bluuebunny/crossref_metadata_2025_split huggingface dataset:
MTHFR Gene Polymorphism Association With Psoriatic Arthritis Risk and the Efficacy and Hepatotoxicity of Methotrexate in Psoriasis
Authors: Zhu Jie , Wang Zhicheng , Tao Lu , Han Ling , Huang Qiong , Fang Xu , Yang Ke , Huang Guiqin , Zheng Zhizhong , Yawalkar Nikhil , Zhang Zhenghua , Yan Kexiang 
Published: April 2022

AimsTo assess whether MTHFR rs1801131 and rs1801133 SNPs are associated with concomitant psoriatic arthritis (PsA) and investigate the efficacy and hepatotoxicity of MTX in patients with psoriasis in the Han Chinese population.MethodsThis prospective, single-arm, interventional study recruited a total of 309 patients with psoriasis, 163 with psoriatic arthritis and 146 without psoriatic arthritis, who completed a 12-week MTX treatment and 1,031 healthy controls. Patients' characteristics including age, gender, disease duration, height, weight, smoking status, alcohol consumption, medical history, disease severity and liver function test results were accessed and recorded. Single nucleotide polymorphism (SNP) genotyping of rs1801131 and rs1801133 in the MTHFR gene was performed.ResultsThe rs1801133 CC genotype was more frequent in patients with PsA than those with PsO and healthy controls (42.3% vs. 28.8% vs. 33.1%, p &lt; 0.05). The 90% reduction from baseline PASI score (PASI 90) response rates to MTX were significantly higher in patients with the rs1801133 TT genotype than those with the CT and CC genotype (33.96% vs. 19.31% vs. 14.41%, OR = 2.76, p = 0.006). The rs1801133 CT+TT genotype was more frequent in PsA patients with abnormal liver function than in those with normal liver function (p &lt; 0.05). In addition, patients with the rs1801131 CT genotype had lower PASI 75 response rates to MTX (OR = 0.49, p = 0.01), and lower risk of ALT elevation (OR = 0.46, p = 0.04).ConclusionsThis study provided some evidence for MTHFR polymorphism association with the risk of PsA and the efficacy and hepatotoxicity of the low-dose MTX in the Chinese population. Given the relatively small sample size and potentially missed diagnosis of PsA, the results from this study warrant further investigation.
A Cancer Associated Fibroblasts-Related Six-Gene Panel for Anti-PD-1 Therapy in Melanoma Driven by Weighted Correlation Network Analysis and Supervised Machine Learning
Authors: Tian Luyao , Long Fei , Hao Youjin , Li Bo , Li Yinghong , Tang Ying , Li Jing , Zhao Qi , Chen Juan , Liu Mingwei 
Published: April 2022

BackgroundMelanoma is a highly aggressive skin cancer with a poor prognosis and mortality. Immune checkpoint blockade (ICB) therapy (e.g., anti-PD-1 therapy) has opened a new horizon in melanoma treatment, but some patients present a non-responsive state. Cancer-associated fibroblasts (CAFs) make up the majority of stromal cells in the tumor microenvironment (TME) and have an important impact on the response to immunotherapy. There is still a lack of identification of CAFs-related predictors for anti-PD-1 therapy, although the establishment of immunotherapy biomarkers is well underway. This study aims to explore the potential CAFs-related gene panel for predicting the response to anti-PD-1 therapy in melanoma patients and elucidating their potential effect on TME.MethodsThree gene expression datasets from melanoma patients without anti-PD-1 treatment, in a total of 87 samples, were downloaded from Gene Expression Omnibus (GEO) as the discovery sets (GSE91061) and validation sets (GSE78220 and GSE122220). The CAFs-related module genes were identified from the discovery sets by weighted gene co-expression network analysis (WGCNA). Concurrently, we utilized differential gene analysis on the discovery set to obtain differentially expressed genes (DEGs). Then, CAFs-related key genes were screened with the intersection of CAFs-related module genes and DEGs, succeeded by supervised machine learning-based identification. As a consequence of expression analysis, gene set enrichment analysis, survival analysis, staging analysis, TME analysis, and correlation analysis, the multidimensional systematic characterizations of the key genes were uncovered. The diagnostic performance of the CAFs-related gene panel was assessed by receiver operating characteristic (ROC) curves in the validation sets. Eventually, the CAFs-related gene panel was verified by the expression from the single-cell analysis.ResultsThe six-gene panel associated with CAFs were finally identified for predicting the response to anti-PD-1 therapy, including CDK14, SYNPO2, TCF4, GJA1, CPXM1, and TFPI. The multigene panel demonstrated excellent combined diagnostic performance with the area under the curve of ROC reaching 90.5 and 75.4% ~100% in the discovery and validation sets, respectively.ConclusionConfirmed by clinical treatment outcomes, the identified CAFs-related genes can be used as a promising biomarker panel for prediction to anti-PD-1 therapy response, which may serve as new immunotherapeutic targets to improve survival outcomes of melanoma patients.
From the PnTx2-6 Toxin to the PnPP-19 Engineered Peptide: Therapeutic Potential in Erectile Dysfunction, Nociception, and Glaucoma
Authors: Silva Carolina Nunes da , Nunes Kenia Pedrosa , Dourado Lays Fernanda Nunes , Vieira Thayllon Oliveira , Mariano Xavier Maia , Cunha Junior Armando da Silva , de Lima Maria Elena 
Published: April 2022

The venom of the “armed” spider Phoneutria nigriventer comprises several potent toxins. One of the most toxic components from this venom is the neurotoxin PnTx2-6 (LD50 = ∼ 0.7 μg/mouse, 48 residues, five disulfide bridges, MW = 5,289.31 Da), which slows down the inactivation of various Na+ channels. In mice and rats, this toxin causes priapism, an involuntary and painful erection, similar to what is observed in humans bitten by P. nigriventer. While not completely elucidated, it is clear that PnTx2-6 potentiates erectile function via NO/cGMP signaling, but it has many off-target effects. Seeking to obtain a simpler and less toxic molecule able to retain the pharmacological properties of this toxin, we designed and synthesized the peptide PnPP-19 (19 residues, MW = 2,485.6 Da), representing a discontinuous epitope of PnTx2-6. This synthetic peptide also potentiates erectile function via NO/cGMP, but it does not target Na+ channels, and therefore, it displays nontoxic properties in animals even at high doses. PnPP-19 effectively potentiates erectile function not only after subcutaneous or intravenous administration but also following topical application. Surprisingly, PnPP-19 showed central and peripheral antinociceptive activity involving the opioid and cannabinoid systems, suggesting applicability in nociception. Furthermore, considering that PnPP-19 increases NO availability in the corpus cavernosum, this peptide was also tested in a model of induced intraocular hypertension, characterized by low NO levels, and it showed promising results by decreasing the intraocular pressure which prevents retinal damage. Herein, we discuss how was engineered this smaller active non-toxic peptide with promising results in the treatment of erectile dysfunction, nociception, and glaucoma from the noxious PnTx2-6, as well as the pitfalls of this ongoing journey.
Paternal High-Fat Diet Altered Sperm 5'tsRNA-Gly-GCC Is Associated With Enhanced Gluconeogenesis in the Offspring
Authors: Wang Bin , Xia Lin , Zhu Dan , Zeng Hongtao , Wei Bin , Lu Likui , Li Weisheng , Shi Yajun , Liu Jingliu , Zhang Yunfang , Sun Miao 
Published: April 2022

Background: Paternal lifestyle, stress and environmental exposures play a crucial role in the health of offspring and are associated with non-genetic inheritance of acquired traits, however the underlying mechanisms are unclear. In this study, we aimed to find out how the sperm tsRNA involved in paternal high-fat diet induced abnormal gluconeogenesis of F1 offspring, and explore the underlying molecular mechanism of its regulation.Method: We generated a paternal high fat diet (42% kcal fat) model to investigate the mechanism by which paternal diet affects offspring metabolism. Four-week-old C57BL/6J male mice were randomly assigned into two groups to receive either a control diet (CD; 10% kcal fat) or a high-fat (HFD; 42% kcal fat) diet for 10 weeks, and mice from each group were then mated with 8-week-old females with control diet in a 1:2 ratio to generate F1. F0 sperms were isolated and small RNAs was sequenced by high-throughput sequencing. Metabolic phenotypes were examined with both F0 and F1.Results: A significant increase in body weight was observed with HFD-F0 mice at 8 weeks of age as compared to CD mice at the same age. F0 mice showed impaired glucose tolerance (GTT), resistance to insulin tolerance (ITT) and increased pyruvate tolerance (PTT) at 14 weeks. HFD-F1 male mice showed no significant difference in body weight. An increase in PTT was found at 13 weeks of age and no significant changes in GTT and ITT. PEPCK and G6Pase that related to gluconeogenesis increased significantly in the liver of HFD-F1 male mice. Sperm sequencing results showed that 5′tsRNA-Gly-GCC derived from tRNA-Gly-GCC-2 specifically was remarkably upregulated in sperm of HFD F0 mice. Q-PCR further showed that this tsRNA was also increased in the liver of HFD-F1 comparison with CD-F1 mice. In addition, we found that 5′tsRNA-Gly-GCC can regulate Sirt6-FoxO1 pathway and be involved in the gluconeogenesis pathway in liver.Conclusion: 5′tsRNA-Gly-GCC that increased in HFD mice mature sperms can promote gluconeogenesis in liver by regulating Sirt6-FoxO1 pathway, which might represent a potential paternal epigenetic factor mediating the intergenerational inheritance of diet-induced metabolic alteration.
Total Cerebral Small Vessel Disease Score and Cerebral Bleeding Risk in Patients With Acute Stroke Treated With Intravenous Thrombolysis
Authors: Du Houwei , Wu Sangru , Lei Hanhan , Ambler Gareth , Werring David J. , Li Hangfeng , Chen Yangui , Chen Dongping , Yuan Qilin , Fang Shuangfang , Chen Ronghua , Zhang Yixian , Wei Jin , Chen Guangliang , Chen Jianhua , Liu Nan 
Published: April 2022

ObjectiveThe aim of this study was to investigate the association of total cerebral small vessel disease (cSVD) score with the risk of intracerebral hemorrhage (ICH) in patients with acute ischemic stroke who received intravenous thrombolysis (IVT) using recombinant tissue-plasminogen activator (rt-PA).MethodsWe retrospectively reviewed clinical data from two stroke registries of patients with acute ischemic stroke treated with IVT. We assessed the baseline magnetic resonance (MR) visible cSVD markers and total cSVD score (ranging from 0 to 4) between patients with and without ICH after IVT. Logistic regression analysis was used to determine the association of total cSVD score with the risk of ICH after IVT, adjusted for cofounders selected by least absolute shrinkage and selection operator (LASSO). We additionally performed an E-value analysis to fully explain away a specific exposure-outcome association. Receiver operating characteristic (ROC) curve analysis was used to quantify the predictive potential of the total cSVD score for any ICH after IVT.ResultsAmong 271 eligible patients, 55 (20.3%) patients experienced any ICH, 16 (5.9%) patients experienced a symptomatic ICH (sICH), and 5 (1.85%) patients had remote intracranial parenchymal hemorrhage (rPH). Logistic regression analysis showed that the risk of any ICH increased with increasing cSVD score [per unit increase, adjusted odds ratio (OR) 2.03, 95% CI 1.22–3.41, P = 0.007]. Sensitivity analyses using E-value revealed that it would need moderately robust unobserved confounding to render the exposure-outcome (cSVD-any ICH) association null. ROC analysis showed that compared with the National Institutes of Health Stroke Scale (NIHSS) score alone, a combination of cSVD and NIHSS score had a larger area under the curve for any ICH (0.811, 95% CI 0.756–0.866 vs. 0.784, 95% CI 0.723–0.846, P = 0.0004).ConclusionThe total cSVD score is associated with an increased risk of any ICH after IVT and improves prediction for any ICH compared with NIHSS alone.
The Top-Cited Original Articles on the Role of Microglia in Neurodegenerative Diseases: A Bibliometric and Visualized Study
Authors: Sun Mengjiao , Li Xiaoling , Sun Jing , Wang Hongxia , Xie Qinfang , Wang Manxia 
Published: April 2022

BackgroundMicroglia participants to neuronal loss during brain development, inflammation, ischemia, and neurodegeneration. This bibliometric and visualized study aimed to confirm the top 100 cited original research in the field and to analyze their characteristics.MethodsThe Web of Science database (WOS) was retrieved using the specific search strategy. The top 100 cited original articles that focused on the role of microglia in neurodegenerative diseases (NDs) were filtered by two researchers independently. The trend of yearly publications and citations, citation densities, languages, and global contributions were analyzed. The highly cited countries, authors, institutions, and journals were visualized by bibliographic coupling analysis. The highly cited authors and journals in the references were visualized by co-citation analysis. The research hotspots were revealed by co-occurrence analysis and burst detection of author keywords.ResultsThe top 100 cited articles were published during the period 1988 to 2019. The peak of publication occurred in 2005 and 2006. The yearly total citations presented a rising trend. The highly cited articles were contributed by 26 countries, the United States was the country with the overwhelming number of publications and cited times. Stevens, Beth was the author with the largest number of cited times. Mcgeer PL was the author most frequently cited in the references. Harvard University was the institution with the greatest number of cited times and publications. Nature was the journal with the largest number of cited times. Journal of neuroscience was both the most often published and most frequently cited journal in the references. “Microglia”, “inflammation”, “Alzheimer’s disease” were the most frequently used keywords, and their average occurred time was around 2005. “Dementia,” “delirium,” “priming” were keywords that averagely occurred around 2010. The burst detection revealed that “TNF-beta,” “macrophage,” and “inflammation” were keywords that frequently burst in recent years.ConclusionThis bibliometric and visualized study revealed the top 100 cited original research that discussed the role of microglia in NDs. The United States was the biggest contributor, Harford University was the most influential institution. Journal of Neuroscience was the most often published and cited journal. Alzheimer’s disease was the hotspot in microglia and NDs. Recent research mainly focused on inflammation.
Endoscopic Endonasal Transsphenoidal Surgery for Recurrent Craniopharyngiomas
Authors: Feng Zhenguang , Li Chuzhong , Cao Lei , Qiao Ning , Wu Wentao , Bai Jiwei , Zhao Peng , Gui Songbai 
Published: April 2022

ObjectAlthough revision surgery for recurrent craniopharyngiomas is more challenging than primary surgery and often accompanies a higher risk of death and complications, endoscopic endonasal transsphenoidal surgery (EETS) is sometimes still an effective and reliable treatment option. In this study, we introduced the surgical outcomes of EETS for recurrent craniopharyngiomas and summarized the surgical experiences.MethodsBetween 2014 and 2018, 28 patients with recurrent craniopharyngiomas underwent 29 EETS in our department. We regarded the patient undergoing two EETS as two independent patients in statistical analysis. Of the 29 patients, 16 had undergone 1 previous surgery, 10 had undergone 2 previous surgeries, and the remaining 3 patients had undergone 3 surgeries. The extent of resection, visual and endocrine outcomes, and complications of all the patients were collected and analyzed.ResultsGross total resection was accomplished in 16 patients (55.17%), subtotal resection in 11 patients (37.93%), and partial resection in 2 patients (6.9%). Among the 22 patients with preoperative visual acuity and visual field impairment, some degree of vision improvement was observed in 18 patients, 3 patients were without visual change, and perpetual deterioration of vision occurred in one patient. The remaining six patients had normal vision before and after surgery. Postoperative endocrine tests showed that, among five patients with normal preoperative pituitary hormone function, only one patient still had normal pituitary hormone function and the other four patients had one or more hypothalamic-pituitary axes involved. None of the patients with preoperative endocrine dysfunction had endocrine function improved. Diabetes insipidus was observed in six new cases postoperatively. Cerebrospinal fluid (CSF) leakage occurred in 1 patient. One patient had bacterial meningitis, which was cured with antibiotics and a lumbar drain. No serious morbidity and mortality occurred in all patients.ConclusionsFor recurrent craniopharyngiomas, a personalized treatment plan should be developed according to the tumor characteristics and the patient's situation. There is no omnipotent method to be used for all patients. The EETS still is a safe and effective way to treat recurrent craniopharyngiomas in appropriate patients.
hsa-miR-518-5p/hsa-miR-3135b Regulates the REL/SOD2 Pathway in Ischemic Cerebral Infarction
Authors: Zhao Boyan , Jiang Xiaofan 
Published: April 2022

ObjectivesIschemic cerebral infarction (ICI) is a fatal neurovascular disorder. A bioinformatics approach based on single-cell and bulk RNA-seq analyses was applied to investigate the pathways and genes involved in ICI and study the expression profile of these genes.MethodsFirst, the aberrantly regulated “small-molecule ribonucleic acids” [microRNA (miRNAs)] and messenger RNAs (mRNAs) were analyzed using transcriptome data from the ischemic brain infarction dataset of the Gene Expression Omnibus (GEO) database. In mouse cerebrovascular monocytes, the single-cell regulatory network inference and clustering (SCENIC) workflow was used to identify key transcription factors (TFs). Then, the two miRNA-TF-mRNA interaction networks were constructed. Moreover, the molecular complex detection (MCODE) extracted the core sub-networks and identified the important TFs within these sub-networks. Finally, whole blood samples were collected for validation of the expression of critical molecules in ICI.ResultsWe identified four cell types and 266 regulons in mouse cerebrovascular monocytes using SCENIC analysis. Moreover, 112 differently expressed miRNAs and 3,780 differentially expressed mRNAs were identified. We discovered potential biomarkers in ICI by building a miRNA-TF-mRNA interaction network. The hsa-miR-518-5p/hsa-miR-3135b/REL/SOD2 was found to play a potential role in ICI progression. The expression of REL and superoxide dismutase 2 (SOD2) was significantly elevated in the ICI group in the clinical cohort (P &lt; 0.05). Furthermore, a REL expression was elevated in endothelial cells and fibroblasts at the single-cell level, indicating that REL is a cell-specific regulon. Functional enrichment analyses revealed that REL is primarily engaged in neurotransmitter activity and oxidative phosphorylation.ConclusionsOur research uncovered novel biomarkers for ICI of neurovascular disease. The hsa-miR-518-5p/hsa-miR-3135b may regulate the REL/SOD2 pathway in ICI progression.
Construction and Evaluation of Multiple Radiomics Models for Identifying the Instability of Intracranial Aneurysms Based on CTA
Authors: Li Ran , Zhou Pengyu , Chen Xinyue , Mossa-Basha Mahmud , Zhu Chengcheng , Wang Yuting 
Published: April 2022

Background and AimsIdentifying unruptured intracranial aneurysm instability is crucial for therapeutic decision-making. This study aims to evaluate the role of Radiomics and traditional morphological features in identifying aneurysm instability by constructing and comparing multiple models.Materials and MethodsA total of 227 patients with 254 intracranial aneurysms evaluated by CTA were included. Aneurysms were divided into unstable and stable groups using comprehensive criteria: the unstable group was defined as aneurysms with near-term rupture, growth during follow-up, or caused compressive symptoms; those without the aforementioned conditions were grouped as stable aneurysms. Aneurysms were randomly divided into training and test sets at a 1:1 ratio. Radiomics and traditional morphological features (maximum diameter, irregular shape, aspect ratio, size ratio, location, etc.) were extracted. Three basic models and two integrated models were constructed after corresponding statistical analysis. Model A used traditional morphological parameters. Model B used Radiomics features. Model C used the Radiomics features related to aneurysm morphology. Furthermore, integrated models of traditional and Radiomics features were built (model A+B, model A+C). The area under curves (AUC) of each model was calculated and compared.ResultsThere were 31 (13.7%) patients harboring 36 (14.2%) unstable aneurysms, 15 of which ruptured post-imaging, 16 with growth on serial imaging, and 5 with compressive symptoms, respectively. Four traditional morphological features, six Radiomics features, and three Radiomics-derived morphological features were identified. The classification of aneurysm stability was as follows: the AUC of the training set and test set in models A, B, and C are 0.888 (95% CI 0.808–0.967) and 0.818 (95% CI 0.705–0.932), 0.865 (95% CI 0.777–0.952) and 0.739 (95% CI 0.636–0.841), 0.605(95% CI 0.470–0.740) and 0.552 (95% CI 0.401–0.703), respectively. The AUC of integrated Model A+B was numerically slightly higher than any single model, whereas Model A+C was not.ConclusionsA radiomics and traditional morphology integrated model seems to be an effective tool for identifying intracranial aneurysm instability, whereas the use of Radiomics-derived morphological features alone is not recommended. Radiomics-based models were not superior to the traditional morphological features model.