bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of Hypoxia in Improving the Therapeutic Potential of Mesenchymal Stromal Cells. A Comparative Study From Healthy Lung and Congenital Pulmonary Airway Malformations in Infants
Authors: Silvestro Serena , Diomede Francesca , Chiricosta Luigi , Zingale Valeria Domenica , Marconi Guya Diletta , Pizzicannella Jacopo , Valeri Andrea , Avanzini Maria Antonietta , Calcaterra Valeria , Pelizzo Gloria , Mazzon Emanuela 
Published: June 2022

Mesenchymal stromal cells (MSCs) play an important role in the field of regenerative medicine thanks to their immunomodulatory properties and their ability to secrete paracrine factors. The use of MSCs has also been tested in children with congenital lung diseases inducing fibrosis and a decrease in lung function. Congenital malformations of the pulmonary airways (CPAM) are the most frequently encountered lung lesion that results from defects in early development of airways. Despite the beneficial properties of MSCs, interventions aimed at improving the outcome of cell therapy are needed. Hypoxia may be an approach aimed to ameliorate the therapeutic potential of MSCs. In this regard, we evaluated the transcriptomic profile of MSCs collected from pediatric patients with CPAM, analyzing similarities and differences between healthy tissue (MSCs-lung) and cystic tissue (MSCs-CPAM) both in normoxia and in cells preconditioned with hypoxia (0.2%) for 24 h. Study results showed that hypoxia induces cell cycle activation, increasing in such a way the cell proliferation ability, and enhancing cell anaerobic metabolism in both MSCs-lung and MSCs-CPAM-lung. Additionally, hypoxia downregulated several pro-apoptotic genes preserving MSCs from apoptosis and, at the same time, improving their viability in both comparisons. Finally, data obtained indicates that hypoxia leads to a greater expression of genes involved in the regulation of the cytoskeleton in MSCs-lung than MSCs-CPAM.
METTL3-Mediated m6A RNA Methylation of ZBTB4 Interferes With Trophoblast Invasion and Maybe Involved in RSA
Authors: Huang Nana , Gao Yue , Zhang Mengting , Guo Liangjie , Qin Litao , Liao Shixiu , Wang Hongdan 
Published: June 2022

N6-methyladenosine (m6A) was the most abundant modification of mRNA and lncRNA in mammalian cells and played an important role in many biological processes. However, whether m6A modification was associated with recurrent spontaneous abortion (RSA) and its roles were still unclear.Methods: Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) was used to study the global m6A modification pattern in RSAs and controls. RNA sequencing (RNA-Seq) was used to study the level of global mRNA in two groups. Real-time quantitative PCR (RT-qPCR) was used to verify the level of mRNA of METTL3 and ZBTB4. MeRIP–qPCR was conducted to test the level of ZBTB4 m6A modification in two groups. In order to further explore whether ZBTB4 was the substrate of METTL3, the HTR-8/SVneo (HTR-8) cell line was selected for the knockdown and overexpression of METTL3. To study whether METTL3 regulated the ZBTB4 expression by recognizing ZBTB4 mRNA m6A motifs in coding sequences (CDS), dual-luciferase reporter assay was conducted. RNA stability assays using actinomycin D were conducted to study the RNA stability of the HTR-8 cell line with METTL3 overexpression and knockdown. To illustrate the role of METTL3 in the invasion of trophoblast, matrigel invasion assays and transwell migration assays were conducted using the HTR-8 cell line with METTL3 overexpression and knockdown.Results: A total of 65 genes were found with significant differences both in m6A modification and mRNA expression. We found m6A methyltransferase METTL3 was significantly down-regulated in the RSA group. Through gene function analysis, RT-qPCR, MeRIP–qPCR validation experiment, knockdown, and overexpression of METTL3 in the HTR-8 cell line, ZBTB4 was selected as one target of METTL3. Furthermore, we clarified that METTL3 regulated the expression of ZBTB4 by recognizing ZBTB4 mRNA m6A motifs in the CDS using the dual-luciferase reporter assay and METTL3 regulated the invasion of trophoblast by altering the stability and expression of ZBTB4 by RNA stability, matrigel invasion, and transwell migration assays.Conclusion: Our study revealed the mechanism by which METTL3 regulated the stability and expression of ZBTB4 and the trophoblast migration ability of RSA. A new perspective was provided for exploring the mechanism of embryonic development in RSA patients.
Expression Profile of Genes Related to the Th17 Pathway in Macrophages Infected by Leishmania major and Leishmania amazonensis: The Use of Gene Regulatory Networks in Modeling This Pathway
Authors: Gonçalves Leilane Oliveira , Pulido Andrés F. Vallejo , Mathias Fernando Augusto Siqueira , Enes Alexandre Estevão Silvério , Carvalho Maria Gabriela Reis , de Melo Resende Daniela , Polak Marta E. , Ruiz Jeronimo C. 
Published: June 2022

Leishmania amazonensis and Leishmania major are the causative agents of cutaneous and mucocutaneous diseases. The infections‘ outcome depends on host–parasite interactions and Th1/Th2 response, and in cutaneous form, regulation of Th17 cytokines has been reported to maintain inflammation in lesions. Despite that, the Th17 regulatory scenario remains unclear. With the aim to gain a better understanding of the transcription factors (TFs) and genes involved in Th17 induction, in this study, the role of inducing factors of the Th17 pathway in Leishmania–macrophage infection was addressed through computational modeling of gene regulatory networks (GRNs). The Th17 GRN modeling integrated experimentally validated data available in the literature and gene expression data from a time-series RNA-seq experiment (4, 24, 48, and 72 h post-infection). The generated model comprises a total of 10 TFs, 22 coding genes, and 16 cytokines related to the Th17 immune modulation. Addressing the Th17 induction in infected and uninfected macrophages, an increase of 2- to 3-fold in 4–24 h was observed in the former. However, there was a decrease in basal levels at 48–72 h for both groups. In order to evaluate the possible outcomes triggered by GRN component modulation in the Th17 pathway. The generated GRN models promoted an integrative and dynamic view of Leishmania–macrophage interaction over time that extends beyond the analysis of single-gene expression.
Prevalence and Predisposing Factors of Non-infectious Cardiac Implantable Electronic Device Lead Masses as Incidental Finding During Transoesophageal Echocardiography: A Retrospective Cohort Study
Authors: Kuecken Tanja , Jasaityte Ruta , Bülow Cara , Gross Jessica , Haase-Fielitz Anja , Neuss Michael , Butter Christian 
Published: June 2022

ObjectivesIn this study, we assessed the prevalence and predisposing factors of non-infectious CIED lead masses as incidental finding during transoesophageal echocardiography (TOE).MethodsIn a retrospective single centre study, we analysed TOE examinations performed for indications other than infectious endocarditis in 141 patients with CIED. Patients with non-suspicious leads and those with incidental non-infectious lead masses were compared with respect to clinical characteristics, anticoagulation, indication for TOE, and CIED lead characteristics. The odds ratios for non-infectious CIED lead masses were calculated.ResultsNon-infectious CIED lead masses were detected in 39 (27.6%) of the 141 patients. They were more often identified on ICD and CRT-D leads compared to pacemaker and CRT-P leads [OR 2.77 (95% CI 1.29–5.95), p = 0.008]. The lifespan of the CIEDs from the first implantation to the index TOE did not differ between both groups. Incidental CIED lead masses were more prevalent in patients who received their device for primary prevention of sudden cardiac death (43.2%) and for resynchronisation (63.6%) but were less prevalent in patients with oral anticoagulation [OR.33 (95% CI.003–1.003), p = 0.048].ConclusionIncidental non-infectious CIED lead masses were frequently found in TOE, with highest prevalence in ICD and CRT-D devices implanted for patients with dilated cardiomyopathy. Patients with therapeutic anticoagulation had significantly lower prevalence of CIED lead masses than those without.
Systematic Construction and Validation of a Novel Macrophage Differentiation–Associated Prognostic Model for Clear Cell Renal Cell Carcinoma
Authors: Liu Chen , Zhang Xuhui , Hu Caoyang , Liang Xuezhi , Cao Xiaoming , Wang Dongwen 
Published: June 2022

Background: Clear cell renal cell carcinoma (ccRCC) is a malignant tumor of the human urinary system. Macrophage differentiation is associated with tumorigenesis. Therefore, exploring the prognostic value of macrophage differentiation–associated genes (MDGs) may contribute to better clinical management of ccRCC patients.Methods: The RNA sequence data of ccRCC were obtained from The Cancer Genome Atlas (TCGA) database. Differentially expressed MDGs were unveiled in ccRCC and normal samples. The prognostic model was established according to the univariate and multivariate Cox regression analyses. By combining clinico-pathological features and prognostic genes, a nomogram was established to predict individual survival probability. The Tumor Immune Estimation Resource (TIMER) database was utilized to analyze the correlation between prognostic genes and immune infiltrating cells. Eventually, the mRNA and protein expression levels of prognostic genes were verified.Results: A total of 52 differentially expressed prognosis-related MDGs were identified in ccRCC. Afterward, a six-gene prognostic model (ABCG1, KDF1, KITLG, TGFA, HAVCR2, and CD14) was constructed through the Cox analysis. The overall survival in the high-risk group was relatively poor. Moreover, the risk score was identified as an independent prognostic factor. We constructed a prognostic nomogram with a well-fitted calibration curve based on risk score and clinical data. Furthermore, the prognostic genes were significantly related to the level of immune cell infiltration including B cells, CD8+T cells, CD4+T cells, macrophages, neutrophils, and dendritic cells. Finally, the mRNA expression of prognostic genes in clinical ccRCC tissues showed that the ABCG1, HAVCR2, CD14, and TGFA mRNA in tumor samples were increased compared with the adjacent control tissue samples, while KDF1 and KITLG were decreased, which was consistent with the verification results in the GSE53757.Conclusion: In conclusion, this study identified and validated a macrophage differentiation–associated prognostic model for ccRCC that could be used to predict the outcomes of the ccRCC patients.
Diagnostic, Prognostic, and Immunological Roles of HELLS in Pan-Cancer: A Bioinformatics Analysis
Authors: Liang Xiao , Li Linji , Fan Yuchao 
Published: June 2022

BackgroundInappropriate repair of DNA damage drives carcinogenesis. Lymphoid-specific helicase (HELLS) is an important component of the chromatin remodeling complex that helps repair DNA through various mechanisms such as DNA methylation, histone posttranslational modification, and nucleosome remodeling. Its role in human cancer initiation and progression has garnered recent attention. Our study aims to provide a more systematic and comprehensive understanding of the role of HELLS in the development and progression of multiple malignancies through analysis of HELLS in cancers.MethodsWe explored the role of HELLS in cancers using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database. Multiple web platforms and software were used for data analysis, including R, Cytoscape, HPA, Archs4, TISIDB, cBioPortal, STRING, GSCALite, and CancerSEA.ResultsHigh HELLS expression was found in a variety of cancers and differentially expressed across molecular and immune subtypes. HELLS was involved in many cancer pathways. Its expression positively correlated with Th2 and Tcm cells in most cancers. It also correlated with genetic markers of immunomodulators in various cancers.ConclusionsOur study elucidates the role HELLS plays in promotion, inhibition, and treatment of different cancers. HELLS is a potential cancer diagnostic and prognostic biomarker with immune, targeted, or cytotoxic therapeutic value. This work is a prerequisite to clinical validation and treatment of HELLS in cancers.
microRNA Expression and Its Association With Disability and Brain Atrophy in Multiple Sclerosis Patients Treated With Glatiramer Acetate
Authors: Dominguez-Mozo María I. , Casanova Ignacio , De Torres Laura , Aladro-Benito Yolanda , Perez-Perez Silvia , Garcia-Martínez Angel , Gomez Patricia , Abellan Sara , De Antonio Esther , Lopez-De-Silanes Carlos , Alvarez-Lafuente Roberto 
Published: June 2022

BackgroundMicroRNAs are small non-coding RNA that regulate gene expression at a post-transcriptional level affecting several cellular processes including inflammation, neurodegeneration and remyelination. Different patterns of miRNAs expression have been demonstrated in multiple sclerosis compared to controls, as well as in different courses of the disease. For these reason they have been postulated as promising biomarkers candidates in multiple sclerosis.Objectiveto correlate serum microRNAs profile expression with disability, cognitive functioning and brain volume in patients with remitting-relapsing multiple sclerosis.Methodscross-sectional study in relapsing-remitting multiple sclerosis patients treated with glatiramer acetate. Disability was measured with Expanded Disability Status Scale (EDSS) and cognitive function was studied with Symbol Digit Modalities Test (SDMT). Brain volume was analyzed with automatic software NeuroQuant®.ResultsWe found an association between miR.146a.5p (rs:0.434, p=0.03) and miR.9.5p (rs:0.516, p=0.028) with EDSS; and miR-146a.5p (rs:-0.476, p=0.016) and miR-126.3p (rs:-0.528, p=0.007) with SDMT. Regarding to the brain volume, miR.9.5p correlated with thalamus (rs:-0.545, p=0.036); miR.200c.3p with pallidum (rs:-0.68, p=0.002) and cerebellum (rs:-0.472, p=0.048); miR-138.5p with amygdala (rs:0.73, p=0.016) and pallidum (rs:0.64, p=0.048); and miR-223.3p with caudate (rs:0.46, p=0.04).ConclusionsThese data support the hypothesis of microRNA as potential biomarkers in this disease. More studies are needed to validate these results and to better understand the role of microRNAs in the pathogenesis, monitoring and therapeutic response of multiple sclerosis.
NETosis in Psoriatic Arthritis: Serum MPO–DNA Complex Level Correlates With Its Disease Activity
Authors: Li Borui , Li Guangtao , Yang Xinlei , Song Zhibo , Wang Yu , Zhang Zhuoli 
Published: June 2022

BackgroundNeutrophil extracellular trap formation (NETosis) has been rarely reported in psoriatic arthritis (PsA). We aimed to explore the involvement of NETosis in the inflammation of PsA.MethodsSerum myeloperoxidase–DNA (MPO-DNA) complex was detected by a modified enzyme-linked immunosorbent assay and compared among 74 patients with PsA, 58 patients with psoriasis (PsO), and 20 healthy controls. The association of MPO–DNA level with disease activity index at baseline and follow-up was analyzed in patients with PsA. Receiver operating characteristic curve was used to evaluate the predictive value of MPO–DNA for treatment response.ResultsMPO–DNA complex level in serum was significantly increased in patients with PsA/PsO compared to healthy controls (p &lt; 0.001). The level of MPO–DNA was positively associated with DAPSA score and its components (including TJC, SJC, PGA, VAS-pain and CRP, r = 0.25–0.409, all p-values &lt; 0.05). Serum MPO–DNA level was downregualted at 12 weeks after treatment compared to baseline (p = 0.022). The decrease of MPO–DNA level was more dramatic in patients with PsA who achieved both ACR50 and PASI50 response than those achieving neither of them at 12 weeks (p = 0.023). ROC analysis revealed that the serum MPO–DNA level predicted both ACR50 and PASI50 achievement at week 12 (p = 0.04; 95% CIs, 0.56–0.94). Moreover, the baseline MPO–DNA level (p = 0.009; 95% CIs, 0.748–1) and change of MPO–DNA at week 12 from baseline (p = 0.004; 95% CIs, 0.802–1) were associated with the achievement of both ACR70 and PASI75 response at week 24.ConclusionsNETosis plays an important role in psoriatic diseases. The level of MPO–DNA complex in serum reflects disease activity. Serum MPO–DNA complex may be a useful biomarker to predict the therapeutic response in PsA.
One-Month Outcomes of Intravitreal Anti-VEGF vs. Dexamethasone Implant in the Treatment of Diabetic Macular Edema in Vitrectomized Eyes
Authors: Liang Youling , Yan Bin , Xie Manyun , Meng Zhishang , Ma Jiayue , Ma Bosheng , Luo Jing 
Published: June 2022

ObjectivesTo compare short-term effect of intravitreal ranibizumab with dexamethasone implant for diabetic macular edema (DME) in vitrectomized eyes.MethodsSingle-center, prospective, randomized study of vitrectomized eyes with DME. Study eyes were divided into two groups, receiving ranibizumab (IVV group, n = 35 eyes) or dexamethasone implant (IVD group, n = 35 eyes) respectively. Patients were evaluated at baseline, Week 1 and Month 1. The main outcome measures included best-corrected visual acuity (BCVA), central retinal thickness (CRT) and intraocular pressure (IOP).ResultsBCVA and CRT were similar in the two groups at baseline. At Week 1, the CRT improvement was significant in two groups (P = 0.041 in IVV group, P = 0.030 in IVD group), but at Month 1, only IVD group had significant improvement in CRT (P &lt; 0.001). And BCVA gains were significant at Week 1 (P = 0.029) and Month 1 (P = 0.001) in IVD group, whereas IVV group did not show significant BCVA gains (P = 0.056 at Week1, P = 0.166 at Month 1). The changes of BCVA and CRT were significantly higher in IVD group than IVV group at Month1, but the changes were not significant at Week1.ConclusionsComparing to anti-VEGF therapy, DEX implant is more effect in improving BCVA and reducing CRT in vitrectomized eyes at 1 month, which indicated DEX implant is a better strategy.
Association Between Vaccination Coverage Disparity and the Dynamics of the COVID-19 Delta and Omicron Waves in the US
Authors: Cuadros Diego F. , Moreno Claudia M. , Musuka Godfrey , Miller F. DeWolfe , Coule Phillip , MacKinnon Neil J. 
Published: June 2022

ObjectiveThe US recently suffered the fourth and most severe wave of the COVID-19 pandemic. This wave was driven by the SARS-CoV-2 Omicron, a highly transmissible variant that infected even vaccinated people. Vaccination coverage disparities have played an important role in shaping the epidemic dynamics. Analyzing the epidemiological impact of this uneven vaccination coverage is essential to understand local differences in the spread and outcomes of the Omicron wave. Therefore, the objective of this study was to quantify the impact of vaccination coverage disparity in the US in the dynamics of the COVID-19 pandemic during the third and fourth waves of the pandemic driven by the Delta and Omicron variants.MethodsThis cross-sectional study used COVID-19 cases, deaths, and vaccination coverage from 2,417 counties. The main outcomes of the study were new COVID-19 cases (incidence rate per 100,000 people) and new COVID-19 related deaths (mortality rate per 100,000 people) at county level and the main exposure variable was COVID-19 vaccination rate at county level. Geospatial and data visualization analyses were used to estimate the association between vaccination rate and COVID-19 incidence and mortality rates for the Delta and Omicron waves.ResultsDuring the Omicron wave, areas with high vaccination rates (&gt;60%) experienced 1.4 (95% confidence interval [CI] 1.3–1.7) times higher COVID-19 incidence rate compared to areas with low vaccination rates (&lt;40%). However, mortality rate was 1.6 (95% CI 1.5–1.7) higher in these low-vaccinated areas compared to areas with vaccination rates higher than 60%. As a result, areas with low vaccination rate had a 2.2 (95% CI 2.1–2.2) times higher case-fatality ratio. Geospatial clustering analysis showed a more defined spatial structure during the Delta wave with clusters with low vaccination rates and high incidence and mortality located in southern states.ConclusionsDespite the emergence of new virus variants with differential transmission potential, the protective effect of vaccines keeps generating marked differences in the distribution of critical health outcomes, with low vaccinated areas having the largest COVID-19 related mortality during the Delta and Omicron waves in the US. Vulnerable communities residing in low vaccinated areas, which are mostly rural, are suffering the highest burden of the COVID-19 pandemic during the vaccination era.
Dysbiosis of the Gut Microbiome Is Associated With Histopathology of Lung Cancer
Authors: Qin Xiong , Bi Ling , Yang Wenxiao , He Yiyun , Gu Yifeng , Yang Yong , Gong Yabin , Wang Yichao , Yan Xiaoxia , Xu Ling , Xiao Haibo , Jiao Lijing 
Published: June 2022

Lung cancer is a malignancy with high incidence and mortality worldwide. Previous studies have shown that the gut microbiome plays an important role in the development and progression of metabolic cancers. However, data on the characteristics of the gut microbiome with different histopathology types of lung cancer remain scant. We collected stool samples from 28 healthy people (HP) and 61 lung cancer patients. The lung cancer patients were classified into three types according to their histopathology: Atypical Adenomatous Hyperplasia/Adenocarcinoma in situ (AAH/AIS), Minimally Invasive Adenocarcinoma (MIA), and Invasive Adenocarcinoma (IA). In addition, we employed 16S rRNA gene amplicon sequencing to analyze the characteristics of the gut microbiome in these patients. Our analysis revealed that the categorized cancer patients had unique intestinal flora characteristics, and had lower density and flora diversity compared to healthy people. Besides, the structure of the flora families and genera was more complex, and each group presented specific pathogenic microbiota. The patients in the AAH/AIS group and HP group had relatively similar flora structure compared with the IA and MIA groups. In addition, we identified several flora markers that showed significant changes with the development of lung cancer. Lung cancer gut microbiota showed a decrease in short-chain fatty acids (SCFAs) producing and anti-inflammatory bacteria compared to healthy people, while some pathogenic bacteria such as proinflammatory or tumor-promoting bacteria were more abundant in lung cancer patients. On the other hand, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Clusters of Orthologous Group (COG) annotation demonstrated suppression of some dominant metabolism-related pathways in lung cancer. These findings provide new biomarkers for the diagnosis and prognostic assessment of lung cancer and lay the basis for novel targeted therapeutic strategies for the prevention and treatment of lung cancer.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [NCT03244605].