bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Stem Cell Related Gene Expression From the Osteosarcoma Cell Core Side
Authors: Lim Chaemoon , Roh Young Ho , Yoo Seung Jin , JEONG DONG KEE , Nam Kwang Woo 
Published: January 2021

Abstract
Background: Osteosarcoma is the most frequent primary malignant bone tumor with higher incidences in children and adolescents. Despite clinical evolutions, patients with osteosarcoma have had a poor prognosis. There has been increasing evidence that cancer is a stem cell disease. This study sought to isolate and characterize cancer stem cells from human osteosarcoma with relevant literature reviews. Here we show that the emerging evidence suggests osteosarcoma should be regarded as a differentiation disease such as stem cell disease. Methods: Two human osteosarcoma cell lines were cultured in non-adherent culture conditions as sarcospheres. Sarcospheres were observed using histomorphology and alkaline phosphatase (ALP) staining. Expression of the embryonic stem cell marker was analyzed with use of Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). Results: Sarcospheres could be reproduced consistently throughout multiple passages and produced adherent osteosarcoma cell cultures. Expression of stem cell-associated genes such as Nanog, octamer-binding transcription factor 3/4 (OCT 3/4), sex determining region Y box 2 (SOX2), C-myc and ALP indicated pluripotent stem-like cells. Conclusion: These results support the extension of cancer stem cell theory to include osteosarcoma. Understanding the cancer stem cell of human osteosarcoma could lead to the evolution of diagnosis and treatment for osteosarcoma patients.
Reading-Skill Associated Grey Matter Abnormalities in Dyslexia: Voxel- and Surface-Based Whole-Brain Analysis
Authors: Kujala Teija , Sihvonen Aleksi , Thiede Anja , Palo-Oja Peter , Virtala Paula , Numminen Jussi , Laasonen Marja 
Published: January 2021

Abstract
Developmental dyslexia (DD) is the most prevalent neurodevelopmental disorder with a substantial negative influence on the individual’s academic achievement and career. Research on its neuroanatomical origins has continued for half a century, yielding, however, inconsistent results, lowered total brain volume being the most consistent finding. We set out to evaluate the grey matter (GM) volume and cortical abnormalities in adult dyslexic individuals, employing a combination of whole-brain voxel- and surface-based morphometry following current recommendations on analysis approaches, coupled with rigorous neuropsychological testing. Whilst controlling for age, sex, total intracranial volume, and performance IQ, we found both decreased GM volume and cortical thickness in the left insula in participants with DD. Moreover, they had decreased GM volume in left superior temporal gyrus, putamen, globus pallidus, and parahippocampal gyrus. Higher GM volumes and cortical thickness in these areas correlated with better reading and phonological skills, deficits of which are pivotal to DD. Crucially, total brain volume did not influence our results, since it did not differ between the groups. Our findings demonstrating abnormalities in brain areas in individuals with DD, which previously were associated with phonological processing, are compatible with the leading hypotheses on the neurocognitive origins of DD.
The TNFRSF13B rs34562254 Polymorphism is Associated with Hepatitis C Infection Risk in the Han Chinese Population
Authors: Fan Haozhi , Fu Zuqiang , Ge Zhijun , Dong Chen , Wang Chunhui , Shen Chao , Li Jun , Yu Rongbin , Zhang Yun , Yue Ming 
Published: January 2021

Abstract
Background

Genetic variations in the tumor necrosis factor receptor superfamily (TNFRSF) 13B have been reported to be associated with immune-related diseases. This study aimed to explore the relationship of tumor necrosis factor superfamily (TNFSF) 13, TNFRSF13B, and TNFRSF14 missense mutations with hepatitis C virus (HCV) infection susceptibility.
Methods

Single-nucleotide polymorphisms (SNPs) in TNFSF13 (rs3803800, rs11552708), TNFRSF13B (rs34562254), and TNFRSF14 (rs4870) were genotyped in 469 intravenous drug users, 728 hemodialysis patients, and 1636 paid blood donors using a TaqMan real-time PCR assay. The USCS browser and RNAfold web servers were used to predict the biological functions of these selected SNPs.
Results

After adjusting for gender, age, levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and route of infection, a logistic regression analysis showed that subjects carrying a homozygous TNFRSF13B rs34562254 TT mutant were more likely to be infected by HCV compared to those homozygous with the rs34562254 CC wild type (co-dominant model: OR = 1.52, 95% CI: 1.17–1.98, P = 0.002; recession model: OR = 1.41, 95% CI: 1.10–1.81, P = 0.007; additive model: OR = 1.21, 95% CI: 1.07–1.37, P = 0.002). The effect of the risk allele rs34562254-T was stronger in subjects that were female, older (≥ 50 years old), paid blood donors, and with lower ALT and AST levels (≤ 40 U/L). A bioinformatics analysis via the UCSC genome browser found that rs34562254 was located at the highest peak of the H3K4Me1 histone marker. Using the RNAfold web servers, the minimum free energy of the centroid secondary structure was found to be higher for the mutant rs34562254-T allele (-38.90 kcal/mol) than its wild type C allele (-45.60 kcal/mol). Additionally, the RegulomeDB score of rs34562254 was 3a. Altogether, the results of the bioinformatics analysis indicate that rs34562254 may affect gene expression levels by regulating the transcriptional activity of corresponding gene regions.
Conclusions

The rs34562254 polymorphisms in TNFRSF13B were significantly associated with HCV infection among the Han Chinese population.
Verifying Extra-Pulmonary Manifestation of COVID-19 in Firoozgar Hospital 2020: An Observational Study
Authors: Mottaghi Azadeh , Roham Maryam , Makiani Mahin Jamshidi , Ranjbar Mitra , Laali Azadeh , Rahimian.n@iums.ac.ir Neda Rahimian 
Published: January 2021

Abstract
Background: COVID-19 is a new emerging disease that causes a pandemic situation in the world. Corona virus can enter into the body via several ways and it damages other organs of the body in addition to the respiratory system. This study aimed at verifying extra-pulmonary manifestation of COVID-19.Methods: The present study was done as cross-sectional in the single center from March 1 to May 1 2020 at Firoozgar educational hospital in Tehran, Iran. 107 patients with confirmed Covid-19 pneumonia according to WHO interim guidance were recruited in this study. Extra-pulmonary manifestations of COVID-19 were recorded. SPSS, version 26 was used for all analyses.Results: The mean (SD) and median of age was 59.3 (17.4) and 62.0 respectively and 58 (54.2%) were men. Body temperature of patients who were equal or less than 60 years was significantly higher than other patients (39.02 vs. 38.08, p=0001). The most common extra-pulmonary manifestation was GI symptoms included nausea, vomiting, abdominal pain, diarrhea, Hepatocellular LFT abnormality, Cholestatic LFT abnormality and Amylase lipase incensement (37 patients (34.6%)). Ophthalmological, cardiac, neurological and dermatological manifestations were shown in 6.5%, 6.5%, 14.9% and 14.0% of patients respectively. Conclusion: Investigating the clinical and radiological symptoms of COVID-19 showed that SARS-CoV-2 infection may also be associated with extrapulmonary symptoms. Therefore, clinicians and radiologists should be familiar with such symptoms of this disease.
Melanin Production and Laccase Mediated Oxidative Stress Alleviation During Fungal-fungal Interaction Among Basidiomycetes Fungi
Authors: Dullah Samim , Hazarika Dibya Jyoti , Goswami Gunajit , Borgohain Tanushree , Ghosh Alokesh , Barooah Madhumita , Bhattacharyya Ashok , Boro Robin Chandra 
Published: January 2021

Abstract
Fungal-fungal interaction often leads to the change in metabolite profile of both the interacting fungus which may have potential implication in industry or agriculture. In the present study, we performed two sets of fungal-fungal interaction - Trametes coccinea (F3) with Leiotrametes lactinea (F9) and Trametes coccinea (F3) with Trametes versicolor (F1) to understand the changes in the metabolite profile during the interaction process and how this process impacts the hyphal/mycelial morphology of the participating fungi. The metabolites produced during interaction of Trametes coccinea (F3) with Leiotrametes lactinea (F9) and Trametes coccinea (F3) with Trametes versicolor (F1) was analysed through Liquid Chromatography coupled to Mass Spectroscopy (LC-MS). Most of the metabolites secreted or produced during interaction are associated with defensive response. Further, visualization with scanning electron microscopy revealed that interaction between the tested fungi led to the change in the hyphal morphology of the one participating fungus. The bipartite fungal interaction resulted in the production of a dark brown colour pigment – melanin as confirmed by the LC-MS, FTIR and NMR analysis. Moreover, the fungal-fungal interaction also led to increase in the production of laccase, a group of multicopper oxidases involved in detoxification of toxic compounds. Further increased activity of superoxide dismutase, an enzyme that catalyzes the dismutation of the superoxide anion to hydrogen peroxide was also recorded during fungal– fungal interaction. Quantitative real-time PCR revealed upregulation of lcc1 (encoding a laccase enzyme) and few other stress related genes of T. versicolor during its hyphal interaction with T. coccinea, suggesting a direct correlation between laccase production and melanin production.
A Predictive in Vitro Risk Assessment Platform for Pro-Arrhythmic Toxicity Using Human 3D Cardiac Microtissues
Authors: Kofron Celinda , Kim Tae Yun , Munarin Fabiola , Soepriatna Arvin , Kant Rajeev , Mende Ulrike , Choi Bum-Rak , Coulombe Kareen 
Published: January 2021

Abstract
Cardiotoxicity of pharmaceutical drugs, industrial chemicals, and environmental toxicants can be severe, even life threatening, which necessitates a thorough evaluation of the human response to chemical compounds. Predicting risks for arrhythmia and sudden cardiac death accurately is critical for defining safety profiles. Currently available approaches have limitations including a focus on single select ion channels, the use of non-human species in vitro and in vivo, and limited direct physiological translation. We have advanced the robustness and reproducibility of in vitro platforms for assessing pro-arrhythmic cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes and human cardiac fibroblasts in 3-dimensional microtissues. Using automated algorithms and statistical analyses of eight comprehensive evaluation metrics of cardiac action potentials, we demonstrate that tissue-engineered human cardiac microtissues respond appropriately to physiological stimuli and effectively differentiate between high-risk and low-risk compounds exhibiting blockade of the hERG channel (E4031 and ranolazine, respectively). Further, we show that the environmental endocrine disrupting chemical bisphenol-A (BPA) causes acute and sensitive disruption of human action potentials in the nanomolar range. Thus, this novel human 3D in vitro pro-arrhythmic risk assessment platform addresses critical needs in cardiotoxicity testing for both environmental and pharmaceutical compounds and can be leveraged to establish safe human exposure levels.
Different Features of Interleukin-37 and Interleukin-18 as Disease Activity Markers of Adult-onset Still’s Disease
Authors: Nam Seoung Wan , Kang SuMan , Lee Jun Hyeok , Yoo Dae Hyun 
Published: January 2021

Abstract

Backgrounds/Aims: The aim of this study was to evaluate the usefulness of serum interleukin (IL)-37 and IL-18 as disease activity markers of adult-onset Still’s disease (AOSD) and to compare their related clinical features. Methods: Forty-five patients with a set of high and subsequent low disease activity status of AOSD that fall within a 12-month period were enrolled. Modified Pouchot (mPouchot) score and serologic disease activity markers including serum levels of IL-37 and IL-18 were compared between high and low disease activity status. The relationships between disease activity parameters and differences in serum levels of IL-37 and IL-18 according to the presence of each disease manifestation of AOSD were evaluated in high disease activity status. Results: mPouchot score and all serologic disease activity markers including ESR, CRP, ferritin, IL-37, and IL-18 significantly declined in low disease activity status (p<0.01). Though both serologic cytokines positively correlated with mPouchot score, the two did not correlate with each other in high disease activity status. IL-18 positively correlated with ferritin, AST, and LDH (p<0.05). In contrast, IL-37 correlated better with CRP (p<0.01). The expression level of IL-37 and presence of leukocytosis were closely related. However, the expression level of IL-18 was closely related to presence of pleuritis. pneumonitis, abnormal LFT, and hyperferritinemia. Conclusions: Both IL-37 and IL-18 can be useful serologic markers of AOSD activity, but their pathologic roles in disease activity might be different.
Identification and integrative analysis of ACLY and related gene panels associated with immune microenvironment reveal prognostic significance in hepatocellular carcinoma
Authors: Xu Yunfeng , Zhang Ze , Xu Da , Zhou Li-Na , Zhu Ying 
Published: January 2021

Abstract
BackgroundCumulating evidence reveals the key role of aberrant lipogenesis and immunogenomic features in hepatocellular carcinoma (HCC). However, there are still obstacles in our understanding of the complicated interaction between metabolic reprogramming and tumor immune microenvironment.MethodsWe compared metabolomic, transcriptomic and immunogenomic characteristics of portal vein tumor thrombosis (PVTT) and primary tumor to seek valuable markers. Human HCC samples with PVTT (n = 28) was analyzed through ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). Transcript levels of mRNA in two cohorts from published database GEO (n = 60) and TCGA (n = 411) were downloaded to explore differentially expressed genes and functional enriched gene set. Evaluation of immune infiltration was estimated and validated from transcriptomic data in both cohorts through six immune deconvolution algorithms (TIMER, CIBERSORT, quanTIseq, xCell, MCP-counter, EPIC) and in a high-resolution mode (CIBERSORTx). Survival analysis (Kaplan-Meier and multivariable Cox regression model) was performed to examine prognostic value of ACLY, related immune checkpoints and immune infiltration levels from TCGA cohort. LASSO regression was further conducted to determine a gene panel to further predict survival outcomes associated with ACLY.ResultsWe identified a novel signature, ATP citrate lyase, through transcriptomic and metabolomic approaches. We demonstrated that the metabolism adaptations in both fatty acid and cholesterol biosynthesis triggered by ACLY oncogenic activation. We illustrated the crucial function of ACLY in lipogenesis and its potential interaction with immune microenvironment. CD276, a promising target in immune checkpoint blockade, showed correlation to ACLY and differential expression in ACLY risk classification. Combination of ACLY, CD276 and immune infiltration level and a novel ACLY-associated panel from a predictive model retrieved from published database validated the prognostic value to risk stratification in patients with HCC. According to the survival outcome and correlation analysis, ACLY blockade to counteract metabolic activation and immunosuppressive status of the tumor microenvironment highlighted attractive prospect for translational application.ConclusionsWe investigated ACLY and its indispensable role in metabolism, immune function and a prognostic gene panel in HCC. We anticipate that the multifaced role of ACLY may reveal the potential value for mechanistic research and combinational therapy, suggesting that the combination blockade of ACLY and immune checkpoints may work as a promising strategy.
RAP1GAP is a novel marker of trabecular pattern and poor sorafenib treatment response in hepatocellular carcinoma
Authors: Wen Xue , Su Kunkai , Liu Zhikun , Ling Sunbin , Lu Di , Xiong Bin , Ye Yufu , Wang Kun , Pan Binhua , Wu Weiqiang , Wei Xuyong , Zheng Shusen , Xu Xiao 
Published: January 2021

Abstract
Background

The trabecular pattern is one of the most common features of hepatocellular carcinoma (HCC). In this study, we aimed to identify the molecular mechanisms underlying different trabecular patterns in HCC, and their interaction with current therapies.
Methods

To screen potential biomarkers of different trabecular patterns, we first linked gene expression data to haematoxylin and eosin (H&E) images from The Cancer Genome Atlas (TCGA). The Gene Expression Omnibus (GEO) database was used to explore potential targets of sorafenib treatment. Selected candidate biomarkers were further verified by immunohistochemistry, and their relationship with sorafenib efficacy was evaluated in 107 HCC samples with trabecular patterns.
Results

Analysis of RNA sequencing data from TCGA showed that the increasing number of cells in the trabecular structure correlated with increase in the expression of related signalling pathways—Ras, Rap1, IL17, TNF, AGE-RAGE, oestrogen, toll-like receptor signalling, and ubiquitin-mediated proteolysis—and genes related to response to oxygen levels and neoangiogenesis. In contrast, the expression of bile acid and carton, tryptophan, butanoate, and lipid metabolism-related pathways was reduced. The GEO database showed that RAP1GAP, TOB1, ACO2, and SCNN1D expression levels were selectively up-regulated in sorafenib non-responders. Based on the combined analysis of the two datasets and our previous studies, two candidate biomarkers, RAP1GAP and HIF1α, were selected. Immunohistochemical staining showed that RAP1GAP and HIF1α were expressed in the tumour tissues. Interestingly, RAP1GAP was also expressed in the tumour sinusoids. Overexpression of RAP1GAP in sinusoids were associated with trabecular patterns. Multivariate analysis also showed that RAP1GAP expression in the sinusoid was an independent predictor of progressive free survival (PFS) and overall survival (OS) in response to sorafenib treatment.
Conclusions

RAP1GAP is an essential microenvironment marker in the trabecular structure of HCC and exhibits an adverse association with outcome in sorafenib treatment.
Overexpression of SMYD3 contributes to sorafenib resistance by epigenetically activating the expression of multiple cancer-promoting genes in hepatocellular carcinoma
Authors: Wang Shanshan , You Xinxin , Zhang Fengwei , Zhou Hongjuan , Shang Xuechai , Long Cai 
Published: January 2021

Abstract
Background

The resistance mechanism to sorafenib in hepatocellular carcinoma (HCC) remains poorly understood. Recent evidence has demonstrated the enrichment of liver cancer stem cells (CSCs) as culprit for treatment resistance. In liver cancer development, SMYD3 epigenetically activates or overexpresses JAK/STAT3 pathway, epithelial-mesenchymal transition (EMT) pathway, SOX4 and MYC oncogenes, which play crucial roles in liver CSC. In this study, we demonstrate the novel role of SMYD3 in HCC resistance to sorafenib therapy.
Methods

We used sorafenib-resistant HCC in vitro and in vivo models to study the relationship between sorafenib resistance and SMYD3 expression. Chromatin immunoprecipitation (ChIP) and quantitative real-time PCR (qRT-PCR) were used to analyze the mechanism of SMYD3 regulation. Stemness and metastatic properties were investigated after treatment with SMYD3 depletion alone or in combination with sorafenib to evaluate the therapeutic effect on sorafenib resistance by in vitro and in vivo experiments.
Result

We identified overexpression of SMYD3 and subsequent increase of histone H3K4me3 as a novel pathway of acquired resistance to sorafenib in HCC. We also found that multiple SMYD3-mediated cancer-promoting genes exhibited up-regulation in sorafenib-resistant HCC cells and tumors. Inhibition of SMYD3 by a small-molecular inhibitor BCL121 or genetic means suppressed the transcription of SMYD3 target genes via the inhibition of the recruitment of H3K4me3-midifed histone tails to the core promoter regions of these genes. Restoration of wide-type SMYD3 protein in sorafenib-resistant cells with SMYD3 knockdown partly rescued the expression of target genes, while mutant SMYD3 did not. As such, modulating SMYD3 expression or activity in vitro and in vivo models inhibited the transcription output of target genes, mainly through SOX4, MYC, JAK1 and ZEB1 genes, and suppressed activation of their associated pathways, including EMT, JAK/STAT3, SOX4 and MYC pathway, and consequently weakened the stemness and metastatic properties of sorafenib-resistant cells in vitro and suppressed the relapse and metastasis of sorafenib-resistant tumors in vivo.
Conclusion

SMYD3 conferred sorafenib-resistant cells enhanced stemness and metastatic properties in HCC by epigenetically activating the expression of multiple cancer-promoting genes. SMYD3 could be a rational target for therapeutic intervention in sorafenib-resistant HCC.
Characterization of novel natural compound derivatives with cancer-selective cytotoxicity
Authors: Nunna Suneetha , Huang Ying-Pei , Rasa Mahdi , Anna Krepelova , Annunziata Francesco , Adam Lisa , Kaeppel Sandra , Hsu Ming-Hua , Neri Francesco 
Published: January 2021

Abstract
BackgroundColorectal cancer (CRC) is one of the most frequent and lethal cancers in the world. The current medical treatment for CRC primarily includes combination of multiple chemotherapeutic, targeted and/or immunotherapeutic drugs. However, these approaches are still not fully successful and cause numerous and severe side effects for the patient. Therefore, there is an urgent need to discover novel and cancer-selective drugs for CRC treatment. As many other natural compounds, a-Mangostin and Paeonol possess anti-cancer properties, but both of these compounds have low solubility and low membrane permeability.Methodsa-Mangostin and Paeonol derivatives were chemically synthesized to increase cytotoxicity versus cancer cell over non-transformed cells. The anticancer properties of these compounds were investigated on human colon cancer cell lines by employing cell viability, apoptosis and cell-cycle analyses. Transcriptome of cancer cells treated with natural compounds were also analyzed by total RNA-sequencing. Finally, we investigated their effects on human colon organoids derived from healthy and cancerous tissue of the same patient.ResultsWe found the two derivative compounds (a-Mangostin-1 (aMan1) and Paeonol-1 (Pae1)) more efficiently induced cytotoxicity in HCT116, HT-29, and SW48 colorectal cancer cell lines than the parental compounds. Both, aMan1 and Pae1 arrested HCT116 cells in G1 and HT-29 and SW48 cells in G2/M phase of the cell cycle. aMan1 and Pae1 induced selective transcriptional responses in CRC cells involving genes related to metabolic stress and DNA damage response signaling pathways. Both aMan1 and Pae1 induced apoptosis in human cancer cells and organoids derived from tumor tissue without affecting the viability of human non-cancer cells and intestinal organoids derived from healthy tissue.ConclusionsOur findings increase the knowledge about natural compound derivatives as anticancer compounds and open new research options on the derivation of lead compounds aimed to the development of novel CRC chemotherapeutic drugs that selectively target cancer, but not healthy cells.