bluuebunny/crossref_metadata_2025 huggingface dataset:
Super-Resolution Arterial Spin Labeling Using Slice-Dithered Enhanced Resolution and Simultaneous Multi-Slice Acquisition
Authors: Shou Qinyang , Shao Xingfeng , Wang Danny J. J.
Published: October 2021

Purpose: To achieve high spatial resolution (isotropic-2 mm) perfusion imaging using 2D simultaneous multi-slice (SMS) pseudo-continuous arterial spin labeling (pCASL) and slice dithered enhanced resolution (SLIDER) technique for super-resolution reconstruction.

Methods: The SLIDER-SMS pCASL with a multiband factor of 4 was implemented at 3T with three numbers of slice shift (2/3/4) for the slice thickness of 4/6/8 mm, respectively. Super-resolution reconstruction was performed with singular value decomposition and different levels of Tikhonov regularizations. Temporal and spatial signal-to-noise ratio (SNR) as well as spatial blurring effects of super-resolution ASL images were measured in five healthy subjects and compared with those of reference high-resolution ASL images.

Results: Compared to conventional 2D SMS ASL, super-resolution ASL images with isotropic-2-mm resolution yielded 42, 61, and 88% higher spatial SNR, and 18, 55, and 105% higher temporal SNR with slice shift number of 2/3/4, respectively. Spatial blurring effect increased for SLIDER reconstruction from two to four slice shifts.

Conclusion: The proposed SLIDER-SMS pCASL technique can achieve whole-brain high-resolution perfusion images with ∼15-min scan time and improved SNR compared to standard 2D SMS pCASL. Caution needs to be exercised on quantifying and controlling blurring effects of SLIDER reconstruction.
Altered Spontaneous Brain Activity Patterns and Functional Connectivity in Adults With Intermittent Exotropia: A Resting-State fMRI Study
Authors: He Xueying , Hong Jie , Wang Qian , Guo Yanan , Li Ting , Qu Xiaoxia , Liu Jing , Li Wei , Zhang Lirong , Fu Jing , Liu Zhaohui
Published: October 2021

The purpose of this study is to investigate brain functional changes in patients with intermittent exotropia (IXT) by analyzing the amplitude of low-frequency fluctuation (ALFF) of brain activity and functional connectivity (FC) using resting-state functional magnetic resonance imaging (rs-fMRI). There were 26 IXT patients and 22 age-, sex-, education-, and handedness-matched healthy controls (HCs) enrolled who underwent rs-fMRI. The ALFF, fractional ALFF (fALFF) values in the slow 4 and slow 5 bands, and FC values were calculated and compared. The correlations between ALFF/fALFF values in discrepant brain regions and clinical features were evaluated. Compared with HCs, ALFF/fALFF values were significantly increased in the right angular gyrus (ANG), supramarginal gyrus (SMG), inferior parietal lobule (IPL), precentral gyrus (PreCG), and the bilateral inferior frontal gyri (IFG), and decreased in the right precuneus gyrus (PCUN), left middle occipital gyrus (MOG), and postcentral gyrus (PoCG) in IXT patients. The Newcastle Control Test score was negatively correlated with ALFF values in the right IFG (r = −0.738, p < 0.001). The duration of IXT was negatively correlated with ALFF values in the right ANG (r = −0.457, p = 0.049). Widespread increases in FC were observed between brain regions, mainly including the right cuneus (CUN), left superior parietal lobule (SPL), right rolandic operculum (ROL), left middle temporal gyrus (MTG), left IFG, left median cingulate gyrus (DCG), left PoCG, right PreCG, and left paracentral gyrus (PCL) in patients with IXT. No decreased FC was observed. Patients with IXT exhibited aberrant intrinsic brain activities and FC in vision- and eye movement-related brain regions, which extend current understanding of the neuropathological mechanisms underlying visual and oculomotor impairments in IXT patients.
Quality of Life and a Surveillant Endocannabinoid System
Authors: de Melo Reis Ricardo Augusto , Isaac Alinny Rosendo , Freitas Hércules Rezende , de Almeida Mariana Macedo , Schuck Patricia Fernanda , Ferreira Gustavo Costa , Andrade-da-Costa Belmira Lara da Silveira , Trevenzoli Isis Hara
Published: October 2021

The endocannabinoid system (ECS) is an important brain modulatory network. ECS regulates brain homeostasis throughout development, from progenitor fate decision to neuro- and gliogenesis, synaptogenesis, brain plasticity and circuit repair, up to learning, memory, fear, protection, and death. It is a major player in the hypothalamic-peripheral system-adipose tissue in the regulation of food intake, energy storage, nutritional status, and adipose tissue mass, consequently affecting obesity. Loss of ECS control might affect mood disorders (anxiety, hyperactivity, psychosis, and depression), lead to drug abuse, and impact neurodegenerative (Alzheimer’s, Parkinson, Huntington, Multiple, and Amyotrophic Lateral Sclerosis) and neurodevelopmental (autism spectrum) disorders. Practice of regular physical and/or mind-body mindfulness and meditative activities have been shown to modulate endocannabinoid (eCB) levels, in addition to other players as brain-derived neurotrophic factor (BDNF). ECS is involved in pain, inflammation, metabolic and cardiovascular dysfunctions, general immune responses (asthma, allergy, and arthritis) and tumor expansion, both/either in the brain and/or in the periphery. The reason for such a vast impact is the fact that arachidonic acid, a precursor of eCBs, is present in every membrane cell of the body and on demand eCBs synthesis is regulated by electrical activity and calcium shifts. Novel lipid (lipoxins and resolvins) or peptide (hemopressin) players of the ECS also operate as regulators of physiological allostasis. Indeed, the presence of cannabinoid receptors in intracellular organelles as mitochondria or lysosomes, or in nuclear targets as PPARγ might impact energy consumption, metabolism and cell death. To live a better life implies in a vigilant ECS, through healthy diet selection (based on a balanced omega-3 and -6 polyunsaturated fatty acids), weekly exercises and meditation therapy, all of which regulating eCBs levels, surrounded by a constructive social network. Cannabidiol, a diet supplement has been a major player with anti-inflammatory, anxiolytic, antidepressant, and antioxidant activities. Cognitive challenges and emotional intelligence might strengthen the ECS, which is built on a variety of synapses that modify human behavior. As therapeutically concerned, the ECS is essential for maintaining homeostasis and cannabinoids are promising tools to control innumerous targets.
Common and Distinct Disruptions of Cortical Surface Morphology Between Autism Spectrum Disorder Children With and Without SHANK3 Deficiency
Authors: Li Dongyun , Liu Chunxue , Huang Ziyi , Li Huiping , Xu Qiong , Zhou Bingrui , Hu Chunchun , Zhang Ying , Wang Yi , Nie Jingxin , Qiao Zhongwei , Yin Dazhi , Xu Xiu
Published: October 2021

SH3 and Multiple Ankyrin Repeat Domains 3 (SHANK3)-caused autism spectrum disorder (ASD) may present a unique opportunity to clarify the heterogeneous neuropathological mechanisms of ASD. However, the specificity and commonality of disrupted large-scale brain organization in SHANK3-deficient children remain largely unknown. The present study combined genetic tests, neurobehavioral evaluations, and magnetic resonance imaging, aiming to explore the disruptions of both local and networked cortical structural organization in ASD children with and without SHANK3 deficiency. Multiple surface morphological parameters such as cortical thickness (CT) and sulcus depth were estimated, and the graph theory was adopted to characterize the topological properties of structural covariance networks (SCNs). Finally, a correlation analysis between the alterations in brain morphological features and the neurobehavioral evaluations was performed. Compared with typically developed children, increased CT and reduced nodal degree were found in both ASD children with and without SHANK3 defects mainly in the lateral temporal cortex, prefrontal cortex (PFC), temporo-parietal junction (TPJ), superior temporal gyrus (STG), and limbic/paralimbic regions. Besides commonality, our findings showed some distinct abnormalities in ASD children with SHANK3 defects compared to those without. Locally, more changes in the STG and orbitofrontal cortex were exhibited in ASD children with SHANK3 defects, while more changes in the TPJ and inferior parietal lobe (IPL) in those without SHANK3 defects were observed. For the SCNs, a trend toward regular network topology was observed in ASD children with SHANK3 defects, but not in those without. In addition, ASD children with SHANK3 defects showed more alterations of nodal degrees in the anterior and posterior cingulate cortices and right insular, while there were more disruptions in the sensorimotor areas and the left insular and dorsomedial PFC in ASD without SHANK3 defects. Our findings indicate dissociable disruptions of local and networked brain morphological features in ASD children with and without SHANK3 deficiency. Moreover, this monogenic study may provide a valuable path for parsing the heterogeneity of brain disturbances in ASD.
Learning to Predict Page View on College Official Accounts With Quality-Aware Features
Authors: Yu Yibing , Shi Shuang , Wang Yifei , Lian Xinkang , Liu Jing , Lei Fei
Published: October 2021

At present, most of departments in colleges have their own official accounts, which have become the primary channel for announcements and news. In the official accounts, the popularity of articles is influenced by many different factors, such as the content of articles, the aesthetics of the layout, and so on. This paper mainly studies how to learn a computational model for predicting page view on college official accounts with quality-aware features extracted from pictures. First, we built a new picture database by collecting 1,000 pictures from the official accounts of nine well-known universities in the city of Beijing. Then, we proposed a new model for predicting page view by using a selective ensemble technology to fuse three sets of quality-aware features that could represent how a picture looks. Experimental results show that the proposed model has achieved competitive performance against state-of-the-art relevant models on the task for inferring page view from pictures on college official accounts.
Extracellular Vesicles in Serum and Central Nervous System Tissues Contain microRNA Signatures in Sporadic Amyotrophic Lateral Sclerosis
Authors: Lo Ting-wen , Figueroa-Romero Claudia , Hur Junguk , Pacut Crystal , Stoll Evan , Spring Calvin , Lewis Rose , Nair Athul , Goutman Stephen A. , Sakowski Stacey A. , Nagrath Sunitha , Feldman Eva L.
Published: October 2021

Amyotrophic lateral sclerosis (ALS) is a terminalneurodegenerative disease. Clinical and molecular observations suggest that ALS pathology originates at a single site and spreads in an organized and prion-like manner, possibly driven by extracellular vesicles. Extracellular vesicles (EVs) transfer cargo molecules associated with ALS pathogenesis, such as misfolded and aggregated proteins and dysregulated microRNAs (miRNAs). However, it is poorly understood whether altered levels of circulating extracellular vesicles or their cargo components reflect pathological signatures of the disease. In this study, we used immuno-affinity-based microfluidic technology, electron microscopy, and NanoString miRNA profiling to isolate and characterize extracellular vesicles and their miRNA cargo from frontal cortex, spinal cord, and serum of sporadic ALS (n = 15) and healthy control (n = 16) participants. We found larger extracellular vesicles in ALS spinal cord versus controls and smaller sized vesicles in ALS serum. However, there were no changes in the number of extracellular vesicles between cases and controls across any tissues. Characterization of extracellular vesicle-derived miRNA cargo in ALS compared to controls identified significantly altered miRNA levels in all tissues; miRNAs were reduced in ALS frontal cortex and spinal cord and increased in serum. Two miRNAs were dysregulated in all three tissues: miR-342-3p was increased in ALS, and miR-1254 was reduced in ALS. Additional miRNAs overlapping across two tissues included miR-587, miR-298, miR-4443, and miR-450a-2-3p. Predicted targets and pathways associated with the dysregulated miRNAs across the ALS tissues were associated with common biological pathways altered in neurodegeneration, including axon guidance and long-term potentiation. A predicted target of one identified miRNA (N-deacetylase and N-sulfotransferase 4; NDST4) was likewise dysregulated in an in vitro model of ALS, verifying potential biological relevance. Together, these findings demonstrate that circulating extracellular vesicle miRNA cargo mirror those of the central nervous system disease state in ALS, and thereby offer insight into possible pathogenic factors and diagnostic opportunities.
Mixed Infant Feeding Is Not Associated With Increased Risk of Decelerated Growth Among WIC-Participating Children in Southern California
Authors: Anderson Christopher E. , Whaley Shannon E. , Crespi Catherine M. , Wang May C. , Chaparro M. Pia
Published: October 2021

Background:The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) provides nutrition assistance to half of infants born in the United States. The nationally representative WIC Infants and Toddler Feeding Practices Study-2 (ITFPS-2) reported a caloric deficit at 7 months among infants receiving WIC mixed feeding packages, suggesting these infants may be at risk for growth deceleration/faltering.

Methods:Longitudinal administrative data collected prospectively from WIC participants in Southern California between 2010 and 2019 were used (n= 16,255). Infant lengths and weights were used to calculate weight-for-length (WLZ), weight-for-age (WAZ) and length-for-age (LAZ) z-scores at different time points. Growth deceleration/faltering was determined at 9, 12, 18, and 24 months by the change in z-score from the last measurement taken ≤ 6 months of age. Infant feeding was categorized by the food package (breastfeeding, mixed feeding, and formula feeding) infants received from WIC at 7 months. Poisson regression models were used to evaluate the association between WIC infant package at 7 months and deceleration/faltering at 9, 12, 18, and 24 months.

Results:The proportion of infants displaying decelerated/faltering growth was low for all infant food package groups. Receiving the WIC mixed feeding package at 7 months of age was not associated with WLZ, WAZ, and LAZ deceleration/faltering growth.

Conclusions:Growth deceleration/faltering rates were very low among WIC participating children in Southern California, highlighting the critical role of nutrition assistance in supporting adequate growth in early childhood.
Egg and Dietary Cholesterol Consumption and Mortality Among Hypertensive Patients: Results From a Population-Based Nationwide Study
Authors: Wu Fei , Zhuang Pan , Zhang Yiju , Zhan Chuchu , Zhang Yu , Jiao Jingjing
Published: October 2021

Background: Hypertensive patients are sensitive to the amount of dietary cholesterol intake, especially cholesterol from the whole eggs. Whether whole egg and dietary cholesterol consumption are suitable for hypertensive patients is still controversial.

Aim: The objective of the study was to examine the associations of intake of eggs as well as the dietary cholesterol with total mortality in a Chinese nationwide cohort.

Methods: We utilized data from the China Health and Nutrition Survey (CHNS) from the year of 1991 to 2015. Cumulative averages of egg and cholesterol intake were calculated to represent the consumption of the long-term diet of the participants in each available round of the survey. Cox regression models were employed to estimate the effects of eggs and dietary cholesterol from the different sources on mortality among hypertensive patients.

Results: A total of 8,095 participants were included in the final analysis and followed up for a mean of 11.4 years. Finally, 927 cases of death were detected. After adjustment for the multivariate factors, consuming more than seven eggs per week was related to 29% lower mortality among the hypertensive patients compared with the consumers with not more than two eggs per week [hazard ratio (HR): 0.71; 95% CI: 0.59–0.85; P < 0.001]. Similarly, the egg-sourced cholesterol intake was inversely associated with mortality (P = 0.002) whereas intake of the dietary cholesterol from the non-egg sources was significantly related to the higher mortality (P < 0.001). However, total cholesterol intake was not related to mortality among hypertensive patients. Substituting eggs for an equivalent amount of non-egg-sourced protein-abundant foods was also associated with lower mortality.

Conclusion: Higher consumption of eggs and egg-sourced dietary cholesterol was associated with lower mortality among the enrolled Chinese hypertensive patients but non-egg-sourced cholesterol intake was related to higher mortality. Therefore, our findings do not support the view that hypertensive patients should avoid whole egg consumption for the purpose of restricting dietary cholesterol intake.
Latest Trend of Milk Derived Exosomes: Cargos, Functions, and Applications
Authors: Feng Xin , Chen Xiaolin , Zheng Xucan , Zhu Hui , Qi Qien , Liu Shen , Zhang Huihua , Che Jianwei
Published: October 2021

Exosomes are nanosized phospholipid bilayer vesicles released to the extracellular environment. Exosomes from various tissues or cells are being studied and there has been a growing interest in milk exosomes research due to their emerging role as messengers between cells and the fact that it can be produced in large quantities with rich source of milk. Milk derived exosomes (MDEs) contain lipids, microRNAs, proteins, mRNAs as well as DNA. Studies of exosome cargo have been conducted widely in many research areas, especially exosomal miRNAs. In this paper, we reviewed the current knowledge in isolation and identification, cargos, functions mainly in intestinal tract and immunity system of MDEs. Its application as drug carriers and diseases biomarker are also discussed. Furthermore, we also consider critical challenges of MDEs application and provide possible directions for future research.
Skimmed Bovine Milk-Derived Extracellular Vesicles Isolated via “Salting-Out”: Characterizations and Potential Functions as Nanocarriers
Authors: Tan Xiao-Hui , Fang Dong , Xu Yong-De , Nan Tie-Gui , Song Wen-Peng , Gu Yang-Yang , Gu Sheng-Ji , Yuan Yi-Ming , Xin Zhong-Cheng , Zhou Li-Qun , Guan Rui-Li , Li Xue-Song
Published: October 2021

Bovine milk-derived extracellular vesicles (BM-EVs) are recognized as promising nanoscale delivery vectors owing to their large availability. However, few isolation methods can achieve high purity and yield simultaneously. Therefore, we developed a novel and cost-effective procedure to separate BM-EVs via “salting-out.” First, BM-EVs were isolated from skimmed milk using ammonium sulfate. The majority of BM-EVs were precipitated between 30 and 40% saturation and 34% had a relatively augmented purity. The separated BM-EVs showed a spherical shape with a diameter of 60–150 nm and expressed the marker proteins CD63, TSG101, and Hsp70. The purity and yield were comparable to the BM-EVs isolated via ultracentrifugation while ExoQuick failed to separate a relatively pure fraction of BM-EVs. The uptake of BM-EVs into endothelial cells was dose- and time-dependent without significant cytotoxicity. The levels of endothelial nitric oxide syntheses were regulated by BM-EVs loaded with icariside II and miRNA-155-5p, suggesting their functions as delivery vehicles. These findings have demonstrated that it is an efficient procedure to isolate BM-EVs via “salting-out,” holding great promise toward therapeutic applications.
Sodium-Glucose Co-Transporter 2 Inhibitors May Change the Development of Urinary Tract and Hematological Malignancies as Compared With Dipeptidyl Peptidase-4 Inhibitors: Data of the Post-Hoc Analysis of a Nationwide Study
Authors: Rokszin György , Kiss Zoltán , Sütő Gábor , Kempler Péter , Jermendy György , Fábián Ibolya , Szekanecz Zoltán , Poór Gyula , Wittmann István , Molnár Gergő Attila
Published: October 2021

Background

In diabetes mellitus, during the last years, cancer became of equivalent importance as a cardiovascular disease in terms of mortality. In an earlier study, we have analyzed data of the National Health Insurance Fund (NHIF) of Hungary with regards all patients treated with sodium-glucose co-transporter 2 (SGLT2) inhibitors (SGLT2is) vs. those treated with dipeptidyl peptidase-4 (DPP-4) inhibitors (DPP-4is) in a given timeframe. In propensity score-matched groups of SGLT2i- vs. DPP-4i-treated patients, we found a lower incidence of cancer in general. In this post-hoc analysis, we aimed to obtain data on the incidence of site-specific cancer.

Patients and Methods

All patients starting an SGLT2i or a DPP-4i between 2014 and 2017 in Hungary were included; the two groups (SGLT2i vs. DPP-4i) were matched for 54 clinical and demographical parameters. The follow-up period was 639 vs. 696 days, respectively. Patients with a letter “C” International Classification of Diseases, 10th Revision (ICD-10) code have been chosen, and those with a known malignancy within a year before the onset of the study have been excluded from the analysis.

Results

We found a lower risk of urinary tract [HR 0.50 (95% CI: 0.32–0.79) p = 0.0027] and hematological malignancies [HR 0.50 (95% CI: 0.28–0.88) p = 0.0174] in patients treated with SGLT2i vs. those on DPP-4i. Risk of other types of cancer (including lung and larynx, lower gastrointestinal (GI) tract, rectum, pancreas, non-melanoma skin cancers, breast, or prostate) did not differ significantly between the two groups. When plotting absolute risk difference against follow-up time, an early divergence of curves was found in case of prostate, urinary tract, and hematological malignancies, whereas late divergence can be seen in case of cancers of the lung and larynx, the lower GI tract, and the breast.

Conclusions

Urinary tract and hematological malignancies were less frequent in patients treated with SGLT2i vs. DPP-4i. An early vs. late divergence could be observed for different cancer types, which deserves further studies.
COVID-19 in Patients With Hematologic Malignancies: A Single Center Retrospective Study
Authors: Wang Xuejun Alice , Binder Adam F. , Gergis Usama , Wilde Lindsay
Published: October 2021

Initial studies that described the novel coronavirus (COVID-19) reported increased morbidity and mortality in patients with cancer. Of this group, patients with hematologic malignancies (HM) had the highest disease severity and death rates. Subsequent studies have attempted to better describe how COVID-19 affects patients with HM. However, these studies have yielded variable and often contradictory results. We present our single-institution experience with patients with HM who were diagnosed with COVID-19 from March 2020 to March 2021. We report 62 total cases with 10 patients who died during this time. The overall mortality was 16.1%. Mortality during the first two waves of COVID was 27.8% and 25%. Mortality during the third wave of COVID was 10%. The median age of patients was 67 years (range 20-89 years). 55% of patients had lymphoid malignancies and the majority had active disease at the time of diagnosis with COVID-19. 87% of patients had more than one co-morbidity. Important co-morbidities included cardiovascular disease and smoking history. 38.7% of patients had asymptomatic or mild disease, 54.8% required hospitalization, and 17.5% required ICU level care. In patients who required ICU level care, the mortality was 60%.
Comparison of Outcomes After Primary Laparoscopic Versus Open Approach for T1b/T2 Gallbladder Cancer
Authors: Cao Jiasheng , Wang Yong , Zhang Bin , Hu Jiahao , Topatana Win , Li Shijie , Juengpanich Sarun , Lu Ziyi , Cai Xiujun , Chen Mingyu
Published: October 2021

Objectives

The primary laparoscopic approach (PLA) for T1b/T2 gallbladder cancer (GBC) remains contradicted. We aimed to compare the perioperative and long-term outcomes after PLA versus open approach (OA) for T1b/T2 GBC.

Methods

Patients with resected T1b/T2 GBC were selected from our hospital between January 2011 and August 2018. Overall survival (OS), disease-free survival (DFS), and several secondary outcomes were used to evaluate safety and effectiveness. Subgroup analyses were performed to identify significant risk factors for OS/DFS in GBC patients undergoing PLA/OA.

Results

A total of 114 patients who underwent OA (n = 61) or PLA (n = 53) were included in the study. The percent of PLA cases was increased over time from 40.0% in 2011 to 70.0% in 2018 (p < 0.05). There was no significant difference in OS [hazard ratio (HR), 1.572; 95% confidence interval (CI), 0.866–2.855; p = 0.13] and DFS (HR, 1.225; 95% CI, 0.677–2.218; p = 0.49). No significance was found for intraoperative drainage placement (p = 0.253), intraoperative blood loss (p = 0.497), operation time (p = 0.105), postoperative hospitalization (p = 0.797), positive LNs (p = 0.494), total harvested LNs (p = 0.067), and recurrence rates (P = 0.334). Subgroup analyses demonstrated no significance of conversion rates after PLA (all p > 0.05). Patients undergoing PLA with good/poor OS would have similar recurrence rates (p = 0.402). Positive LNs (p = 0.032) and tumor differentiation (p = 0.048) were identified as risk factors for OS after PLA, while positive LNs (p = 0.005) was identified for OS after OA. Moreover, age (p = 0.013), gallbladder stone (p = 0.008), tumor size (p = 0.028), and positive LNs (p = 0.044) were potential risk factors for DFS after OA.

Conclusions

PLA for T1b/T2 GBC was comparable to OA in terms of perioperative and long-term outcomes. Less positive LNs and well-differentiated tumors were independent predictors for better OS after PLA, and less positive LNs were also identified for better OS after OA. Additionally, younger age, without gallbladder stone, smaller tumor size, and less positive LNs were potential risk factors for better DFS after OA.
Treatment-Free Remission in Chronic Myeloid Leukemia and New Approaches by Targeting Leukemia Stem Cells
Authors: Chen Yilin , Zou Jing , Cheng Fanjun , Li Weiming
Published: October 2021

The therapeutic landscape for chronic myeloid leukemia (CML) has improved significantly with the approval of tyrosine kinase inhibitors (TKIs) for therapeutic use. Most patients with optimal responses to TKIs can have a normal life expectancy. Treatment-free remission (TFR) after discontinuing TKI has increasingly become a new goal for CML treatment. However, TKI only “control“ CML, and relapse after discontinuation has become a key factor hindering patient access to attempt TFR. In this study, we reviewed studies on TKI discontinuation, including both first and second-generation TKI. We also reviewed predictors of relapse, new monitoring methods, and strategies targeting leukemic stem cells.
Immunosuppression in Glioblastoma: Current Understanding and Therapeutic Implications
Authors: Himes Benjamin T. , Geiger Philipp A. , Ayasoufi Katayoun , Bhargav Adip G. , Brown Desmond A. , Parney Ian F.
Published: October 2021

Glioblastoma (GBM) is the most common primary brain tumor in adults an carries and carries a terrible prognosis. The current regiment of surgical resection, radiation, and chemotherapy has remained largely unchanged in recent years as new therapeutic approaches have struggled to demonstrate benefit. One of the most challenging hurdles to overcome in developing novel treatments is the profound immune suppression found in many GBM patients. This limits the utility of all manner of immunotherapeutic agents, which have revolutionized the treatment of a number of cancers in recent years, but have failed to show similar benefit in GBM therapy. Understanding the mechanisms of tumor-mediated immune suppression in GBM is critical to the development of effective novel therapies, and reversal of this effect may prove key to effective immunotherapy for GBM. In this review, we discuss the current understanding of tumor-mediated immune suppression in GBM in both the local tumor microenvironment and systemically. We also discuss the effects of current GBM therapy on the immune system. We specifically explore some of the downstream effectors of tumor-driven immune suppression, particularly myeloid-derived suppressor cells (MDSCs) and other immunosuppressive monocytes, and the manner by which GBM induces their formation, with particular attention to the role of GBM-derived extracellular vesicles (EVs). Lastly, we briefly review the current state of immunotherapy for GBM and discuss additional hurdles to overcome identification and implementation of effective therapeutic strategies.
Devices Used to Measure Force-Time Characteristics of Spinal Manipulations and Mobilizations: A Mixed-Methods Scoping Review on Metrologic Properties and Factors Influencing Use
Authors: Mercier Marie-Andrée , Rousseau Philippe , Funabashi Martha , Descarreaux Martin , Pagé Isabelle
Published: October 2021

Background: Spinal manipulations (SMT) and mobilizations (MOB) are interventions commonly performed by many health care providers to manage musculoskeletal conditions. The clinical effects of these interventions are believed to be, at least in part, associated with their force-time characteristics. Numerous devices have been developed to measure the force-time characteristics of these modalities. The use of a device may be facilitated or limited by different factors such as its metrologic properties.

Objectives: This mixed-method scoping review aimed to characterize the metrologic properties of devices used to measure SMT/MOB force-time characteristics and to determine which factors may facilitate or limit the use of such devices within the context of research, education and clinical practice.

Methods: This study followed the Joanna Briggs Institute's framework. The literature search strategy included four concepts: (1) devices, (2) measurement of SMT or MOB force-time characteristics on humans, (3) factors facilitating or limiting the use of devices, and (4) metrologic properties. Two reviewers independently reviewed titles, abstracts and full articles to determine inclusion. To be included, studies had to report on a device metrologic property (e.g., reliability, accuracy) and/or discuss factors that may facilitate or limit the use of the device within the context of research, education or clinical practice. Metrologic properties were extracted per device. Limiting and facilitating factors were extracted and themes were identified.

Results: From the 8,998 studies initially retrieved, 46 studies were finally included. Ten devices measuring SMT/MOB force-time characteristics at the clinician-patient interface and six measuring them at patient-table interfaces were identified. Between zero and eight metrologic properties were reported per device: measurement error (defined as validity, accuracy, fidelity, or calibration), reliability/repeatability, coupling/crosstalk effect, linearity/correlation, sensitivity, variability, drift, and calibration. From the results, five themes related to the facilitating and limiting factors were developed: user-friendliness and versatility, metrologic/intrinsic properties, cost and durability, technique application, and feedback.

Conclusion: Various devices are available to measure SMT/MOB force-time characteristics. Metrologic properties were reported for most devices, but terminology standardization is lacking. The usefulness of a device in a particular context should be determined considering the metrologic properties as well as other potential facilitating and limiting factors.
A Novel System for Evaluating the Inhibition Effect of Drugs on Cytochrome P450 Enzymes in vitro Based on Human-Induced Hepatocytes (hiHeps)
Authors: Li Yan , Lu Ying-Yuan , Jia Jun , Fang Meng , Zhao Lin , Jiang Yong , Shi Yan , Tu Peng-Fei , Guo Xiao-Yu
Published: October 2021

Cytochrome P450 (CYP) is the most important phase I drug-metabolizing enzyme, and the effect of drugs on CYP enzymes can lead to decreased pharmacological efficacy or enhanced toxicity of drugs, but there are many deficiencies in the evaluation models of CYP enzymes in vitro. Human-induced hepatocytes (hiHeps) derived from human fibroblasts by transdifferentiation have mature hepatocyte characteristics. The aim was to establish a novel evaluation system for the effect of drugs on CYP3A4, 1A2, 2B6, 2C9, and 2C19 in vitro based on hiHeps. Curcumin can inhibit many CYP enzymes in vitro, and so the inhibition of curcumin on CYP enzymes was compared by human liver microsomes, human hepatocytes, and hiHeps using UPLC-MS and the cocktail method. The results showed that the IC50 values of CYP enzymes in the hiHeps group were similar to those in the hepatocytes group, which proved the effectiveness and stability of the novel evaluation system in vitro. Subsequently, the evaluation system was applied to study the inhibitory activity of notoginseng total saponins (NS), safflower total flavonoids (SF), and the herb pair of NS–SF on five CYP enzymes. The mechanism of improving efficacy after NS and SF combined based on CYP enzymes was elucidated in vitro. The established evaluation system will become a powerful tool for the research of the effect of drugs on the activity of CYP enzymes in vitro, which has broad application prospects in drug research.
Metabolomics Study of Guizhi Fuling Capsules in Rats With Cold Coagulation Dysmenorrhea
Authors: Zhang Yu , Su Na , Liu Weiyi , Wang Qingqing , Sun Jianguo , Peng Ying
Published: October 2021

Dysmenorrhea refers to a kind of uterine cramping pain that occurs in women during the period of menstrual. Guizhi Fuling Capsules are mainly used for the treatment of various pain syndromes and especially effective in treating primary dysmenorrhea. However, the research on its modern pharmacology and mechanism of action have not been thoroughly carried out. It is not clear about the main active ingredients, potential targets and metabolic pathways involved in its efficacy. Therefore, this research project employed estradiol benzoate sensitization combined with oxytocin pain to construct the cold coagulation syndrome dysmenorrhea model, observed the anti-dysmenorrhea effect of Guizhi Fuling Capsules, and used the metabolomics to explore its mechanism. The results showed that Guizhi Fuling Capsules could considerably reduce the number of writhing times in dysmenorrhea rats, increasing the level of PGE2 and β-EP and reducing the contents of PGF2α in rat serum. Pathological sections of uterus and ovaries also showed that Guizhi Fuling Capsules could significantly relieve endometrial hyperplasia and improve ovarian function. The LC/MS-based metabolomics of rat uterine indicated that the model group has a great deviation from the control group. Compared with the model group, the Guizhi Fuling Capsules group had a tendency to shift to the control group, and the main metabolic changes was mainly concentrated on saturated and unsaturated fatty acids. Among them, arachidonic acid is in a pivotal position, and the expression of its rate-limiting enzyme (COX-2) involved in its cyclooxygenase metabolic pathway was significantly up-regulated in the model group, but significantly decreased after the intervention of Guizhi Fuling Capsules. In conclusion, Guizhi Fuling Capsules can effectively relieve primary dysmenorrhea, and this effect may be attributed to the regulation effects of Guizhi Fuling Capsules on endogenous metabolism, such as inhibiting arachidonic acid converted to prostaglandins through downregulate the expression of COX-2, which plays an anti-inflammatory effect.
Imprecision in Precision Medicine: Differential Response of a Disease-Linked GluN2A Mutant to NMDA Channel Blockers
Authors: Gale Jenna R. , Kosobucki Gabrielle J. , Hartnett-Scott Karen A. , Aizenman Elias
Published: October 2021

Mutations in N-methyl-d-aspartate receptors (NMDAR) subunits have been implicated in a growing number of human neurodevelopmental disorders. Previously, a de novo mutation in GRIN2A, encoding the GluN2A subunit, was identified in a patient with severe epilepsy and developmental delay. This missense mutation, which leads to GluN2A-P552R, produces significant dendrotoxicity in transfected rodent cortical neurons, as evidenced by pronounced dendritic blebbing. This injurious process can be prevented by treatment with the NMDA antagonist memantine. Given the increasing use of FDA approved NMDA antagonists to treat patients with GRIN mutations, who may have seizures refractory to traditional anti-epileptic drugs, we investigated whether additional NMDA antagonists were effective in attenuating neurotoxicity associated with GluN2A-P552R expression. Intriguingly, we found that while treatment with memantine can effectively block GluN2A-P552R-mediated dendrotoxicity, treatment with ketamine does not, despite the fact that both drugs work as open NMDAR channel blockers. Interestingly, we found that neurons expressing GluN2A-P552R were more vulnerable to an excitotoxic insult—an effect that, in this case, could be equally rescued by both memantine and ketamine. These findings suggest that GluN2A-P552R induced dendrotoxicity and increased vulnerability to excitotoxic stress are mediated through two distinct mechanisms. The differences between memantine and ketamine in halting GluN2A-P552R dendrotoxicity could not be explained by NMDA antagonist induced changes in MAP or Src kinase activation, previously shown to participate in NMDA-induced excitotoxicity. Our findings strongly suggest that not all NMDA antagonists may be of equal clinical utility in treating GRIN2A-mediated neurological disorders, despite a shared mechanism of action.
Bioactive Herbal Extracts of Traditional Chinese Medicine Applied with the Biomaterials: For the Current Applications and Advances in the Musculoskeletal System
Authors: Li Haotao , Wu Rongjie , Yu Haiyang , Zheng Qiujian , Chen Yuanfeng
Published: October 2021

Traditional Chinese medicine (TCM) has demonstrated superior therapeutic effect for musculoskeletal diseases for thousands of years. Recently, the herbal extracts of TCM have received rapid advances in musculoskeletal tissue engineering (MTE). A literature review collecting both English and Chinese references on bioactive herbal extracts of TCM in biomaterial-based approaches was performed. This review provides an up-to-date overview of application of TCMs in the field of MTE, involving regulation of multiple signaling pathways in osteogenesis, angiogenesis, anti-inflammation, and chondrogenesis. Meanwhile, we highlight the potential advantages of TCM, opening the possibility of its extensive application in MTE. Overall, the superiority of traditional Chinese medicine turns it into an attractive candidate for coupling with advanced additive manufacturing technology.
High-Resolution Distributed Radiation Detector System Assisted by Intelligent Image Recognition
Authors: Shao Hong , Wang Chenyue , Fu Zhixin , Liu Zhen
Published: October 2021

With the development of machine learning and image recognition technology, the detector system tends to be standardized and intelligent. However, large numbers of distributed radiation detectors connected to the power grid will bring huge uncertainty to the operation of the power grid and even cause certain interference. The monitoring system of the distributed radiation detectors can control the running status of the distributed photoelectric detection system in real-time and guarantee the safe and stable operation of the detector system. This article proposes an improved genetic detector system to avoid “blind spots” in the radiation detector monitoring based on the characteristics of photovoltaic (PV) arrays, which are considered as individual pixels, and then the reliability of the monitoring is ensured by the monitoring coverage of these pixels by the detector nodes. The performance of the radiation detector monitoring is restored by activating those spare nodes with sufficient energy to replace those that fail, ensuring that the distributed detection system can be monitored in a timely and efficient manner at all times. The simulation results confirm the reasonable validity of the algorithm.
Exercise Training and Circulating Small Extracellular Vesicles: Appraisal of Methodological Approaches and Current Knowledge
Authors: Darragh Ian A. J. , O’Driscoll Lorraine , Egan Brendan
Published: October 2021

In response to acute exercise, an array of metabolites, nucleic acids, and proteins are enriched in circulation. Collectively termed “exercise factors,” these molecules represent a topical area of research given their speculated contribution to both acute exercise metabolism and adaptation to exercise training. In addition to acute changes induced by exercise, the resting profile of circulating exercise factors may be altered by exercise training. Many exercise factors are speculated to be transported in circulation as the cargo of extracellular vesicles (EVs), and in particular, a sub-category termed “small EVs.” This review describes an overview of exercise factors, small EVs and the effects of exercise, but is specifically focused on a critical appraisal of methodological approaches and current knowledge in the context of changes in the resting profile small EVs induced by exercise training, and the potential bioactivities of preparations of these “exercise-trained” small EVs. Research to date can only be considered preliminary, with interpretation of many studies hindered by limited evidence for the rigorous identification of small EVs, and the conflation of acute and chronic responses to exercise due to sample timing in proximity to exercise. Further research that places a greater emphasis on the rigorous identification of small EVs, and interrogation of potential bioactivity is required to establish more detailed descriptions of the response of small EVs to exercise training, and consequent effects on exercise adaptation.
Prediction of Atrial Fibrillation Using Machine Learning: A Review
Authors: Tseng Andrew S. , Noseworthy Peter A.
Published: October 2021

There has been recent immense interest in the use of machine learning techniques in the prediction and screening of atrial fibrillation, a common rhythm disorder present with significant clinical implications primarily related to the risk of ischemic cerebrovascular events and heart failure. Prior to the advent of the application of artificial intelligence in clinical medicine, previous studies have enumerated multiple clinical risk factors that can predict the development of atrial fibrillation. These clinical parameters include previous diagnoses, laboratory data (e.g., cardiac and inflammatory biomarkers, etc.), imaging data (e.g., cardiac computed tomography, cardiac magnetic resonance imaging, echocardiography, etc.), and electrophysiological data. These data are readily available in the electronic health record and can be automatically queried by artificial intelligence algorithms. With the modern computational capabilities afforded by technological advancements in computing and artificial intelligence, we present the current state of machine learning methodologies in the prediction and screening of atrial fibrillation as well as the implications and future direction of this rapidly evolving field.
Altering Early Life Gut Microbiota Has Long-Term Effect on Immune System and Hypertension in Spontaneously Hypertensive Rats
Authors: Abboud Francois M. , Cicha Michael Z. , Ericsson Aaron , Chapleau Mark W. , Singh Madhu V.
Published: October 2021

Hypertension is regulated by immunological components. Spontaneously hypertensive rats (SHR) display a large population of proinflammatory CD161 + immune cells. We investigated the effect of early post-natal gut microbiota on the development of the immune system and resulting hypertension in the SHR. We first examined the microbial populations in the fecal samples of SHR and normotensive control WKY using 16S rDNA sequencing. We found that in the newborn SHR (1-week old) the gut microbiota was qualitatively and quantitatively different from the newborns of normotensive WKY. The representation of the predominant bacterial phylum Proteobacteria was significantly less in 1-week old SHR pups than in WKY (94.5% Proteobacteria in WKY vs. 65.2% in SHR neonates). Even within the phylum Proteobacteria, the colonizing genera in WKY and SHR differed dramatically. Whereas WKY microbiota was predominantly comprised of Escherichia-Shigella, SHR microbiota was represented by other taxa of Enterobacteriaceae and Pasteurellaceae. In contrast, the representation of phylum Firmicutes in the neonatal SHR gut was greater than WKY. Cross-fostering newborn SHR pups by lactating WKY dams caused a dramatic shift in 1-week old cross-fostered SHR gut microbiota. The two major bacterial taxa of phylum Proteobacteria, Enterobacteriaceae and Pasteurellaceae as well as Lactobacillus intestinalis, Proteus, Romboustia and Rothia were depleted after cross-fostering and were replaced by the predominant genera of WKY (Escherichia-Shigella). A proinflammatory IL-17F producing CD161 + immune cell population in the spleen and aorta of cross-fostered SHR was also reduced (30.7% in self-fostered SHR vs. 12.6% in cross-fostered SHR at 30 weeks of age) as was the systolic blood pressure in adult cross-fostered SHR at 10 weeks of age. Thus, altered composition of gut microbiota of SHR toward WKY at early neonatal age had a long-lasting effect on immune system by reducing proinflammatory immune cells and lowering systolic blood pressure.
Roles of Endothelial Motilin Receptor and Its Signal Transduction Pathway in Motilin-Induced Left Gastric Artery Relaxation in Dogs
Authors: Li HongYu , Yang LanLan , Jin Ying , Jin ChunXiang
Published: October 2021

Background: Motilin increases left gastric artery (LGA) blood flow in dogs via the endothelial motilin receptor (MLNR). This article investigates the signaling pathways of endothelial MLNR.

Methods: Motilin-induced relaxation of LGA rings was assessed using wire myography. Nitric oxide (NO), and cyclic guanosine monophosphate (cGMP) levels were measured using an NO assay kit and cGMP ELISA kit, respectively.

Results: Motilin concentration-dependently (EC50=9.1±1.2×10−8M) relaxed LGA rings precontracted with U46619 (thromboxane A2 receptor agonist). GM-109 (MLNR antagonist) significantly inhibited motilin-induced LGA relaxation and the production of NO and cGMP. N-ethylmaleimide (NEM; G-protein antagonist), U73122 [phospholipase C (PLC) inhibitor], and 2-aminoethyl diphenylborinate [2-APB; inositol trisphosphate (IP3) blocker] partially or completely blocked vasorelaxation. In contrast, chelerythrine [protein kinase C (PKC) inhibitor] and H89 [protein kinase A (PKA) inhibitor] had no such effect. Low-calcium or calcium-free Krebs solutions also reduced vasorelaxation. N-nitro-L-arginine methyl ester [L-NAME; nitric oxide synthase (NOS) inhibitor] and ODQ [soluble guanylyl cyclase (sGC) inhibitor] completely abolished vasodilation and synthesis of NO and cGMP. Indomethacin (cyclooxygenase inhibitor), 18α-glycyrrhetinic acid [18α-GA; myoendothelial gap junction (MEGJ) inhibitor], and K+ channel inhibition through high K+ concentrations or tetraethylammonium (TEA-Cl; KCa channel blocker) partially decreased vasorelaxation, whereas glibenclamide (KATP channel blocker) had no such effect.

Conclusion: The current study suggests that motilin-induced LGA relaxation is dependent on endothelial MLNR through the G protein-PLC-IP3 pathway and Ca2+ influx. The NOS-NO-sGC-cGMP pathway, prostacyclin, MEGJ, and K+ channels (especially KCa) are involved in endothelial-dependent relaxation of vascular smooth muscle (VSM) cells.