bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Tissue-Specific Expressed Hub Genes and Potential Drugs in Rheumatoid Arthritis Using Bioinformatics Analysis
Authors: Xing Xuewu , Xia Qun , Gong Baoqi , Shen Zhongyang , Zhang Yingze 
Published: March 2022

Background: Rheumatoid arthritis (RA) is a common autoimmune disease characterized by progressive, destructive polyarthritis. However, the cause and underlying molecular events of RA are not clear. Here, we applied integrated bioinformatics to identify tissue-specific expressed hub genes involved in RA and reveal potential targeted drugs.Methods: Three expression profiles of human microarray datasets involving fibroblast-like synoviocytes (FLS) were downloaded from the Gene Expression Omnibus (GEO) database, the differentially expressed mRNAs (DEGs), miRNAs (DEMs), and lncRNAs (DELs) between normal and RA synovial samples were screened using GEO2R tool. BioGPS was used to identified tissue-specific expressed genes. Functional and pathway enrichment analyses were performed for common DEGs using the DAVID database, and the protein-protein interaction (PPI) network of common DEGs was constructed to recognize hub genes by the STRING database. Based on receiver operating characteristic (ROC) curve, we further investigated the prognostic values of tissue-specific expressed hub genes in RA patients. Connectivity Map (CMap) was run to identify novel anti-RA potential drugs. The DEM–DEG pairs and ceRNA network containing key DEMs were established by Cytoscape.Results: We obtain a total of 418 DEGs, 23 DEMs and 49 DELs. 64 DEGs were verified as tissue-specific expressed genes, most derive from the hematologic/immune system (20/64, 31.25%). GO term and KEGG pathway enrichment analysis showed that DEGs focused primarily on immune-related biological process and NF-κB pathway. 10 hub genes were generated via using MCODE plugin. Among them, SPAG5, CUX2, and THEMIS2 were identified as tissue-specific expressed hub genes, these 3 tissue-specific expressed hub genes have superior diagnostic value in the RA samples compared with osteoarthritis (OA) samples. 5 compounds (troleandomycin, levodopa, trichostatin A, LY-294002, and levamisole) rank among the top five in connectivity score. In addition, 5 miRNAs were identified to be key DEMs, the lncRNA–miRNA–mRNA network with five key DEMs was formed. The networks containing tissue-specific expressed hub genes are as follows: ARAP1-AS2/miR-20b-3p/TRIM3, ARAP1-AS2/miR-30c-3p/FRZB.Conclusion: This study indicates that screening for identify tissue-specific expressed hub genes and ceRNA network in RA using integrated bioinformatics analyses could help us understand the mechanism of development of RA. Besides, SPAG5 and THEMIS2 might be candidate biomarkers for diagnosis of RA. LY-294002, trichostatin A, and troleandomycin may be potential drugs for RA.
MMPs Regulate Neuronal Substance P After a Painful Equibiaxial Stretch in a Co-Culture Collagen Gel Model Simulating Injury of an Innervated Ligament
Authors: Ita Meagan E. , Winkelstein Beth A. 
Published: March 2022

Chronic joint pain is a major health problem that can result from abnormal loading of the innervated ligamentous capsule that surrounds synovial joints. The matrix metalloproteinases-1 (MMP-1) and MMP-9 are hypothesized pain mediators from stretch-induced injuries since they increase in pathologic joint tissues and are implicated in biomechanical and nociceptive pathways that underlay painful joint injuries. There is also emerging evidence that MMP-1 and MMP-9 have mechanistic interactions with the nociceptive neuropeptide substance P. Yet, how a ligament stretch induces painful responses during sub-failure loading and whether MMP-1 or MMP-9 modulates nociception via substance P are unknown. We used a neuron–fibroblast co-culture collagen gel model of the capsular ligament to test whether a sub-failure equibiaxial stretch above the magnitude for initiating nociceptive responses in neurons also regulates MMP-1 and MMP-9. Pre-stretch treatment with the MMP inhibitor ilomastat also tested whether inhibiting MMPs attenuates the stretch-induced nociceptive responses. Because of the role of MMPs in collagen remodeling, collagen microstructural kinematics were measured in all tests. Co-culture gels were incubated for one week in either normal conditions, with five days of ilomastat treatment, or with five days of a vehicle control solution before a planar equibiaxial stretch that imposed strains at magnitudes that induce pain in vivo and increase nociceptive modulators in vitro. Force, displacement, and strain were measured, and polarized light imaging captured collagen fiber kinematics during loading. At 24 h after stretch, immunolabeling quantified substance P, MMP-1, and MMP-9 protein expression. The same sub-failure equibiaxial stretch was imposed on all co-cultures, inducing a significant re-organization of collagen fibers (p ≤ 0.031) indicative of fiber realignment. Stretch induces a doubling of substance P expression in normal and vehicle-treated co-cultures (p = 0.038) that is prevented with ilomastat treatment (p = 0.114). Although MMP-1 and MMP-9 expression are unaffected by the stretch in all co-culture groups, ilomastat treatment abolishes the correlative relationships between MMP-1 and substance P (p = 0.002; R2 = 0.13) and between MMP-1 and MMP-9 (p = 0.007; R2 = 0.11) that are detected without an inhibitor. Collectively, these findings implicate MMPs in a painful ligamentous injury and contribute to a growing body of work linking MMPs to nociceptive-related signaling pathways and/or pain.
Differentiation Between Malignant and Benign Pulmonary Nodules by Using Automated Three-Dimensional High-Resolution Representation Learning With Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography
Authors: Lai Yung-Chi , Wu Kuo-Chen , Tseng Neng-Chuan , Chen Yi-Jin , Chang Chao-Jen , Yen Kuo-Yang , Kao Chia-Hung 
Published: March 2022

BackgroundThe investigation of incidental pulmonary nodules has rapidly become one of the main indications for 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), currently combined with computed tomography (PET-CT). There is also a growing trend to use artificial Intelligence for optimization and interpretation of PET-CT Images. Therefore, we proposed a novel deep learning model that aided in the automatic differentiation between malignant and benign pulmonary nodules on FDG PET-CT.MethodsIn total, 112 participants with pulmonary nodules who underwent FDG PET-CT before surgery were enrolled retrospectively. We designed a novel deep learning three-dimensional (3D) high-resolution representation learning (HRRL) model for the automated classification of pulmonary nodules based on FDG PET-CT images without manual annotation by experts. For the images to be localized more precisely, we defined the territories of the lungs through a novel artificial intelligence-driven image-processing algorithm, instead of the conventional segmentation method, without the aid of an expert; this algorithm is based on deep HRRL, which is used to perform high-resolution classification. In addition, the 2D model was converted to a 3D model.ResultsAll pulmonary lesions were confirmed through pathological studies (79 malignant and 33 benign). We evaluated its diagnostic performance in the differentiation of malignant and benign nodules. The area under the receiver operating characteristic curve (AUC) of the deep learning model was used to indicate classification performance in an evaluation using fivefold cross-validation. The nodule-based prediction performance of the model had an AUC, sensitivity, specificity, and accuracy of 78.1, 89.9, 54.5, and 79.4%, respectively.ConclusionOur results suggest that a deep learning algorithm using HRRL without manual annotation from experts might aid in the classification of pulmonary nodules discovered through clinical FDG PET-CT images.
Relationship Between C-Reactive Protein/Serum Albumin Ratio, Neutrophil/Lymphocyte Ratio, and ANCA-Associated Vasculitis Activity: A Retrospective Single Center Cohort Study
Authors: Tian Yao , Liu Na , Yin Hui , Duan Lihua 
Published: March 2022

ObjectivesTo evaluate the role of C-reactive protein/albumin ratio (CAR), neutrophil/lymphocyte ratio (NLR), and mean platelet volume (MPV) in newly diagnosed AAV patients and examine their clinical significance.MethodsData from 79 untreated newly diagnosed AAV patients were collected and 76 health examination subjects were included in the healthy control group. All clinical characteristics of AAV patients were extracted from their medical records. The NLR, CAR, and MPV levels of AAV patients and the healthy controls were compared and the correlation between these markers and clinical characteristics was analyzed. Patients were then divided into two groups based on the 2003 Birmingham Vasculitis Activity Score (BVAS). The correlation between NLR, CAR, and MPV and disease activity was analyzed and their effects on the cumulative survival rate were analyzed.ResultsCompared with the healthy control group, elevated CAR, NLR, and MPV were observed in AAV patients. CAR (r = 0.701, P &lt; 0.0001) and NLR (r = 0.369, P &lt; 0.05) were positively correlated with the BVAS while MPV did not show any significant correlation (P = 0.85). The optimal cutoff value for disease activity evaluation using CAR was 0.80 (sensitivity: 85% and specificity: 82%, P &lt; 0.05). The optimal cutoff value for disease activity evaluation using NLR was 5.15 (sensitivity: 66% and specificity: 72%, P &lt; 0.05). Kaplan–Meier survival analysis revealed that the all-cause mortality rate was higher in patients with CAR ≥ 0.8 than in patients with CAR &lt; 0.8 (P &lt; 0.05). Patients with low NLR also showed a lower cumulative survival rate (P &lt; 0.05).ConclusionsNLR and CAR can reflect the inflammatory response and disease activity in AAV patients, while MPV is not significantly correlated with disease activity in AAV patients. The all-cause mortality rate was higher in patients with high CAR and NLR than in patients with low CAR and NLR.
Phase 1 Clinical Trial Evaluating the Safety and Anti-Tumor Activity of ADP-A2M10 SPEAR T-Cells in Patients With MAGE-A10+ Head and Neck, Melanoma, or Urothelial Tumors
Authors: Hong David S. , Butler Marcus O. , Pachynski Russell K. , Sullivan Ryan , Kebriaei Partow , Boross-Harmer Sarah , Ghobadi Armin , Frigault Matthew J. , Dumbrava Ecaterina E. , Sauer Amy , Brophy Francine , Navenot Jean-Marc , Fayngerts Svetlana , Wolchinsky Zohar , Broad Robyn , Batrakou Dzmitry G. , Wang Ruoxi , Solis Luisa M. , Duose Dzifa Yawa , Sanderson Joseph P. , Gerry Andrew B. , Marks Diane , Bai Jane , Norry Elliot , Fracasso Paula M. 
Published: March 2022

BackgroundADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T-cells are genetically engineered autologous T-cells that express a high-affinity melanoma-associated antigen (MAGE)-A10-specific T-cell receptor (TCR) targeting MAGE-A10-positive tumors in the context of human leukocyte antigen (HLA)-A*02. ADP-0022-004 is a phase 1, dose-escalation trial to evaluate the safety and anti-tumor activity of ADP-A2M10 in three malignancies (https://clinicaltrials.gov: NCT02989064).MethodsEligible patients were HLA-A*02 positive with advanced head and neck squamous cell carcinoma (HNSCC), melanoma, or urothelial carcinoma (UC) expressing MAGE-A10. Patients underwent apheresis; T-cells were isolated, transduced with a lentiviral vector containing the MAGE-A10 TCR, and expanded. Patients underwent lymphodepletion with fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 was administered in two dose groups receiving 0.1×109 and &gt;1.2 to 6×109 transduced cells, respectively, and an expansion group receiving 1.2 to 15×109 transduced cells.ResultsTen patients (eight male and two female) with HNSCC (four), melanoma (three), and UC (three) were treated. Three patients were treated in each of the two dose groups, and four patients were treated in the expansion group. The most frequently reported adverse events grade ≥3 were leukopenia (10), lymphopenia (10), neutropenia (10), anemia (nine), and thrombocytopenia (five). Two patients reported cytokine release syndrome (one each with grade 1 and grade 3), with resolution. Best response included stable disease in four patients, progressive disease in five patients, and not evaluable in one patient. ADP-A2M10 cells were detectable in peripheral blood from patients in each dose group and the expansion group and in tumor tissues from patients in the higher dose group and the expansion group. Peak persistence was greater in patients from the higher dose group and the expansion group compared with the lower dose group.ConclusionsADP-A2M10 has shown an acceptable safety profile with no evidence of toxicity related to off-target binding or alloreactivity in these malignancies. Persistence of ADP-A2M10 in the peripheral blood and trafficking of ADP-A2M10 into the tumor was demonstrated. Because MAGE-A10 expression frequently overlaps with MAGE-A4 expression in tumors and responses were observed in the MAGE-A4 trial (NCT03132922), this clinical program closed, and trials with SPEAR T-cells targeting the MAGE-A4 antigen are ongoing.
Multiscale Local Enhancement Deep Convolutional Networks for the Automated 3D Segmentation of Gross Tumor Volumes in Nasopharyngeal Carcinoma: A Multi-Institutional Dataset Study
Authors: Yang Geng , Dai Zhenhui , Zhang Yiwen , Zhu Lin , Tan Junwen , Chen Zefeiyun , Zhang Bailin , Cai Chunya , He Qiang , Li Fei , Wang Xuetao , Yang Wei 
Published: March 2022

PurposeAccurate segmentation of gross target volume (GTV) from computed tomography (CT) images is a prerequisite in radiotherapy for nasopharyngeal carcinoma (NPC). However, this task is very challenging due to the low contrast at the boundary of the tumor and the great variety of sizes and morphologies of tumors between different stages. Meanwhile, the data source also seriously affect the results of segmentation. In this paper, we propose a novel three-dimensional (3D) automatic segmentation algorithm that adopts cascaded multiscale local enhancement of convolutional neural networks (CNNs) and conduct experiments on multi-institutional datasets to address the above problems.Materials and MethodsIn this study, we retrospectively collected CT images of 257 NPC patients to test the performance of the proposed automatic segmentation model, and conducted experiments on two additional multi-institutional datasets. Our novel segmentation framework consists of three parts. First, the segmentation framework is based on a 3D Res-UNet backbone model that has excellent segmentation performance. Then, we adopt a multiscale dilated convolution block to enhance the receptive field and focus on the target area and boundary for segmentation improvement. Finally, a central localization cascade model for local enhancement is designed to concentrate on the GTV region for fine segmentation to improve the robustness. The Dice similarity coefficient (DSC), positive predictive value (PPV), sensitivity (SEN), average symmetric surface distance (ASSD) and 95% Hausdorff distance (HD95) are utilized as qualitative evaluation criteria to estimate the performance of our automated segmentation algorithm.ResultsThe experimental results show that compared with other state-of-the-art methods, our modified version 3D Res-UNet backbone has excellent performance and achieves the best results in terms of the quantitative metrics DSC, PPR, ASSD and HD95, which reached 74.49 ± 7.81%, 79.97 ± 13.90%, 1.49 ± 0.65 mm and 5.06 ± 3.30 mm, respectively. It should be noted that the receptive field enhancement mechanism and cascade architecture can have a great impact on the stable output of automatic segmentation results with high accuracy, which is critical for an algorithm. The final DSC, SEN, ASSD and HD95 values can be increased to 76.23 ± 6.45%, 79.14 ± 12.48%, 1.39 ± 5.44mm, 4.72 ± 3.04mm. In addition, the outcomes of multi-institution experiments demonstrate that our model is robust and generalizable and can achieve good performance through transfer learning.ConclusionsThe proposed algorithm could accurately segment NPC in CT images from multi-institutional datasets and thereby may improve and facilitate clinical applications.
Prognostic Implication of Patient Age in H3K27M-Mutant Midline Gliomas
Authors: Vuong Huy Gia , Ngo Tam N. M. , Le Hieu Trong , Jea Andrew , Hrachova Maya , Battiste James , McNall-Knapp Rene , Dunn Ian F. 
Published: March 2022

IntroductionPediatric and adult H3K27M-mutant midline gliomas have variable clinical presentations, prognoses, and molecular backgrounds. In this study, we integrated data from published studies to investigate the differences between these two groups.MethodsPubMed and Web of Science were searched for potential data. Studies were included if they had available individual participant data on patients age of H3K27M-mutant midline gliomas. For time-to-event analyses, Kaplan-Meier analysis and Cox regression models were carried out; corresponding hazard ratios (HR) and 95% confidence intervals (CI) were computed to analyze the impact of age and clinical covariates on progression-free survival (PFS) and overall survival (OS).ResultsWe included 43 studies comprising 272 adults and 657 pediatric midline gliomas with H3K27M mutation for analyses. In adults, there was a male predilection whereas females were slightly more common than males in the pediatric group. Spinal cord tumors were more frequent in adults. The prevalence of H3.1 K27M mutation was significantly higher in the pediatric cohort. Compared to adult patients, pediatric H3K27M-mutant midline gliomas exhibited more aggressive features including higher rates of pathologic features of high-grade tumors and Ki67 proliferation index, and had a shorter PFS and OS. Genetically, ACVR1 mutations were more common whereas MGMT methylation, FGFR1, and NF1 mutations were less prevalent in the pediatric cohort.ConclusionPediatric H3K27M-mutant midline gliomas were demographically, clinically, and molecularly distinct from adult patients, highlighting an opportunity to refine the risk stratification for these neoplasms.
Determinants for Perinatal Mortality in South China: A Prospective Cohort Study
Authors: Liu Yiping , Li Qiongxuan , Wang Tingting , Zhang Senmao , Chen Letao , Li Yihuan , Diao Jingyi , Li Jinqi , Song Xinli , Sun Mengting , Wei Jianhui , Shu Jing , Yang Tubao , Qin Jiabi 
Published: March 2022

ObjectiveTo estimate the association of selected maternal and fetal characteristics with the risk of perinatal mortality in South China.MethodsA prospective cohort study was conducted from March 2013 to December 2019. The exposures of interest were maternal sociodemographic characteristics, lifestyle and habits during early pregnancy, and complications of pregnancy. Their effects on the development of perinatal death were analyzed in our study.ResultsA total of 44,048 eligible pregnant women were included in the analysis. Of these, 596 fetuses were perinatal deaths (perinatal mortality was 13.5 per 1,000 births). After adjustment, maternal obesity, being employed, history of gestational hypertension, taking antidepressants during early pregnancy, history of gestational diabetes mellitus, gestational diabetes mellitus, infertility drug treatment and assisted reproductive techniques, history of neonatal death, preterm birth, and congenital malformations all significantly increased the risk of perinatal death. Ethnic minority, income &gt; 5,000, multiparous women, and cesarean section associated with reduced risk of perinatal death.ConclusionSome factors of maternal sociodemographic characteristics, abnormal pregnancy history, lifestyle and habits during early pregnancy, and complications of pregnancy were associated with the risk of perinatal death.
Safety Assessment of Ultrasound-Assisted Intravesical Chemotherapy in Normal Dogs: A Pilot Study
Authors: Sasaki Noboru , Ikenaka Yoshinori , Aoshima Keisuke , Aoyagi Teiichiro , Kudo Nobuki , Nakamura Kensuke , Takiguchi Mitsuyoshi 
Published: March 2022

Intravesical chemotherapy after transurethral resection is a treatment option in patients with non-muscle invasive bladder cancer. The efficacy of intravesical chemotherapy is determined by the cellular uptake of intravesical drugs. Therefore, drug delivery technologies in the urinary bladder are promising tools for enhancing the efficacy of intravesical chemotherapy. Ultrasound-triggered microbubble cavitation may enhance the permeability of the urothelium, and thus may have potential as a drug delivery technology in the urinary bladder. Meanwhile, the enhanced permeability may increase systemic absorption of intravesical drugs, which may increase the adverse effects of the drug. The aim of this preliminary safety study was to assess the systemic absorption of an intravesical drug that was delivered by ultrasound-triggered microbubble cavitation in the urinary bladder of normal dogs. Pirarubicin, a derivative of doxorubicin, and an ultrasound contrast agent (Sonazoid) microbubbles were administered in the urinary bladder. Ultrasound (transmitting frequency 5 MHz; pulse duration 0.44 μsec; pulse repetition frequency 7.7 kHz; peak negative pressure −1.2 MPa) was exposed to the bladder using a diagnostic ultrasound probe (PLT-704SBT). The combination of ultrasound and microbubbles did not increase the plasma concentration of intravesical pirarubicin. In addition, hematoxylin and eosin staining showed that the combination of ultrasound and microbubble did not cause observable damages to the urothelium. Tissue pirarubicin concentration in the sonicated region was higher than that of the non-sonicated region in two of three dogs. The results of this pilot study demonstrate the safety of the combination of intravesical pirarubicin and ultrasound-triggered microbubble cavitation, that is, ultrasound-assisted intravesical chemotherapy.