bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin-10 Attenuates Liver Fibrosis Exacerbated by Thermoneutrality
Authors: Nga Ha Thi , Moon Ji Sun , Tian Jingwen , Lee Ho Yeop , Kim Seok-Hwan , Lee Young-Sun , Jeon Jae-Han , Yi Hyon-Seung 
Published: May 2021

Background: Crosstalk between brown adipose tissue (BAT) and the liver is receiving increasing attention. This study investigated the effect of BAT dysfunction by thermoneutral (TN) housing on liver fibrosis in mice and examined the effect of secreted factors from brown adipocytes on the activation of hepatic stellate cells (HSCs).Methods: The carbon tetrachloride (CCl4)-induced liver fibrosis mouse model was used to evaluate fibrotic changes in the livers of mice housed under standard and TN conditions. The effect of BAT on the activation of HSCs was examined using cultured cells treated with conditioned media from brown adipocytes.Results: Under TN conditions, mice with CCl4-induced liver fibrosis exhibited increased liver injury, collagen deposition, and alpha smooth muscle actin (α-SMA) expression in the liver compared with mice maintained at room temperature. The numbers of liver-infiltrating immune cells and T cells producing IL-17A and IFN-γ were also significantly increased in the livers of mice housed under TN conditions. Treatment of HSCs with conditioned media from brown adipocytes markedly attenuated HSC activation, as shown by down-regulated α-SMA expression at day 4, day 7 and day 10 of culture. At thermoneutrality, with CCl4 administration, IL-10-deficient mice exhibited more severe liver fibrosis than wild-type mice. Interestingly, conditioned media from IL-10-deficient brown adipocytes could up-regulate the expression of α-SMA and induce HSCs activation.Conclusions: BAT inactivation by thermoneutrality contributes to the activation of pro-inflammatory and pro-fibrotic pathways in mice with CCl4-induced liver fibrosis. Normal brown adipocytes secreted factors that impair the activation of HSCs, while this protective effect was lost in IL-10-deficient brown adipocytes. Thus, the BAT–liver axis may serve as a potential therapeutic target for liver fibrosis, and IL-10 may be a key factor regulating the activation of HSCs by BAT.
Decreased Resting-State Functional Connectivity of Periaqueductal Gray in Temporal Lobe Epilepsy Comorbid With Migraine
Authors: Wang Long , Cai Xin-Ting , Zu Mei-Dan , Zhang Juan , Deng Zi-Ru , Wang Yu 
Published: May 2021

Objective: Patients with temporal lobe epilepsy (TLE) are at high risk for having a comorbid condition of migraine, and these two common diseases are proposed to have some shared pathophysiological mechanisms. Our recent study indicated the dysfunction of periaqueductal gray (PAG), a key pain-modulating structure, contributes to the development of pain hypersensitivity and epileptogenesis in epilepsy. This study is to investigate the functional connectivity of PAG network in epilepsy comorbid with migraine.Methods: Thirty-two patients with TLE, including 16 epilepsy patients without migraine (EwoM) and 16 epilepsy patients with comorbid migraine (EwM), and 14 matched healthy controls (HCs) were recruited and underwent resting functional magnetic resonance imaging (fMRI) scans to measure the resting-state functional connectivity (RsFC) of PAG network. The frequency and severity of migraine attacks were assessed using the Migraine Disability Assessment Questionnaire (MIDAS) and Visual Analog Scale/Score (VAS). In animal experiments, FluoroGold (FG), a retrograde tracing agent, was injected into PPN and its fluorescence detected in vlPAG to trace the neuronal projection from vlPAG to PPN. FG traced neuron number was used to evaluate the neural transmission activity of vlPAG-PPN pathway. The data were processed and analyzed using DPARSF and SPSS17.0 software. Based on the RsFC finding, the excitatory transmission of PAG and the associated brain structure was studied via retrograde tracing in combination with immunohistochemical labeling of excitatory neurons.Results: Compared to HCs group, the RsFC between PAG and the left pedunculopontine nucleus (PPN), between PAG and the corpus callosum (CC), was decreased both in EwoM and EwM group, while the RsFC between PAG and the right PPN was increased only in EwoM group but not in EwM group. Compared to EwoM group, the RsFC between PAG and the right PPN was decreased in EwM group. Furthermore, the RsFC between PAG and PPN was negatively correlated with the frequency and severity of migraine attacks. In animal study, a seizure stimulation induced excitatory transmission from PAG to PPN was decreased in rats with chronic epilepsy as compared to that in normal control rats.Conclusion: The comorbidity of epilepsy and migraine is associated with the decreased RsFC between PAG and PPN.
Liver Transplantation Versus Liver Resection for Stage I and II Hepatocellular Carcinoma: Results of an Instrumental Variable Analysis
Authors: Li Wei , Xiao Haitao , Wu Hong , Xu Xuewen , Zhang Yange 
Published: May 2021

BackgroundThis study aimed to compare the long-term outcomes of liver transplantation (LT) and liver resection (LR) among patients with stage I and II hepatocellular carcinoma (HCC).MethodsSEER 18 registry from 2004 to 2015 was retrieved for this study. We included 1,765 and 1,746 cases with stage I–II (AJCC, 7th) HCC in the multivariable analyses and instrumental variable (IV) analyses, respectively. Propensity score matching (PSM) was further carried out to ensure comparability. Propensity score to receive LT was adjusted by stabilized inverse probability of treatment weighting (IPTW) and standardized mortality ratio weighting (SMRW) methods. In addition, IV analysis was performed to adjust both measured and unmeasured confounding factors.ResultsWe identified 1,000 (56.7%) and 765 (43.3%) patients treated with LR and LT, respectively. In the multivariable adjusted cohort, after adjusting potential confounders, patients undergoing LT offered significant prognostic advantages over LR in overall survival (OS, P &lt; 0.001) and disease-free survival (DSS, P &lt; 0.001). The instrument variable in this study is LT rates in various Health Service Areas (HSAs). Results from the IV analysis showed that cases treated with LT had significantly longer OS (P = 0.001) and DSS (P &lt; 0.001). In IV analysis stratified by clinicopathologic variables, the treatment effect of LT vs. LR in OS was consistent across all subgroups. Regarding DSS in IV analyses, the subgroup analyses observed that LT had better DSS across all subgroups, except for similar results in the older patients (interaction P value = 0.039) and the non-White patients (interaction P value = 0.041). In the propensity-matched cohort, patients with LT still had better OS (P &lt; 0.001) and DSS (P &lt; 0.001) in comparison to cases who underwent LR. In both IPTW and SMRW cohorts, patients who underwent LT had better OS (both P values &lt; 0.001) and DSS (both P values &lt; 0.001).ConclusionsLT provided a survival benefit for cases with stage I–II HCC. These results indicated that if LT rate was to increase in the future, average long-term survival may also increase. However, for some special populations such as the elderly patients, owing to the similar outcomes between LT and LR, the selection of LT should be cautious.
Correlation Between Lung Density Changes Under Different Dose Gradients and Radiation Pneumonitis—Based on an Analysis of Computed Tomography Scans During Esophageal Cancer Radiotherapy
Authors: Du Feng , Liu Hong , Wang Wei , Zhang Yingjie , Li Jianbin 
Published: May 2021

PurposeTo assess the relationship between different doses of radiation and lung density changes and to determine the ability of this correlation to identify esophageal cancer (EC) patients who develop radiation pneumonitis (RP) and the occurrence time of RP.MethodsA planning computed tomography (CT) scan and a re-planning CT scan were retrospectively collected under institutional review board approval for each of 103 thoracic segment EC patients who underwent radiotherapy (RT). The isodose curve was established on the planning CT with an interval of 5 Gy, which was used as the standard for dividing different gradient doses. Planning CT and re-planning CT scans were matched and the mean lung CT value (HU) between different doses gradients was automatically obtained by the software system. The density change value (ΔHU) was the difference of CT value between each dose gradient before and after treatment. The correlation between ΔHU and the corresponding dose was calculated, as well as the regression coefficients. Additionally the correlation between ΔHU and the occurrence and time of RP (&lt; 4 weeks, 4–12 weeks, &gt; 12 weeks) was calculated.ResultsThe radiation dose and ΔHU was positively correlated, but the correlation coefficient and regression coefficient were lower, 0.261 (P &lt;0.001) and 0.127 (P &lt;0.001), respectively. With the increase of radiation dose gradient, ΔHU in RP≥2 group was higher than that in RP&lt;2 group, and there was significant difference between two groups in ΔHU20-25, ΔHU25-30, ΔHU30-35, ΔHU35-40, ΔHU40-45, ΔHU45-50 (p&lt;0.05). The occurrence time of RP was negatively correlated with the degree of ΔHU (P&lt;0.05), with a high correlation coefficient (Y = week actual value −0.521, P &lt; 0.001) (Y = week grade value −0.381, P = 0.004) and regression coefficient (Y = week actual value −0.503, P&lt;0.001) (Y = week rating value −0.401, P=0.002).ConclusionsA relationship between radiation dose and lung density changes was observed. For most dose intervals, there was an increase of ΔHU with an increased radiation dose, although low correlation coefficient. ΔHU were obvious after irradiation with dose ≥20 Gy which was closely related to the occurrence of RP. For patients with RP, the more obvious ΔHU, the earlier the occurrence of RP, there was a significant negative correlation between them.
Identification of an m6A-Related lncRNA Signature for Predicting the Prognosis in Patients With Kidney Renal Clear Cell Carcinoma
Authors: Yu JunJie , Mao WeiPu , Sun Si , Hu Qiang , Wang Can , Xu ZhiPeng , Liu RuiJi , Chen SaiSai , Xu Bin , Chen Ming 
Published: May 2021

PurposeThis study aimed to construct an m6A-related long non-coding RNAs (lncRNAs) signature to accurately predict the prognosis of kidney clear cell carcinoma (KIRC) patients using data obtained from The Cancer Genome Atlas (TCGA) database.MethodsThe KIRC patient data were downloaded from TCGA database and m6A-related genes were obtained from published articles. Pearson correlation analysis was implemented to identify m6A-related lncRNAs. Univariate, Lasso, and multivariate Cox regression analyses were used to identifying prognostic risk-associated lncRNAs. Five lncRNAs were identified and used to construct a prognostic signature in training set. Kaplan–Meier curves and receiver operating characteristic (ROC) curves were applied to evaluate reliability and sensitivity of the signature in testing set and overall set, respectively. A prognostic nomogram was established to predict the probable 1-, 3-, and 5-year overall survival of KIRC patients quantitatively. GSEA was performed to explore the potential biological processes and cellular pathways. Besides, the lncRNA/miRNA/mRNA ceRNA network and PPI network were constructed based on weighted gene co-expression network analysis (WGCNA). Functional Enrichment Analysis was used to identify the biological functions of m6A-related lncRNAs.ResultsWe constructed and verified an m6A-related lncRNAs prognostic signature of KIRC patients in TCGA database. We confirmed that the survival rates of KIRC patients with high-risk subgroup were significantly poorer than those with low-risk subgroup in the training set and testing set. ROC curves indicated that the prognostic signature had a reliable predictive capability in the training set (AUC = 0.802) and testing set (AUC = 0.725), respectively. Also, we established a prognostic nomogram with a high C-index and accomplished good prediction accuracy. The lncRNA/miRNA/mRNA ceRNA network and PPI network, as well as functional enrichment analysis provided us with new ways to search for potential biological functions.ConclusionsWe constructed an m6A-related lncRNAs prognostic signature which could accurately predict the prognosis of KIRC patients.
Arterial Infusion Chemotherapy for Neoplastic Esophagogastric Anastomotic Strictures After Esophagectomy
Authors: Xie Pengfei , Yin Meipan , He Wei , Ma Yaozhen , Li Chunxia , Li Zhen , Li Xiaobing , Wang Shuai , Wu Gang 
Published: May 2021

BackgroundNeoplastic esophagogastric anastomotic strictures after resection of esophageal cancer is a very difficult problem in clinical practice. We aim at to investigate the safety and feasibility of arterial infusion chemotherapy in treatment of neoplastic esophagogastric anastomotic strictures after esophagectomy.MethodsFrom October 2014 to December 2019, 50 patients with Neoplastic esophagogastric anastomotic strictures after resection of esophageal cancer were assessed retrospectively. Preoperative dysphagia was grade III in 34 cases and grade IV in 16 cases. Thirty-eight patients had different degrees of dyspnea before surgery Twenty-five patients had intolerable (grade IV) dyspnea and airway stenting was undertaken before surgery. Thirteen patients had tolerable dyspnea that did not require airway stenting, and preoperative dyspnea was grade III.ResultsAll patients were successfully treated with arterial infusion chemotherapy, no paraplegia or death occurred. The dysphagia grade of 50 patients after AIC was compared: one case had grade I, 40 cases had grade II, and nine cases had grade III. Thirteen patients had tolerable dyspnea that did not necessitate airway stenting. Dyspnea was classified as grade I in five cases and grade II in eight cases. After 1–3 courses of AIC, 50 patients were followed up for a complete response (eight cases), partial response (28) and stable disease (14 cases). Total objective effective rate (complete response+ partial response) and disease control rate(complete response + partial response + stable disease)were 72.0% and 100.0%, respectively. The median duration of follow-up was 8.5 months. One-year survival was 46.0%.ConclusionArterial infusion chemotherapy is safe and efficacious treatment for Neoplastic esophagogastric anastomotic strictures after esophagectomy.
Clinical Factors and Outcomes of Atypical Meningioma: A Population-Based Study
Authors: Zhang Gui-Jun , Liu Xiao-Yin , You Chao 
Published: May 2021

ObjectiveAtypical meningioma is a non-benign tumor, and its prognostic factors and treatment strategies are unclear.MethodsPatients with atypical meningioma, between 2004 and 2016, were collected from the Surveillance, Epidemiology, and End Results database. Then, we randomly divided patients into a training set and a validation set at a ratio of 8:2. The nomogram was constructed based on the multivariate Cox regression analyses. And the concordance index, calibration curves, and receiver operating character were used to assess the predictive ability of the nomogram. We divided the patient scores into three groups and constructed a survival curve using Kaplan–Meier analysis.ResultsAfter our inclusion and exclusion criteria, 2358 patients were histologically diagnosed of atypical meningioma. The prognostic nomogram comprised factors of overall survival, including age, tumor size and surgery. The concordance index was 0.715 (95%CI=0.688-0.742) for overall survival in the training set and 0.688 (95%CI=0.629-0.747) for overall survival in the validation set. The calibration curves and receiver operating character also indicated the good predictability of the nomogram. Risk stratification revealed a statistically significant difference among the three groups of patients according to quartiles of risk score.ConclusionGross total resection is an independent factor for survival, and radiation after non-gross total resection potentially confers a survival advantage for patients with atypical meningioma.
Impact of Non-steroidal Anti-inflammatory Drug Administration for 12 Months on Renal Function
Authors: Hayashi Kazuhiro , Miki Kenji , Kajiyama Hiroshi , Ikemoto Tatsunori , Yukioka Masao 
Published: May 2021

Background: The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of renal complications. Resolution of renal adverse effects after NSAID administration has been observed after short-term use. Thus, the present study aimed to investigate a series of patients with chronic musculoskeletal pain who underwent long-term NSAID administration followed by switching to tramadol hydrochloride/acetaminophen (TA) combination tablets to study the impact of NSAID-induced renal adverse effects.Methods: This was a longitudinal retrospective study of 99 patients with chronic musculoskeletal pain. The patients were administrated with NSAIDs daily during the first 12 months, followed by daily TA combination tablets for 12 months. Estimated glomerular filtration rate (eGFR) and serum levels of aspartate aminotransferase and alanine transaminase were measured at baseline, after NSAID administration and after TA administration.Results: eGFR was significantly reduced after 12-month NSAID administration (median, from 84.0 to 72.8 ml/min/1.73 m2), and the reduction was not shown after the subsequent 12-month TA administration (median, 71.5 ml/min/1.73 m2). Reduction in eGFR was less in patients who received celecoxib (median, −1.8 ml/min/1.73 m2) during the first 12 months. There was no significant difference in aspartate aminotransferase and alanine transaminase in each period.Conclusions: Thus, patients receiving NSAIDs for 12 months displayed both reversible and irreversible reduction of eGFR upon cessation of NSAIDs and switching to TA. Our data highlight the potential safety benefit of utilizing multimodal analgesic therapies to minimize the chronic administration of NSAIDs.
Heat Shock Protein-70 Levels Are Associated With a State of Oxidative Damage in the Development of Bronchopulmonary Dysplasia
Authors: Hsiao Chien-Chou , Lee Cheng-Han , Yang Rei-Cheng , Chen Jia-Yuh , Su Tzu-Cheng , Chang Yu-Jun , Lin Ching-Yuang , Tsai Yi-Giien 
Published: May 2021

Background: Heat shock protein-70 (Hsp-70) exhibits cytoprotective effects against oxidative stress-induced airway injury. This study aimed to examine Hsp-70 and 8-hydroxy-2′-deoxyguanosine (8-OHdG) from tracheal aspirates (TA) in very low-birth weight (VLBW) preterm infants to predict the development of bronchopulmonary dysplasia (BPD).Methods: This birth cohort study enrolled 109 VLBW preterm infants, including 32 infants who developed BPD. Hsp-70 and 8-OHdG concentrations from TA were measured by immunoassay. The apoptosis of TA epithelial cells obtained on Day 28 after birth was measured using annexin-V staining assay.Results: Hsp-70 and 8-OHdG levels in TA fluid were persistently increased from Day 1 to Day 28 of life in the BPD group. Multiple linear regression analysis demonstrated that BPD was significantly associated with gestational age, respiratory distress syndrome, and TA Hsp-70 and 8-OHdG levels on post-natal Day 28. The TA Hsp-70 level positively correlated with TA 8-OHdG level on the Day 1 (r = 0.47) and Day 28 of life (r = 0.68). Incubation of recombinant Hsp-70 with primary epithelial cells derived from TA of patients decreased hydrogen peroxide-induced epithelial cell death.Conclusions: Hsp-70 levels are associated with a state of oxidative injury in the development of BPD.
Real-World Prevalence of Direct Oral Anticoagulant Off-Label Doses in Atrial Fibrillation: An Epidemiological Meta-Analysis
Authors: Shen Nan-Nan , Zhang Chi , Hang Ying , Li Zheng , Kong Ling-Cong , Wang Na , Wang Jia-Liang , Gu Zhi-Chun 
Published: May 2021

Background: The use of direct oral anticoagulant (DOAC) off-label doses in atrial fibrillation (AF) patients may result in poor clinical outcomes. However, the true prevalence remains scarce. This study aims at estimating the prevalence of DOAC off-label doses in AF patients.Methods: Databases of MEDLINE, EMBASE, and COCHRANE were searched from inception through February 2020 for real-world studies that reported the off-label definition and prevalence data of AF patients using DOACs. The primacy outcomes were the overall prevalence of DOAC off-label doses and the corresponding underdose and overdose. The random-effects model was used for data synthesis. Variations on individual DOAC and different regions were examined by subgroup analyses.Results: A total of 23 studies involving 162,474 AF patients were finally included. The overall prevalence of DOAC off-label doses was 24% (95% CI, 19–28%), with 18% for dabigatran, 27% for rivaroxaban, 24% for apixaban, and 26% for edoxaban. The prevalence of underdosed DOACs was 20% (95% CI, 16–24%) with significant difference among individual anticoagulants (13% for dabigatran, 22% for rivaroxaban, 22% for apixaban, and 18% for edoxaban; Pinteraction=0.02). The prevalence of overdosed DOACs was 5% (95% CI, 3–7%), with the lowest prevalence observed in apixaban (2%). Subgroup analyses by regions demonstrated that the prevalence of DOAC off-label doses was higher in Asia (32%) than in North America (14%) and in Europe (22%), with underdose being predominant. Regardless of different regions, the prevalence of overdose was relatively low (4–6%).Conclusion: This study provides an estimation of DOAC off-label doses in the real-world setting. The prevalence rate of DOAC off-label doses in AF patients was relatively high, with underdose being predominant. Clinicians in Asia preferred to prescribe underdose of DOACs to AF patients. More evidence about the appropriateness of DOAC off-label doses in AF patients is urgently needed. Education programs concerning the appropriate prescription of DOACs within the drug labels and accepted guidelines are necessary to DOAC prescribers to ensure the safety and effectiveness of anticoagulation therapy for patients with AF.
Discovery of Potent EGFR Inhibitors With 6-Arylureido-4-anilinoquinazoline Derivatives
Authors: Li Meng , Xue Na , Liu Xingang , Wang Qiaoyun , Yan Hongyi , Liu Yifan , Wang Lei , Shi Xiaowei , Cao Deying , Zhang Kai , Zhang Yang 
Published: May 2021

According to the classical pharmacophore fusion strategy, a series of 6-arylureido-4-anilinoquinazoline derivatives (Compounds 7a–t) were designed, synthesized, and biologically evaluated by the standard CCK-8 method and enzyme inhibition assay. Among the title compounds, Compounds 7a, 7c, 7d, 7f, 7i, 7o, 7p, and 7q exhibited promising anti-proliferative bioactivities, especially Compound 7i, which had excellent antitumor activity against the A549, HT-29, and MCF-7 cell lines (IC50 = 2.25, 1.72, and 2.81 μM, respectively) compared with gefitinib, erlotinib, and sorafenib. In addition, the enzyme activity inhibition assay indicated that the synthesized compounds had sub-micromolar inhibitory levels (IC50, 11.66–867.1 nM), which was consistent with the results of the tumor cell line growth inhibition tests. By comparing the binding mechanisms of Compound 7i (17.32 nM), gefitinib (25.42 nM), and erlotinib (33.25 nM) to the EGFR, it was found that Compound 7i could extend into the effective region with a similar action conformation to that of gefitinib and interact with residues L85, D86, and R127, increasing the binding affinity of Compound 7i to the EGFR. Based on the molecular hybridization strategy, 14 compounds with EGFR inhibitory activity were designed and synthesized, and the action mechanism was explored through computational approaches, providing valuable clues for the research of antitumor agents based on EGFR inhibitors.