bluuebunny/crossref_metadata_2025 huggingface dataset:
Inter- and Intra-Scanner Variability of Automated Brain Volumetry on Three Magnetic Resonance Imaging Systems in Alzheimer’s Disease and Controls
Authors: Wittens Mandy Melissa Jane , Allemeersch Gert-Jan , Sima Diana Maria , Naeyaert Maarten , Vanderhasselt Tim , Vanbinst Anne-Marie , Buls Nico , De Brucker Yannick , Raeymaekers Hubert , Fransen Erik , Smeets Dirk , van Hecke Wim , Nagels Guy , Bjerke Maria , de Mey Johan , Engelborghs Sebastiaan
Published: October 2021

Magnetic Resonance Imaging (MRI) has become part of the clinical routine for diagnosing neurodegenerative disorders. Since acquisitions are performed at multiple centers using multiple imaging systems, detailed analysis of brain volumetry differences between MRI systems and scan-rescan acquisitions can provide valuable information to correct for different MRI scanner effects in multi-center longitudinal studies. To this end, five healthy controls and five patients belonging to various stages of the AD continuum underwent brain MRI acquisitions on three different MRI systems (Philips Achieva dStream 1.5T, Philips Ingenia 3T, and GE Discovery MR750w 3T) with harmonized scan parameters. Each participant underwent two subsequent MRI scans per imaging system, repeated on three different MRI systems within 2 h. Brain volumes computed by icobrain dm (v5.0) were analyzed using absolute and percentual volume differences, Dice similarity (DSC) and intraclass correlation coefficients, and coefficients of variation (CV). Harmonized scans obtained with different scanners of the same manufacturer had a measurement error closer to the intra-scanner performance. The gap between intra- and inter-scanner comparisons grew when comparing scans from different manufacturers. This was observed at image level (image contrast, similarity, and geometry) and translated into a higher variability of automated brain volumetry. Mixed effects modeling revealed a significant effect of scanner type on some brain volumes, and of the scanner combination on DSC. The study concluded a good intra- and inter-scanner reproducibility, as illustrated by an average intra-scanner (inter-scanner) CV below 2% (5%) and an excellent overlap of brain structure segmentation (mean DSC > 0.88).
The Epic of the Thalamus in Anatomical Language
Authors: García-Cabezas Miguel Ángel , Pérez-Santos Isabel , Cavada Carmen
Published: October 2021

Understanding the origin of Greek and Latin words used as metaphors to label brain structures gives a unique window into how scientific and medical knowledge was produced, preserved, and transmitted through generations. The history of the term thalamus exemplifies the complex historical process that led to the current anatomical terminology. From its first mention by Galen of Pergamon in the 2nd century A.D. to its definitive and current use by Thomas Willis in 1664, the thalamus had an epical journey through 1500 years across Europe, the Middle East, and the North of Africa. The thalamus was confusingly described by Galen, in the Greek language, as a chamber to the brain ventricles. The term thalamus was transferred from Greek to Syriac through the translations of Galen’s books done in Baghdad and also from Syriac to Arabic. Then, it was translated in Europe during the Middle Ages from the Arabic versions of Galen’s books to Latin. Later, during the Early Renaissance, it was translated again to Latin directly from the Greek versions of Galen’s books. Along this epical journey through languages, the term thalamus switched from referring to a hollow structure connected to brain ventricles to naming a solid structure at the rostral end of the brainstem. Finally, the thalamus was translated from Latin to modern languages, where it is used, until today, to name a nuclear complex of subcortical gray matter in the lateral walls of the third ventricle.
Shaping of Regional Differences in Oligodendrocyte Dynamics by Regional Heterogeneity of the Pericellular Microenvironment
Authors: Sherafat Amin , Pfeiffer Friederike , Nishiyama Akiko
Published: October 2021

Oligodendrocyte precursor cells (OPCs) are glial cells that differentiate into mature oligodendrocytes (OLs) to generate new myelin sheaths. While OPCs are distributed uniformly throughout the gray and white matter in the developing and adult brain, those in white matter proliferate and differentiate into oligodendrocytes at a greater rate than those in gray matter. There is currently lack of evidence to suggest that OPCs comprise genetically and transcriptionally distinct subtypes. Rather, the emerging view is that they exist in different cell and functional states, depending on their location and age. Contrary to the normal brain, demyelinated lesions in the gray matter of multiple sclerosis brains contain more OPCs and OLs and are remyelinated more robustly than those in white matter. The differences in the dynamic behavior of OL lineage cells are likely to be influenced by their microenvironment. There are regional differences in astrocytes, microglia, the vasculature, and the composition of the extracellular matrix (ECM). We will discuss how the regional differences in these elements surrounding OPCs might shape their phenotypic variability in normal and demyelinated states.
Neurodegenerative Disease: What Potential Therapeutic Role of Acid-Sensing Ion Channels?
Authors: Mango Dalila , Nisticò Robert
Published: October 2021

Acidic pH shift occurs in many physiological neuronal activities such as synaptic transmission and synaptic plasticity but also represents a characteristic feature of many pathological conditions including inflammation and ischemia. Neuroinflammation is a complex process that occurs in various neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and Huntington’s disease. Acid-sensing ion channels (ASICs) represent a widely expressed pH sensor in the brain that play a key role in neuroinflammation. On this basis, acid-sensing ion channel blockers are able to exert neuroprotective effects in different neurodegenerative diseases. In this review, we discuss the multifaceted roles of ASICs in brain physiology and pathology and highlight ASIC1a as a potential pharmacological target in neurodegenerative diseases.
Short- and Long-Term Effects of DBS on Gait in Parkinson's Disease
Authors: Brozova Hana , Barnaure Isabelle , Ruzicka Evzen , Stochl Jan , Alterman Ron , Tagliati Michele
Published: October 2021

The aim was to compare the short and long-term effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on gait dysfunction and other cardinal symptoms of Parkinson's disease (PD). Two groups of patients were studied. The first group (short-term DBS, n = 8) included patients recently implanted with STN DBS (mean time since DBS 15.8 months, mean age 58.8 years, PD duration 13 years); the second group (long-term DBS, n = 10) included patients with at least 5 years of DBS therapy (mean time since DBS 67.6 months, mean age 61.7 years, PD duration 17.1 years). Both groups were examined using the Unified Parkinson's Disease Rating Scale (UPDRS) and Gait and Balance scale (GABS) during four stimulation/medication states (ON/OFF; OFF/OFF; OFF/ON; ON/ON). Data were analyzed using repeated measures ANOVA with time since implantation (years) between groups and medication or DBS effect (ON, OFF) within groups. In the short-term DBS group, stimulation improved all UPDRS subscores similar to dopaminergic medications. In particular, average gait improvement was over 40% (p = 0.01), as measured by the UPDRS item 29 and GABS II. In the long-term DBS group, stimulation consistently improved all clinical subscores with the exception of gait and postural instability. In these patients, the effect of levodopa on gait was partially preserved. Short-term improvement of gait abnormalities appears to significantly decline after 5 years of STN DBS in PD patients, while effectiveness for other symptoms remains stable. Progressive non-dopaminergic (non-DBS responsive) mechanisms or deleterious effects of high frequency STN stimulation on gait function may play a role.
Intracranial EEG Biomarkers for Seizure Lateralization in Rapidly-Bisynchronous Epilepsy After Laser Corpus Callosotomy
Authors: Khuvis Simon , Hwang Sean T. , Mehta Ashesh D.
Published: October 2021

Objective: It has been asserted that high-frequency analysis of intracranial EEG (iEEG) data may yield information useful in localizing epileptogenic foci.

Methods: We tested whether proposed biomarkers could predict lateralization based on iEEG data collected prior to corpus callosotomy (CC) in three patients with bisynchronous epilepsy, whose seizures lateralized definitively post-CC. Lateralization data derived from algorithmically-computed ictal phase-locked high gamma (PLHG), high gamma amplitude (HGA), and low-frequency (filtered) line length (LFLL), as well as interictal high-frequency oscillation (HFO) and interictal epileptiform discharge (IED) rate metrics were compared against ground-truth lateralization from post-CC ictal iEEG.

Results: Pre-CC unilateral IEDs were more frequent on the more-pathologic side in all subjects. HFO rate predicted lateralization in one subject, but was sensitive to detection threshold. On pre-CC data, no ictal metric showed better predictive power than any other. All post-corpus callosotomy seizures lateralized to the pathological hemisphere using PLHG, HGA, and LFLL metrics.

Conclusions: While quantitative metrics of IED rate and ictal HGA, PHLG, and LFLL all accurately lateralize based on post-CC iEEG, only IED rate consistently did so based on pre-CC data.

Significance: Quantitative analysis of IEDs may be useful in lateralizing seizure pathology. More work is needed to develop reliable techniques for high-frequency iEEG analysis.
Epileptogenic Zone Localization in Refractory Epilepsy by FDG-PET: The Comparison of SPM and SPM-CAT With Different Parameter Settings
Authors: Bacon Eric Jacob , Jin Chaoyang , He Dianning , Hu Shuaishuai , Wang Lanbo , Li Han , Qi Shouliang
Published: October 2021

Refractory epilepsy is a complex case of epileptic disease. The quantitative analysis of fluorodeoxyglucose positron emission tomography (FDG-PET) images complements visual assessment and helps localize the epileptogenic zone (EZ) for better curative treatment. Statistical parametric mapping (SPM) and its computational anatomy toolbox (SPM-CAT) are two commonly applied tools in neuroimaging analysis. This study compares SPM and SPM-CAT with different parameters to find the optimal approach for localizing EZ in refractory epilepsy. The current study enrolled 45 subjects, including 25 refractory epilepsy patients and 20 healthy controls. All of the 25 patients underwent surgical operations. Pathological results and the postoperative outcome evaluation by the Engel scale were likewise presented. SPM and SPM-CAT were used to assess FDG-PET images with three different uncorrected p-values and the corresponding cluster sizes (k), as in voxels in the cluster, namely p < 0.0002, k > 25; p < 0.001, k > 100; p < 0.005, and k > 200. When combining three settings, SPM and SPM-CAT yielded overall positive finding scores of 96.0% (24/25) and 100.0% (25/25) respectively. However, for the individual setting, SPM-CAT achieved the diverse positive finding scores of 96.0% (24/25), 96.0% (24/25), and 88.0% (22/24), which are higher than those of SPM [88.0% (22/25), 76.0% (19/25), and 72.0% (18/25)]. SPM and SPM-CAT localized EZ correctly with 28.0% (7/25) and 64.0% (16/25), respectively. SPM-CAT with parameter settings p < 0.0002 and k > 25 yielded a correct localization at 56.0% (14/25), which is slightly higher than that for the other two settings (48.0 and 20.0%). Moderate concordance was found between the confirmed and pre-surgical EZs, identified by SPM-CAT (kappa value = 0.5). Hence, SPM-CAT is more efficient than SPM in localizing EZ for refractory epilepsy by quantitative analysis of FDG-PET images. SPM-CAT with the setting of p < 0.0002 and k > 25 might perform as an objective complementary tool to the visual assessment for EZ localization.
Sabotage Detection Using DL Models on EEG Data From a Cognitive-Motor Integration Task
Authors: Chaudhary Mahima , Adams Meaghan S. , Mukhopadhyay Sumona , Litoiu Marin , Sergio Lauren E.
Published: October 2021

Objective clinical tools, including cognitive-motor integration (CMI) tasks, have the potential to improve concussion rehabilitation by helping to determine whether or not a concussion has occurred. In order to be useful, however, an individual must put forth their best effort. In this study, we have proposed a novel method to detect the difference in cortical activity between best effort (no-sabotage) and willful under-performance (sabotage) using a deep learning (DL) approach on the electroencephalogram (EEG) signals. The EEG signals from a wearable four-channel headband were acquired during a CMI task. Each participant completed sabotage and no-sabotage conditions in random order. A multi-channel convolutional neural network with long short term memory (CNN-LSTM) model with self-attention has been used to perform the time-series classification into sabotage and no-sabotage, by transforming the time-series into two-dimensional (2D) image-based scalogram representations. This approach allows the inspection of frequency-based, and temporal features of EEG, and the use of a multi-channel model facilitates in capturing correlation and causality between different EEG channels. By treating the 2D scalogram as an image, we show that the trained CNN-LSTM classifier based on automated visual analysis can achieve high levels of discrimination and an overall accuracy of 98.71% in case of intra-subject classification, as well as low false-positive rates. The average intra-subject accuracy obtained was 92.8%, and the average inter-subject accuracy was 86.15%. These results indicate that our proposed model performed well on the data of all subjects. We also compare the scalogram-based results with the results that we obtained by using raw time-series, showing that scalogram-based gave better performance. Our method can be applied in clinical applications such as baseline testing, assessing the current state of injury and recovery tracking and industrial applications like monitoring performance deterioration in workplaces.
A Novel Sleep Staging Network Based on Data Adaptation and Multimodal Fusion
Authors: Duan Lijuan , Li Mengying , Wang Changming , Qiao Yuanhua , Wang Zeyu , Sha Sha , Li Mingai
Published: October 2021

Sleep staging is one of the important methods to diagnosis and treatment of sleep diseases. However, it is laborious and time-consuming, therefore, computer assisted sleep staging is necessary. Most of the existing sleep staging researches using hand-engineered features rely on prior knowledges of sleep analysis, and usually single channel electroencephalogram (EEG) is used for sleep staging task. Prior knowledge is not always available, and single channel EEG signal cannot fully represent the patient’s sleeping physiological states. To tackle the above two problems, we propose an automatic sleep staging network model based on data adaptation and multimodal feature fusion using EEG and electrooculogram (EOG) signals. 3D-CNN is used to extract the time-frequency features of EEG at different time scales, and LSTM is used to learn the frequency evolution of EOG. The nonlinear relationship between the High-layer features of EEG and EOG is fitted by deep probabilistic network. Experiments on SLEEP-EDF and a private dataset show that the proposed model achieves state-of-the-art performance. Moreover, the prediction result is in accordance with that from the expert diagnosis.
Complexity-Based Analysis of the Variations of Brain and Muscle Reactions in Walking and Standing Balance While Receiving Different Perturbations
Authors: Pakniyat Najmeh , Namazi Hamidreza
Published: October 2021

In this article, we evaluated the variations of the brain and muscle activations while subjects are exposed to different perturbations to walking and standing balance. Since EEG and EMG signals have complex structures, we utilized the complexity-based analysis. Specifically, we analyzed the fractal dimension and sample entropy of Electroencephalogram (EEG) and Electromyogram (EMG) signals while subjects walked and stood, and received different perturbations in the form of pulling and rotation (via virtual reality). The results showed that the complexity of EEG signals was higher in walking than standing as the result of different perturbations. However, the complexity of EMG signals was higher in standing than walking as the result of different perturbations. Therefore, the alterations in the complexity of EEG and EMG signals are inversely correlated. This analysis could be extended to investigate simultaneous variations of rhythmic patterns of other physiological signals while subjects perform different activities.
Assessment of Neuronal Damage in Brain Slice Cultures Using Machine Learning Based on Spatial Features
Authors: Hohmann Urszula , Dehghani Faramarz , Hohmann Tim
Published: October 2021

Neuronal damage presents a major health issue necessitating extensive research to identify mechanisms of neuronal cell death and potential therapeutic targets. Commonly used models are slice cultures out of different brain regions extracted from mice or rats, excitotoxically, ischemic, or traumatically lesioned and subsequently treated with potential neuroprotective agents. Thereby cell death is regularly assessed by measuring the propidium iodide (PI) uptake or counting of PI-positive nuclei. The applied methods have a limited applicability, either in terms of objectivity and time consumption or regarding its applicability. Consequently, new tools for analysis are needed. Here, we present a framework to mimic manual counting using machine learning algorithms as tools for semantic segmentation of PI-positive dead cells in hippocampal slice cultures. Therefore, we trained a support vector machine (SVM) to classify images into either “high” or “low” neuronal damage and used naïve Bayes, discriminant analysis, random forest, and a multilayer perceptron (MLP) as classifiers for segmentation of dead cells. In our final models, pixel-wise accuracies of up to 0.97 were achieved using the MLP classifier. Furthermore, a SVM-based post-processing step was introduced to differentiate between false-positive and false-negative detections using morphological features. As only very few false-positive objects and thus training data remained when using the final model, this approach only mildly improved the results. A final object splitting step using Hough transformations was used to account for overlap, leading to a recall of up to 97.6% of the manually assigned PI-positive dead cells. Taken together, we present an analysis tool that can help to objectively and reproducibly analyze neuronal damage in brain-derived slice cultures, taking advantage of the morphology of pycnotic cells for segmentation, object splitting, and identification of false positives.
New and Emerging Approaches to Better Define Sleep Disruption and Its Consequences
Authors: Lechat Bastien , Scott Hannah , Naik Ganesh , Hansen Kristy , Nguyen Duc Phuc , Vakulin Andrew , Catcheside Peter , Eckert Danny J.
Published: October 2021

Current approaches to quantify and diagnose sleep disorders and circadian rhythm disruption are imprecise, laborious, and often do not relate well to key clinical and health outcomes. Newer emerging approaches that aim to overcome the practical and technical constraints of current sleep metrics have considerable potential to better explain sleep disorder pathophysiology and thus to more precisely align diagnostic, treatment and management approaches to underlying pathology. These include more fine-grained and continuous EEG signal feature detection and novel oxygenation metrics to better encapsulate hypoxia duration, frequency, and magnitude readily possible via more advanced data acquisition and scoring algorithm approaches. Recent technological advances may also soon facilitate simple assessment of circadian rhythm physiology at home to enable sleep disorder diagnostics even for “non-circadian rhythm” sleep disorders, such as chronic insomnia and sleep apnea, which in many cases also include a circadian disruption component. Bringing these novel approaches into the clinic and the home settings should be a priority for the field. Modern sleep tracking technology can also further facilitate the transition of sleep diagnostics from the laboratory to the home, where environmental factors such as noise and light could usefully inform clinical decision-making. The “endpoint” of these new and emerging assessments will be better targeted therapies that directly address underlying sleep disorder pathophysiology via an individualized, precision medicine approach. This review outlines the current state-of-the-art in sleep and circadian monitoring and diagnostics and covers several new and emerging approaches to better define sleep disruption and its consequences.
Characteristics of the School Food Environment Affect the Consumption of Sugar-Sweetened Beverages Among Adolescents
Authors: Rocha Luana Lara , Pessoa Milene Cristine , Gratão Lúcia Helena Almeida , Carmo Ariene Silva do , Cordeiro Nayhanne Gomes , Cunha Cristiane de Freitas , Oliveira Tatiana Resende Prado Rangel de , Mendes Larissa Loures
Published: October 2021

Sugar-sweetened beverages are widely available and accessible in school environment, and their presence and characteristics of this environment can influence their consumption. This study examines the association of drinking fountains per 100 students, soft drink sales, soft drink advertising, and the presence of street vendors and sugar-sweetened beverages consumption among adolescents in Brazil. This cross-sectional study was carried out using data from the Study of Cardiovascular Risk in Adolescents that was conducted between March 2013 and December 2014. The sample comprised 71,475 adolescents aged 12–17 years from 1,247 public and private schools in Brazilian cities. Sugar-sweetened beverages consumption was the dependent variable. The main effect was the school food environment, which was evaluated based on drinking fountains per 100 students, soft drink sales, soft drink advertising, and the presence of street vendors. Public and private schools that sold soft drinks were associated with higher average sugar-sweetened beverages consumption among adolescents. Our study highlights the importance of creating healthy school food environments by banning sugar-sweetened beverages in schools accordingly.
Exploring CT Texture Parameters as Predictive and Response Imaging Biomarkers of Survival in Patients With Metastatic Melanoma Treated With PD-1 Inhibitor Nivolumab: A Pilot Study Using a Delta-Radiomics Approach
Authors: Guerrisi Antonino , Russillo Michelangelo , Loi Emiliano , Ganeshan Balaji , Ungania Sara , Desiderio Flora , Bruzzaniti Vicente , Falcone Italia , Renna Davide , Ferraresi Virginia , Caterino Mauro , Solivetti Francesco Maria , Cognetti Francesco , Morrone Aldo
Published: October 2021

In the era of artificial intelligence and precision medicine, the use of quantitative imaging methodological approaches could improve the cancer patient’s therapeutic approaches. Specifically, our pilot study aims to explore whether CT texture features on both baseline and first post-treatment contrast-enhanced CT may act as a predictor of overall survival (OS) and progression-free survival (PFS) in metastatic melanoma (MM) patients treated with the PD-1 inhibitor Nivolumab. Ninety-four lesions from 32 patients treated with Nivolumab were analyzed. Manual segmentation was performed using a free-hand polygon approach by drawing a region of interest (ROI) around each target lesion (up to five lesions were selected per patient according to RECIST 1.1). Filtration-histogram-based texture analysis was employed using a commercially available research software called TexRAD (Feedback Medical Ltd, London, UK; https://fbkmed.com/texrad-landing-2/) Percentage changes in texture features were calculated to perform delta-radiomics analysis. Texture feature kurtosis at fine and medium filter scale predicted OS and PFS. A higher kurtosis is correlated with good prognosis; kurtosis values greater than 1.11 for SSF = 2 and 1.20 for SSF = 3 were indicators of higher OS (fine texture: 192 HR = 0.56, 95% CI = 0.32–0.96, p = 0.03; medium texture: HR = 0.54, 95% CI = 0.29–0.99, p = 0.04) and PFS (fine texture: HR = 0.53, 95% CI = 0.29–0.95, p = 0.03; medium texture: HR = 0.49, 209 95% CI = 0.25–0.96, p = 0.03). In delta-radiomics analysis, the entropy percentage variation correlated with OS and PFS. Increasing entropy indicates a worse outcome. An entropy variation greater than 5% was an indicator of bad prognosis. CT delta-texture analysis quantified as entropy predicted OS and PFS. Baseline CT texture quantified as kurtosis also predicted survival baseline. Further studies with larger cohorts are mandatory to confirm these promising exploratory results.
Folate-Receptor Positive Circulating Tumor Cell Is a Potential Diagnostic Marker of Prostate Cancer
Authors: Lian Shenyi , Yang Lujing , Feng Qin , Wang Ping , Wang Yue , Li Zhongwu
Published: October 2021

Folate-receptor positive circulating tumor cells (FR+CTCs) shows an important role in the diagnosis and dynamic monitoring for many solid tumors; however, the application of FR+CTCs in prostate cancer remains unclear. We explored the potential application of FR+CTCs in this retrospective study. The levels of FR+CTCs were detected in 30 prostate cancer patients and 7 bladder cancer patients in Peking University Cancer Hospital from August 2017 to August 2021. Clinical and pathology data were collected. One-way ANOVA was used to compare the difference in FR+CTCs levels in patients with prostate cancer, bladder cancer, and benign disease. The area under the receiver operating curve (AUROC) was used to compare the accuracy of FR+CTCs and tPSA in the diagnosis of prostate cancer. We found that levels of FR+CTCs were significantly higher in cancer patients (both prostate and bladder cancer) than in patients with benign urinary disease (p < 0.001). Besides, FR+CTCs level was consistently high in the prostate cancer patients with different tPSA levels (p < 0.001), and it was significantly higher in the patients with f/tPSA levels <0.16 than in those patients with f/tPSA levels >0.16 (12.20 ± 1.31 vs. 8.73 ± 0.92 FU/3 ml, p = 0.043). The diagnosis efficiency of FR+CTCs is better than the tPSA in prostate cancer patients with tPSA <10 ng/ml (0.871 vs. 0.857). In the prostate cancer patients with tPSA <10 ng/ml and f/tPSA <0.16, a combination of FR+CTCs and tPSA (AUROC, 0.934) further increased the diagnosis efficiency of each of these biomarkers alone (FR+CTCs, 0.912; tPSA, 0.857). Therefore, FR+CTCs could serve as an early diagnosis marker in the prostate cancer patients with uncertain tPSA levels.
Role of the Tyrosine Phosphatase SHP-2 in Mediating Adrenomedullin Proangiogenic Activity in Solid Tumors
Authors: Sigaud Romain , Dussault Nadège , Berenguer-Daizé Caroline , Vellutini Christine , Benyahia Zohra , Cayol Mylène , Parat Fabrice , Mabrouk Kamel , Vázquez Ramiro , Riveiro Maria E. , Metellus Philippe , Ouafik L’Houcine
Published: October 2021

VE-cadherin is an essential adhesion molecule in endothelial adherens junctions, and the integrity of these complexes is thought to be regulated by VE-cadherin tyrosine phosphorylation. We have previously shown that adrenomedullin (AM) blockade correlates with elevated levels of phosphorylated VE-cadherin (pVE-cadherinY731) in endothelial cells, associated with impaired barrier function and a persistent increase in vascular endothelial cell permeability. However, the mechanism underlying this effect is unknown. In this article, we demonstrate that the AM-mediated dephosphorylation of pVE-cadherinY731 takes place through activation of the tyrosine phosphatase SHP-2, as judged by the rise of its active fraction phosphorylated at tyrosine 542 (pSHP-2Y542) in HUVECs and glioblastoma-derived-endothelial cells. Both pre-incubation of HUVECs with SHP-2 inhibitors NSC-87877 and SHP099 and SHP-2 silencing hindered AM-induced dephosphorylation of pVE-cadherinY731 in a dose dependent-manner, showing the role of SHP-2 in the regulation of endothelial cell contacts. Furthermore, SHP-2 inhibition impaired AM-induced HUVECs differentiation into cord-like structures in vitro and impeded AM-induced neovascularization in in vivo Matrigel plugs bioassays. Subcutaneously transplanted U87-glioma tumor xenograft mice treated with AM-receptors-blocking antibodies showed a decrease in pSHP-2Y542 associated with VE-cadherin in nascent tumor vasculature when compared to control IgG-treated xenografts.

Our findings show that AM acts on VE-cadherin dynamics through pSHP-2Y542 to finally modulate cell-cell junctions in the angiogenesis process, thereby promoting a stable and functional tumor vasculature.
Histone H3K36me2-Specific Methyltransferase ASH1L Promotes MLL-AF9-Induced Leukemogenesis
Authors: Aljazi Mohammad B. , Gao Yuen , Wu Yan , Mias George I. , He Jin
Published: October 2021

ASH1L and MLL1 are two histone methyltransferases that facilitate transcriptional activation during normal development. However, the roles of ASH1L and its enzymatic activity in the development of MLL-rearranged leukemias are not fully elucidated in Ash1L gene knockout animal models. In this study, we used an Ash1L conditional knockout mouse model to show that loss of ASH1L in hematopoietic progenitor cells impaired the initiation of MLL-AF9-induced leukemic transformation in vitro. Furthermore, genetic deletion of ASH1L in the MLL-AF9-transformed cells impaired the maintenance of leukemic cells in vitro and largely blocked the leukemia progression in vivo. Importantly, the loss of ASH1L function in the Ash1L-deleted cells could be rescued by wild-type but not the catalytic-dead mutant ASH1L, suggesting the enzymatic activity of ASH1L was required for its function in promoting MLL-AF9-induced leukemic transformation. At the molecular level, ASH1L enhanced the MLL-AF9 target gene expression by directly binding to the gene promoters and modifying the local histone H3K36me2 levels. Thus, our study revealed the critical functions of ASH1L in promoting the MLL-AF9-induced leukemogenesis, which provides a molecular basis for targeting ASH1L and its enzymatic activity to treat MLL-AF9-induced leukemias.
Targeted Lipid Nanoparticles Encapsulating Dihydroartemisinin and Chloroquine Phosphate for Suppressing the Proliferation and Liver Metastasis of Colorectal Cancer
Authors: Peng Jianqing , Wang Qin , Zhou Jia , Zhao Shuli , Di Pan , Chen Yan , Tao Ling , Du Qianming , Shen Xiangchun , Chen Yi
Published: October 2021

Antimalarial drugs Dihydroartemisinin (DHA) and chloroquine phosphate (CQ) exhibit evident anti-cancer activity, particularly as combination therapy. DHA and CQ combination therapy has been proved to exhibit higher cytotoxic effect in tumor cells and lower toxicity to normal cells than combination of artemisinin derivatives (ARTs) and anticancer chemotherapy drugs. However, different physiochemical properties of DHA and CQ, leading to distinctive in vivo outcomes, considerably limited their synergistic effect in cancer treatment. Herein, we developed a lipid nanoparticle (LNP) for co-delivery of DHA and CQ to inhibit proliferation and metastasis of colorectal cancer. Considering the beneficial effects of acid/reactive oxide species (ROS)-sensitive phospholipids and targeting ligands for colorectal cancer cells, an RGD peptide-modified pH/ROS dual-sensitive LNP loaded with DHA and CQ (RLNP/DC) was prepared. It exhibited optimal cytotoxicity and suppression of invasion and metastasis in HCT116 cells in vitro, attributable to irreversible upregulation of intracellular ROS levels, downregulation of VEGF expression, and upregulation of paxillin expression. A mouse model of orthotopic metastasis of colorectal cancer was established to evaluate anti-proliferation and anti-metastasis effects of RLNP/DC in vivo. Thus, an optimized nanoplatform for DHA and CQ combination therapy was developed in this study that offered potential antitumor efficacy against colorectal cancer.
Berberine and Its Main Metabolite Berberrubine Inhibit Platelet Activation Through Suppressing the Class I PI3Kβ/Rasa3/Rap1 Pathway
Authors: Wang Can , Cheng Yangyang , Zhang Yuanhui , Jin Hongtao , Zuo Zengyan , Wang Aiping , Huang Jianmei , Jiang Jiandong , Kong Weijia
Published: October 2021

Background: Berberine (BBR), a natural product, was reported to inhibit platelet aggregation; however, the molecular mechanisms remain unclear. This study aims to investigate the effects and mechanisms of BBR in inhibiting platelet activation and thrombus formation.

Methods: Flow cytometry, immunofluorescence, and Western blot were used to determine the inhibitory effects and mechanisms of BBR and its main metabolite berberrubine (M2) on platelet activation in vitro and ex vivo. Purified integrin αIIbβ3, class I PI3K kit, and molecular docking were used to identify the possible targets of BBR and M2. A carrageenan-induced mouse thrombosis model was used to evaluate the effects of BBR on thrombus formation in vivo.

Results:In vitro, BBR and M2 significantly inhibited ADP-induced integrin αIIbβ3 activation, reduced the level of P-selectin on the platelet membrane, and suppressed the binding of fibrinogen to the platelets. In this process, BBR and M2 greatly suppressed the PI3K/Akt pathway and inhibited Rasa3 membrane translocation and Rap1 activation. Furthermore, BBR and M2 selectively inhibited class I PI3Kβ, perhaps through binding to its active site. The activities of BBR were stronger than those of M2. After oral administration, BBR significantly inhibited the PI3K/Akt pathway and Rap1 activation and suppressed ADP-induced platelet activation and carrageenan-induced thrombosis in mice without prolonging bleeding time.

Conclusions: We reveal for the first time the possible targets and mechanisms of BBR and M2 in inhibiting platelet activation. Our research may support the future clinical application of BBR as an antiplatelet drug in the prevention or treatment of thrombotic diseases.
Trimetazidine Modulates Mitochondrial Redox Status and Disrupted Glutamate Homeostasis in a Rat Model of Epilepsy
Authors: Al-Shorbagy Muhammad Y. , Wadie Walaa , El-Tanbouly Dalia M.
Published: October 2021

Mitochondrial oxidative status exerts an important role in modulating glia–neuron interplay during epileptogenesis. Trimetazidine (TMZ), a well-known anti-ischemic drug, has shown promising potential against a wide range of neurodegenerative disorders including epilepsy. Nevertheless, the exact mechanistic rationale behind its anti-seizure potential has not been fully elucidated yet. Herein, the impact of TMZ against mitochondrial oxidative damage as well as glutamate homeostasis disruption in the hippocampus has been investigated in rats with lithium/pilocarpine (Li/PIL) seizures. Animals received 3 mEq/kg i.p. LiCl3 followed by PIL (single i.p.; 150 mg/kg) 20 h later for induction of seizures with or without TMZ pretreatment (25 mg/kg; i.p.) for five consecutive days. Seizure score and seizure latency were observed. Mitochondrial redox status as well as ATP and uncoupling protein 2 was recorded. Moreover, glutamate homeostasis was unveiled. The present findings demonstrate the TMZ-attenuated Li/PIL seizure score and latency. It improved mitochondrial redox status, preserved energy production mechanisms, and decreased reactive astrocytes evidenced as decreased glial fibrillary acidic protein immune-stained areas in hippocampal tissue. In addition, it modulated phosphorylated extracellular signal-regulated kinases (p-ERK1/2) and p-AMP–activated protein kinase (p-AMPK) signaling pathways to reflect a verified anti-apoptotic effect. Consequently, it upregulated mRNA expression of astroglial glutamate transporters and reduced the elevated glutamate level. The current study demonstrates that TMZ exhibits robust anti-seizure and neuroprotective potentials. These effects are associated with its ability to modulate mitochondrial redox status, boost p-ERK1/2 and p-AMPK signaling pathways, and restore glutamate homeostasis in hippocampus.
Lychee Seed as a Potential Hypoglycemic Agent, and Exploration of its Underlying Mechanisms
Authors: Zhang Yuehong , Jin De , An Xuedong , Duan Liyun , Duan Yingying , Lian Fengmei
Published: October 2021

Food is people’s primal want. A reasonable diet and healthy food not only provide nutrients for human growth but also contribute to disease prevention and treatment, while following an unhealthy diet can lead to an increased risk of many diseases, especially metabolic disorders, such as diabetes. Nature is enriched with different food sources, and it seems that purely natural products are more in line with the current concept of health, which enhance the formation of the notion that “Food/Diet Supplements from Natural Sources as a Medicine.” As a delicious fruit, the medicinal values such as anticancer, antibacterial, antioxidation, and antiglycating properties of lychee have been found. Lychee (Litchi in Chinese) is a subtropical fruit plant belonging to the family Sapindaceae. It has been widely cultivated in warm climates worldwide, particularly in China, for thousands of years. In recent years, various phytochemical components such as quercetin, procyanidin A2, and (2R)-naringenin-7-O-(3-O-αL-rhamnopyranosyl-β-D-glucopyranoside) have been identified in a lychee seed, which may lend a lychee seed as a relatively safe and inexpensive adjuvant treatment for diabetes and diabetic complications. In fact, accumulating evidence has shown that lychee seed, lychee seed extracts, and related compounds have promising antihyperglycemic activities, including improving insulin resistance, anti-inflammatory effect, lipid regulation, neuroprotection, antineurotoxic effect, and renoprotection effect. In this review, we summarized publications on antiglycemic effects and mechanisms of lychee seed, lychee seed extracts, and related compounds, which included their efficacies as a cure for diabetes and diabetic complications in cells, animals, and humans, attempting to obtain a robust evidence basis for the clinical application and value of lychee seed.
Kidney Disease Management in the Hospital Setting: A Focus on Inappropriate Drug Prescriptions in Older Patients
Authors: Arcoraci Vincenzo , Barbieri Maria Antonietta , Rottura Michelangelo , Nobili Alessandro , Natoli Giuseppe , Argano Christiano , Squadrito Giovanni , Squadrito Francesco , Corrao Salvatore ,   on behalf of the REPOSI investigators
Published: October 2021

Aging with multimorbidity and polytherapy are the most significant factors that could led to inappropriate prescribing of contraindicated medications in patients with chronic kidney disease (CKD). The aim of this study was to evaluate the prescriptions of contraindicated drugs in older adults in CKD and to identify their associated factors in a hospital context. An observational retrospective study was carried out considering all patients ≥65 years with at least one serum creatinine value recorded into the REPOSI register into 2010–2016 period. The estimated glomerular filtration rate (eGFR) was applied to identify CKD. A descriptive analysis was performed to compare demographic and clinical characteristics; logistic regression models were used to estimate factors of inappropriate and percentage changes of drug use during hospitalization. A total of 4,713 hospitalized patients were recorded, of which 49.8% had an eGFR <60 ml/min/1.73 m2; the 21.9% were in treatment with at least one inappropriate drug at the time of hospital admission with a decrease of 3.0% at discharge (p = 0.010). The probability of using at least one contraindicated drug was significantly higher in patients treated with more several drugs (OR 1.21, 95% CI 1.16–1.25, p <0.001) and with CKD end-stages (G4: 16.90, 11.38–25.12, p < 0.001; G5: 19.38, 11.51–32.64, p < 0.001). Low-dose acetylsalicylic acid was the contraindicated drug mainly used at the time of admission, reducing 1.2% at discharge. An overall increase in therapeutic appropriateness in hospitalized older patients with CKD was observed, despite a small percentage of therapeutic inappropriateness at discharge that underlines the need for a closer collaboration with the pharmacologist to improve the drug management.
Health Technology Assessment of Advanced Therapy Medicinal Products: Comparison Among 3 European Countries
Authors: Gozzo Lucia , Romano Giovanni Luca , Romano Francesca , Brancati Serena , Longo Laura , Vitale Daniela Cristina , Drago Filippo
Published: October 2021

Even for centrally approved products, each European country is responsible for the effective national market access. This step can result in inequalities in terms of access, due to different opinions about the therapeutic value assessed by health technology assessment (HTA) bodies. Advanced therapy medicinal products (ATMPs) represent a major issue with regard to the HTA in order to make them available at a national level. These products are based on genes, tissues, or cells, commonly developed as one-shot treatment for rare or ultrarare diseases and mandatorily authorized by the EMA with a central procedure. This study aims to provide a comparative analysis of HTA recommendations issued by European countries (France, Germany, and Italy) following EMA approval of ATMPs. We found a low rate of agreement on the therapeutic value (in particular the “added value” compared to the standard of care) of ATMPs. Despite the differences in terms of clinical assessment, the access has been usually guaranteed, even with different timing and limitations. In view of the importance of ATMPs as innovative therapies for unmet needs, it is crucial to understand and act on the causes of disagreement among the HTA. In addition, the adoption of the new EU regulation on HTA would be useful to reduce disparities of medicine’s assessment among European countries.
Buddleoside-Rich Chrysanthemum indicum L. Extract has a Beneficial Effect on Metabolic Hypertensive Rats by Inhibiting the Enteric-Origin LPS/TLR4 Pathway
Authors: Wang Ya-Jun , Su Jie , Yu Jing-Jing , Yan Mei-Qiu , Shi Meng-Lin , Huang Qi-Di , Li Bo , Wu Wen-Yan , Xia Rong-Shuang , Li Si-Fan , Chen Su-Hong , Lv Gui-Yuan
Published: October 2021

As the number of patients with metabolic hypertension (MH) is increasing, there is an essential require for global measures to prevent and treat MH. Flavonoids such as buddleoside (BUD) from Chrysanthemum indicum L. are the main pharmacological components of cardiovascular activities. Previous studies have suggested that the buddleoside-rich Chrysanthemum indicum L. extract (BUDE) can reduce blood pressure in spontaneously hypertensive rats (SHR). However, its effect on MH and how it works remains to be researched. In this study, it was observed that BUDE could lower blood pressure, improve dyslipidemia, and decrease the level of plasma LPS in MH rats. Moreover, BUDE improved intestinal flora and increased the expression of occludin and claudin-1 in the colon, and improved the pathological injury of the colon. Western bolt and qRT-PCR experiments showed that BUDE could down-regulate TLR4 and MyD88 protein and mRNA expression and inhibit phosphorylation of IKKβ, IκBα and NF-κB p65 in vessels of MH rats. These results showed that BUDE could regulate intestinal flora, improve intestinal barrier function, reduce the production and penetration of LPS, thereby inhibiting the vascular TLR4/MyD88 pathway, improving vascular endothelial function, and ultimately lowering blood pressure in MH rats. This study provides a new mechanism of BUDE against MH by inhibiting the enteric-origin LPS/TLR4 pathway.
Compound Kushen Injection Induces Immediate Hypersensitivity Reaction Through Promoting the Production of Platelet-Activating Factor via de Novo Pathway
Authors: Gao Yuan , Hai Lina , Kang Yuan , Qin Wenjie , Liu Fang , Cai Runlan , Yang Xiuwei , Qi Yun
Published: October 2021

Compound Kushen Injection (CKI) is abis-herbal formulation extracted from Kushen (Radix Sophorae Flavescentis) and Baituling (Rhizoma Heterosmilacis Yunnanensis). Clinically, it is used as the adjuvant treatment of cancer. However, with the increased application, the cases of immediate hypersensitivity reactions (IHRs) also gradually rise. In this study, we investigated the underlying mechanism(s) and active constituent(s) for CKI-induced IHRs in experimental models. The obtained results showed that CKI did not elevate serum total IgE (tIgE) and mouse mast cell protease 1 (MMCP1) after consecutive immunization for 5 weeks, but could induce Evans blue extravasation (local) and cause obvious hypothermia (systemic) after a single injection. Further study showed that alkaloids in Kushen, especially matrine, were responsible for CKI-induced IHRs. Mechanism study showed that various platelet-activating factor (PAF) receptor antagonists could significantly counter CKI-induced IHRs locally or systemically. In cell system, CKI was able to promote PAF production in a non-cell-selective manner. In cell lysate, the effect of CKI on PAF production became stronger and could be abolished by blockingde novopathway. In conclusion, our study identifies, for the first time, that CKI is a PAF inducer. It causes non-immunologic IHRs, rather than IgE-dependent IHRs, by promoting PAF production throughde novopathway. Alkaloids in Kushen, especially matrine, are the prime culprits for IHRs. Our findings may provide a potential approach for preventing and treating CKI-induced IHRs.
Sterols, Oxysterols, and Accessible Cholesterol: Signalling for Homeostasis, in Immunity and During Development
Authors: Griffiths William J. , Wang Yuqin
Published: October 2021

In this article we discuss the concept of accessible plasma membrane cholesterol and its involvement as a signalling molecule. Changes in plasma membrane accessible cholesterol, although only being minor in the context of total cholesterol plasma membrane cholesterol and total cell cholesterol, are a key regulator of overall cellular cholesterol homeostasis by the SREBP pathway. Accessible cholesterol also provides the second messenger between patched 1 and smoothened in the hedgehog signalling pathway important during development, and its depletion may provide a mechanism of resistance to microbial pathogens including SARS-CoV-2. We revise the hypothesis that oxysterols are a signalling form of cholesterol, in this instance as a rapidly acting and paracrine version of accessible cholesterol.