bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of TCF7L2 in Glioma and Its Relationship With Clinicopathological Characteristics and Patient Overall Survival
Authors: Jing Shiyuan , Chen Lei , Han Song , Liu Ning , Han MingYang , Yang Yakun , Yan Changxiang
Published: July 2021

Background: The TCF7L2 gene is known as transcription factor 7-like 2 which has been identified as a novel transcription factor epithelial-mesenchymal transition (EMT) in tumor cells at 10q25.3. TCF7L2 may affect cancer progression and plays a central role in cancer proliferation, migration, and invasion. However, its clinical and prognostic value have not been researched in glioma. The purpose of our study was to research TCF7L2 expression and evaluate the clinical value of prognosis.

Method: We collected glioma specimens including low-grade glioma (n = 46) and glioblastoma (n = 51) from September 2015 to September 2017. Expression of TCF7L2 in 97 specimens was detected by quantitative real-time PCR (qRT-PCR). The chi-square test was applied to analyze the relationship between TCF7L2 expression and clinicopathological characteristics. The overall survival (OS) was estimated by log-rank tests among strata, and the survival curves were drawn by Kaplan-Meier. Univariate and multivariate analysis were utilized to analyze the relationship between prognosis and clinicopathological characteristics including TCF7L2 expression.

Results: Compared with the low-grade glioma group, the expression of TCF7L2 was significantly increased in the glioblastoma group (p = 0.001). TCF7L2 overexpression was associated with higher WHO grade (p = 0.001), isocitrate dehydrogenase (IDH) wild-type (p = 0.001), and lack of O(6)-methylguanine-DNA methyltransferase (MGMT) methylation (p = 0.001). Moreover, Kaplan-Meier analysis proved that overexpressed TCF7L2 was associated with poor OS (p = 0.010). The multivariate analysis suggested that TCF7L2 expression was an independent prognostic factor (p = 0.020).

Conclusions: Our research proved that TCF7L2 was overexpressed in glioblastoma, and related with tumor long-term prognosis, which, therefore, could be an independent prognostic factor for glioma patients.
A Dissipation Function–Based Method for Calculating the Energy Loss of Intracranial Aneurysms
Authors: Mo Xiao , Yu Hongshi , Chen Rong , Chen Zhenpeng , Li Haiyun
Published: July 2021

At present, the energy loss (EL) mechanism of intracranial aneurysm (IA) rupture is explored based on the global EL calculated by Bernoulli equation, but the details of EL are still unclear. This study aimed to explore the temporal and spatial characteristics of EL of IAs and reveal its mechanism. A novel method for calculating the EL of IAs based on dissipation function (DF) was proposed. DF was derived from the differential form of the energy equation and reflected the irreversible conversion from mechanical energy to internal energy caused by the friction between the fluid micelles. Eight sidewall IAs located at the posterior communicating segment of the internal carotid artery were collected; the three-dimensional (3D) geometric models of IAs were established employing image segmentation and 3D reconstruction. Computational fluid dynamics was applied to obtain hemodynamic parameters of IAs. The temporal and spatial characteristics of EL of IAs were achieved utilizing our proposed method. The simulation results indicated that EL occurred mainly in the boundary layer and the region adjacent to high-velocity inflow jet, EL increased rapidly during cardiac systole and reached its maximum at end-systolic phase and then decreased gradually during diastole until the end of cardiac cycle. The proposed method achieved some improvements over the traditional Bernoulli equation–based method by acquiring the temporal and spatial characteristics of EL, and it could provide insights into the EL of IAs and contribute to further rupture mechanism investigation.
Perampanel and Visuospatial Skills in Children With Epilepsy
Authors: Operto Francesca Felicia , Vivenzio Valentina , Scuoppo Chiara , Padovano Chiara , Roccella Michele , Quatrosi Giuseppe , Pastorino Grazia Maria Giovanna
Published: July 2021

Introduction: Perampanel (PER) is a non-competitive AMPA glutamate receptor antagonist approved for focal and generalized seizures as add-on therapy. PER does not seem to negatively affect the cognitive profile in children and adolescents, but its influence on visuospatial abilities is still to be assessed. The aim of our study was to assess visuospatial skills through a standardized neuropsychological evaluation in adolescents taking PER for 12 months.

Methods: Our sample included 46 adolescents aged 12–18 years with focal and generalized drug-resistant epilepsy already in therapy with one or two antiseizure medications. Changes in visuospatial perception and memory were assessed by the Rey–Osterrieth Complex Figure Test at baseline (before taking PER) and after 12 months of pharmacological treatment. Executive functions and non-verbal intelligence were also assessed at baseline.

Results: After 12 months of PER therapy, the mean scores on the Rey–Osterrieth Complex Figure Test remained almost unchanged for both visuospatial perception and visuospatial memory skills. At baseline, visuospatial memory was related to executive function, and visuospatial perception was related to executive function and non-verbal intelligence.

Conclusions: Adjunctive treatment with PER did not negatively affect visuospatial skills. No adverse event effects have been reported after 12 months of follow-up, and this suggests a good tolerability in the middle-to-long term.
Genetics of Paroxysmal Dyskinesia: Novel Variants Corroborate the Role of KCNA1 in Paroxysmal Dyskinesia and Highlight the Diverse Phenotypic Spectrum of KCNA1- and SLC2A1-Related Disorders
Authors: Kegele Josua , Krüger Johanna , Koko Mahmoud , Lange Lara , Marco Hernandez Ana Victoria , Martinez Francisco , Münchau Alexander , Lerche Holger , Lauxmann Stephan
Published: July 2021

Paroxysmal dyskinesias (PxD) are rare movement disorders with characteristic episodes of involuntary mixed hyperkinetic movements. Scientific efforts and technical advances in molecular genetics have led to the discovery of a variety of genes associated with PxD; however, clinical and genetic information of rarely affected genes or infrequent variants is often limited. In our case series, we present two individuals with PxD including one with classical paroxysmal kinesigenic dyskinesia, who carry new likely pathogenicde novovariants inKCNA1(p.Gly396Val and p.Gly396Arg). The gene has only recently been discovered to be causative for familial paroxysmal kinesigenic dyskinesia. We also provide genetic evidence for pathogenicity of two newly identified disease-causing variants inSLC2A1(p.Met96Thr and p.Leu231Pro) leading to paroxysmal exercise-induced dyskinesia. Since clinical information of carriers of variants in known disease-causing genes is often scarce, we encourage to share clinical data of individuals with rare or novel (likely) pathogenic variants to improve disease understanding.
Electrophysiological Proxy of Cognitive Reserve Index
Authors: Khachatryan Elvira , Wittevrongel Benjamin , Perovnik Matej , Tournoy Jos , Schoenmakers Birgitte , Van Hulle Marc M.
Published: July 2021

Cognitive reserve (CR) postulates that individual differences in task performance can be attributed to differences in the brain’s ability to recruit additional networks or adopt alternative cognitive strategies. Variables that are descriptive of lifetime experience such as socioeconomic status, educational attainment, and leisure activity are common proxies of CR. CR is mostly studied using neuroimaging techniques such as functional MRI (fMRI) in which case individuals with a higher CR were observed to activate a smaller brain network compared to individuals with a lower CR, when performing a task equally effectively (higher efficiency), and electroencephalography (EEG) where a particular EEG component (P300) that reflects the attention and working memory load, has been targeted. Despite the contribution of multiple factors such as age, education (formal and informal), working, leisure, and household activities in CR formation, most neuroimaging studies, and those using EEG in particular, focus on formal education level only. The aim of the current EEG study is to investigate how the P300 component, evoked in response to an oddball paradigm, is associated with other components of CR besides education, such as working and leisure activity in older adults. We have used hereto a recently introduced CR index questionnaire (CRIq) that quantifies both professional and leisure activities in terms of their cognitive demand and number of years practiced, as well as a data-driven approach for EEG analysis. We observed complex relationships between CRIq subcomponents and P300 characteristics. These results are especially important given that, unlike previous studies, our measurements (P300 and CRIq) do not require active use of the same executive function and, thus, render our results free of a collinearity bias.
Resting State EEG Related to Mathematical Improvement After Spatial Training in Children
Authors: Zhang Da-Wei , Zaphf Anna , Klingberg Torkel
Published: July 2021

Spatial cognitive abilities, including mental rotation (MR) and visuo-spatial working memory (vsWM) are correlated with mathematical performance, and several studies have shown that training of these abilities can enhance mathematical performance. Here, we investigated the behavioral and neural correlates of MR and vsWM training combined with number line (NL) training. Fifty-seven children, aged 6–7, performed 25 days of NL training combined with either vsWM or MR and participated in an Electroencephalography (EEG)-session in school to measure resting state activity and steady-state visual evoked potentials during a vsWM task before and after training. Fifty children, aged 6–7, received usual teaching and acted as a control group. Compared to the control group, both training groups improved on a combined measure of mathematics. Cognitive improvement was specific to the training. Significant pre-post changes in resting state-EEG (rs-EEG), common to both training groups, were found for power as well as for coherence, with no significant differences in rs-EEG-changes between the vsWM and MR groups. Two of the common rs-EEG changes were correlated with mathematical improvement: (1) an increase in coherence between the central frontal lobe and the right parietal lobe in frequencies ranging from 16 to 25 Hz, and (2) an increase in coherence between the left frontal lobe and the right parietal lobe ranging from 23 to 25 Hz. These results indicate that changes in fronto-parietal coherence are related to an increase in mathematical performance, which thus might be a useful measure in further investigations of mathematical interventions in children.
Altered Gray Matter Volume and Functional Connectivity in Patients With Vestibular Migraine
Authors: Zhe Xia , Zhang Xiaoling , Chen Li , Zhang Li , Tang Min , Zhang Dongsheng , Li Longchao , Lei Xiaoyan , Jin Chenwang
Published: July 2021

Subjects

Vestibular migraine (VM) is the most common neurological cause of vertigo in adults. Previous neuroimaging studies have reported structural alterations in areas associated with pain and vestibular processing. However, it is unclear whether altered resting-state functional connectivity (FC) exists in brain regions with structural abnormalities in patients with VM.

Methods

Resting-state functional magnetic resonance imaging (MRI) and three-dimensional T1-weighed MRI were performed in 30 patients with VM and 30 healthy controls (HCs). Patients underwent an evaluation of migraine and dizziness severity. FC and voxel-based morphometry (VBM) were performed using DPABI 4.3 and CAT12, respectively. The association between changes in gray matter (GM) volume or FC and clinical parameters was also analyzed.

Results

Compared with HCs, patients with VM demonstrated a reduced GM volume in the bilateral parietoinsular vestibular cortex (PIVC), right middle frontal gyrus, and precuneus. The GM volume of the left PIVC was negatively associated with Dizziness Handicap Inventory score in patients with VM. Taking this region as a seed region, we further observed increased FC between the left primary somatosensory cortex (S1)/inferior parietal lobule (IPL) and the left PIVC in patients with VM.

Conclusion

FC between regions with a decline in GM volume (the PIVC and S1/IPL) is altered in patients with VM, suggesting that abnormalities in vestibular cortical network could be useful for understanding the underlying mechanisms of VM.
Estimating the Minimal Number of Repeated Examinations for Random Responsiveness With the Coma Recovery Scale—Revised as an Example
Authors: Yang Hao , Ye Chengyin , Liu Xiaochen , Sun Lingxiu , Wang Anqi , Wang Jing , Hu Nantu , Hu Xiaohua , Gosseries Olivia , Laureys Steven , Di Haibo , Fang Jiqian
Published: July 2021

Objective: The aim of this study was to develop a general method to estimate the minimal number of repeated examinations needed to detect patients with random responsiveness, given a limited rate of missed diagnosis.

Methods: Basic statistical theory was applied to develop the method. As an application, 100 patients with disorders of consciousness (DOC) were assessed with the Coma Recovery Scale–Revised (CRS-R). DOC patients were supposed to be examined for 13 times over 20 days, while anyone who was diagnosed as a minimally conscious state (MCS) in a round would no longer be examined in the subsequent rounds. To test the validation of this method, a series of the stochastic simulation was completed by computer software under all the conditions of possible combinations of three kinds of distributions for p, five values of p, and four sizes of the sample and repeated for 100 times.

Results: A series of formula was developed to estimate the probability of a positive response to a single examination given by a patient and the minimal number of successive examinations needed based on the numbers of patients detected in the first i (i =1, 2,.) rounds of repeated examinations. As applied to the DOC patients assessed with the CRS-R, with a rate of missed diagnosis < 0.0001, the estimate of the minimal number of examinations was six in traumatic brain injury patients and five in non-traumatic brain injury patients. The outcome of the simulation showed that this method performed well under various conditions possibly occurring in practice.

Interpretation: The method developed in this paper holds in theory and works well in application and stochastic simulation. It could be applied to any other kind of examinations for random responsiveness, not limited to CRS-R for detecting MCS; this should be validated in further research.
Spatial RNA Sequencing Identifies Robust Markers of Vulnerable and Resistant Human Midbrain Dopamine Neurons and Their Expression in Parkinson’s Disease
Authors: Aguila Julio , Cheng Shangli , Kee Nigel , Cao Ming , Wang Menghan , Deng Qiaolin , Hedlund Eva
Published: July 2021

Defining transcriptional profiles of substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) dopamine neurons is critical to understanding their differential vulnerability in Parkinson’s Disease (PD). Here, we determine transcriptomes of human SNc and VTA dopamine neurons using LCM-seq on a large sample cohort. We apply a bootstrapping strategy as sample input to DESeq2 and identify 33 stably differentially expressed genes (DEGs) between these two subpopulations. We also compute a minimal sample size for identification of stable DEGs, which highlights why previous reported profiles from small sample sizes display extensive variability. Network analysis reveal gene interactions unique to each subpopulation and highlight differences in regulation of mitochondrial stability, apoptosis, neuronal survival, cytoskeleton regulation, extracellular matrix modulation as well as synapse integrity, which could explain the relative resilience of VTA dopamine neurons. Analysis of PD tissues showed that while identified stable DEGs can distinguish the subpopulations also in disease, the SNc markers SLIT1 and ATP2A3 were down-regulated and thus appears to be biomarkers of disease. In summary, our study identifies human SNc and VTA marker profiles, which will be instrumental for studies aiming to modulate dopamine neuron resilience and to validate cell identity of stem cell-derived dopamine neurons.
Frequent Genetic Alterations and Their Clinical Significance in Patients With Thymic Epithelial Tumors
Authors: Xu Song , Li Xiongfei , Zhang Hongyi , Zu Lingling , Yang Lingqi , Shi Tao , Zhu Shuai , Lei Xi , Song Zuoqing , Chen Jun
Published: July 2021

Purpose

Thymic epithelial tumors (TETs) are relatively rare neoplasms, including thymomas (types A, AB, B1, B2, and B3) and thymic carcinomas (TCs). The current knowledge about the biological properties of TETs is limited due to their low incidence. This study aimed to detect genetic alterations in TETs using next-generation sequencing(NGS) and explore their clinical significance in survival.

Methods

Tumor tissues and clinical data were collected from 34 patients with resected TETs in the Tianjin Medical University General Hospital between January 2011 and January 2019, and 56 cancer-associated genes were analyzed. The data of 123 TETs were retrieved from TCGA, and the information on their clinical and somatic mutations was explored.

Results

The cohort comprised 34 TETs including 17 thymomas and 17 TCs. The NGS results indicated that 73.08% of TCs+type B3 TETs and 37.50% of non-TCs+type B3 TETs each exhibited gene mutations. For patients with type B3/C, TP53 was the most frequent mutation (19.23%), followed by CDKN2A (11.54%). Similarly, in 123 TETs from the TCGA cohort, TP53 mutations were more frequent in patients with type B3/C than in patients with non-type B3/C (11.53% vs 3.09%). Further, patients with TET with TP53 mutations in the present cohort and the TCGA cohort had a worse prognosis compared with those without TP53 mutations.

Conclusions

Gene mutation profiles between TCs+type B3 TETs and non-TCs+type B3 TETs were significantly different. The presence of TP53 mutations was more frequent in TCs+type B3 TETs than in non-TCs+type B3 TETs, which was associated with a worse prognosis.
The Enhanced Inhibitory Effect of Estrogen on PD-L1 Expression Following Nrf2 Deficiency in the AOM/DSS Model of Colitis-Associated Cancer
Authors: Kang Changhee , Song Chin-Hee , Kim Nayoung , Nam Ryoung Hee , Choi Soo In , Yu Jeong Eun , Nho Heewon , Choi Jin A. , Kim Jin Won , Na Hee Young , Lee Ha-Na , Surh Young-Joon
Published: July 2021

Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a dual role in carcinogenesis. We previously reported that Nrf2 deficiency enhances the anti-tumorigenic effect of 17β-estradiol (E2) in an azoxymethane (AOM)/dextran sodium sulfate (DSS) model of colitis-associated cancer (CAC). Herein, we aimed to determine a possible explanation for our recent work and investigated the immune microenvironment represented by programmed death-ligand 1 (PD-L1) expression. One week after the AOM injection, mice were administered with DSS in drinking water for seven days; daily E2 injections were intraperitoneally administered during this period. The mice were sacrificed 16 weeks after AOM injection and analyzed for PD-L1 expression in the distal colon tissues using Western blotting and immunohistochemistry (IHC). Based on Western blotting results, PD-L1 expression was reduced in Nrf2 knockout (KO) female and E2-treated male mice when compared with their wild-type counterparts, following AOM/DSS treatment; this supports the association of PD-L1 expression with tumor progression. Additionally, this finding was in good agreement with the IHC results for PD-L1. Furthermore, we observed that PD-L1 is predominantly expressed in stromal cells rather than on epithelial cells in the colon. Western blotting revealed that PD-L1 expression in the colon positively correlates with expressions of inducible nitric oxide synthase (iNOS) (male, P = 0.002; female, P <0.001) and cyclooxygenase-2 (COX-2) (male, P <0.001; female, P <0.001). Collectively, our findings indicate that estrogen ameliorates the immune microenvironment represented by PD-L1 expression and enhances its effect in the absence of Nrf2.
CASK Silence Overcomes Sorafenib Resistance of Hepatocellular Carcinoma Through Activating Apoptosis and Autophagic Cell Death
Authors: Ding Bisha , Bao Chang , Jin Luqi , Xu Liang , Fan Weimin , Lou Weiyang
Published: July 2021

Hepatocellular carcinoma (HCC) patients usually fail to be treated because of drug resistance, including sorafenib. In this study, the effects of CASK in HCC were investigated using gain- or loss-of-function strategies by performing cell counting kit-8 assay, colony formation assay, flow cytometry, transmission electron microscopy, immunofluorescent confocal laser microscopy, tumor xenograft experiment and immunohistochemistry staining. The current results suggested that CASK expression was positively associated with sorafenib resistance and poor prognosis of HCC. Moreover, inhibition of CASK increased the role of sorafenib partially by promoting apoptosis and autophagy, while CASK overexpression presented the opposite effects. Besides, when treatment with sorafenib, inhibition of apoptosis using the pan-caspase inhibitor Z-VAD-FMK and inhibition of autophagy using autophagy inhibitor 3-Methyladenine (3-MA) or small interfering RNA (siRNA) of LC3B all significantly reversed CASK knockout-induced effects, suggesting that both apoptosis and autophagy were involved in CASK-mediated above functions and autophagy played a pro-death role in this research. Intriguingly, similar results were observed in vivo. In molecular level, CASK knockout activated the c-Jun N-terminal kinase (JNK) pathway, and treatment with JNK inhibitor SP600125 or transiently transfected with siRNA targeting JNK significantly attenuated CASK knockout-mediated autophagic cell death. Collectively, all these results together indicated that CASK might be a promising biomarker and a potential therapeutic target for HCC patients.
Role of HOXC10 in Cancer
Authors: Fang Jinyong , Wang Jianjun , Yu Liangliang , Xu Wenxia
Published: July 2021

The HOXC10 gene, a member of the HOX genes family, plays crucial roles in mammalian physiological processes, such as limb morphological development, limb regeneration, and lumbar motor neuron differentiation. HOXC10 is also associated with angiogenesis, fat metabolism, and sex regulation. Additional evidence suggests that HOXC10 dysregulation is closely associated with various tumors. HOXC10 is an important transcription factor that can activate several oncogenic pathways by regulating various target molecules such as ERK, AKT, p65, and epithelial mesenchymal transition-related genes. HOXC10 also induces drug resistance in cancers by promoting the DNA repair pathway. In this review, we summarize HOXC10 gene structure and expression as well as the role of HOXC10 in different human cancer processes. This review will provide insight into the status of HOXC10 research and help identify novel targets for cancer therapy.
A Nomogram Based on Combining Clinical Features and Contrast Enhanced Ultrasound LI-RADS Improves Prediction of Microvascular Invasion in Hepatocellular Carcinoma
Authors: Zhou Hang , Sun Jiawei , Jiang Tao , Wu Jiaqi , Li Qunying , Zhang Chao , Zhang Ying , Cao Jing , Sun Yu , Jiang Yifan , Liu Yajing , Zhou Xianli , Huang Pintong
Published: July 2021

Purposes

To establish a predictive model incorporating clinical features and contrast enhanced ultrasound liver imaging and reporting and data system (CEUS LI-RADS) for estimation of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) patients.

Methods

In the retrospective study, 127 HCC patients from two hospitals were allocated as training cohort (n=98) and test cohorts (n=29) based on cutoff time-point, June 2020. Multivariate regression analysis was performed to identify independent indicators for developing predictive nomogram models. The area under receiver operating characteristic (AUC) curve was also determined to establish the diagnostic performance of different predictive models. Corresponding sensitivities and specificities of different models at the cutoff nomogram value were compared.

Results

In the training cohort, clinical information (larger tumor size, higher AFP level) and CEUS LR-M were significantly correlated with the presence of MVI (all p<0.05). By incorporating clinical information and CEUS LR-M, the predictive model (LR-M+Clin) achieved a desirable diagnostic performance (AUC=0.80 and 0.84) in both cohorts at nomogram cutoff score value of 89. The sensitivity of LR-M+Clin when predicting MVI in HCC patients was higher than that of the clinical model alone (86.7% vs. 46.7%, p=0.027), while specificities were 78.6% and 85.7% (p=0.06), respectively, in the test cohort. In addition, LR-M+Clin exhibited similar AUC and specificity, but a significantly higher sensitivity (86.7%) than those of LR-M alone and LR-5(No)+Clin (both sensitivities=73.3%, both p=0.048).

Conclusion

The predictive model incorporating CEUS LR-M and clinical features was able to predict the MVI status of HCC and is a potential reliable preoperative tool for informing treatment.
Childhood Idiopathic Nephrotic Syndrome: Does the Initial Steroid Treatment Modify the Outcome? A Multicentre, Prospective Cohort Study
Authors: Pasini Andrea , Bertulli Cristina , Casadio Luca , Corrado Ciro , Edefonti Alberto , Ghiggeri GianMarco , Ghio Luciana , Giordano Mario , La Scola Claudio , Malaventura Cristina , Maringhini Silvio , Mastrangelo Antonio P. , Materassi Marco , Mencarelli Francesca , Messina Giovanni , Monti Elena , Morello William , Puccio Giuseppe , Romagnani Paola , Montini Giovanni ,   the NefroKid Study Group
Published: July 2021

Background: A great majority of children with idiopathic nephrotic syndrome will relapse after successful treatment of the initial episode. The possibility that different steroid dosing regimens at onset, adjusted for risk factors, can reduce the rate of relapse represents an interesting option to investigate.

Objectives: To evaluate the effect of the initial steroid regimen, adjusted for time to remission (TTR), on the frequency of relapses and steroid dependence, and to verify the influence of prognostic factors on disease course.

Methods: A multicentre, prospective, cohort study. Children with nephrotic syndrome, with TTR ≤ 10 days (Group A), were given a 20-week prednisone regimen (2,828 mg/m2) and those with a TTR >10 days, a 22-week regimen (3,668 mg/m2) (Group B). Previously published retrospective data from the same centers were also evaluated. Main outcomes were: relapse rate, number of frequent relapsers + steroid dependent children and total prednisone dose after induction.

Results: 143 children were enrolled. Rate of relapsed subjects (77 vs. 79%) and frequent relapsers + steroid dependent subjects (40 vs. 53%) did not differ between Groups A and B, or between the retrospective and prospective cohorts. The cumulative prednisone dose taken after the induction treatment was similar in both groups and in the retrospective and prospective cohorts. TTR was not associated with relapse risk. Age at onset and total serum protein were significantly lower in relapsing patients. At ROC analysis, the best cut-off was 5.3 years for age at onset and 4.2 g/dL for total serum protein. According to these cut-offs, older children with higher total serum protein had a higher relapse free survival rate (58%) than younger children with lower total serum protein (17%).

Conclusions: TTR was not found to be a prognostic factor of relapse; because of this, different steroid regimens, adjusted for TTR, did not modify the relapse rate in any relevant measure. Conversely, younger age and low total serum protein were independent predictors of relapse risk, however this outcome was not modified by higher prednisone regimens.

Clinical Trial Registration:https://www.ClinicalTrials.gov/, identifier: NCT01386957 (www.nefrokid.it).
National Trends in Disease Activity for COVID-19 Among Children in the US
Authors: Hutch Meghan R. , Liu Molei , Avillach Paul ,   Consortium for Clinical Characterization of COVID-19 by EHR (4CE), Luo Yuan , Bourgeois Florence T.
Published: July 2021

Ongoing monitoring of COVID-19 disease burden in children will help inform mitigation strategies and guide pediatric vaccination programs. Leveraging a national, comprehensive dataset, we sought to quantify and compare disease burden and trends in hospitalizations for children and adults in the US.
Targeting Tumor-Associated Antigen: A Promising CAR-T Therapeutic Strategy for Glioblastoma Treatment
Authors: Zhu Guidong , Zhang Qing , Zhang Junwen , Liu Fusheng
Published: July 2021

Chimeric antigen receptor T cells (CAR-T) therapy is a prospective therapeutic strategy for blood cancers tumor, especially leukemia, but it is not effective for solid tumors. Glioblastoma (GBM) is a highly immunosuppressive and deadly malignant tumor with poor responses to immunotherapies. Although CAR-T therapeutic strategies were used for glioma in preclinical trials, the current proliferation activity of CAR-T is not sufficient, and malignant glioma usually recruit immunosuppressive cells to form a tumor microenvironment that hinders CAR-T infiltration, depletes CAR-T, and impairs their efficacy. Moreover, specific environments such as hypoxia and nutritional deficiency can hinder the killing effect of CAR-T, limiting their therapeutic effect. The normal brain lack lymphocytes, but CAR-T usually can recognize specific antigens and regulate the tumor immune microenvironment to increase and decrease pro- and anti-inflammatory factors, respectively. This increases the number of T cells and ultimately enhances anti-tumor effects. CAR-T therapy has become an indispensable modality for glioma due to the specific tumor-associated antigens (TAAs). This review describes the characteristics of CAR-T specific antigen recognition and changing tumor immune microenvironment, as well as ongoing research into CAR-T therapy targeting TAAs in GBM and their potential clinical application.
Untargeted LC/MS-Based Metabolic Phenotyping of Hypopituitarism in Young Males
Authors: Zhang Yuwen , Sun Shouyue , Wang Ming , Yu Wenjuan , Chen Peizhan , Yuan Fei , Fang Xuqian
Published: July 2021

Objective: Hypopituitarism (Hypo-Pit) is partial or complete insufficiency of anterior pituitary hormones. Besides hormone metabolism, the global metabolomics in Hypo-Pit are largely unknown. We aimed to explore potential biomarkers to aid in diagnosis and personalized treatment.

Methods: Using both univariate and multivariate statistical methods, we identified 72 differentially abundant features through liquid chromatography coupled to high-resolution mass spectrometry, obtained in 134 males with Hypo-Pit and 90 age matched healthy controls.

Results: Hypopituitarism exhibits an increased abundance of metabolites involved in amino acid degradation and glycerophospholipid synthesis, but decreased content of metabolites in steroid hormone synthesis and fatty acid beta-oxidation. Significantly changed metabolites included creatine, creatinine, L-alanine, phosphocholines, androstenedione, hydroprenenolone, and acylcarnitines. In Hypo-Pit patients, the increased ratio of creatine/creatinine suggested reduced creatine uptake and impaired creatine utilization, whereas the decreased level of beta-hydroxybutyrate, acetylcarnitine (C2) and a significantly decreased ratio of decanoylcarnitine (C10) to free carnitine suggested an impaired beta-oxidation. Furthermore, the creatine/creatinine and decanoylcarnitine/carnitine ratio were identified as diagnostic biomarkers for Hypo-Pit with AUCs of 0.976 and 0.988, respectively. Finally, we found that the creatinine and decanoylcarnitine/carnitine ratio could distinguish cases that were sensitive vs. resistant to human chorionic gonadotropin therapy.

Conclusion: We provided a global picture of altered metabolic pathways in Hypo-Pit, and the identified biomarkers in creatine metabolism and beta-oxidation might be useful for the preliminary screening and diagnosis of Hypo-Pit.
PTEN Methylation Promotes Inflammation and Activation of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis
Authors: Li Xiao-Feng , Wu Sha , Yan Qi , Wu Yuan-Yuan , Chen He , Yin Su-Qin , Chen Xin , Wang Hua , Li Jun
Published: July 2021

Rheumatoid arthritis (RA) is characterized by a tumor-like expansion of the synovium and subsequent destruction of adjacent articular cartilage and bone. In our previous work we showed that phosphatase and tension homolog deleted on chromosome 10 (PTEN) contributes to the activation of fibroblast-like synoviocytes (FLS) in adjuvant-induced arthritis (AIA), but the underlying mechanism is not unknown. In this study, we show that PTEN is downregulated while DNA methyltransferase (DNMT)1 is upregulated in FLS from RA patients and a rat model of AIA. DNA methylation of PTEN was increased by administration of tumor necrosis factor (TNF)-α in FLS of RA patients, as determined by chromatin immunoprecipitation and methylation-specific PCR. Treatment with the methylation inhibitor 5-azacytidine suppressed cytokine and chemokine release and FLS activation in vitro and alleviated paw swelling in vivo. PTEN overexpression reduced inflammation and activation of FLS via protein kinase B (AKT) signaling in RA, and intra-articular injection of PTEN-expressing adenovirus into the knee of AIA rats markedly reduced inflammation and paw swelling. Thus, PTEN methylation promotes the inflammation and activation of FLS in the pathogenesis of RA. These findings provide insight into the molecular basis of articular cartilage destruction in RA, and indicate that therapeutic strategies that prevent PTEN methylation may an effective treatment.
Atrial Natriuretic Peptide31–67: A Novel Therapeutic Factor for Cardiovascular Diseases
Authors: da Silva Gustavo Jose Justo , Altara Raffaele , Booz George W. , Cataliotti Alessandro
Published: July 2021

The characterization of the cardiac hormone atrial natriuretic peptide (ANP99–126), synthesized and secreted predominantly by atrial myocytes under stimulation by mechanical stretch, has established the heart as an endocrine organ with potent natriuretic, diuretic, and vasodilating actions. Three additional distinct polypeptides resulting from proteolytic cleavage of proANP have been identified in the circulation in humans. The mid-sequence proANP fragment 31–67 (also known as proANP31–67) has unique potent and prolonged diuretic and natriuretic properties. In this review, we report the main effects of this circulating hormone in different tissues and organs, and its mechanisms of actions. We further highlight recent evidence on the cardiorenal protective actions of chronic supplementation of synthetic proANP31–67 in preclinical models of cardiorenal disease. Finally, we evaluate the use of proANP31–67 as a new therapeutic strategy to repair end-organ damage secondary to hypertension, diabetes mellitus, renal diseases, obesity, heart failure, and other morbidities that can lead to impaired cardiac function and structure.
RETRACTED: Mitofusin-2 Enhances Mitochondrial Contact With the Endoplasmic Reticulum and Promotes Diabetic Cardiomyopathy
Authors: Zhang Jing , Zhang Feng , Wang Yanou
Published: July 2021

Diabetic cardiomyopathy has been associated with mitochondrial damage. Mitochondria–endoplasmic reticulum (ER) contact is an important determinant of mitochondrial function and ER homeostasis. We therefore investigated whether hyperglycemia can damage the mitochondria by increasing their contact with the ER in cardiomyocytes. We found that hyperglycemia induced mitochondria–ER contact in cardiomyocytes, as evidenced by the increased MMM1, MDM34, and BAP31 expressions. Interestingly, the silencing of Mfn2 reduced the cooperation between the mitochondria and the ER in cardiomyocytes. Mfn2 silencing improved cardiomyocyte viability and function under hyperglycemic conditions. Additionally, the silencing of Mfn2 markedly attenuated the release of calcium from the ER to the mitochondria, thereby preserving mitochondrial metabolism in cardiomyocytes under hyperglycemic conditions. Mfn2 silencing reduced mitochondrial reactive oxygen species production, which reduced mitochondria-dependent apoptosis in hyperglycemia-treated cardiomyocytes. Finally, Mfn2 silencing attenuated ER stress in cardiomyocytes subjected to high-glucose stress. These results demonstrate that Mfn2 promotes mitochondria–ER contact in hyperglycemia-treated cardiomyocytes. The silencing of Mfn2 sustained mitochondrial function, suppressed mitochondrial calcium overload, prevented mitochondrial apoptosis, and reduced ER stress, thereby enhancing cardiomyocyte survival under hyperglycemic conditions.
The Exocyst Complex Subunit EXO70E1-V From Haynaldia villosa Interacts With Wheat Powdery Mildew Resistance Gene CMPG1-V
Authors: Zhao Jia , Zhang Heng , Zhang Xu , Wang Zongkuan , Niu Ying , Chen Yiming , Sun Li , Wang Haiyan , Wang Xiue , Xiao Jin
Published: July 2021

EXO70 belongs to the exocyst complex subunit that plays a critical role in regulating plant cell polarity establishment and defense response. A previous study proved that the E3 ligase CMPG1-V fromHaynaldia villosa, a diploid wheat relative, positively regulates the resistance to wheat powdery mildew (Pm), caused by fungusBlumeria graminisf.sptritici(Bgt). In this study, a member of EXO70 superfamily namedEXO70E1-Vwas isolated fromH. villosa, andEXO70E1-Vinteracted with CMPG1-V were shown by yeast two-hybrid (Y2H), pull-down assay, bimolecular fluorescence complementation (BiFC) assay, and luciferase complementation imaging (LCI) assay. It is localized in various subcellular organs, i.e., plasma membrane (PM) and endoplasmic reticulum. Co-expression of EXO70E1-V and CMPG1-V showed dot-like structure fluorescence signals that were mainly in PM and nucleus. Expression ofEXO70E1-Vwas relatively higher in leaf and was significantly induced byBgtinfection and exogenous application of hormones such as salicylic acid. Transient or stable overexpression ofEXO70E1-Vcould not enhance/decrease thePmresistance level, suggesting overexpression of EXO70E1-V alone has no impact onPmresistance in wheat.
Agronomic, Physiological and Genetic Changes Associated With Evolution, Migration and Modern Breeding in Durum Wheat
Authors: Royo Conxita , Ammar Karim , Villegas Dolors , Soriano Jose M.
Published: July 2021

A panel of 172 Mediterranean durum wheat landraces and 200 modern cultivars was phenotyped during three years for 21 agronomic and physiological traits and genotyped with 46,161 DArTseq markers. Modern cultivars showed greater yield, number of grains per spike (NGS) and harvest index (HI), but similar number of spikes per unit area (NS) and grain weight than the landraces. Modern cultivars had earlier heading but longer heading-anthesis and grain-filling periods than the landraces. They had greater RUE (Radiation Use Efficiency) up to anthesis and lower canopy temperature at anthesis than the landraces, but the opposite was true during the grain-filling period. Landraces produced more biomass at both anthesis and maturity. The 120 genotypes with a membership coefficientq> 0.8 to the five genetic subpopulations (SP) that structured the panel were related with the geographic distribution and evolutionary history of durum wheat. SP1 included landraces from eastern countries, the domestication region of the “Fertile Crescent.” SP2 and SP3 consisted of landraces from the north and the south Mediterranean shores, where durum wheat spread during its migration westward. Decreases in NS, grain-filling duration and HI, but increases in early soil coverage, days to heading, biomass at anthesis, grain-filling rate, plant height and peduncle length occurred during this migration. SP4 grouped modern cultivars gathering the CIMMYT/ICARDA genetic background, and SP5 contained modern north-American cultivars. SP4 was agronomically distant from the landraces, but SP5 was genetically and agronomically close to SP1. GWAS identified 2,046 marker-trait associations (MTA) and 144 QTL hotspots integrating 1,927 MTAs. Thirty-nine haplotype blocks (HB) with allelic differences among SPs and associated with 16 agronomic traits were identified within 13 QTL hotspots. Alleles in chromosomes 5A and 7A detected in landraces were associated with decreased yield. The late heading and short grain-filling period of SP2 and SP3 were associated with a hotspot on chromosome 7B. The heavy grains of SP3 were associated with hotspots on chromosomes 2A and 7A. The greater NGS and HI of modern cultivars were associated with allelic variants on chromosome 7A. A hotspot on chromosome 3A was associated with the high NGS, earliness and short stature of SP4.
Leaf and Community Photosynthetic Carbon Assimilation of Alpine Plants Under in-situ Warming
Authors: Zhou Zijuan , Su Peixi , Wu Xiukun , Shi Rui , Ding Xinjing
Published: July 2021

The Tibetan Plateau is highly sensitive to elevated temperatures and has experienced significant climate warming in the last decades. While climate warming is known to greatly impact alpine ecosystems, the gas exchange responses at the leaf and community levels to climate warming in alpine meadow ecosystems remain unclear. In this study, the alpine grass, Elymus nutans, and forb, Potentilla anserina, were grown in open-top chambers (OTCs) for 3 consecutive years to evaluate their response to warming. Gas exchange measurements were used to assess the effects of in-situ warming on leaf- and community-level photosynthetic carbon assimilation based on leaf photosynthetic physiological parameters. We introduced a means of up-scaling photosynthetic measurements from the leaf level to the community level based on six easily measurable parameters, including leaf net photosynthetic rate, fresh leaf mass per unit leaf area, fresh weight of all plant leaves in the community, the percentage of healthy leaves, the percentage of received effective light by leaves in the community, and community coverage. The community-level photosynthetic carbon assimilation and productivity all increased with warming, and the net photosynthetic rate at the leaf level was significantly higher than at the community level. Under elevated temperature, the net photosynthetic rate of E. nutans decreased, while that of P. anserina increased. These results indicated that climate warming may significantly influence plant carbon assimilation, which could alter alpine meadow community composition in the future.
Achieving Operational Excellence Through Artificial Intelligence: Driving Forces and Barriers
Authors: Tariq Muhammad Usman , Poulin Marc , Abonamah Abdullah A.
Published: July 2021

This paper presents an in-depth literature review on the driving forces and barriers for achieving operational excellence through artificial intelligence (AI). Artificial intelligence is a technological concept spanning operational management, philosophy, humanities, statistics, mathematics, computer sciences, and social sciences. AI refers to machines mimicking human behavior in terms of cognitive functions. The evolution of new technological procedures and advancements in producing intelligence for machines creates a positive impact on decisions, operations, strategies, and management incorporated in the production process of goods and services. Businesses develop various methods and solutions to extract meaningful information, such as big data, automatic production capabilities, and systematization for business improvement. The progress in organizational competitiveness is apparent through improvements in firm’s decisions, resulting in increased operational efficiencies. Innovation with AI has enabled small businesses to reduce operating expenses and increase revenues. The focused literature review reveals the driving forces for achieving operational excellence through AI are improvement in computing abilities of machines, development of data-based AI, advancements in deep learning, cloud computing, data management, and integration of AI in operations. The barriers are mainly cultural constraints, fear of the unknown, lack of employee skills, and strategic planning for adopting AI. The current paper presents an analysis of articles focused on AI adoption in production and operations. We selected articles published between 2015 and 2020. Our study contributes to the literature reviews on operational excellence, artificial intelligence, driving forces for AI, and AI barriers in achieving operational excellence.
The Meaning of Musicing in the Post-traumatic Growth of Individuals With Adventitious Visual Impairment: Applying the Life History Method by Mandelbaum
Authors: Park Hye Young
Published: July 2021

This study investigated individuals with adventitious visual impairment (AVI) acquired during adulthood through a traumatic event, for an in-depth and contextual understanding of the factors and processes that led to positive changes in their post-traumatic growth. The life history method was applied on 15 individuals with AVI (seven males and eight females) through in-depth interviews about their life. The study’s analytical framework involved three domains: dimensions, turnings, and adaptations of life, as proposed by Mandelbaum. The results revealed the following key factors: of the dimensions of life—family, rehabilitation center, and music groups; of turnings of life—positive change through awareness and tolerance of impairments, new challenge posed by rehabilitation training, and finding inner resources through music; and of adaptations of life—accepting one’s life in a harsh social environment, actively establishing relationships with others as an individual with visual impairment, and re-finding meaning of life through musicing. This study contributes by revealing the role of each of the above-mentioned factors and identifying their correlations. The results suggest that musicing may help individuals with AVI develop empathy and engage in social communication through active self-disclosure.
Neurophysiological Evaluation of Right-Ear Advantage During Dichotic Listening
Authors: Tanaka Keita , Ross Bernhard , Kuriki Shinya , Harashima Tsuneo , Obuchi Chie , Okamoto Hidehiko
Published: July 2021

Right-ear advantage refers to the observation that when two different speech stimuli are simultaneously presented to both ears, listeners report stimuli more correctly from the right ear than the left. It is assumed to result from prominent projection along the auditory pathways to the contralateral hemisphere and the dominance of the left auditory cortex for the perception of speech elements. Our study aimed to investigate the role of attention in the right-ear advantage. We recorded magnetoencephalography data while participants listened to pairs of Japanese two-syllable words (namely, “/ta/ /ko/” or “/i/ /ka/”). The amplitudes of the stimuli were modulated at 35 Hz in one ear and 45 Hz in the other. Such frequency-tagging allowed the selective quantification of left and right auditory cortex responses to left and right ear stimuli. Behavioral tests confirmed the right-ear advantage, with higher accuracy for stimuli presented to the right ear than to the left. The amplitude of the auditory steady-state response was larger when attending to the stimuli compared to passive listening. We detected a correlation between the attention-related increase in the amplitude of the auditory steady-state response and the laterality index of behavioral accuracy. The right-ear advantage in the free-response dichotic listening was also found in neural activities in the left auditory cortex, suggesting that it was related to the allocation of attention to both ears.