (102–114) steps/min during the 6MWT. Median (IQR) gait cadence was higher in participants that walked more than 370 m during the 6MWT 112 (108–118) versus 106 (96–114) steps/min; p = 0.0157). The final multivariable model to identify participants that could not walk 370 m included only median gait cadence. The Youden’s index cut-point was 107 steps/min with a sensitivity of 0.81 (95% CI: 0.77, 0.85) and a specificity of 0.57 (95% CI: 0.55, 0.59) and an AUCROC of 0.69 (95% CI: 0.51, 0.87). Conclusions: Our pilot study demonstrates the feasibility of using gait cadence as a measure to estimate functional capacity. Our study was limited by a smaller than expected sample size due to COVID-19, and thus, a prospective study with preoperative patients that measures outcomes is necessary to validate our findings.
Interstitial Pulmonary Fibrosis and Extensive Dendriform Ossification with Persistent Viral Load: A Rare Presentation of Post-COVID-19 Condition in Need of Lung Transplantation
Authors: Haslbauer Jasmin Dionne , Bratic-Hench Ivana , Cima Katharina , Luger Anna Katharina , Schmitz Katja , Augustin Florian , Krapf Christoph , Hoefer Daniel , Tancevski Ivan , Tzankov Alexandar , Löffler-Ragg Judith
Published: July 2022

The incidence, presentation, and predisposing factors of post-acute sequelae of COVID-19 (PASC) are currently poorly understood. Lung explants may provide a rare insight into terminal SARS-CoV-2-associated lung damage and its pathophysiology. A 62-year-old man presented with progressively worsening respiratory symptoms after recovering from mild COVID-19 3 months earlier. No underlying pulmonary comorbidities were reported. A chest CT revealed bilateral extensive ground-glass and reticular opacities, suspicious of pulmonary fibrosis. Despite initial high-dose glucocorticoid therapy, the interstitial lung disease progressed, and after exhausting all viable therapeutic options, bilateral lung transplantation was successfully conducted. Histological analysis revealed extensive end-stage interstitial fibrosis with diffuse dendriform ossification and bronchiolar and transitional cell metaplasia. Signs of interstitial remodeling such as an increased interstitial collagen deposition, a pathological accumulation of CD163+/CD206+ M2-polarized macrophages with an increased expression of phosphorylated ERK, and an increased density of CD105+ newly formed capillaries were observed. qRT-PCR and immunohistochemistry for SARS-CoV-2 N-protein in the endothelium of medium-sized vessels confirmed a persistence of SARS-CoV-2. Our findings highlight a highly unusual presentation of SARS-CoV-2-associated lung fibrosis, implying that incomplete viral clearance in the vascular compartment may play a vital pathophysiological role in the development of PASC.
COVID-19 Infection in Renal Transplant Recipients at Dubai Hospital: Incidence, Clinical Profile, and Outcome
Authors: Gulzar Kashif , Alalawi Fakhriya , Kumar Dileep Nanik Ram , Al Jaghoub Hebah Rami , Alhadari Amna Khalifa
Published: July 2022

Background: Renal transplant recipients are at risk to acquire COVID-19 infection quite frequently, owing to their immunocompromized state. Nevertheless, data on the effects of this infection on patients and graft function are sparse from the Arab world. Methods: This retrospective cohort study was conducted in Dubai Hospital from April 1, 2020, to August 1, 2021. We analyzed 42 COVID-19-positive renal transplant recipients’ data. Information concerning demographics, comorbidities, medications, clinical and laboratory data, and outcomes was collected from the electronic medical records. Univariate analyses were performed to determine the association of acute kidney injury (AKI) with in-hospital mortality. Results: Median age was 47.46 (17–66) years; about 59% of patients were male. Eleven (26.19%) patients developed AKI during hospitalization. On admission high ferritin, C-reactive protein, creatinine, and low absolute lymphocyte count are identified risk factors for in-hospital AKI. Seven (21.87%) patients had their calcineurin inhibitor levels touch a toxic peak possibly due to an interaction with antivirals. Mortality was 14.28%, and the same number of patients required mechanical ventilation during treatment. Conclusion: A significant number of renal transplant recipients suffered from AKI during COVID-19 infection, and the mortality rate in this study population was less than in studies from other countries in the region. More insights are required to manage this infection in renal transplant recipients.
Intravitreal Aflibercept versus Brolucizumab for Treatment-Naive Neovascular Age-Related Macular Degeneration with Type 1 Macular Neovascularization: Comparison of Short-Term Outcomes
Authors: Hoshino Junki , Matsumoto Hidetaka , Mukai Ryo , Nakamura Kosuke , Akiyama Hideo
Published: July 2022

Introduction: The purpose of this study was to evaluate the outcomes of loading-phase treatment with intravitreal aflibercept (IVA) or brolucizumab (IVBr) for treatment-naïve neovascular age-related macular degeneration (nAMD) associated with type 1 macular neovascularization (MNV). Methods: We retrospectively studied 108 consecutive eyes undergoing IVA and 103 consecutive eyes administered IVBr. Best-corrected visual acuity (BCVA), central macular thickness (CMT), central choroidal thickness (CCT), dry macula achievement, polypoidal lesion regression, and development of intraocular inflammation (IOI) were all assessed. Results: During the loading-phase treatment, IOI was detected in 18 eyes (17.5%) in the IVBr but none of those in the IVA group (p < 0.01). The loading-phase treatment was completed in 101 eyes in the IVA and 85 eyes in the IVBr group. In those cases, BCVA improved significantly, and CMT and CCT showed significant reductions after the loading-phase treatment in both groups (all p < 0.01). The CCT reduction was significantly greater with IVBr than with IVA (32 ± 28 μm vs. 40 ± 25 μm, p < 0.01). The dry macula achievement rate was significantly higher in the IVBr than in the IVA group (71.3 vs. 85.9%, p < 0.05). We observed complete regression of polypoidal lesions significantly more frequently with IVBr than with IVA (47.5 vs. 77.3%, p < 0.01). Discussion/Conclusion: Loading-phase treatment with IVA or IVBr for treatment-naïve nAMD with type 1 MNV effectively improved BCVA and diminished exudative changes. The CCT reduction, dry macula achievement, and polypoidal lesion regression rates were all significantly greater in the IVBr than in the IVA group. The incidence of IOI was significantly higher with IVBr than with IVA.
Limited Effect of Y Chromosome Variation on Coronary Artery Disease and Mortality in UK Biobank—Brief Report
Authors: Timmers Paul R.H.J. , Wilson James F.
Published: July 2022

Background:

The effect of genetic variation in the male-specific region of the Y chromosome (MSY) on coronary artery disease and cardiovascular risk factors has been disputed. In this study, we systematically assessed the association of MSY genetic variation on these traits using a kin-cohort analysis of family disease history in the largest sample to date.

Methods:

We tested 90 MSY haplogroups against coronary artery disease, hypertension, blood pressure, classical lipid levels, and all-cause mortality in up to 152 186 unrelated, genomically British individuals from UK Biobank. Unlike previous studies, we did not adjust for heritable lifestyle factors (to avoid collider bias) and instead adjusted for geographic variables and socioeconomic deprivation, given the link between MSY haplogroups and geography. For family history traits, subject MSY haplogroups were tested against father and mother disease as validation and negative control, respectively.

Results:

Our models find little evidence for an effect of any MSY haplogroup on cardiovascular risk in participants. Parental models confirm these findings.

Conclusions:

Kin-cohort analysis of the Y chromosome uniquely allows for discoveries in subjects to be validated using family history data. Despite our large sample size, improved models, and parental validation, there is little evidence to suggest cardiovascular risk in UK Biobank is influenced by genetic variation in MSY.
Evaluation of locomotor activity in female Chelonoidis chilensis (Testudinidae, Gray 1870) in response to artificial photoperiod and temperature treatments
Authors: Arfuso Francesca , Cerutti Raúl D. , Scaglione Maria C. , Sciabarrasi Antonio , Giannetto Claudia , Piccione Giuseppe
Published: July 2022

Turtles as many other reptiles are capable of orientating their bodies toward the sun. This conduct requires the presence of an internal biological chronometer in the organism that regulates this behavior. Thus, a description of the internal clock in these reptiles is of interest. The assessment of locomotor activity can be considered a reliable indicator of biological clock function. This study aimed to investigate the effect of different artificial photoperiod and ambient temperature schedules on total locomotor activity of female Chelonoidis chilensis and its rhythmicity. Six C. chilensis specimens were exposed to different artificial photoperiods and temperature regimes each fixed for seven days. It was observed that the activity period during the different experimental schedules was close to the 24 hours indicating a daily rhythmicity. Moreover, all tortoises showed a similar total locomotor activity pattern displaying the most of motion during light phase. Under the condition of constant light tortoises exhibited a self-sustaining rhythm not entrained to light and temperature zeitgebers, thus, suggesting its possible endogenous periodicity. Though this study deepens the knowledge on the rhythmic system of C. chilensis, further investigations are needed to achieve a more detailed understanding of tortoise biological clock.