bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systematic identification of key extracellular proteins as the potential biomarkers in lupus nephritis
Authors: Zhou Xue , Zhang Yuefeng , Wang Ning 
Published: July 2022

BackgroundLupus nephritis (LN) is the most common and severe clinical manifestation of systemic lupus erythematosus (SLE) with considerable morbidity/mortality and limited treatment options. Since kidney biopsy is a relative hysteretic indicator, it is indispensable to investigate potential biomarkers for early diagnosis and predicting clinical outcomes of LN patients. Extracellular proteins may become the promising biomarkers by the secretion into body fluid. Our study linked extracellular proteins with lupus nephritis to identify the emerging biomarkers.MethodsThe expression profiling data were acquired from the Gene Expression Omnibus (GEO) database. Meanwhile, the two gene lists encoding extracellular proteins were collected from the Human Protein Atlas (HPA) and UniProt database. Subsequently, the extracellular protein-differentially expressed genes (EP-DEGs) were screened out, and the key EP-DEGs were determined by MCODE, MCC, and Degree methods via the protein–protein interaction (PPI) network. The expression level, immune characteristics, and diagnostic value of these candidate biomarkers were investigated. Finally, the Nephroseq V5 tool was applied to evaluate the clinical significance of the key EP-DEGs.ResultsA total of 164 DEGs were acquired by comparing LN samples with healthy controls based on GSE32591 datasets. Then, 38 EP-DEGs were screened out through the intersection between DEGs and extracellular protein gene lists. Function enrichment analysis indicated that these EP-DEGs might participate in immune response and constitute the extracellular matrix. Four key EP-DEGs (LUM, TGFBI, COL1A2, and POSTN) were eventually identified as candidate biomarkers, and they were all overexpressed in LN samples. Except that LUM expression was negatively correlated with most of the immune regulatory genes, there was a positive correlation between the remaining three biomarkers and the immune regulatory genes. In addition, these biomarkers had high diagnostic value, especially the AUC value of the LUM–TGFBI combination which reached almost 1 (AUC = 0.973), demonstrating high accuracy in distinguishing LN from controls. Finally, we found a meaningful correlation of these biomarkers with sex, WHO class, and renal function such as glomerular filtration rate (GFR), serum creatinine level, and proteinuria.ConclusionIn summary, our study comprehensively identified four key EP-DEGs exerting a vital role in LN diagnosis and pathogenesis and serving as promising therapeutic targets.
Six macrophage-associated genes in synovium constitute a novel diagnostic signature for osteoarthritis
Authors: Liu Yiying , Lu Taoyuan , Liu Zaoqu , Ning Wenhua , Li Siying , Chen Yanru , Ge Xiaoyong , Guo Chunguang , Zheng Youyang , Wei Xiangyang , Wang Haiming 
Published: July 2022

BackgroundSynovial macrophages play important roles in the formation and progression of osteoarthritis (OA). This study aimed to explore the biological and clinical significance of macrophage-associated genes (MAGs) in OA.MethodsThe OA synovial gene expression profiles GSE89408 and GSE82107 were obtained from the GEO database. Single-sample gene set enrichment analysis (ssGSEA) and GSEA were employed to decipher differences in immune infiltration and macrophage-associated biological pathways, respectively. Protein–protein interaction (PPI) network analysis and machine learning were utilized to establish a macrophage-associated gene diagnostic signature (MAGDS). RT-qPCR was performed to test the expression of key MAGs in murine models.ResultsOA synovium presented high levels of immune infiltration and activation of macrophage-associated biological pathways. A total of 55 differentially expressed MAGs were identified. Using PPI analysis and machine learning, a MAGDS consisting of IL1B, C5AR1, FCGR2B, IL10, IL6, and TYROBP was established for OA diagnosis (AUC = 0.910) and molecular pathological evaluation. Patients with high MAGDS scores may possess higher levels of immune infiltration and expression of matrix metalloproteinases (MMPs), implying poor biological alterations. The diagnostic value of MAGDS was also validated in an external cohort (AUC = 0.886). The expression of key MAGs was validated in a murine model using RT-qPCR. Additionally, a competitive endogenous RNA network was constructed to reveal the potential posttranscriptional regulatory mechanisms.ConclusionsWe developed and validated a MAGDS model with the ability to accurately diagnose and characterize biological alterations in OA. The six key MAGs may also be latent targets for immunoregulatory therapy.
Glycyrrhetinic acid regulates impaired macrophage autophagic flux in the treatment of non-alcoholic fatty liver disease
Authors: Fan Yadong , Dong Wenjin , Wang Ying , Zhu Shan , Chai Rundong , Xu Zhe , Zhang Xiaoyu , Yan Yiqi , Yang Long , Bian Yuhong 
Published: July 2022

Macrophages are involved in hepatocyte steatosis and necroinflammation and play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Impaired autophagy function (decreased autophagy or blocked autophagic flow) leads to cell damage and death and promotes NAFLD progression. The experimental and clinical research of glycyrrhetinic acid (GA) in the treatment of NAFLD has gradually attracted attention with clear pharmacological activities such as immune regulation, antiviral, antitumor, antioxidant, liver protection, and anti-inflammatory. However, the effects of GA on the STAT3-HIF-1α pathway and autophagy in macrophages are still unclear, and its mechanism of action in the treatment of NAFLD remains to be further elucidated. We constructed a NAFLD mouse model through a high-fat and high-sugar diet to investigate the therapeutic effects of GA. The results showed that GA reduced weight, improved the pathological changes and hepatic lipid deposition of liver, and abnormally elevated the levels of serum biochemical (AST, ALT, TG, T-CHO, LDL-C, and HDL-C) and inflammatory indexes (IL-1β, IL-4, IL-6, MCP-1, and TNF-α) in NAFLD mice. Further examination revealed that GA ameliorates excessive hepatic macrophage infiltration and hepatocyte apoptosis. The results of the cell experiments further elaborated that GA modulated the PA-induced macrophage STAT3-HIF-1α pathway and ameliorated impaired autophagic flux (blockade of autophagosome–lysosome fusion) and overactivation of inflammation. Excessive hepatocyte apoptosis caused by the uncontrolled release of inflammatory cytokines was also suppressed by GA.ConclusionThis study demonstrated that GA could regulate the STAT3-HIF-1α pathway of macrophages, ameliorate the impaired autophagy flux, and reduce the excessive production of inflammatory cytokines to improve the excessive apoptosis of liver cells, thus playing a therapeutic role on NAFLD.
The impact of antibiotic use on clinical features and survival outcomes of cancer patients treated with immune checkpoint inhibitors
Authors: Zhou Jiaxin , Huang Guowei , Wong Wan-Ching , Hu Da-hai , Zhu Jie-wen , Li Ruiman , Zhou Hong 
Published: July 2022

BackgroundNowadays, immune checkpoint inhibitors (ICIs) have become one of the essential immunotherapies for cancer patients. However, the impact of antibiotic (ATB) use on cancer patients treated with ICIs remains controversial.MethodsOur research included retrospective studies and a randomized clinical trial (RCT) with cancer patients treated with ICIs and ATB, from the public database of PubMed, Web of Science, Embase, Cochrane, clinical trials, and JAMA. The survival outcomes included progression-free survival (PFS) and overall survival (OS). Meanwhile, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated, and subgroup analyses were performed to determine the concrete association between ATB use and the prognosis of cancer patients treated in ICIs.ResultsOur results revealed that ATB use was associated with poor survival outcomes, including OS (HR: 1.94, 95% CI: 1.68–2.25, p &lt;0.001) and PFS (HR: 1.83, 95% CI: 1.53–2.19, p &lt;0.001). The subgroup analysis learned about the association between ATB use and the prognosis of cancer patients with ICI treatment, including 5 cancer types, 3 kinds of ICI, 5 different ATP windows, broad-spectrum ATB class, and ECOG score. ATB treatment was associated with poor OS of non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), esophageal cancer (EC), and melanoma (MEL) in patients treated in ICIs, while non-small-cell lung cancer (NSCLC) and renal cell carcinoma (RCC) were associated with poor PFS. Meanwhile, it was strongly related to the ICI type and ATB window. Furthermore, it is firstly mentioned that the use of broad-spectrum ATB class was strongly associated with poor PFS.ConclusionIn conclusion, our meta-analysis indicated that ATB use was significantly associated with poor OS and PFS of cancer patients treated with ICI immunotherapy, especially for patients with ATB use in the period of (−60 days; +30 days) near the initiation of ICI treatment. Also, different cancer types and the ICI type can also impact the survival outcome. This first reveals the strong relationship between the broad-spectrum ATB class and poor PFS. Still, more studies are needed for further study.
High secondary attack rate and persistence of SARS-CoV-2 antibodies in household transmission study participants, Finland 2020–2021
Authors: Dub Timothée , Solastie Anna , Hagberg Lotta , Liedes Oona , Nohynek Hanna , Haveri Anu , Virta Camilla , Vara Saimi , Lasander Mervi , Ekström Nina , Österlund Pamela , Lind Katja , Valtonen Hanna , Hemmilä Heidi , Ikonen Niina , Lukkarinen Timo , Palmu Arto A. , Melin Merit 
Published: July 2022

BackgroundHousehold transmission studies offer the opportunity to assess both secondary attack rate (SAR) and persistence of SARS-CoV-2 antibodies over time.MethodsIn Spring 2020, we invited confirmed COVID-19 cases and their household members to four visits, where we collected nasopharyngeal and serum samples over 28 days after index case onset. We calculated SAR based on the presence of SARS-CoV-2 neutralizing antibodies (NAb) and assessed the persistence of NAb and IgG antibodies (Ab) against SARS-CoV-2 spike glycoprotein and nucleoprotein.ResultsSAR was 45% (39/87), including 35 symptomatic secondary cases. During the initial 28-day follow-up, 62% (80/129) of participants developed NAb. Of those that seroconverted, 90% (63/70), 85% (63/74), and 78% (45/58) still had NAb to early B-lineage SARS-CoV-2 3, 6, and 12 months after the onset of the index case. Anti-spike IgG Ab persisted in 100% (69/69), 97% (72/74), and 93% (55/59) of seroconverted participants after 3, 6, and 12 months, while anti-nucleoprotein IgG Ab levels waned faster, persisting in 99% (68/69), 78% (58/74), and 55% (39/71) of participants, respectively.ConclusionFollowing detection of a COVID-19 case in a household, other members had a high risk of becoming infected. NAb to early B-lineage SARS-CoV-2 persisted for at least a year in most cases.
Arterial and venous vascular complications in patients requiring peripheral venoarterial extracorporeal membrane oxygenation
Authors: Fisser Christoph , Armbrüster Corina , Wiest Clemens , Philipp Alois , Foltan Maik , Lunz Dirk , Pfister Karin , Schneckenpointner Roland , Schmid Christof , Maier Lars S. , Müller Thomas , Lubnow Matthias 
Published: July 2022

IntroductionThe aim of this study was to investigate the prevalence of arterial and venous complications in patients requiring peripheral venoarterial extracorporeal membrane oxygenation (VA ECMO) and its risk factors at the time of cannulation and during extracorporeal membrane oxygenation (ECMO) support and to assess vascular complications in association with decannulation.Material and methodsBetween January 2010 to January 2020, out of 1,030 eligible patients requiring VA-ECMO, 427 with analyzable vascular screening were included. Duplex sonography and/or CT scan after decannulation were used to screen for thrombosis and pulmonary embolism as well as arterial complications. Near-infrared spectrometry (NIRS) was established at the time of cannulation and was continuously monitored during the ECMO therapy.ResultsThe prevalence of venous complications was 27%. Thrombosis and pulmonary embolism were observed in 21 and 7% of patients, respectively. Pulmonary embolism was more frequently diagnosed in patients with thrombosis (22 vs. 3%, p &lt; 0.001). In multivariate analysis, cannulation in the jugular vein was determined as a risk factor for venous thrombosis in contrast to the extent of anticoagulation. The prevalence of arterial complications was 37%, mainly ischemia followed by bleeding, dissection, and compartment syndrome. Vascular surgery was necessary for 19% of the patients, of whome 1% required major amputations. A distal perfusion cannula (DPC) was implanted at cannulation in 24% of patients and secondarily in 16% of patients after cannulation as required during ECMO support. In the multivariate analysis, risk factors for leg ischemia at the time of cannulation were elevated D-dimers, lower NIRS on the cannulated leg, and lack of a DPC. The best discriminative parameter was the difference in NIRS between the non-cannulated leg and the cannulated leg. In contrast, during ECMO support, only the lack of a DPC was associated with leg ischemia. A similar rate of complications associated with decannulation, mainly arterial thrombosis, ischemia, or bleeding, was seen with percutaneous and surgical approaches (18 vs. 17%, p = 0.295).ConclusionPatients requiring VA ECMO should be routinely screened for vascular complications. The decision to insert a DPC should be evaluated individually. However, NIRS monitoring of the cannulated leg and the non-cannulated leg is essential to identify the legs at risk for critical ischemia. As complications associated with decannulation were equally distributed between percutaneous and surgical approaches, the applied method may be chosen according to local experience.
Response Predictors of Repetitive Neuromuscular Magnetic Stimulation in the Preventive Treatment of Episodic Migraine
Authors: Börner Corinna , Renner Tabea , Trepte-Freisleder Florian , Urban Giada , Schandelmaier Paul , Lang Magdalena , Lechner Matthias F. , Koenig Helene , Klose Birgit , Albers Lucia , Krieg Sandro M. , Baum Thomas , Heinen Florian , Landgraf Mirjam N. , Sollmann Nico , Bonfert Michaela V. 
Published: July 2022

BackgroundRepetitive neuromuscular magnetic stimulation (rNMS) of the trapezius muscles showed beneficial effects in preventing episodic migraine. However, clinical characteristics that predict a favorable response to rNMS are unknown. The objective of this analysis is to identify such predictors.MethodsThirty participants with a diagnosis of episodic migraine (mean age: 24.8 ± 4.0 years, 29 females), who were prospectively enrolled in two non-sham-controlled studies evaluating the effects of rNMS were analyzed. In these studies, the interventional stimulation of the bilateral trapezius muscles was applied in six sessions and distributed over two consecutive weeks. Baseline and follow-up assessments included the continuous documentation of a headache calendar over 30 days before and after the stimulation period, the Migraine Disability Assessment Score (MIDAS) questionnaire (before stimulation and 90 days after stimulation), and measurements of pain pressure thresholds (PPTs) above the trapezius muscles by algometry (before and after each stimulation session). Participants were classified as responders based on a ≥25% reduction in the variable of interest (headache frequency, headache intensity, days with analgesic intake, MIDAS score, left-sided PPTs, right-sided PPTs). Post-hoc univariate and multivariate binary logistic regression analyses were performed.ResultsLower headache frequency (P = 0.016) and intensity at baseline (P = 0.015) and a migraine diagnosis without a concurrent tension-type headache component (P = 0.011) were significantly related to a ≥25% reduction in headache frequency. Higher headache frequency (P = 0.052) and intensity at baseline (P = 0.014) were significantly associated with a ≥25% reduction in monthly days with analgesic intake. Lower right-sided PPTs at baseline were significantly related to a ≥25% increase in right-sided PPTs (P = 0.015) and left-sided PPTs (P =0.030). Performance of rNMS with higher stimulation intensities was significantly associated with a ≥25% reduction in headache intensity (P = 0.046).ConclusionsClinical headache characteristics at baseline, the level of muscular hyperalgesia, and stimulation intensity may inform about how well an individual patient responds to rNMS. These factors may allow an early identification of patients that would most likely benefit from rNMS.
Short Report of Longitudinal CGRP-Measurements in Migraineurs During a Hypoxic Challenge
Authors: Frank Florian , Kaltseis Katharina , Messlinger Karl , Broessner Gregor 
Published: July 2022

BackgroundCalcitonin gene related peptide (CGRP) plays a key role in the pathophysiology of migraine and is therefore considered a potential biomarker for primary headache disorders. The challenge remaining is establishing standardized protocols for its assessment in various extracellular compartments and identifying pathological situations associated with an increase in CGRP.MethodsWe performed longitudinal measurements of CGRP plasma levels in 30 volunteers with the diagnosis of episodic migraine with and without aura under controlled circumstances during an induced migraine attack under a hypoxic challenge. Blood samples were collected from a cubital vein and CGRP plasma levels measured using ELISA.ResultsCGRP levels varied significantly between the subjects at baseline (15.48–1,889.31 pg/ml) but were neither associated with socio-demographic data nor with headache/migraine frequency or intensity collected before hypoxic exposure. CGRP levels during hypoxia fluctuated around baseline and increased with prolonged hypoxia but did not differ significantly in subjects with migraine or headache compared to those without. However, subjects experiencing migraine without aura showed significantly higher levels than those with aura. Ictal CGRP levels were increased in females, in subjects with a negative family history regarding headaches, in those older than 30 years of age or with a recent headache attack before the experiment (p &lt; 0.05).ConclusionCGRP plasma levels seem to be highly variable even at baseline in migraine patients and increased during hypoxic challenge and migraine attacks. This is the first in human longitudinal measurement of peripheral CGRP levels during induced migraine attacks using a highly standardized protocol.
Luteolin alleviates methionine–choline-deficient diet-induced non-alcoholic steatohepatitis by modulating host serum metabolome and gut microbiome
Authors: Guo Wei , Luo Lianxiang , Meng Yan , Chen Wen , Yu Lixiu , Zhang Cong , Qiu Zhenpeng , Cao Peng 
Published: July 2022

Background and purposePrevious studies have indicated the protective effects of luteolin against non-alcoholic steatohepatitis (NASH), but the definite underlying mechanism still remains unclear. This study aimed to explore the metabolomic and metagenomic signatures of NASH with luteolin supplementation.Experimental approachMice were fed with a methionine–choline-deficient (MCD) diet containing 0.05% luteolin for 6 weeks. NASH severity was determined based on the liver histological observations, serum and hepatic biochemical measurements. Targeted metabolomics was conducted to identify differential metabolites in mice serum. 16S rRNA sequencing was conducted to assess the gut microbiota composition and function in mice colon.ResultsIn detail, luteolin treatment significantly alleviated MCD diet-induced hepatic lipid deposition, liver function damage, and oxidative stress. Targeted plasma metabolomics revealed that 5-hydroxyindole, LPE (0:0/22:5), indole 3-phosphate, and N-phenylacetylphenylalanine were remarkably elevated, and homogentisic acid, thiamine, KN-93, PC (16:1e/8, 9-EpETE), carnitine C9:1-OH, FFA (18:4) and carnitine C8:1 were significantly decreased in NASH group as compared to normal group, which could be profoundly reversed after luteolin treatment. 16S rRNA sequencing indicated that luteolin supplementation significantly increased Erysipelatoclostridium and Pseudomonas as well as decreased Faecalibaculum at genus level. Most importantly, a negative association between thiamine and Faecalibaculum was observed based on Spearman's correlation analysis, which may play an important role in the preventive effects of luteolin against NASH.ConclusionCollectively, luteolin may alleviate the NASH by modulating serum metabolome and gut microbiome, which supports its use as a dietary supplement for NASH prevention.
A-Kinase Interacting Protein 1 Knockdown Restores Chemosensitivity via Inactivating PI3K/AKT and β-Catenin Pathways in Anaplastic Thyroid Carcinoma
Authors: Zheng Haiyan , Lin Qingyuan , Rao Yamin 
Published: July 2022

BackgroundA-kinase interacting protein 1 (AKIP1) promotes tumor progression and chemoresistance in several malignancies; meanwhile, it is related to higher tumor size and recurrence risk of papillary thyroid carcinoma, while the role of AKIP1 in anaplastic thyroid carcinoma (ATC) is unclear. The aim of this study is to explore the effect of AKIP1 knockdown on cell malignant behaviors and doxorubicin resistance in ATC.MethodsAKIP1 knockdown was conducted in ATC cell lines (8505C and CAL-62 cells) by siRNA; then, cell viability, apoptosis, invasion, PI3K/AKT and β-catenin pathways, and doxorubicin sensitivity were detected. Subsequently, doxorubicin-resistant 8505C cells (8505C/Dox) were established. Additionally, AKIP1 was modified in 8505C and 8505C/Dox cells that underwent doxorubicin treatment by siRNA or overexpression plasmid, followed by cellular function and pathway detection.ResultsAKIP1 was elevated in FRO, 8505C, CAL-62, and KHM-5M cells compared to control cells (all p &lt; 0.05). Subsequently, AKIP1 knockdown elevated apoptosis, inhibited viability and invasion, and inactivated PI3K/AKT and β-catenin pathways in 8505C and CAL-62 cells (all p &lt; 0.05). AKIP1 knockdown decreased relative cell viability in doxorubicin-treated 8505C and CAL-62 cells; then, AKIP1 was elevated in 8505C/Dox cells compared to 8505C cells (all p &lt; 0.05). Furthermore, AKIP1 knockdown restored doxorubicin sensitivity (reflected by decreased cell viability and invasion, and increased apoptosis), but inactivated PI3K/AKT and β-catenin pathways in doxorubicin-treated 8505C/Dox cells. However, AKIP1 overexpression presented an opposite effect on these functions and pathways in doxorubicin-treated 8505C cells.ConclusionAKIP1 knockdown decreases cell survival and invasion while promoting sensitivity to doxorubicin via inactivating PI3K/AKT and β-catenin pathways in ATC.