bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor Cell-Derived Exosomal miR-770 Inhibits M2 Macrophage Polarization via Targeting MAP3K1 to Inhibit the Invasion of Non-small Cell Lung Cancer Cells
Authors: Liu Jixian , Luo Ruixing , Wang Junbin , Luan Xinyu , Wu Da , Chen Hua , Hou Qinghua , Mao Guangxian , Li Xiaoqiang 
Published: June 2021

BackgroundNon-small cell lung carcinoma (NSCLC) is a type lung cancer with high malignant behaviors. MicroRNAs (miRNAs) are known to be involved in progression of NSCLC. In order to explore potential targets for the treatment of NSCLC, bioinformatics tool was used to analyze differential expressed miRNAs between NSCLC and adjacent normal tissues.MethodsBioinformatics tool was used to find potential targets for NSCLC. Cell proliferation was investigated by Ki67 staining. Cell apoptosis was measured by flow cytometry. mRNA and protein expression in NSCLC cells were detected by RT-qPCR and Western-blot, respectively. Transwell assay was performed to test the cell migration and invasion. In order to investigate the function of exosomal miRNA in NSCLC, in vivo model of NSCLC was constructed.ResultsMiR-770 was identified to be downregulated in NSCLC, and miR-770 agomir could significantly inhibit NSCLC cell proliferation through inducing the apoptosis. Additionally, the metastasis of NSCLC cells was decreased by miR-770 agomir. MAP3K1 was identified to be the target mRNA of miR-770. Meanwhile, tumor cell-derived exosomal miR-770 inhibited M2 macrophage polarization via downregulation of MAP3K1, which in turn suppressed NSCLC cell invasion. Besides, tumor cell-derived exosomal miR-770 markedly decreased NSCLC tumor growth in vivo through suppressing M2 macrophage polarization.ConclusionTumor cell-derived exosomal miR-770 inhibits M2 macrophage polarization to inhibit the invasion of NSCLC cells via targeting MAP3K1. Thus, this study provided a new strategy for the treatment of NSCLC.
VRK1 Depletion Facilitates the Synthetic Lethality of Temozolomide and Olaparib in Glioblastoma Cells
Authors: Navarro-Carrasco Elena , Lazo Pedro A. 
Published: June 2021

BackgroundGlioblastomas treated with temozolomide frequently develop resistance to pharmacological treatments. Therefore, there is a need to find alternative drug targets to reduce treatment resistance based on tumor dependencies. A possibility is to target simultaneously two proteins from different DNA-damage repair pathways to facilitate tumor cell death. Therefore, we tested whether targeting the human chromatin kinase VRK1 by RNA interference can identify this protein as a novel molecular target to reduce the dependence on temozolomide in combination with olaparib, based on synthetic lethality.Materials and MethodsDepletion of VRK1, an enzyme that regulates chromatin dynamic reorganization and facilitates resistance to DNA damage, was performed in glioblastoma cells treated with temozolomide, an alkylating agent used for GBM treatment; and olaparib, an inhibitor of PARP-1, used as sensitizer. Two genetically different human glioblastoma cell lines, LN-18 and LN-229, were used for these experiments. The effect on the DNA-damage response was followed by determination of sequential steps in this process: H4K16ac, γH2AX, H4K20me2, and 53BP1.ResultsThe combination of temozolomide and olaparib increased DNA damage detected by labeling free DNA ends, and chromatin relaxation detected by H4K16ac. The combination of both drugs, at lower doses, resulted in an increase in the DNA damage response detected by the formation of γH2AX and 53BP1 foci. VRK1 depletion did not prevent the generation of DNA damage in TUNEL assays, but significantly impaired the DNA damage response induced by temozolomide and olaparib, and mediated by γH2AX, H4K20me2, and 53BP1. The combination of these drugs in VRK1 depleted cells resulted in an increase of glioblastoma cell death detected by annexin V and the processing of PARP-1 and caspase-3.ConclusionDepletion of the chromatin kinase VRK1 promotes tumor cell death at lower doses of a combination of temozolomide and olaparib treatments, and can be a novel alternative target for therapies based on synthetic lethality.
A Novel Photosensitizer for Lipid Droplet–Location Photodynamic Therapy
Authors: Xia Xiang , Wang Ran , Hu Yingqi , Liu WeiJian , Liu Ting , Sun Wen , Fan Jiangli , Peng Xiaojun 
Published: June 2021

Lipid droplets (LDs), an extremely important cellular organelle, are responsible for the storage of neutral lipids in multiple biological processes, which could be a potential target site for photodynamic therapy (PDT) of cancer. Herein, a lipid droplet–targeted photosensitizer (BODSeI) is developed, allowing for fluorescence imaging–guided PDT. Owing to the location of lipid droplets, BODSeI demonstrates enhanced PDT efficiency with an extremely low IC50 value (around 125 nM). Besides, BODSeI shows good biocompatibility and high photostability. Therefore, BODSeI is promising for droplet-location PDT, which may trigger wide interest for exploring the pathway of lipid droplet–location PDT.
Association of Body-Weight Fluctuation With Outcomes in Heart Failure With Preserved Ejection Fraction
Authors: Li Yi , Yu Yuan , Wu Yuzhong , Liang Weihao , Dong Bin , Xue Ruicong , Dong Yugang , Zhu Wengen , Huang Peisen 
Published: June 2021

Aims: To investigate the relationship between body-weight fluctuation and risks of clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF).Methods and Results:We measured intra-individual variations in body weight from baseline and follow-up visits in 1,691 participants with HFpEF from the Americas from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. The primary endpoint was any cardiovascular events (a composite of death from cardiovascular disease, non-fatal myocardial infarction, aborted cardiac arrest, or hospitalization for HF). The body-weight fluctuation was measured according to average successive variability and high variability was defined as greater than or equal to the median. After adjustment for risk factors, mean body weight and weight change, each increase of 1 standard deviation in body-weight variability was significantly associated with increased risks of any cardiovascular events (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.15–1.33, P &lt; 0.001). Patients with high variability had a 47% increased risk of any cardiovascular events and 27% increased risk of all-cause death compared with those with low variability. Such association was similar among patients with New York Heart Association functional class I/II vs. III/IV, obesity vs. non-obesity, and weight loss, gain vs. stability (the P-values for interaction were all insignificant).Conclusion: Among patients with HFpEF, body-weight fluctuation was associated with increased risks of cardiovascular events independent of traditional cardiovascular risk factors, and regardless of HF severity, baseline weight or weight change direction.Clinical Trial Registration: Aldosterone antagonist therapy for adults with heart failure and preserved systolic function (TOPCAT), https://clinicaltrials.gov, identifier [NCT00094302].
Development of an Immune-Related LncRNA Prognostic Signature for Glioma
Authors: Cao Yudong , Zhu Hecheng , Tan Jun , Yin Wen , Zhou Quanwei , Xin Zhaoqi , Wu Zhaoping , Jiang Zhipeng , Guo Youwei , Kuang Yirui , Li Can , Zhao Ming , Jiang Xingjun , Peng Jiahui , Ren Caiping 
Published: June 2021

IntroductionGlioma is the most common primary cancer of the central nervous system with dismal prognosis. Long noncoding RNAs (lncRNAs) have been discovered to play key roles in tumorigenesis in various cancers, including glioma. Because of the relevance between immune infiltrating and clinical outcome of glioma, identifying immune-related lncRNAs is urgent for better personalized management.Materials and methodsSingle-sample gene set enrichment analysis (ssGSEA) was applied to estimate immune infiltration, and glioma samples were divided into high immune cell infiltration group and low immune cell infiltration group. After screening differentially expressed lncRNAs in two immune groups, least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to construct an immune-related prognostic signature. Additionally, we explored the correlation between immune infiltration and the prognostic signature.ResultsA total of 653 samples were appropriate for further analyses, and 10 lncRNAs were identified as immune-related lncRNAs in glioma. After univariate Cox regression and LASSO Cox regression analysis, six lncRNAs were identified to construct a prognostic signature for glioma, which could be taken as independent prognostic factors in both univariate and multivariate Cox regression analyses. Moreover, risk score was significantly correlated with all the 29 immune-related checkpoint expression (p &lt; 0.05) in ssGSEA except neutrophils (p = 0.43).ConclusionThe study constructed an immune-related prognostic signature for glioma, which contributed to improve clinical outcome prediction and guide immunotherapy.
Impaired Meningeal Lymphatic Flow in NMOSD Patients With Acute Attack
Authors: Wang Xinxin , Tian Haiyan , Liu Han , Liang Dongxiao , Qin Chi , Zhu Qingyong , Meng Lin , Fu Yu , Xu Shuqin , Zhai Yanping , Ding Xuebing , Wang Xuejing 
Published: June 2021

The meningeal lymphatic vessels (mLVs) in central nervous system (CNS) have been validated by rodent and human studies. The mLVs play a vital role in draining soluble molecules and trafficking lymphocytes, antigens and antibodies from CNS into cervical lymph nodes (CLNs). This indicates that mLVs may serve as a link between the CNS and peripheral immune system, perhaps involving in the neuroinflammatory disease. However, the morphology and drainage function of mLVs in patients with neuroinflammatory disease, such as neuromyelitis optica spectrum disorders (NMOSD), remains unexplored. Using the dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), we found that slower flow through mLVs along superior sagittal sinus in NMOSD patients with acute attack instead of NMOSD patients in chronic phase. The reduced flow in mLVs correlated with the disease severity evaluated by expanded disability status scale (EDSS). The receiver operating characteristic curve (ROC) indicated DCE-MRI might provide objective evidence to predict the acute relapse of NMOSD through evaluating the function of mLVs. Promoting or restoring the function of mLVs might be a new target for the treatment of NMOSD relapse.
Impact of Anti-Citrullinated Protein Antibodies on Progressive Systemic Bone Mineral Density Loss in Patients With Early Rheumatoid Arthritis After Two Years of Treat-to-Target
Authors: Bugatti Serena , Bogliolo Laura , Manzo Antonio , De Stefano Ludovico , Delvino Paolo , Motta Francesca , Montecucco Carlomaurizio 
Published: June 2021

ObjectivesTo investigate the association of anti-citrullinated protein antibodies (ACPA) with changes in systemic bone mineral density (BMD) in patients with early rheumatoid arthritis (RA) after two years of treat-to-target.MethodsBMD was measured at the lumbar spine (LS) and femoral neck (FN) in 100 patients with recent onset RA at baseline and after 24 months of treatment aimed at low disease activity (LDA) according to the 28-joints disease activity score (DAS28 &lt;3.2). Multivariable regression analyses were performed to determine independent associations between autoantibodies and other disease and treatment-related parameters with BMD loss.ResultsAfter 24 months, the majority of the patients were at least in LDA (78%), with slightly more ACPA-positive subjects achieving the target. The BMD had significantly decreased at both the LS (mean [SD] percent loss -1.8 [6.2], p=0.03) and the FN (-2.4 [7.3], p=0.03) in ACPA-positive but not in ACPA-negative patients. Consequently, the proportion of patients with reduced BMD (Z score ≤-1) after 24 months was significantly higher among ACPA-positive patients at both the spine (39.5% vs 19.3%, p=0.05) and the hip (37.2% vs 12.2%, p=0.007). The association between ACPA and BMD loss was independent of other variables including age, gender, disease activity, cumulative dose of glucocorticoids and duration of therapy with bisphosphonates at the LS but not the FN.ConclusionsACPA are associated with ongoing BMD loss at the spine despite suppression of inflammation and adoption of prophylactic measures. ACPA-positive RA patients should be therefore strictly monitored for the development of osteoporosis.
Thrombin Generation and Platelet Function in ICU Patients Undergoing CVVHD Using Regional Citrate Anticoagulation
Authors: Wiegele Marion , Infanger Lukas , Lacom Conrad , Koch Stefan , Baierl Andreas , Schaden Eva 
Published: June 2021

Background: To investigate pro- and anticoagulant alterations in uremic critically ill patients prior to and during continuous renal replacement therapy. In addition to the conventional thrombin generation assay (TGA), we performed a thrombomodulin-modified variant to better elucidate procoagulant imbalances. Platelet function was determined via multiple electrode aggregometry (MEA) to round off hemostatic analysis.Methods: We prospectively enrolled patients at surgical intensive care units (ICU) with acute kidney injury undergoing continuous veno-venous hemodialysis using regional citrate anticoagulation. TGA and platelet function testing were performed at baseline (≤ 12 h prior to continuous renal replacement therapy) and on 3 consecutive days (day A–C) of extracorporeal therapy.Results: We did not observe significant changes in thrombin generation after start or during renal replacement therapy. Ratios of endogenous thrombin potential in patients were significantly increased (p &lt; 0.001) compared to standardized plasma of healthy donors confirming the assumed procoagulant alterations in ICU patients. Test results of the conventional TGA differed significantly (p &lt; 0.05) from those of the thrombomodulin-modified assay. The area under the curve remained below MEA reference values during the entire observation period, indicating a persistent reduction in platelet function.Conclusion: In summary, in-depth analysis using standard and modified TGA, as well as calculation of endogenous thrombin potential (ETP) ratios, revealed no further aggravation of the procoagulatory shift in the critically ill patient during CVVHD using regional citrate anticoagulation. MEA ruled out the potential impact of platelets.Clinical Trial Registration: German Clinical Trials Register (DRKS00004336), 29 August 2012; www.drks.de.
Abnormal Fibrinogen Level as a Prognostic Indicator in Coronavirus Disease Patients: A Retrospective Cohort Study
Authors: Long Wei , Yang Jie , Li Zhengwei , Li Jinpeng , Chen Sichao , Chen Danyang , Wang Shipei , Li Qianqian , Hu Di , Huang Jianglong , Zeng Wen , Guo Liang , Wu Xiaohui 
Published: June 2021

Purpose: The coronavirus disease (COVID-19) pandemic poses a global threat, and identification of its prognostic biomarkers could prove invaluable. Fibrinogen (FIB) could be one such indicator as coagulation and fibrinolysis abnormalities are common among COVID-19 patients. We examined the role of FIB levels in the prognosis of COVID-19.Methods: This retrospective cohort study enrolled 1,643 COVID-19 patients from the Leishenshan Hospital in Wuhan, China. The follow-up was conducted from February 8, 2020 to April 15, 2020. The cohort was divided into three groups according to the FIB level on admission, and associations with mortality and disease severity were determined using Cox and logistic regression analyses, respectively. Further, Kaplan–Meier (K–M) analyses by log-rank tests were used to assess the survival of patients with varying FIB levels.Results: Patients with FIB &lt; 2.2 g/L [hazard ratio (HR): 9.02, 95% confidence interval (CI): 1.91–42.59, P = 0.006] and &gt;4.2 g/L (HR: 4.79, 95% CI: 1.14–20.20, P = 0.033) showed higher mortality risks compared to those with FIB between 2.2 and 4.2 g/L. The survival curves showed similar results in K–M analyses (P &lt; 0.001). Additionally, an elevated FIB level was associated with a greater risk of developing critical disease (odds ratio: 2.16, 95% CI: 1.04–4.46, P = 0.038) than a FIB level within the normal range.Conclusion: Abnormal FIB levels may be associated with mortality risk among COVID-19 patients and could predict critical disease development. Thus, assessment of FIB levels may assist in determining the prognosis of COVID-19 patients.
Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives
Authors: Cabri Walter , Cantelmi Paolo , Corbisiero Dario , Fantoni Tommaso , Ferrazzano Lucia , Martelli Giulia , Mattellone Alexia , Tolomelli Alessandra 
Published: June 2021

Targeting protein-protein interactions (PPIs) has been recently recognized as an emerging therapeutic approach for several diseases. Up today, more than half a million PPI dysregulations have been found to be involved in pathological events. The dynamic nature of these processes and the involvement of large protein surfaces discouraged anyway the scientific community in considering them promising therapeutic targets. More recently peptide drugs received renewed attention since drug discovery has offered a broad range of structural diverse sequences, moving from traditionally endogenous peptides to sequences possessing improved pharmaceutical profiles. About 70 peptides are currently on the marked but several others are in clinical development. In this review we want to report the update on these novel APIs, focusing our attention on the molecules in clinical development, representing the direct consequence of the drug discovery process of the last 10 years. The comprehensive collection will be classified in function of the structural characteristics (native, analogous, heterologous) and on the basis of the therapeutic targets. The mechanism of interference on PPI will also be reported to offer useful information for novel peptide design.
Mild Cognitive Impairment and Neurofeedback: A Randomized Controlled Trial
Authors: Lavy Yotam , Dwolatzky Tzvi , Kaplan Zeev , Guez Jonathan , Todder Doron 
Published: June 2021

Background and Objectives: Mild cognitive impairment (MCI) is often a precursor of dementia, and in particular of Alzheimer's Disease (AD) which is the most common cause of dementia. Individuals with amnestic MCI are several-fold more likely to develop AD than the general population. Therefore, MCI comprises a well-detectable, early stage time-point for therapeutic intervention and strategic prevention. Based on common electroencephalographical (EEG) pattern changes seen in individuals with MCI, we postulated that EEG-based neurofeedback could help improve the memory performance of patients with MCI. Memory performance is of particular importance in these patients, since memory decline is the most prominent symptom in most patients with MCI, and is the most predictive symptom for cognitive deterioration and the development of AD.Methods: In order to improve the memory performance of patients with MCI we used a system of EEG-based neurofeedback in an attempt to reverse alterations of the EEG that are known to be common in patients with MCI. Our protocol comprised the provision of positive feedback in order to enhance the activity level of the upper alpha band. Participants were divided to two groups receiving either neurofeedback training to enhance the upper alpha frequency (Experimental group) or random feedbacks (Sham group)Results: We witnessed a significant improvement in memory performance in subjects in the experimental group compared to those in the sham group. This improvement was maintained for at least 1 month.Conclusions: Neurofeedback may be a promising and affordable novel approach for treating the decline in memory witnessed in patients with MCI.
TDP-43 and Phosphorylated TDP-43 Levels in Paired Plasma and CSF Samples in Amyotrophic Lateral Sclerosis
Authors: Ren Yuting , Li Siyuan , Chen Siyu , Sun Xiaosun , Yang Fei , Wang Hongfen , Li Mao , Cui Fang , Huang Xusheng 
Published: June 2021

Objective: The aim of this study was to measure both plasma and cerebrospinal fluid (CSF) TAR DNA-binding protein 43 (TDP-43) and phosphorylated TDP-43 (pTDP-43) levels in sporadic amyotrophic lateral sclerosis (sALS) patients, and to compare them with that of healthy controls. The correlation between plasma or CSF TDP-43/pTDP-43 and clinical indicators of ALS patients was assessed.Methods: Paired plasma and CSF TDP-43/pTDP-43 levels in 69 ALS patients and 59 healthy controls were measured by sandwich ELISA. Time to generalization (TTG), an indicator suggested that the time of symptoms spreading from spinal or bulbar localization to both, was evaluated in all patients screened for mutations in genes associated with ALS.Results: Both of the plasma TDP-43 and pTDP-43 levels were significantly higher in ALS patients than HCs (P &lt; 0.001). The pTDP-43/TDP-43 ratios in plasma were significantly higher in HCs than ALS patients (P &lt; 0.001). The area under the curve (AUC) value was 0.924 for plasma TDP-43 level, with a 91.3% sensitivity and 91.5% specificity. Moreover, the correlation between plasma and CSF TDP-43 was observed in each ALS patient (r = 0.195, P = 0.027). A correlation between CSF pTDP-43 levels and the ALSFRS-R (r = −0.245; P = 0.042) was established. A correlation was observed between plasma TDP-43 levels and TTG in ALS patients, which indicated that high levels of plasma TDP-43 correlated with prolonged TTG (r = 0.415; P = 0.004).Conclusion: The plasma TDP-43 and pTDP-43 levels might play an important role in diagnosis in the future study of ALS. The plasma TDP-43 might differentiate ALS and HC groups based on high sensitivity and specificity, and as an indicator of progression of disease.
Radiofrequency Lesioning for Movement and Psychiatric Disorders-Experience of 107 Cases
Authors: Doshi Paresh K. 
Published: June 2021

BackgroundRadiofrequency lesioning (RFL) though used since the 1950s, had been replaced by DBS in the 1990s. The availability of magnetic resonance-guided focused ultrasound for lesioning has renewed the interest in RFL.ObjectiveThis paper analysis RFL in contemporary Functional Neurosurgery for various indications and its outcome. Complication rates of RFL are compared with the same author’s experience of DBS.MethodsOne hundred and seven patients underwent RFL between 1998 and 2019. Indications included Parkinson’s Disease (PD), tremors, dystonia, and obsessive-compulsive disorders (OCD). The surgeries performed include thalamotomy (29), pallidotomy (49), subthalamotomy (23), and anterior capsulotomy/nucleus accumbens lesioning (6). Appropriate rating scales were used for preoperative and postoperative evaluations.ResultsThere was a 25% recurrence rate of tremors for PD after thalamotomy. Writer’s cramp rating scale improved from a mean of 10.54–1.6 in task specific dystonia (TSD) patients, after thalamotomy. In PD patients, after pallidotomy, contralateral motor Unified Parkinson’s Disease Rating Scale (UPDRS) and dyskinesia scores, improved by 41 and 57%, respectively, at 1-year. Burke-Fahn-Marsden Dystonia Rating Scale in hemidystonia patients improved from 18.04 to 6.91, at 1-year. There was 32 and 31% improvement in total and motor UPDRS, respectively, in the subthalamotomy patients, at 2-year. All patients of OCD were in remission. There were three deaths in the pallidotomy group. Postoperative, dysarthria, confusion, hemiparesis, dyskinesia, and paraesthesia occurred in 12 patients, of which, 7 were transient.ConclusionRFL is a useful option in a select group of patients with tremors and dystonia. It is our preferred treatment option for TSD and OCD.