bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Aortic Valve Replacement vs. Conservative Management in Asymptomatic Severe Aortic Stenosis Patients With Preserved Ejection Fraction: A Meta-Analysis
Authors: Yuan Tan , Lu Yi , Bian Chang , Cai Zhejun 
Published: February 2021

Background: Aortic stenosis (AS) is the most common valvular disease in developed countries. Until now, the specific timing of intervention for asymptomatic patients with severe aortic stenosis and preserved ejection fraction remains controversial.Methods: A systematic search of four databases (Pubmed, Web of science, Cochrane library, Embase) was conducted. Studies of asymptomatic patients with severe AS or very severe AS and preserved left ventricular ejection fraction underwent early aortic valve replacement (AVR) or conservative care were included. The end points included all-cause mortality, cardiac mortality, and non-cardiac mortality.Results: Four eligible studies were identified with a total of 1,249 participants. Compared to conservative management, patients who underwent early AVR were associated with lower all-cause mortality, cardiac mortality, and non-cardiac mortality rate (OR 0.16, 95% CI 0.09–0.31, P &lt; 0.00001; OR 0.12, 95% CI 0.02–0.62, P = 0.01; OR 0.36, 95% CI 0.21–0.63, P = 0.0003, respectively).Conclusions: Early AVR is preferable for asymptomatic severe AS patients with preserved ejection fraction.
Improved Functionality of Exhausted Intrahepatic CXCR5+ CD8+ T Cells Contributes to Chronic Antigen Clearance Upon Immunomodulation
Authors: Kumashie Kingsley Gideon , Cebula Marcin , Hagedorn Claudia , Kreppel Florian , Pils Marina C. , Koch-Nolte Friedrich , Rissiek Björn , Wirth Dagmar 
Published: February 2021

Chronic hepatotropic viral infections are characterized by exhausted CD8+ T cells in the presence of cognate antigen in the liver. The impairment of T cell response limits the control of chronic hepatotropic viruses. Immune-modulatory strategies are attractive options to re-invigorate exhausted T cells. However, in hepatotropic viral infections, the knowledge about immune-modulatory effects on the in-situ regulation of exhausted intrahepatic CD8+ T cells is limited. In this study, we elucidated the functional heterogeneity in the pool of exhausted CD8+ T cells in the liver of mice expressing the model antigen Ova in a fraction of hepatocytes. We found a subpopulation of intrahepatic CXCR5+ Ova-specific CD8+ T cells, which are profoundly cytotoxic, exhibiting efficient metabolic functions as well as improved memory recall and self-maintenance. The intrahepatic Ova-specific CXCR5+ CD8+ T cells are possibly tissue resident cells, which may rely largely on OXPHOS and glycolysis to fuel their cellular processes. Importantly, host conditioning with CpG oligonucleotide reinvigorates and promotes exhausted T cell expansion, facilitating complete antigen eradication. The CpG oligonucleotide-mediated reinvigoration may support resident memory T cell formation and the maintenance of CXCR5+ Ova-specific CD8+ T cells in the liver. These findings suggest that CpG oligodinucleotide may preferentially target CXCR5+ CD8+ T cells for expansion to facilitate the revival of exhausted T cells. Thus, therapeutic strategies aiming to expand CXCR5+ CD8+ T cells might provide a novel approach against chronic liver infection.
Therapeutic Potential of Pharmacological Targeting NLRP3 Inflammasome Complex in Cancer
Authors: Tezcan Gulcin , Garanina Ekaterina E. , Alsaadi Mohammad , Gilazieva Zarema E. , Martinova Ekaterina V. , Markelova Maria I. , Arkhipova Svetlana S. , Hamza Shaimaa , McIntyre Alan , Rizvanov Albert A. , Khaiboullina Svetlana F. 
Published: February 2021

IntroductionDysregulation of NLRP3 inflammasome complex formation can promote chronic inflammation by increased release of IL-1β. However, the effect of NLRP3 complex formation on tumor progression remains controversial. Therefore, we sought to determine the effect of NLRP3 modulation on the growth of the different types of cancer cells, derived from lung, breast, and prostate cancers as well as neuroblastoma and glioblastoma in-vitro.MethodThe effect of Caspase 1 inhibitor (VX765) and combination of LPS/Nigericin on NLRP3 inflammasome activity was analyzed in A549 (lung cancer), MCF-7 (breast cancer), PC3 (prostate cancer), SH-SY5Y (neuroblastoma), and U138MG (glioblastoma) cells. Human fibroblasts were used as control cells. The effect of VX765 and LPS/Nigericin on NLRP3 expression was analyzed using western blot, while IL-1β and IL-18 secretion was detected by ELISA. Tumor cell viability and progression were determined using Annexin V, cell proliferation assay, LDH assay, sphere formation assay, transmission electron microscopy, and a multiplex cytokine assay. Also, angiogenesis was investigated by a tube formation assay. VEGF and MMPs secretion were detected by ELISA and a multiplex assay, respectively. Statistical analysis was done using one-way ANOVA with Tukey’s analyses and Kruskal–Wallis one-way analysis of variance.ResultsLPS/Nigericin increased NRLP3 protein expression as well as IL-1β and IL-18 secretion in PC3 and U138MG cells compared to A549, MCF7, SH-SY5Y cells, and fibroblasts. In contrast, MIF expression was commonly found upregulated in A549, PC3, SH-SY5Y, and U138MG cells and fibroblasts after Nigericin treatment. Nigericin and a combination of LPS/Nigericin decreased the cell viability and proliferation. Also, LPS/Nigericin significantly increased tumorsphere size in PC3 and U138MG cells. In contrast, the sphere size was reduced in MCF7 and SH-SY5Y cells treated with LPS/Nigericin, while no effect was detected in A549 cells. VX765 increased secretion of CCL24 in A549, MCF7, PC3, and fibroblasts as well as CCL11 and CCL26 in SH-SY5Y cells. Also, VX765 significantly increased the production of VEGF and MMPs and stimulated angiogenesis in all tumor cell lines.DiscussionOur data suggest that NLRP3 activation using Nigericin could be a novel therapeutic approach to control the growth of tumors producing a low level of IL-1β and IL-18.
Radiation-Induced Optical Coherence Tomography Angiography Retinal Alterations in Patients With Nasopharyngeal Carcinoma
Authors: Li Zijing , Zhan Zongyi , Xiao Jianhui , Lan Yuqing 
Published: February 2021

Aim: The aim of the study was to investigate the early neurovascular alterations of the retina in radiation encephalopathy (RE) patients with normal-ranged visual acuity after radiotherapy for nasopharyngeal carcinoma.Methods: Fifty-five RE patients and 54 healthy age-matched subjects were enrolled in this retrospective cross-sectional case–control study. The best corrected visual acuity (LogMAR) of the included eye should not be more than 0. The vessel density and thickness of different locations in the retina were acquired automatically using optical coherence tomography angiography (OCTA). The data were then compared between the RE patients and the controls. The location included the whole retina, the superficial vascular plexus (SVP)/the ganglion cell complex (GCC), the deep vascular plexus (DVP), and the choroid in the macular area, as well as the inside disc and peripapillary area in the optic nerve head (ONH). The risk factors in OCTA retinal impairments were analyzed using a backward multiple linear regression. The relationships between mean deviation (MD) and pattern standard deviation (PSD) in the visual field (VF) and the OCTA parameters were also analyzed in RE patients.Results: The vessel density of the GCC was significantly reduced in RE patients compared with controls (p = 0.018), and the reductions were mainly shown in the parafoveal (p = 0.049) and perifoveal fields (p = 0.006). The thickness of the GCC was correspondingly reduced (whole image GCC mean thickness: p = 0.044; parafoveal thickness: p = 0.038; perifoveal thickness: p = 0.038). In addition, the sub-foveal choroidal thickness (p = 0.039) was also reduced in RE patients. The vessel density of the GCC (R2 = 0.643) and DVP (R2 = 0.777) had a significant positive correlation with high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (ApoA1) and had a significant negative correlation with age (GCC: HDL-C, β = 29.89, p = 0.005; ApoA1, β = 78.92, p = 0.002; age, β = −0.886, p = 0.001; DVP: HDL-C, β = 40.09, p = 0.003; ApoA1, β = 62.65, p = 0.013; age, β = −1.31, p = 0.001). The vessel density of the GCC also had a significant negative correlation with apolipoprotein B (ApoB) (β = −32.18, p = 0.006). In the VF, MD had a significant positive correlation with the vessel density inside disc (R2 = 0.241, β = 0.304, p = 0.045), whereas PSD showed a significant negative correlation with the vessel density inside disc and the average GCC thickness, respectively (R2 = 0.437; vessel density inside disc, β = −0.358, p = 0.004; average GCC thickness, β = −0.510, p &lt; 0.001).Conclusion: With the aid of OCTA, we found that neurovascular alterations of the retina may exist in RE patients with normal-ranged visual acuity. Herein, we suggest the implementation of OCTA to assist ophthalmologists in the early detection and consistent monitoring of radiation-related eye diseases to avoid delayed diagnosis.
Clinical and Genetic Characteristics of Mitochondrial Encephalopathy Due to FOXRED1 Mutations: Two Chinese Case Reports and a Review of the Literature
Authors: Hu Chaoping , Xu Qiong , Shen Jin , Wang Yi 
Published: February 2021

Background: As one of the assembly factors of complex I in the mitochondrial respiratory chain, FOXRED1 plays an important role in mitochondrial function. However, only a few patients with mitochondrial encephalopathy due to FOXRED1 defects have been reported.Methods: Two Chinese patients with mitochondrial encephalopathy due to mutations in FOXRED1 were identified through trio whole-exome sequencing. The clinical presentation, laboratory data, brain imaging findings, and genetic results were collected and reviewed. All previously reported cases with FOXRED1-related mitochondrial encephalopathy were collected using a PubMed search, and their data were reviewed.Results: Two patients presented with severe neurodevelopmental delay, epilepsy, high lactic acid levels, and remarkable diffuse brain atrophy and polycystic encephalomalacia during early infancy. Trio whole-exome sequencing revealed compound heterozygous variants in both patients: one case harbored a c.606_607delAG frameshift variant and a c.1054C&gt;T (p.R352W) variant. At the same time, the other carried a novel c.352C&gt;T (p.Q118X) variant and a reported c.1054C&gt;T (p.R352W) variant. To date, nine patients have been reported with FOXRED1 defects, including our two cases. The most common presentations were neurodevelopment delay (100%), epilepsy (80%), poor feeding (30%), and vision loss (20%). Multisystem involvement comprised cardiovascular dysfunction (30%), abnormal liver function (20%), and hypoglycemia (10%). The neuroimaging results ranged from normal to severe cerebral atrophy and polycystic encephalomalacia in early infancy. Eleven pathogenic variants in FOXRED1 have been reported, comprising six missense variants, two non-sense variants, two frameshift variants, and one splice variant; among these the c.1054C&gt;T (p.R352W) and c.612_615dupAGTG (p.A206SfsX15) variants are more common.Conclusion:FOXRED1-related mitochondrial disorders have high clinical and genetic heterogeneity. Our study expanded the clinical and genetic spectrum of FOXRED1 defects. Early infantile onset and progressive encephalopathy are the most common clinical presentations, while the variants c.1054C&gt;T (p.R352W) and c.612_615dupAGTG (p.A206SfsX15) may be critical founder mutations.
Phenotypic Resemblance to Neuropsychiatric Disorder and Altered mRNA Profiles in Cortex and Hippocampus Underlying IL15Rα Knockout
Authors: He Yi , Yu Yuxin , Li Yanan , Duan Weicheng , Sun Zuoli , Yang Jian , Kastin Abba J. , Pan Weihong , Zhang Yan , Wang Kang 
Published: February 2021

BackgroundPrevious studies of the functions of IL15Rα have been limited to immune activities and skeletal muscle development. Immunological factors have been identified as one of the multiple causes of psychosis, and neurological symptoms have been described in IL15Rα knockout (KO) mice. Seeking to explore possible mechanisms for this in the IL15Rα–/– mouse brain, we analyzed gene expression patterns in the cortex and hippocampus using the RNA-seq technique.MethodsIL15Rα KO mice were generated and littermate wildtype (WT) mice were used as a control group. A Y-maze was used to assess behavior differences between the two groups. The cortex and hippocampus of 3-month-old male mice were prepared and RNA-seq and transcriptome analysis were performed by gene set enrichment analysis (GSEA).ResultsCompared with the WT group, IL15Rα KO animals showed higher speed in the novel arm and more entrance frequency in the old arm in the Y-maze experiment. GSEA indicated that 18 pathways were downregulated and 13 pathways upregulated in both cortex and hippocampus from the GO, KEGG, and Hallmark gene sets. The downregulated pathways formed three clusters: respiratory chain and electron transport, regulation of steroid process, and skeletal muscle development.ConclusionIL15Rα KO mice exhibit altered expression of multiple pathways, which could affect many functions of the brain. Lipid biosynthesis and metabolism in the central nervous system (CNS) should be investigated to provide insights into the effect of IL15Rα on psychosis in this murine model.
S100A8 Promotes Inflammation via Toll-Like Receptor 4 After Experimental Traumatic Brain Injury
Authors: He Guo-Yuan , Zhao Chen-Hui , Wu De-Gang , Cheng Hao , Sun Le-An , Zhang De-Long , Yang Xin-Jie , Fan Xi-Ran , Di Guang-Fu , Jiang Xiao-Chun 
Published: February 2021

IntroductionS100 calcium-binding protein A8 (S100A8) is also known as macrophage-related protein 8, which is involved in various pathological processes in the central nervous system post-traumatic brain injury (TBI), and plays a critical role in inducing inflammatory cytokines. Accumulating evidences have indicated that toll-like receptor 4 (TLR4) is considered to be involved in inflammatory responses post TBI. The present study was designed to analyze the hypothesis that S100A8 is the key molecule that induces inflammation via TLR4 in TBI.MethodsThe weight-drop TBI model was used and randomly implemented on mice that were categorized into six groups: Sham, NS, S100A8, S100A8+TAK-242, TBI, and TBI+TAK-242 groups. In the S100A8+TAK-242 and TBI+TAK-242 groups, at half an hour prior to the intracerebroventricular administration of S100A8 or TBI, mice were intraperitoneally treated with TAK-242 that acts as a selective antagonist and inhibitor of TLR4. Furthermore, the protein recombinant of S100A8 was injected into the lateral ventricle of the brain of mice in the S100A8 and S100A8+TAK-242 groups. Sterile normal saline was injected into the lateral ventricle in the NS group. To evaluate the association between S100A8 and TLR4, Western blot, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and Nissl staining were employed. Simultaneously, the neurological score and brain water content were assessed. In the in vitro analysis, BV-2 microglial cells were stimulated with lipopolysaccharide LPS or S100A8 recombinant protein, with or without TAK-242. The expression of the related proteins was subsequently detected by Western blot or enzyme-linked immunosorbent assay.ResultsThe levels of S100A8 protein and pro-inflammatory cytokines were significantly elevated after TBI. There was a reduction in the neurological scores of non-TBI animals with remarkable severe brain edema after the intracerebroventricular administration of S100A8. Furthermore, the TLR4, p-p65, and myeloid differentiation factor 88 (MyD88) levels were elevated after the administration of S100A8 or TBI, which could be restored by TAK-242. Meanwhile, in the in vitro analysis, due to the stimulation of S100A8 or LPS, there was an upregulation of p-p65 and MyD88, which could also be suppressed by TAK-242.ConclusionThe present study demonstrated that the TLR4-MyD88 pathway was activated by S100A8, which is essential for the development of inflammation in the brain after TBI.
The Impact of Preoperative Radiomics Signature on the Survival of Breast Cancer Patients With Residual Tumors After NAC
Authors: Zhang Ling , Jiang Xinhua , Xie Xiaoming , Wu Yaopan , Zheng Shaoquan , Tian Wenwen , Xie Xinhua , Li Li 
Published: February 2021

BackgroundResidual cancer cells remaining after chemotherapy may have more aggressive behavior that promotes recurrence or metastasis, and which patients would benefit from subsequent additional treatment is controversial. The purpose of our study was to evaluate the prognostic value of the preoperative radiomics features of computed tomography (CT) imaging in breast cancer (BC) patients with residual tumors after neoadjuvant chemotherapy (NAC).MethodsPost-NAC CT images were reviewed from 114 patients who had received breast surgery and had residual breast tumors. The association of the 110 radiomics features derived from CT images with 5-year disease-free survival (DFS) was assessed by log-rank test in the training cohort, resulting in 13 prognostic radiomics features.ResultsWe constructed a radiomics signature consisting of four selected features by using least absolute shrinkage and selection operator (LASSO) Cox regression analysis, which performed well in the discrimination with an area under the curve (AUC) of 0.78 (95% CI, 0.67–0.89) and 0.73 (95% CI, 0.59–0.87) in the training and validation cohorts, respectively. Radiomics nomogram, incorporating the radiomics signature with the conventional clinical variables, also performed well in the two cohorts (training cohort: AUC, 0.84; validation cohort: AUC, 0.82). Moreover, we found that the high-risk patients determined by our radiomics nomogram could benefit from postoperative adjuvant chemotherapy, while the low-risk and total patient groups could not.ConclusionsOur novel radiomics nomogram is a promising and favorable prognostic biomarker for preoperatively predicting survival outcomes and may aid in clinical decision-making in BC patients with residual tumors after NAC.
The Cancer Rehabilitation Medicine Metrics Consortium: A Path to Enhanced, Multi-Site Outcome Assessment to Enhance Care and Demonstrate Value
Authors: Smith Sean R. , Vargo Mary , Zucker David S. , Henderson Maryanne , Shahpar Samman , Wisotzky Eric M. , Custodio Christian , Basford Jeffrey , Jay Gina , Gerber Lynn , Cheville Andrea 
Published: February 2021

PurposeA primary objective stated at the Cancer Rehabilitation Symposium at the National Institutes of Health was to improve outcome measurement. The purpose of this project was for the Cancer Rehabilitation Medicine Metrics Consortium (CRMMC) to develop an assessment tool to evaluate function in cancer patients via a data-driven and methodologically sound process. There is no agreed-upon measure of physical and cognitive function for cancer patients, making it difficult to demonstrate the value of rehabilitation interventions. Cancer patients are a particularly challenging population, with many tumor- and treatment-related variables impacting function.MethodsInvestigators from nine different cancer rehabilitation programs participated in a modified-Delphi process to delineate necessary aspects of an ideal patient assessment tool, including instrument type, domains evaluated, applicability across a range of patient traits, clinical feasibility, and item response characteristics. This involved numerous meetings, data review, and analysis of items involved in patient assessment.ResultsThe CRMMC developed a 21-item patient-reported outcome measure based on item response theory. The process by which the short form was developed was documented and provides a framework for other clinicians to follow. ConclusionThis document provides a framework for rehabilitation providers to follow when developing an assessment tool. This process is described in a stepwise fashion for reproducibility even in different, non-cancer populations.
Cardiotoxicity After Anthracycline Chemotherapy for Childhood Cancer in a Multiethnic Asian Population
Authors: Tan Varen Zhi Zheng , Chan Nicole Min , Ang Wai Lin , Mya Soe Nwe , Chan Mei Yoke , Chen Ching Kit 
Published: February 2021

Background: Anthracyclines are widely used to treat childhood cancers; however, they cause cardiotoxicity. To address the paucity of clinical data from Asian populations, this study investigated the epidemiology of pediatric anthracycline-induced cardiotoxicity, during and after chemotherapy, in a multiethnic Asian population.Procedure: This was a single-center, retrospective analysis of 458 anthracycline-treated pediatric oncology patients at KK Women's and Children's Hospital, a tertiary children's hospital in Singapore from 2005 through 2015. We investigated cardiotoxicity (defined as left ventricular fractional shortening &lt;28% on echocardiography) and its risk factors using univariate logistic regression as well as survival estimates through the Kaplan-Meier method to compare survival distribution between patients with and without cardiotoxicity.Results: Over a follow-up period of almost 4 years, we found that 7% (32/458) of the cohort developed cardiotoxicity, with 37.5% (12/32) of these manifesting as clinical heart failure, whilst the rest were asymptomatic. The cardiotoxic cohort demonstrated a significantly higher mortality rate compared to the non-cardiotoxic group at 46.9 vs. 19.2% (p &lt; 0.001), of whom 3 (9.4%) died from end-stage heart failure. We found that traditional predictors such as female sex, age at diagnosis, and cumulative doxorubicin equivalent dose were not predictors of cardiotoxicity.Conclusion: Our study reaffirms that freedom from symptoms does not ensure normal heart function and suggests that children with abnormal ventricular systolic function have higher mortality risk compared to those with normal systolic function. The findings contribute to improved understanding of the Asian burden to aid development of measures to prevent or reduce the risk of cardiotoxicity.