bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating Cytokines Predict 1H-Proton MRS Cerebral Metabolites in Healthy Older Adults
Authors: Langer Kailey , Cohen Ronald A. , Porges Eric C. , Williamson John B. , Woods Adam J. 
Published: August 2021

Background: Changes in both circulating cytokines and neurochemical concentrations have been observed in aging. Patterns of change across these factors are associated with age-related pathologies, including neurodegenerative disease. More evidence to define patterns of change that are characteristic of healthy aging is needed, as is an investigation into how age-related changes in blood cytokines and brain neurochemicals may relate to one another in a healthy older adult population.Methods: Single voxel 1H-proton magnetic resonance spectroscopy was collected in medial frontal and medial parietal regions. Phosphocholine and glycerophosphocholine (Cho), myo-inositol (MI), N-acetylaspertate and N-acetylasperglutamate (NAA), creatine and phosphocreatine (Cr), and glutamate and glutamine (Glx) were measured in a sample of 83 healthy, cognitively normal adults aged 52–89. Blood data were collected to quantify 12 cytokines: interleukins (IL-) 2, 5, 6, 7, 8, 10, 12, 13, IL-1 β, tumor necrosis factor α (TNF-α), interferon γ (IFN-γ), and IL-17 α. Correlation analyses were performed to assess age relationships between each of these factors. Backward linear regressions were performed. Cytokine data and age were used as predictors of each cerebrospinal fluid (CSF)-corrected metabolite concentration in both voxels.Results: Associations were identified between a variety of cytokines and concentrations of frontal NAA, Cr, and Glx, and of parietal MI, Cho, NAA, and Cr. In the frontal voxel, NAA was predicted by more IL-1B and less TNF-α, Cr by less TNF-α and more IL-5, and Glx by less TNF-α. In the parietal voxel, MI was predicted by more IL-10 and IL-8 and less IL-2, Cho by more TNF-α and less IL-2, NAA by more IL-1B and TNF-α and less IL-13, IL-2, and IL-7, and Cr by more IL-10 and less IL-2.Conclusions: Associations were identified between circulating cytokines and neurometabolite concentrations in this sample of older adults. The present results serve as the initial evidence of relationships between circulating cytokines and neurophysiology. Findings invite further investigation to understand the physiological consequences of aging, and how peripheral inflammatory markers may relate to neurochemical concentrations in healthy aging.
L-3,4-Dihydroxyphenylalanine Recovers Circadian Rhythm Disturbances in the Rat Models of Parkinson's Disease by Regulating the D1R-ERK1/2-mTOR Pathway
Authors: Yang Shuyuan , Wan Ying , Wu Na , Song Lu , Liu Zhihua , Zhao Jiahao , Liu Ying , Liu Zhenguo , Gan Jing 
Published: August 2021

Objective: Patients with Parkinson's disease (PD) frequently experience disruptions in the 24-h daily profile of both behavioral and biological markers. However, whether L-3,4-dihydroxyphenylalanine (L-dopa) influences these markers associated with circadian rhythm or not is still an open question. This study aims to explore the L-dopa effects on the rhythmic expression of core clock proteins [brain and muscle Arnt-like protein-1 (BMAL1) and circadian locomotor cycle kaput (CLOCK)], in the striatum of the rat model of PD and its underlying molecular mechanisms.Methods: Unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat models were used in this study. L-dopa administrations were adopted to investigate the changes of circadian rhythm in PD. The behavioral tests and the measurements of the blood pressure (BP) and temperature were evaluated. The striatum was collected at intervals of 4 h. Western blot was used to examine the expressions of clock protein and the molecular protein of the D1R-ERK1/2-mTOR pathway. The rhythmic expressions of symptom parameters and circadian proteins were analyzed using the Cosinor model and/or the coefficient of variability (CV) that was used to describe the variability of the 24-h rhythm.Results: The circadian rhythms of BP and temperature were disrupted in 6-OHDA-lesioned PD rats compared with the sham group, while this process was reversed mildly by L-dopa treatment. The expressions of BMAL1 and CLOCK protein were rhythmic fluctuated without significant phase alterations when 6-OHDA or L-dopa was applied. Furthermore, the expressions of striatal BMAL1 protein in the 6-OHDA-lesioned group were significantly lower than those in the sham group at 04:00, 08:00, and 12:00, and the CLOCK protein was decreased at 04:00, 08:00, 12:00, 16:00, and 20:00 (all p &lt; 0.05). The CV of the expressions of both BMAL1 and CLOCK was decreased in the 6-OHDA group; this process was reversed by L-dopa. Moreover, the CV of BMAL1 and CLOCK was elevated in the L-dopa rats. The phosphorylation levels of ERK1/2, S6K1, and 4E-BP1 in 6-OHDA-lesioned striatum were increased by L-dopa or D1 receptor agonist SKF38393 (p &lt; 0.05, respectively), not by the combination of L-dopa and D1 receptor antagonist SCH23390, which was similar to the expressions of BMAL1 and CLOCK.Conclusion: L-dopa recovers the circadian rhythm disturbances in PD rats by regulating the D1R-ERK1/2-mTOR pathway.
Multiple-Factor Analyses of Futile Recanalization in Acute Ischemic Stroke Patients Treated With Mechanical Thrombectomy
Authors: Pan Hui , Lin Changchun , Chen Lina , Qiao Yuan , Huang Peisheng , Liu Bin , Zhu Yueqi , Su Jingjing , Liu Jianren 
Published: August 2021

Background and Purpose: Acute ischemic stroke (AIS) is a serious threat to the life and health of middle-aged and elderly people. Mechanical thrombectomy offers the advantages of rapid recanalization, but the response of patients to this treatment varies greatly. This study investigated the risk factors for futile recanalization in AIS patients after thrombectomy through multivariate analyses.Methods: A retrospective study was conducted in AIS patients with anterior circulation occlusion from a derivation cohort and a validation cohort who underwent thrombectomy and reperfusion defined as a modified Thrombolysis in Cerebral Infarction (mTICI) score of 2b/3. Using the modified Rankin Scale (mRS) at 90 days after the operation, the patients were divided into two groups, the meaningful recanalization group (mRS ≤ 2), and the futile recanalization group (mRS &gt; 2). Multivariate logistic regression analyses were performed, and the receiver operating characteristic (ROC) curve was used to construct a risk prediction model for futile recanalization. The performance of prediction model was evaluated on the validation cohort.Results: A total of 140 patients in the derivation cohort were enrolled, 46 patients in the meaningful recanalization group and 94 patients in the futile recanalization group. The two groups were significantly different in age, preoperative National Institute of Health Stroke Scale (NIHSS) score, and collateral circulation ASITN/SIR grade (P &lt; 0.05). In multivariate regression analyses, patients' age ≥ 71, NIHSS ≥ 12, and ASITN/SIR ≤ 3 were risk factors for futile recanalization. Hence, an ANA (Age-NIHSS-ASITN/SIR) score scale consisting of age, NIHSS score, and ASITN/SIR grade factors can effectively predict the risk for futile recanalization (area under curve 0.75, 95% CI 0.67–0.83, specificity 67.4%, and sensitivity 73.4%). The proportion of patients with futile recanalization in ANA groups 0, 1, 2, and 3 were 21.05, 56.76, 79.03, and 90.91%, respectively. Furthermore, ANA score scale had also a good performance for predicting futile recanalization on the validation cohort.Conclusions: Old age, high baseline NIHSS, and poor collateral circulation are risk factors for futile recanalization in AIS patients treated with thrombectomy. An ANA score that considers age, NIHSS, and collateral ASITN/SIR can effectively predict the risk for futile recanalization. Further studies with a larger sample size are needed to validate the prognostic value of this combined score for futile recanalization.
Prognostic Role of EGFR/p-EGFR in Patients With Nasopharyngeal Carcinoma: A Meta-Analysis
Authors: Chen Xishan , Liang Renba , Lai Lin , Chen Kaihua , Zhu Xiaodong 
Published: August 2021

BackgroundThe prognostic value of epidermal growth factor receptor (EGFR)/phosphorylated EGFR (p-EGFR) expression in nasopharyngeal carcinoma remains controversial. A meta-analysis was performed to investigate prognostic significance of EGFR/p-EGFR expression in patients with nasopharyngeal carcinoma.MethodsLiteratures published before November 2020 were systematically searched in relevant databases, including PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), and Wan fang databases. STATA 13 statistical software was used to analyze the pooled hazard ratio (HR) and 95% confidence interval (CI). Heterogeneity of the studies was examined by I2. Sensitivity and subgroup analysis were performed to explore sources of heterogeneity. The potential publication bias was assessed using both Egger’s and Begg’s tests.ResultsA total of 20 literatures with 1545 patients were included for the meta-analysis. The meta-analysis results suggested that high expression of EGFR was significantly associated with poor overall survival (OS) (HR = 1.70, 95% CI: 1.24–3.15, P = 0.001) and disease-free survival (DFS) (HR = 2.58, 95% CI: 1.87–3.56, P = 0.000). However, it was not significantly associated with progression-free survival (PFS) (HR = 1.85, 95% CI: 0.90–3.82, P = 0.09) and distant metastasis-free survival (DMFS) (HR = 1.39, 95% CI: 0.73–2.67, P = 0.319). The subgroup analysis indicated that patients with EGFR high expression in studies of higher TNM stage (III–IV) ratio had significantly poor OS (HR = 2.27, 95% CI: 1.09–4.73, P = 0.03), but heterogeneity existed in studies (I2  =  95.1%, P = 0.000). Sensitivity analyses revealed that EGFR expression did not significantly affect OS by an individual study solely, indicating there was inherent heterogeneity in OS cohorts. There was no significant heterogeneity among eight studies in the DFS cohorts (I2 = 0%, P = 0.606). There was significant heterogeneity between EGFR expression and DMFS (I2 = 82.8%, P = 0.000). Sub-group analysis in differentiated carcinoma demonstrated a smaller heterogeneity (I2 = 33.2%). In addition, p-EGFR high expression had no significant correlation with OS (HR = 1.00, 95% CI: 0.88–1.14, P = 0.982) and DMFS (HR = 1.21, 95% CI: 0.96–1.52, P = 0.112). The heterogeneity among p-EGFR and OS studies was small (I2 = 21%, P = 0.26). There was no significant heterogeneity in the DMFS cohorts (I2 = 0%, P = 0.497).ConclusionEGFR high-expression was significantly associated with poor OS and DFS, which may serve as a prognostic predictor for nasopharyngeal cancer.Systematic Review Registration[https://www.crd.york.ac.uk/PROSPERO], identifier [number CRD42021258457].
Exosome-Derived Long Non-Coding RNAs as Non-Invasive Biomarkers of Bladder Cancer
Authors: Su Quanxin , Wu Hao , Zhang Ziyi , Lu Chao , Zhang Lifeng , Zuo Li 
Published: August 2021

ObjectiveAs a result of the inconsistency between reports, a meta-analysis was designed to appraise the clinical implications of long non-coding RNAs (lncRNAs) in exosomes for the diagnosis of bladder cancer.MethodsThe PubMed, EMBASE, and Cochrane library databases were searched to identify the relevant literature on lncRNAs in exosomes for bladder cancer diagnosis from database inception to May 2021. The literature was screened according to the inclusion and exclusion criteria, and the Quality Assessment of Diagnostic Accuracy Studies-2 entry tool was applied to evaluate the quality of the literature, and the sources of heterogeneity were explored using meta-regression and subgroup analysis. Stata 14.0 and RevMan 5.3 software were used for statistical analysis.ResultsA total of 23 studies described in 10 articles were included, with a total of 1883 patients with bladder cancer and 1721 patients in the non-cancerous control group. The exosome-derived lncRNAs performed better in the diagnosis of bladder cancer with a pooled sensitivity of 0.74 (95% CI, 0.69-0.77), specificity of 0.76 (95% CI, 0.72-0.80), and area under the curve of 0.83. The heterogeneity between studies was partly as a result of differences in specimen type, number of lncRNAs, lncRNA expression form, and reference gene type. Subgroup analysis showed that the detection efficacy based on the combination of multiple lncRNAs (0.86, 95% CI, 0.82-0.88) was higher than that based on a single lncRNA (0.81, 95% CI, 0.78-0.85), and exosomal lncRNAs with blood as the detection sample had a high diagnostic efficacy (0.86, 95% CI, 0.82-0.86).ConclusionsExosome-derived lncRNAs hold great promise as non-invasive diagnostic biomarkers of bladder cancer. However, their clinical value needs to be examined in further comprehensive prospective studies.
Telomere Shortening in Peripheral Leukocytes Is Associated With Poor Survival in Cancer Patients Treated With Immune Checkpoint Inhibitor Therapy
Authors: Rolles Benjamin , Gorgulho Joao , Tometten Mareike , Roderburg Christoph , Vieri Margherita , Abels Anne , Vucur Mihael , Heymann Felix , Tacke Frank , Brümmendorf Tim H. , Luedde Tom , Beier Fabian , Loosen Sven H. 
Published: August 2021

BackgroundImmune checkpoint inhibitor (ICI) therapy represents a new standard of care for an increasing number of malignancies. Nevertheless, response rates and outcome of ICI treatment vary between individuals and the identification of predictive markers or hints towards immune cell exhaustion during therapy has remained a major challenge. Leukocyte telomere length is an established predictive biomarker of replicative aging and cellular proliferative potential in various hematological diseases. However, its relevance in the context of ICI therapy has not been investigated to date. Here, we analyze the age-adapted delta telomere length (ΔTL) of peripheral leukocytes as a potential predictive and prognostic marker in patients undergoing ICI therapy.MethodsAge-adapted delta telomere length (ΔTL) of 84 patients treated with ICIs for solid malignancies was measured via quantitative real-time PCR. ΔTL was correlated with outcome and clinical data.ResultsΔTL was not significantly altered between patients with different tumor entities or tumor stages and did not predict tumor response to ICI therapy. However, ΔTLs at initiation of treatment were a prognostic marker for overall survival (OS). When using a calculated ideal cut-off value, the median OS in patients with shorter ΔTL was 5.7 months compared to 18.0 months in patients showing longer ΔTL. The prognostic role of age-adapted ΔTL was further confirmed by uni- and multivariate Cox-regression analyses.ConclusionIn the present study, we demonstrate that shorter telomere lengths in peripheral blood leukocytes are associated with a significantly impaired outcome in patients receiving ICI therapy across different malignancies. We explain our findings by hypothesizing an older replicative age in peripheral leukocytes of patients with an impaired overall survival, reflected by a premature TL shortening. Whether this association is ICI-specific remains unknown. Further follow-up studies are needed to provide insights about the exact mechanism of how shortened telomeres eventually affect OS and could help guiding therapeutic decisions in future.
The Versatility of the Free Vastus Lateralis Muscle Flap: Orbital Reconstruction After Removal of Complex Vascular Malformation in a Pediatric Patient
Authors: Grussu Francesca , Santecchia Luigino , Urbani Urbano , Spuntarelli Giorgio , Rollo Massimo , El Hachem May , Romanzo Antonino , Zama Mario 
Published: August 2021

Introduction: Vascular orbital lesions in pediatric population represent a demanding therapeutic challenge which requires a multidisciplinary team. In severe cases, orbital enucleation can be considered. Surgical management of enucleated orbital region in children, differently from the adults, represents a challenging procedure owing to the intrinsic relation between volume replacement and normal orbital growth. Many reconstructive options have been proposed, and many donor sites have been utilized for this purpose but each one have demonstrated potential disadvantages. Despite its well-known versatility, no report of the vastus lateralis free flap in children requiring orbital reconstruction exists in literature. Herein, we propose this surgical strategy as a valid option for the reconstruction of an extended orbital defect in a pediatric patient suffering from a mixed type of vascular malformation.Material and Methods: A patient was referred from a foreign country with an unclear medical history, presenting exorbitism and exophthalmos, proptosis of the eyeball, visus 4/10, and limited ocular motility. We made clinical-instrumental investigations with a diagnosis of complex vascular malformation. It expanded in intraorbital and retrorbital space with bulb anterior dislocation and optic nerve involvement. We performed an emptying of the orbital content via transconjunctival and via coronal incision with eyelid preservation. A free vastus lateralis muscle flap was used for reconstruction, filling the orbital cavity. We anastomosed the flap on the superficial temporal artery. An ocular conformator was then positioned.Results: We report the result at 12 months, showing a good orbital rehabilitation with an adequate prosthetic cavity, a good recovery of volume and facial symmetry, guaranteeing balanced orbital and periorbital growth. There were no major or minor complications associated with the procedure.Discussion: The reconstruction of the orbit remains a “surgical challenge” both in adults, whose goal is the restoration of volume, adequate symmetry and facial esthetics, and children, in which correcting the asymmetry has the additional objective to balance orbital growth. Many reconstructive techniques have been proposed, including the use of free flaps. The versatility of the free vastus lateralis muscle flap is well-known. It offers adequate amount of tissue with minimal morbidity to the donor site, provides a long pedicle, gives the possibility of simultaneous work in a double team, and has a constant anatomy and a safe and rapid dissection. There are no descriptions of its use for pediatric orbital reconstructions.Conclusions: In our opinion, the free vastus lateralis flap should be included as one of the best option for orbital pediatric reconstruction after enucleation.
Dynamic Modeling of Mitochondrial Membrane Potential Upon Exposure to Mitochondrial Inhibitors
Authors: Yang Huan , van der Stel Wanda , Lee Randy , Bauch Caroline , Bevan Sam , Walker Paul , van de Water Bob , Danen Erik H. J. , Beltman Joost B. 
Published: August 2021

Mitochondria are the main bioenergetic organelles of cells. Exposure to chemicals targeting mitochondria therefore generally results in the development of toxicity. The cellular response to perturbations in cellular energy production is a balance between adaptation, by reorganisation and organelle biogenesis, and sacrifice, in the form of cell death. In homeostatic conditions, aerobic mitochondrial energy production requires the maintenance of a mitochondrial membrane potential (MMP). Chemicals can perturb this MMP, and the extent of this perturbation depends both on the pharmacokinetics of the chemicals and on downstream MMP dynamics. Here we obtain a quantitative understanding of mitochondrial adaptation upon exposure to various mitochondrial respiration inhibitors by applying mathematical modeling to partially published high-content imaging time-lapse confocal imaging data, focusing on MMP dynamics in HepG2 cells over a period of 24 h. The MMP was perturbed using a set of 24 compounds, either acting as uncoupler or as mitochondrial complex inhibitor targeting complex I, II, III or V. To characterize the effect of chemical exposure on MMP dynamics, we adapted an existing differential equation model and fitted this model to the observed MMP dynamics. Complex III inhibitor data were better described by the model than complex I data. Incorporation of pharmacokinetic decay into the model was required to obtain a proper fit for the uncoupler FCCP. Furthermore, oligomycin (complex V inhibitor) model fits were improved by either combining pharmacokinetic (PK) decay and ion leakage or a concentration-dependent decay. Subsequent mass spectrometry measurements showed that FCCP had a significant decay in its PK profile as predicted by the model. Moreover, the measured oligomycin PK profile exhibited only a limited decay at high concentration, whereas at low concentrations the compound remained below the detection limit within cells. This is consistent with the hypothesis that oligomycin exhibits a concentration-dependent decay, yet awaits further experimental verification with more sensitive detection methods. Overall, we show that there is a complex interplay between PK and MMP dynamics within mitochondria and that data-driven modeling is a powerful combination to unravel such complexity.
Weekly Variations of Short-Duration Maximal Jumping Performance in Soccer Players: Exploring Relationships With Accumulated Training Load and Match Demands
Authors: Silva Rui , Clemente Filipe Manuel , González-Fernández Francisco Tomás , Bernardo André , Ardigò Luca Paolo 
Published: August 2021

Purpose: The aim of this study was 2-fold: (1) to analyze variations of short-duration maximal jumping performance in players exposed to a match and those who were not and (2) to analyze the relationships between changes in the short-duration maximal jumping performance and different accumulated training load and match demands measures.Methods: Twenty-four professional soccer players (age: 20.3 ± 1.7 years) were monitored daily for their training load and match demands over 6 weeks. In addition, they performed a weekly short-duration maximal jumping performance test (72 h after the last match).Results: Negative moderate correlations were found between percentage of change of countermovement jump (CMJ) height and Acummulated training load (ATL) of total distance (TD), high metabolic load (HML), accelerations (ACC), and decelerations (DEC) (r = −0.38, p = 0.004; r = −0.33, p = 0.013; r = −0.39, p = 0.003; and r = −0.30, p = 0.026). No correlations were found for match load (ML). TD, HML, ACC, and DCC (r = 0.27, r = 0.25, r = 0.31, and r = 0.22, respectively) were used to predict the percentage of change of CMJ height.Conclusion: Match participation has negative effects on CMJ performance. The ATL of HML, ACC, DCC, and TD have a significant influence on both CMJ measures changes. Also, the ATL values of those metrics are the best predictors of the percentage changes of CMJ performance.