bluuebunny/crossref_metadata_2025 huggingface dataset:
Postural and Head Control Given Different Environmental Contexts
Authors: Lubetzky Anat V. , Kelly Jennifer L. , Hujsak Bryan D. , Liu Jenny , Harel Daphna , Cosetti Maura
Published: June 2021

Virtual reality allows for testing of multisensory integration for balance using portable Head Mounted Displays (HMDs). HMDs provide head kinematics data while showing a moving scene when participants are not. Are HMDs useful to investigate postural control? We used an HMD to investigate postural sway and head kinematics changes in response to auditory and visual perturbations and whether this response varies by context. We tested 25 healthy adults, and a small sample of people with diverse monaural hearing (n= 7), or unilateral vestibular dysfunction (n= 7). Participants stood naturally on a stable force-plate and looked at 2 environments via the Oculus Rift (abstract “stars;” busy “street”) with 3 visual and auditory levels (static, “low,” “high”). We quantified medio-lateral (ML) and anterior-posterior (AP) postural sway path from the center-of-pressure data and ML, AP, pitch, yaw and roll head path from the headset. We found no difference between the different combinations of “low” and “high” visuals and sounds. We then combined all perturbations data into “dynamic” and compared it to the static level. The increase in path between “static” and “dynamic” was significantly larger in the city environment for: Postural sway ML, Head ML, AP, pitch and roll. The majority of the vestibular group moved more than controls, particularly around the head, when the scenes, especially the city, were dynamic. Several patients with monaural hearing performed similar to controls whereas others, particularly older participants, performed worse. In conclusion, responses to sensory perturbations are magnified around the head. Significant differences in performance between environments support the importance of context in sensory integration. Future studies should further investigate the sensitivity of head kinematics to diagnose vestibular disorders and the implications of aging with hearing loss to postural control. Balance assessment and rehabilitation should be conducted in different environmental contexts.
Interictal Epileptiform Discharge Dynamics in Peri-sylvian Polymicrogyria Using EEG-fMRI
Authors: Cohen Noa , Ebrahimi Yoram , Medvedovsky Mordekhay , Gurevitch Guy , Aizenstein Orna , Hendler Talma , Fahoum Firas , Gazit Tomer
Published: June 2021

Polymicrogyria (PMG) is a common malformation of cortical development associated with a higher susceptibility to epileptic seizures. Seizures secondary to PMG are characterized by difficult-to-localize cerebral sources due to the complex and widespread lesion structure. Tracing the dynamics of interictal epileptiform discharges (IEDs) in patients with epilepsy has been shown to reveal the location of epileptic activity sources, crucial for successful treatment in cases of focal drug-resistant epilepsy. In this case series IED dynamics were evaluated with simultaneous EEG-fMRI recordings in four patients with unilateral peri-sylvian polymicrogyria (PSPMG) by tracking BOLD activations over time: before, during and following IED appearance on scalp EEG. In all cases, focal BOLD activations within the lesion itself preceded the activity associated with the time of IED appearance on EEG, which showed stronger and more widespread activations. We therefore propose that early hemodynamic activity corresponding to IEDs may hold important localizing information potentially leading to the cerebral sources of epileptic activity. IEDs are suggested to develop within a small area in the PSPMG lesion with structural properties obscuring the appearance of their electric field on the scalp and only later engage widespread structures which allow the production of large currents which are recognized as IEDs on EEG.
Characterizing Brain Tumor Regions Using Texture Analysis in Magnetic Resonance Imaging
Authors: Yu Yun , Wu Xi , Chen Jiu , Cheng Gong , Zhang Xin , Wan Cheng , Hu Jie , Miao Shumei , Yin Yuechuchu , Wang Zhongmin , Shan Tao , Jing Shenqi , Wang Wenming , Guo Jianjun , Hu Xinhua , Liu Yun
Published: June 2021

Purpose

To extract texture features from magnetic resonance imaging (MRI) scans of patients with brain tumors and use them to train a classification model for supporting an early diagnosis.

Methods

Two groups of regions (control and tumor) were selected from MRI scans of 40 patients with meningioma or glioma. These regions were analyzed to obtain texture features. Statistical analysis was conducted using SPSS (version 20.0), including the Shapiro–Wilk test and Wilcoxon signed-rank test, which were used to test significant differences in each feature between the tumor and healthy regions. T-distributed stochastic neighbor embedding (t-SNE) was used to visualize the data distribution so as to avoid tumor selection bias. The Gini impurity index in random forests (RFs) was used to select the top five out of all features. Based on the five features, three classification models were built respectively with three machine learning classifiers: RF, support vector machine (SVM), and back propagation (BP) neural network.

Results

Sixteen of the 25 features were significantly different between the tumor and healthy areas. Through the Gini impurity index in RFs, standard deviation, first-order moment, variance, third-order absolute moment, and third-order central moment were selected to build the classification model. The classification model trained using the SVM classifier achieved the best performance, with sensitivity, specificity, and area under the curve of 94.04%, 92.3%, and 0.932, respectively.

Conclusion

Texture analysis with an SVM classifier can help differentiate between brain tumor and healthy areas with high speed and accuracy, which would facilitate its clinical application.
Innate Signaling in the CNS Prevents Demyelination in a Focal EAE Model
Authors: Dubik Magdalena , Marczynska Joanna , Mørch Marlene T. , Webster Gill , Jensen Kirstine Nolling , Wlodarczyk Agnieszka , Khorooshi Reza , Owens Trevor
Published: June 2021

The pathological hallmark of multiple sclerosis (MS) is the formation of multifocal demyelinating lesions in the central nervous system (CNS). Stimulation of innate receptors has been shown to suppress experimental autoimmune encephalomyelitis (EAE), an MS-like disease in mice. Specifically, targeting Toll-like receptor 9 (TLR9) and NOD-like receptor 2 (NOD2) significantly reduced disease severity. In the present work we have developed a novel focal EAE model to further study the effect of innate signaling on demyelinating pathology. Focal lesions were induced by stereotactic needle insertion into the corpus callosum (CC) of mice previously immunized for EAE. This resulted in focal pathology characterized by infiltration and demyelination in the CC. We find that intrathecal delivery of MIS416, a TLR9 and NOD2 bispecific innate ligand, into the cerebrospinal fluid reduced focal lesions in the CC. This was associated with upregulation of type I and II interferons, interleukin-10, arginase-1, CCL-2 and CXCL-10. Analysis of draining cervical lymph nodes showed upregulation of type II interferons and interleukin 10. Moreover, intrathecal MIS416 altered the composition of early CNS infiltrates, increasing proportions of myeloid and NK cells and reducing T cells at the lesion site. This study contributes to an increased understanding of how innate immune responses can play a protective role, which in turn may lead to additional therapeutic strategies for the prevention and treatment of demyelinating pathologies.
Amyloid-β Impairs Dendritic Trafficking of Golgi-Like Organelles in the Early Phase Preceding Neurite Atrophy: Rescue by Mirtazapine
Authors: Fabbretti Elsa , Antognolli Giulia , Tongiorgi Enrico
Published: June 2021

Neurite atrophy with loss of neuronal polarity is a pathological hallmark of Alzheimer’s disease (AD) and other neurological disorders. While there is substantial agreement that disruption of intracellular vesicle trafficking is associated with axonal pathology in AD, comparatively less is known regarding its role in dendritic atrophy. This is a significant gap of knowledge because, unlike axons, dendrites are endowed with the complete endomembrane system comprising endoplasmic reticulum (ER), ER–Golgi intermediate compartment (ERGIC), Golgi apparatus, post-Golgi vesicles, and a recycling-degradative route. In this study, using live-imaging of pGOLT-expressing vesicles, indicative of Golgi outposts and satellites, we investigate how amyloid-β (Aβ) oligomers affect the trafficking of Golgi-like organelles in the different dendritic compartments of cultured rat hippocampal neurons. We found that short-term (4 h) treatment with Aβ led to a decrease in anterograde trafficking of Golgi vesicles in dendrites of both resting and stimulated (with 50 mM KCl) neurons. We also characterized the ability of mirtazapine, a noradrenergic and specific serotonergic tetracyclic antidepressant (NaSSA), to rescue Golgi dynamics in dendrites. Mirtazapine treatment (10 μM) increased the number and both anterograde and retrograde motility, reducing the percentage of static Golgi vesicles. Finally, mirtazapine reverted the neurite atrophy induced by 24 h treatment with Aβ oligomers, suggesting that this drug is able to counteract the effects of Aβ by improving the dendritic trafficking of Golgi-related vesicles.
3,3’-Diindolylmethane Enhances Paclitaxel Sensitivity by Suppressing DNMT1-Mediated KLF4 Methylation in Breast Cancer
Authors: Xiang Fenfen , Zhu Zhaowei , Zhang Mengzhe , Wang Jie , Chen Zixi , Li Xiaoxiao , Zhang Tao , Gu Qing , Wu Rong , Kang Xiangdong
Published: June 2021

Paclitaxel (PTX) is a first-line chemotherapeutic drug for the treatment of breast cancer, but drug resistance seriously limits its clinical use. The aim of the present work was to explore the effect of 3,3’-diindolylmethane (DIM) on PTX sensitivity and its possible mechanism in breast cancer. The expression of Krüppel-like factor 4 (KLF4) and DNA-methyltransferase 1 (DNMT1) in breast cancer tissues were assessed by immunohistochemistry and Western blotting. The methylation of KLF4 was evaluated by the MassARRAY platform. The lentivirus carrying KLF4 and DNMT1 gene or shRNA targeting DNMT1 were used to overexpress KLF4 or knockdown DNMT1 in MCF-7 and T47D breast cancer cells and the role of KLF4 and DNMT1 in regulation of PTX sensitivity was investigated. The effect of PTX on inhibiting the proliferation of MCF-7 and T47D cells was measured by CCK-8 assay. Flow cytometry was used to examine cell apoptosis. The expression of mRNA and protein was evaluated by qRT-PCR and Western blotting analysis, respectively. Our data showed that the expression of DNMT1 was increased, and the methylation level of CpG sites (−148 bp) in the KLF4 promoter was increased while the KLF4 expression was significantly decreased in breast cancer tissues. Overexpression of KLF4 increased the sensitivity of MCF-7 and T47D cells to PTX. DNMT1 increased the methylation of the KLF4 promoter and decrease the expression of KLF4. Knockdown of DNMT1 increased the sensitivity of MCF-7 and T47D cells to PTX. DIM enhanced the PTX sensitivity of MCF-7 and T47D cells, decreased the expression of DNMT1 and the methylation level of KLF4 promoter, thus increasing the level of KLF4. Furthermore, overexpression of DNMT1 attenuated the effect of DIM on the regulation of PTX sensitivity. Collectively, our data indicated that DNMT1-mediated hypermethylation of KLF4 promoter leads to downregulation of KLF4 in breast cancer. The level of KLF4 is correlated with the sensitivity of MCF-7 and T47D cells to PTX. DIM could enhance the antitumor efficacy of PTX on MCF-7 and T47D cells by regulating DNMT1 and KLF4.
Identification of Methylation-Regulated Differentially Expressed Genes and Related Pathways in Hepatocellular Carcinoma: A Study Based on TCGA Database and Bioinformatics Analysis
Authors: Liang Yu , Ma Bin , Jiang Peng , Yang Hong-Mei
Published: June 2021

Background

In recent years, DNA methylation modification has been shown to be a critical mechanism in the field of epigenetics.

Methods

Hepatocellular carcinoma (HCC) data were obtained from The Cancer Genome Atlas project, including RNA expression profiles, Illumina Human Methylation 450K BeadChip data, clinical information, and pathological features. Then, differentially expressed genes (DEGs) and differentially methylated genes were identified using R software. Methylation-regulated DEGs (MeDEGs) were further analyzed using Spearman’s correlation analysis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using the DAVID database and ClueGO in Cytoscape software. Kaplan–Meier survival analysis explored the relationship between methylation, expression of MeDEGs, and survival time. Gene set enrichment analysis (GSEA) was conducted to predict the function of prognosis-related MeDEGs.

Results

A total of nine up-regulated and 72 down-regulated MeDEGs were identified. GO and KEGG pathway analyses results indicated that multiple cancer-related terms were enriched. Kaplan–Meier survival analysis showed that the methylation status of four MeDEGs (CTF1, FZD8, PDK4, and ZNF334) was negatively associated with overall survival. Moreover, the methylation status of CDF1 and PDK4 was identified as an independent prognostic factor. According to GSEA, hypermethylation of prognosis-related MeDEGs was enriched in pathways that included “Spliceosome”, “Cell cycle”, “RNA degradation”, “RNA polymerase”, “DNA replication”, “Mismatch repair”, “Base excision repair”, “Nucleotide excision repair”, “Homologous recombination”, “Protein export”, and “Pyrimidine metabolism”.

Conclusions

Aberrant DNA methylation plays a critical role in malignant progression of HCC. Prognosis-related MeDEGs identified in this research may be potential biomarkers and targets in diagnosis and treatment.
Risk of Endometrial Cancer and Frequencies of Invasive Endometrial Procedures in Young Breast Cancer Survivors Treated With Tamoxifen: A Nationwide Study
Authors: Choi Soojeong , Lee Young Jae , Jeong Jae Ho , Jung Jinhong , Lee Jong Won , Kim Hee Jeong , Ko Beom Seok , Son Byung Ho , Ahn Sei Hyun , Lee Yura , Chung Il Yong
Published: June 2021

Background

Although the guidelines recommend gynecological assessment and close monitoring for symptoms of endometrial cancer in postmenopausal breast cancer survivors taking tamoxifen (TAM), the risk of endometrial cancer in young breast cancer survivors has not yet been fully assessed. This study aimed to investigate the risk of developing endometrial cancer and the frequencies of gynecological examinations in young breast cancer survivors taking TAM in South Korea.

Methods

A nationwide retrospective cohort study was conducted using the Health Insurance Review and Assessment Service claims data. Kaplan–Meier analyses and log-rank tests were used to assess the probability of endometrial cancer, benign endometrial conditions, and the probability of invasive endometrial procedure. To analyze the risk of endometrial cancer and benign endometrial conditions, we used a multivariable Cox proportional hazards regression model.

Results

Between 2010 and 2015, 60,545 newly diagnosed female breast cancer survivors were included. The total person–years were 256,099 and 140 (0.23%) patients developed endometrial cancer during the study period. In breast cancer survivors aged ≥60 years [hazard ratio (HR), 5.037; 95% confidence interval (CI), 2.185–11.613], 50–59 years (HR, 4.343; 95% CI, 2.122–8.891), and 40–49 years (HR, 2.121; 95% CI, 1.068–4.213), TAM was associated with an increased risk of endometrial cancer. In subjects aged below 40 years, TAM did not significantly increase the risk of endometrial cancer. However, among the TAM subgroups, breast cancer survivors aged below 40 years [1.61 per 1,000 person–years (PY); HR, 12.460; 95% CI, 2.698–57.522] and aged 40–49 years (2.22 per 1,000 PY; HR, 9.667; 95% CI, 4.966–18.819) with TAM-related endometrial diseases showed significantly increased risks of endometrial cancer. Among the TAM subgroup with benign endometrial conditions, the ratios of the frequency of invasive diagnostic procedures to the incidence of endometrial cancer were higher in subjects under 40 than subjects aged 60 or more.

Conclusion

Young breast cancer survivors with TAM-related benign endometrial diseases are at a higher risk of developing endometrial cancer. Gynecological surveillance should be tailored to the risk of endometrial cancer in young breast cancer survivors to improve the early detection of endometrial cancer and avoid unnecessary invasive procedures.
Chrysin Induced Cell Apoptosis Through H19/let-7a/COPB2 Axis in Gastric Cancer Cells and Inhibited Tumor Growth
Authors: Chen Lin , Li Qirong , Jiang Ziping , Li Chengshun , Hu Haobo , Wang Tiedong , Gao Yan , Wang Dongxu
Published: June 2021

Background

Chrysin is a natural flavone that is present in honey and has exhibited anti-tumor properties. It has been widely studied as a therapeutic agent for the treatment of various types of cancers. The objectives of this present study were to elucidate how chrysin regulates non-coding RNA expression to exert anti-tumor effects in gastric cancer cells.

Methods

Through the use of RNA sequencing, we investigated the differential expression of mRNAs in gastric cancer cells treated with chrysin. Furthermore, COPB2, H19 and let-7a overexpression and knockdown were conducted. Other features, including cell growth, apoptosis, migration and invasion, were also analyzed. Knockout of the COPB2 gene was generated using the CRISPR/Cas9 system for tumor growth analysis in vivo.

Results

Our results identified COPB2 as a differentially expressed mRNA that is down-regulated following treatment with chrysin. Moreover, the results showed that chrysin can induce cellular apoptosis and inhibit cell migration and invasion. To further determine the underlying mechanism of COPB2 expression, we investigated the expression of the long non-coding RNA (lncRNA) H19 and microRNA let-7a. Our results showed that treatment with chrysin significantly increased let-7a expression and reduced the expression of H19 and COPB2. In addition, our results demonstrated that reduced expression of COPB2 markedly promotes cell apoptosis. Finally, in vivo data suggested that COPB2 expression is related to tumor growth.

Conclusions

This study suggests that chrysin exhibited anti-tumor effects through a H19/let-7a/COPB2 axis.
A Poliovirus Receptor (CD155)-Related Risk Signature Predicts the Prognosis of Bladder Cancer
Authors: Luo Cong , Ye Wenrui , Hu Jiao , Othmane Belaydi , Li Huihuang , Chen Jinbo , Zu Xiongbing
Published: June 2021

Background

Bladder cancer is an aggressive and heterogeneous disease associated with high morbidity and mortality. And poliovirus receptor (PVR or CD155) played crucial roles in tumor immune microenvironment and cancer development. However, their association remains obscure.

Methods

A total of 797 patients from TCGA and GEO databases were employed in our study, in which 285 cases were set as the training cohort and 512 were defined as the validation cohort. Our own Xiangya cohort with 57 samples was also used for the validation. Survival differences were evaluated by Kaplan-Meier analysis between groups. The immune infiltration was evaluated by ESTIMATE, TIMER, and CIBERSORT algorithms. The risk signature was constructed by LASSO Cox regression analysis. And a nomogram model was generated subsequent to the multivariate Cox proportional hazards analysis to predict 3- and 5-year survival of patients with bladder cancer.

Results

PVR was overexpressed across various cancers including bladder cancer and related to poorer overall survival in bladder urothelial carcinoma (BLCA). Samples with higher World Health Organization (WHO) grade or higher tumor stage tended to express higher level of PVR. And PVR-related genes were involved in several immune processes and oncological pathways. When the patients were divided into low- and high-risk groups based on their risk scores, we found that patients in the high-risk group had shorter overall survival time. Besides, samples with high risk were consistently correlated with tumor hallmarks and higher abundance of immune infiltration. Additionally, chemotherapy showed potent efficacy in high-risk group. Moreover, a nomogram including clinicopathologic features and the established risk signature could predict 3- and 5-year survival in patients with bladder cancer.

Conclusion

Our study revealed that PVR was overexpressed and related to poor prognosis in bladder cancer. A risk signature and nomogram model based on PVR-related genes could predict the prognosis and therapeutic efficacy and were also associated with the immune infiltration in bladder cancer.
Isolation of Circulating Tumour Cells in Patients With Glioblastoma Using Spiral Microfluidic Technology – A Pilot Study
Authors: Müller Bark Juliana , Kulasinghe Arutha , Hartel Gunter , Leo Paul , Warkiani Majid Ebrahimi , Jeffree Rosalind L. , Chua Benjamin , Day Bryan W. , Punyadeera Chamindie
Published: June 2021

Glioblastoma (GBM) is the most common and aggressive type of tumour arising from the central nervous system. GBM remains an incurable disease despite advancement in therapies, with overall survival of approximately 15 months. Recent literature has highlighted that GBM releases tumoural content which crosses the blood-brain barrier (BBB) and is detected in patients’ blood, such as circulating tumour cells (CTCs). CTCs carry tumour information and have shown promise as prognostic and predictive biomarkers in different cancer types. Currently, there is limited data for the clinical utility of CTCs in GBM. Here, we report the use of spiral microfluidic technology to isolate CTCs from whole blood of newly diagnosed GBM patients before and after surgery, followed by characterization for GFAP, cell-surface vimentin protein expression and EGFR amplification. CTCs were found in 13 out of 20 patients (9/20 before surgery and 11/19 after surgery). Patients with CTC counts equal to 0 after surgery had a significantly longer recurrence-free survival (p=0.0370). This is the first investigation using the spiral microfluidics technology for the enrichment of CTCs from GBM patients and these results support the use of this technology to better understand the clinical value of CTCs in the management of GBM in future studies.
Clinical Benefits and Safety of FMS-Like Tyrosine Kinase 3 Inhibitors in Various Treatment Stages of Acute Myeloid Leukemia: A Systematic Review, Meta-Analysis, and Network Meta-Analysis
Authors: Xu Qingyu , He Shujiao , Yu Li
Published: June 2021

Background

Given the controversial roles of FMS-like tyrosine kinase 3 inhibitors (FLT3i) in various treatment stages of acute myeloid leukemia (AML), this study was designed to assess this problem and further explored which FLT3i worked more effectively.

Methods

A systematic review, meta-analysis and network meta-analysis (NMA) were conducted by filtering PubMed, Embase, Cochrane library, and Chinese databases. We included studies comparing therapeutic effects between FLT3i and non-FLT3i group in AML, particularly FLT3(+) patients, or demonstrating the efficiency of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in FLT3(+) AML. Relative risk (RR) with 95% confidence intervals (CI) was used for estimating complete remission (CR), early death and toxicity. Hazard ratio (HR) was used to assess overall survival (OS), event-free survival (EFS), relapse-free survival (RFS) and cumulative incidence of relapse (CIR).

Results

After addressing all criteria, 39 studies were eventually analyzed. Better CR was accomplished by FLT3i in untreated AML (RR 0.88, p = 0.04) and refractory and relapsed FLT3(+) AML (rrAML) (RR 0.61, p < 0.01) compared to non-FLT3i arm, followed by improved survival (untreated AML: OS, HR 0.76; EFS, HR 0.67; RFS, HR 0.72; all p < 0.01; FLT3(+) rrAML: OS, HR 0.60, p < 0.01; RFS, HR 0.40, p = 0.01). In addition, allo-HSCT improved survival in FLT3(+) AML (OS, HR 0.53; EFS, HR 0.50; RFS, HR 0.57; CIR, HR 0.26; all p < 0.01), which was further prolonged by FLT3i administrated after allo-HSCT (OS, HR 0.45; RFS, HR 0.34; CIR, HR 0.32; all p < 0.01). Additionally, FLT3i consistently improved OS (p < 0.05) regardless of FLT3-ITD ratio, when compared to non-FLT3i group. Besides, FLT3i showed significantly increased risk of thrombocytopenia, neutropenia, anemia, skin- and cardiac-related adverse effects, increased alanine aminotransferase, and increased risk of cough and dyspnea (p < 0.05). In NMA, gilteritinib showed the highest probability for improved prognosis.

Conclusions

FLT3i safely improved prognosis in induction/reinduction stage of FLT3(+) AML and further boosted survival benefits from allo-HSCT as maintenance therapy, suggesting better prognosis if FLT3i is combined before and after allo-HSCT. In NMA, gilteritinib potentially achieved the best prognosis, which should be identified in direct trials.
Incidence of Skin Cancer in Patients With Chronic Inflammatory Cutaneous Diseases on Targeted Therapies: A Systematic Review and Meta-Analysis of Observational Studies
Authors: Crisafulli Salvatore , Bertino Lucrezia , Fontana Andrea , Calapai Fabrizio , Ingrasciotta Ylenia , Berretta Massimiliano , Trifirò Gianluca , Guarneri Claudio
Published: June 2021

Cancer is one of the several comorbidities that have been linked with chronic cutaneous inflammatory diseases namely psoriasis/psoriatic arthritis and hidradenitis suppurativa. Although the chronic inflammatory state, typical of the diseases, may induce pro-tumorigenic effects, the debate whether or not the drugs currently used in clinical practice do in facts increase a patient’s risk of malignancy remains largely unsolved. The therapeutic armamentarium has been greatly enhanced at least in the last two decades with the advent of biologics, a heterogeneous group of laboratory-engineered agents with more in the pipeline, and other targeted small molecules. Among the organ systems, skin results as one of the most commonly affected, non-melanoma skin cancers being the main drug-induced manifestations as side effect in course of these treatments. The objective of the study is to systematically review the cutaneous malignancy risk of the newer therapies through an overview of meta-analyses and observational studies on the topic.
Metformin Adjunct With Antineoplastic Agents for the Treatment of Lung Cancer: A Meta-Analysis of Randomized Controlled Trials and Observational Cohort Studies
Authors: Luo Xiaofeng , Chen Xi , Wang Lin , Yang Bowen , Cai Shuang
Published: June 2021

Objective: Resistance to anticancer agents ensures a poor prognosis in patients with lung cancer. Metformin could enhance the anticancer effects of standard antineoplastic agents [traditional chemotherapy drugs, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), or immune checkpoint inhibitors (ICIs)]; however, it is unclear whether metformin can be combined with antineoplastic agents in the treatment of lung cancer. To explore the efficacy of combinational strategies, we performed a systematic review and meta-analysis for diabetic and non-diabetic patients with lung cancer.

Method: An electronic literature search was performed to obtain relevant randomized controlled trials (RCTs) and observational cohort studies. Hazard ratios (HR) with 95% confidence intervals (CI) of overall survival (OS) and progression-free survival (PFS) outcomes were extracted. Subgroup analysis by antineoplastic agents, study type, histology and clinical stage were investigated.

Results: 14 studies (three RCTs and eleven observational cohort studies) consisting 3,856 patients were included in the meta-analysis. Compared to standard antineoplastic agents alone (traditional chemotherapy drugs, EGFR-TKIs or ICIs), the antineoplastic agents combined with metformin significantly improved OS (HR 0.73, 95% CI 0.66–0.81, p < 0.00001) and PFS (HR 0.72, 95% CI 0.59–0.88, p = 0.001); a similar association was found in observational evidence. Limited data from RCTs showed no differences in OS or PFS.

Conclusion: Metformin plus antineoplastic agents may improve survival outcomes of patients with lung cancer. Further investigation is needed.
Notopterol Attenuates Estrogen Deficiency-Induced Osteoporosis via Repressing RANKL Signaling and Reactive Oxygen Species
Authors: Chen Delong , Wang Qingqing , Li Ying , Sun Ping , Kuek Vincent , Yuan Jinbo , Yang Junzheng , Wen Longfei , Wang Haibin , Xu Jiake , Chen Peng
Published: June 2021

Integrity of the skeleton is sustained through the balanced activities of osteoblasts and osteoclasts in bone remodeling unit. The balance can be disrupted by excessive osteoclasts activation commonly seen in osteoporosis. Notopterol (NOT) is a main component of Notopterygium incisum which exerts a wide spectrum effect on biomedical pharmacology. In our study, we found NOT serves as an inhibitor in regulating RANKL-activated osteoclasts formation and bone resorption function by calculating tartrate resistant acid phosphatase (TRAcP) staining and hydroxyapatite resorption assays. Furthermore, RANKL-mediated signaling pathways including MAPK, NF-κB and calcium ossification were hampered, whereas ROS scavenging enzymes in Nrf2/Keap1/ARE signaling pathways were promoted by NOT. In addition, the activation of the essential transcription factor NFATc1 in RANKL-mediated osteoclastogenesis was almost totally suppressed by NOT. What is more, NOT diminished the loss of bone mass in preclinical model of OVX mice by blocking osteoclastogenesis determined by bone histomorphometry, TRAcP staining and H&E staining. Conclusively, our findings demonstrated that NOT could arrest osteoclastogenesis and bone resorptive activity by attenuating RANKL-mediated MAPK, NF-κB, calcium and NFATc1 signaling transduction pathways and enhancing ROS scavenging enzymes in Nrf2/Keap1/ARE pathways in vitro, and prohibit bone loss induced by OVX in vivo. Taken together, NOT may be identified to be a natural and novel treatment for osteolytic diseases.
Generation and Characterization of Mouse Models of C3 Glomerulonephritis With CFI D288G and P467S Mutations
Authors: Song Hui , Zhang Mingchao , Li Xue , Xu Feng , Zhang Difei , Zhu Xiaodong , Zhang Jiong , Qin Weisong , Shi Shaolin , Wen Jiqiu
Published: June 2021

C3 glomerulopathy (C3GP) is a disease entity caused by abnormality of the complement alternative pathway (AP) and characterized by C3 deposition in glomeruli. Many variations or mutations of complement factors are believed to underlie the susceptibility to C3GP, but there is a lack of experimental evidence. We have recently reported a patient with C3 glomerulonephritis (C3GN) and compound heterozygosity of two novel variations in the complement factor (CFI). Here, we generated a mouse model to mimic the CFI variations for studying pathogenicity of CFI variations in C3GN development. We used the CRISPR/Cas9 system to make mutant mouse lines that carried D288G and P467S mutations in CFI, respectively, and crossed them to generate mice with compound heterozygosity of CFI D288G and P467S. The mice were all normal in either SPF (specific pathogen free) or regular environment. When treated with lipopolysaccharides (LPS), a bacterial endotoxin that mimics infection and sepsis, the mice developed albuminuria, kidney function impairment, and C3 glomerular deposition at levels comparable with the wild-type mice. The mice with other genotypes concerning CFI D288G and P467S were also tested in parallel. Unexpectedly, we found that the D288G homozygotes all developed severe mesangial deposition of C3 in the LPS model, indicating that CFI D288G variation was involved in the C3 deposition, a key feature of C3GN. The mouse lines generated in the present study can be used to further study the role of CFI variations in C3GN development; in addition, they may be used to screen and test infections and environmental factors capable of triggering C3GN.
Protective Effects of Complement Component 8 Gamma Against Blood-Brain Barrier Breakdown
Authors: Kim Jong-Heon , Han Jin , Suk Kyoungho
Published: June 2021

The blood-brain barrier (BBB) regulates the traffic of micromolecules and macromolecules between the peripheral blood and the central nervous system, to maintain brain homeostasis. BBB disruption and dysfunction accompany a variety of neurological disorders and are closely related with the neuroinflammatory cascades that are triggered by leukocyte infiltration and glial activation. Here, we explored the role of complement component 8 gamma (C8G) in the maintenance of BBB integrity. Previously, C8G was shown to inhibit neuroinflammation by interfering with the sphingosine-1-phosphate (S1P)-S1PR2 interaction. The results of the present study revealed that C8G is localized in perivascular astrocytes, whereas S1PR2 is expressed in endothelial cells (ECs). In the lipopolysaccharide (LPS)-induced neuroinflammation model, the intracerebroventricular administration of the recombinant C8G protein protected the integrity of the BBB, whereas shRNA-mediated C8G knockdown enhanced BBB permeability and neutrophil infiltration. Using pharmacological agonists and antagonists of S1PR2, we demonstrated that C8G inhibited the inflammatory activation of ECs in culture by antagonizing S1PR2. In the in vitro BBB model, the addition of the recombinant C8G protein preserved endothelial integrity, whereas the knockdown of C8G exacerbated endothelial leakage under inflammatory conditions. Together, our findings indicate an important role for astrocytic C8G in protecting the BBB in the inflamed brain, suggesting a novel mechanism of cross talk between astrocytes and ECs in terms of BBB maintenance.
Aerobic Exercise During Advance Stage of Uncontrolled Arterial Hypertension
Authors: Pagan Luana U. , Gomes Mariana J. , Damatto Ricardo L. , Lima Aline R. R. , Cezar Marcelo D. M. , Damatto Felipe C. , Reyes David R. A. , Campos Dijon H. S. , Caldonazo Tulio M. M. , Polegato Bertha F. , Fernandes Denise C. , Laurindo Francisco R. , Fernandes Ana A. H. , Lloret Ana , Cicogna Antonio C. , Okoshi Marina P. , Okoshi Katashi
Published: June 2021

Aim

To evaluate the influence of physical training on myocardial function, oxidative stress, energy metabolism, and MAPKs and NF-κB signaling pathways in spontaneously hypertensive rats (SHR), at advanced stage of arterial hypertension, which precedes heart failure development.

Methods

We studied four experimental groups: normotensive Wistar rats (W, n = 27), trained W (W-EX, n = 31), SHR (n = 27), and exercised SHR (SHR-EX, n = 32). At 13 months old, the exercise groups underwent treadmill exercise 5 days a week for 4 months. In vitro myocardial function was analyzed in left ventricular (LV) papillary muscle preparations. Antioxidant enzyme activity and energy metabolism were assessed by spectrophotometry. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was analyzed by lucigenin reduction and protein expression by Western blot. Statistical analyzes: ANOVA and Tukey or Kruskal–Wallis and Dunn tests.

Results

SHR-EX had a lower frequency of heart failure features than SHR. Myocardial function and antioxidant enzyme activity were better in SHR-EX than SHR. Lipid hydroperoxide concentration, and phosphorylated JNK and total IkB protein expression were higher in hypertensive than control groups. Malondialdehyde, NADPH oxidase activity, total JNK, phosphorylated p38, phosphorylated and total p65 NF-κB, and phosphorylated IkB did not differ between groups. Protein expression from total p38, and total and phosphorylated ERK were higher in SHR than W. Lactate dehydrogenase and phosphorylated ERK were lower and citrate synthase and β-hydroxyacyldehydrogenase were higher in SHR-EX than SHR.

Conclusion

Exercise improves physical capacity, myocardial function, and antioxidant enzyme activity; reduces the frequency of heart failure features and ERK phosphorylation; and normalizes energy metabolism in SHR.
The Influence of Forefoot Bending Stiffness of Futsal Shoes on Multiple V-Cut Run Performance
Authors: Ismail Shariman Ismadi , Nunome Hiroyuki , Tamura Yuji
Published: June 2021

A forefoot bending stiffness (FBS) property of footwear is known to benefit athletes in running performance. To date, the efficacy of bending stiffness on performance is rather unknown from the perspective of futsal shoes. This study investigates the influence of bending stiffness property of three commercial futsal shoes on change of direction run resultant performance. Nineteen university level athletes participated in the human performance test (multiple V-cut change of direction run) on a hardwood flooring facility using three pairs of futsal shoes (i.e., S1, S2, and S3) with different models but similar in outsole material (S1—mass: 311 g, heel-to-toe drop: 10 mm, friction coefficient, 1.25; S2—mass: 232 g, heel-to-toe drop: 8 mm, friction coefficient: 1.34; and S3—mass: 276 g, heel-to-toe drop: 7 mm, friction coefficient: 1.30). The FBS properties for each shoe were mechanically measured. Results from the analysis of variance indicated that there was a significant difference of FBS value among the three shoes (S1: 0.32 Nm/deg., S2: 0.26 Nm/deg., and S3: 0.36 Nm/deg.) [F(2,8) = 28.50 (p < 0.001)]. Shoes with relatively higher shoe-playing surface friction coefficient (S2 and S3) had significant impact on the V-cut performance (p < 0.05) when compared with the shoe with lower friction coefficient (S1). In contrast to the literature, the shoe with the lowest FBS (S2) did not suffer any detriments on the resultant performance in the test conducted. These findings suggested that there could be other performance limiting factors, such as the friction coefficient, rather than FBS that have greater influence on the test outcomes.
Women Leaders Transcending the Demands of Covid-19: A Positive Psychology 2.0 Perspective
Authors: Mayer Claude-Hélène , May Michelle S.
Published: June 2021

This article explores selected speeches of three global women leaders during the time of the Covid-19 pandemic from positive psychology perspectives. It focuses on speeches to address and manage the pandemic of global women leaders, such as Angela Merkel (Germany), Jacinda Ardern (New Zealand), and Tsai Ing-Wen (Taiwan). This study explores the question what global women leaders' leadership actions and responses are and how they address their nations with regard to the four pillars of PP2.0 and the PURE model during Covid-19. The study uses a post-modernist qualitative research design. It is anchored in the hermeneutical-phenomenological research paradigm, using leadership theories and PP2.0 as a lens to explore and understand their strengths with regard to the Covid-19 pandemic. The authors use thematic analysis to analyse the selected speeches made by the three women leaders at the onset of the pandemic in Germany, New Zealand and Taiwan. The study contributes to improve the understanding of global women leadership during Covid-19. Conclusions are drawn. Recommendations will be made accordingly.
Resilience in Adult Health Science Revisited—A Narrative Review Synthesis of Process-Oriented Approaches
Authors: Hiebel Nina , Rabe Milena , Maus Katja , Peusquens Frank , Radbruch Lukas , Geiser Franziska
Published: June 2021

Purpose: This article aims to identify how the term “resilience” is addressed in adult health science due to ongoing criticism about the lack of consistency in its conceptualization.

Method: Two databases (PubMed and PsycArticles) were searched to retrieve reviews published from 2015 up until 2020 on the general conceptualization of resilience. All reviews had to meet specific inclusion criteria, which resulted in the inclusion of 18 articles. After discussing different conceptualizations regarding the process-oriented approach of resilience in adult health research, we will highlight some mechanisms that are supposed to be involved in the resilience process.

Results: Research on resilience in health sciences confronts three core difficulties: defining positive outcome for a processual construct, describing different trajectories within the process, and identifying mechanisms that mediate resilience.

Conclusion: The definition of resilience in mental health research as a multidimensional adaptation process is widely accepted, and multiple research paradigms have contributed to a better understanding of the concept. However, the definition of a processual construct in a way that allows for high expert consensus and a valid operationalization for empirical studies remains a challenge. Future research should focus on the assessment of multiple cross-domain outcomes and international and interdisciplinary prospective mixed-method longitudinal designs to fill in the missing links.
Executive Function, Language, and the Toddler’s Discovery of Representational Drawing
Authors: Panesi Sabrina , Morra Sergio
Published: June 2021

Working memory capacity and executive functions play important roles in the early development of drawing and language, but we lack models that specify the relationships among these representational systems and cognitive functions in toddlers. To respond to this need, the present study investigated the relations between drawing and language in very young children, and the role of working memory capacity, inhibition, and shifting in the association between these two representational systems. The participants were 80 children, 25–37 months old. The results revealed that in toddlers (a) all the measures of working memory, inhibition, and shifting loaded on a single factor of general executive functioning; (b) language and drawing are two distinct, but substantially correlated, representational systems; and (c) the development of executive function has a strong impact on language development, which in turn influences the development of drawing.
Self-Esteem and Academic Engagement Among Adolescents: A Moderated Mediation Model
Authors: Zhao Ying , Zheng Zeqing , Pan Chenchen , Zhou Lulu
Published: June 2021

As an important predictor of academic achievement and an effective indicator of learning quality, academic engagement has attracted the attention of researchers. The present study explores the relationship among adolescent self-esteem and academic engagement, the mediating effect of academic self-efficacy, and the moderating effect of perceived social support. Four-hundred and eighty adolescents (Mage = 14.92) from the Hebei Province of China were recruited to complete anonymous questionnaires. The results show that self-esteem positively predicted adolescent academic engagement through the indirect mediating role of academic self-efficacy, and the percentage of this mediation effect of the total effect was 73.91%. As a second-stage moderator, perceived social support moderated the mediating effect of academic self-efficacy. Specifically, when students felt more perceived social support, the impact of academic self-efficacy on their academic engagement was greater. Our findings suggest that adolescent self-esteem, academic self-efficacy, and perceived social support are key factors that should be considered together to improve adolescent academic engagement. Therefore, parents and school educators should actively guide adolescents to improve their self-esteem and academic self-efficacy. Parents and educators should also construct an effective social support system to improve students’ perceived social support and enhance their academic engagement.
A Coupled Hydrologic-Economic Modeling Framework for Scenario Analysis
Authors: Amaya Maria , Baran Ayden , Lopez-Morales Carlos , Little John C.
Published: June 2021

To capture the interactions between hydrologic and economic systems necessary for modeling water quality at a sufficient level of spatial detail, we have designed a modular framework that couples an economic model with a watershed model. To represent the economic system, the Rectangular Choice-of-Technology (RCOT) model was used because it represents both the physical and monetary aspects of economic activities and, unlike traditional input-output or general equilibrium models, it can optimize choices among operational technologies in addition to the amount and location of production. For the first implementation of this modeling framework, RCOT is coupled with a watershed model, Hydrological Simulation Program-Fortran (HSPF), which was calibrated to represent Cedar Run Watershed in northern Virginia. This framework was used to analyze eight scenarios related to the expansion of agricultural activity in Fauquier County. The database for RCOT used county-level input-output data representative of the region in 2012. Thus, when crop farming was expanded to fully utilize the farmland available in the watershed, the nitrogen concentration at the outflow of the watershed increased from 0.6 to 4.3 mg/L. However, when RCOT could select between a standard and a more nitrogen-efficient management practice, the outflow nitrogen concentration only increased to 2.6 mg/L because RCOT selected the more resource-efficient practice. Building on this modular framework, future work will involve designing more realistic scenarios that can test policy options and regional planning decisions in a wide range of watersheds.
Managing Vineyard Topography and Seasonal Variability to Improve Grape Quality and Vineyard Sustainability
Authors: Mania Elena , Petrella Fabio , Giovannozzi Matteo , Piazzi Mauro , Wilson Alena , Guidoni Silvia
Published: June 2021

Topography may induce variability in meteorological conditions at the meso-scale level and could influence grape quality. Understanding the impact of topography on grape ripening allows for the development of sustainable management practices that include topographical influences in their consideration. This is also important for applying proactive strategies able to counter the expected changes of climate. This study was conducted on cv. Nebbiolo vineyards in North-West Italy. The topographic traits were performed in 17 vineyards within the region, which had previously been identified as belonging to different terroir units. An analysis of historical meteorological data series was also carried out to characterize the units from the meteorological point of view. The grape composition was investigated during 2012 and 2013. Based on the topography traits, a Cluster Analysis classified the 17 vineyards into four groups. Differences among groups mainly concerned insolation and heat accumulation. Topography influenced the individual components of grape quality differently depending on the seasonal weather trend. Interactions between topography and vintage were observed for a few parameters. Better understanding the grapevine reaction to external factors/site characteristics can allow for improved site and season-specific management decision making and can contribute to improving vineyard sustainability while maintaining winery objectives and wine typicity.