bluuebunny/crossref_metadata_2025 huggingface dataset:
Early-Stage Repetitive Transcranial Magnetic Stimulation Altered Posterior–Anterior Cerebrum Effective Connectivity in Methylazoxymethanol Acetate Rats
Authors: Guo Huiling , Xiao Yao , Sun Dandan , Yang Jingyu , Wang Jie , Wang Huaning , Pan Chunyu , Li Chao , Zhao Pengfei , Zhang Yanbo , Wu Jinfeng , Zhang Xizhe , Wang Fei
Published: May 2021

The aim of the current resting-state functional magnetic resonance imaging (fMRI) study was to investigate the potential mechanism of schizophrenia through the posterior–anterior cerebrum imbalance in methylazoxymethanol acetate (MAM) rats and to evaluate the effectiveness of repetitive transcranial magnetic stimulation (rTMS) as an early-stage intervention. The rats were divided into four groups: the MAM-sham group, vehicle-sham group, MAM-rTMS group, and vehicle-rTMS group. The rTMS treatment was targeted in the visual cortex (VC) in adolescent rats. Granger Causality Analysis (GCA) was used to evaluate the effective connectivity between regions of interest. Results demonstrated a critical right VC–nucleus accumbens (Acb)–orbitofrontal cortex (OFC) pathway in MAM rats; significant differences of effective connectivity (EC) were found between MAM-sham and vehicle-sham groups (from Acb shell to OFC: t = −2.553, p = 0.021), MAM-rTMS and MAM-sham groups (from VC to Acb core: t = −2.206, p = 0.043; from Acb core to OFC: t = 4.861, p < 0.001; from Acb shell to OFC: t = 4.025, p = 0.001), and MAM-rTMS and vehicle-rTMS groups (from VC to Acb core: t = −2.482, p = 0.025; from VC to Acb shell: t = −2.872, p = 0.012; from Acb core to OFC: t = 4.066, p = 0.001; from Acb shell to OFC: t = 3.458, p = 0.004) in the right hemisphere. Results of the early-stage rTMS intervention revealed that right nucleus accumbens played the role as a central hub, and VC was a potentially novel rTMS target region during adolescent schizophrenia. Moreover, the EC of right nucleus accumbens shell and orbitofrontal cortex was demonstrated to be a potential biomarker. To our knowledge, this was the first resting-state fMRI study using GCA to assess the deficits of a visual-reward neural pathway and the effectiveness of rTMS treatment in MAM rats. More randomized controlled trials in both animal models and schizophrenia patients are needed to further elucidate the disease characteristics.
Energy-Period Profiles of Brain Networks in Group fMRI Resting-State Data: A Comparison of Empirical Mode Decomposition With the Short-Time Fourier Transform and the Discrete Wavelet Transform
Authors: Cordes Dietmar , Kaleem Muhammad F. , Yang Zhengshi , Zhuang Xiaowei , Curran Tim , Sreenivasan Karthik R. , Mishra Virendra R. , Nandy Rajesh , Walsh Ryan R.
Published: May 2021

Traditionally, functional networks in resting-state data were investigated with linear Fourier and wavelet-related methods to characterize their frequency content by relying on pre-specified frequency bands. In this study, Empirical Mode Decomposition (EMD), an adaptive time-frequency method, is used to investigate the naturally occurring frequency bands of resting-state data obtained by Group Independent Component Analysis. Specifically, energy-period profiles of Intrinsic Mode Functions (IMFs) obtained by EMD are created and compared for different resting-state networks. These profiles have a characteristic distribution for many resting-state networks and are related to the frequency content of each network. A comparison with the linear Short-Time Fourier Transform (STFT) and the Maximal Overlap Discrete Wavelet Transform (MODWT) shows that EMD provides a more frequency-adaptive representation of different types of resting-state networks. Clustering of resting-state networks based on the energy-period profiles leads to clusters of resting-state networks that have a monotone relationship with frequency and energy. This relationship is strongest with EMD, intermediate with MODWT, and weakest with STFT. The identification of these relationships suggests that EMD has significant advantages in characterizing brain networks compared to STFT and MODWT. In a clinical application to early Parkinson’s disease (PD) vs. normal controls (NC), energy and period content were studied for several common resting-state networks. Compared to STFT and MODWT, EMD showed the largest differences in energy and period between PD and NC subjects. Using a support vector machine, EMD achieved the highest prediction accuracy in classifying NC and PD subjects among STFT, MODWT, and EMD.
Simultaneous CMOS-Based Imaging of Calcium Signaling of the Central Amygdala and the Dorsal Raphe Nucleus During Nociception in Freely Moving Mice
Authors: Rebusi Romeo , Olorocisimo Joshua Philippe , Briones Jeric , Ohta Yasumi , Haruta Makito , Takehara Hironari , Tashiro Hiroyuki , Sasagawa Kiyotaka , Ohta Jun
Published: May 2021

Fluorescence imaging devices have been indispensable in elucidating the workings of the brain in living animals, including unrestrained, active ones. Various devices are available, each with their own strengths and weaknesses in terms of many factors. We have developed CMOS-based needle-type imaging devices that are small and lightweight enough to be doubly implanted in freely moving mice. The design also allowed angled implantations to avoid critical areas. We demonstrated the utility of the devices by using them on GCaMP6 mice in a formalin test experiment. Simultaneous implantations to the capsular-lateral central amygdala (CeLC) and dorsal raphe nucleus (DRN) were proven to be safe and did not hinder the execution of the study. Analysis of the collected calcium signaling data, supported by behavior data, showed increased activity in both regions as a result of pain stimulation. Thus, we have successfully demonstrated the various advantages of the device in its application in the pain experiment.
Growth Factors as Axon Guidance Molecules: Lessons From in vitro Studies
Authors: Onesto Massimo M. , Short Caitlin A. , Rempel Sarah K. , Catlett Timothy S. , Gomez Timothy M.
Published: May 2021

Growth cones at the tips of extending axons navigate through developing organisms by probing extracellular cues, which guide them through intermediate steps and onto final synaptic target sites. Widespread focus on a few guidance cue families has historically overshadowed potentially crucial roles of less well-studied growth factors in axon guidance. In fact, recent evidence suggests that a variety of growth factors have the ability to guide axons, affecting the targeting and morphogenesis of growth conesin vitro.This review summarizesin vitroexperiments identifying responses and signaling mechanisms underlying axon morphogenesis caused by underappreciated growth factors.
The Abnormal Functional Connectivity in the Locus Coeruleus-Norepinephrine System Associated With Anxiety Symptom in Chronic Insomnia Disorder
Authors: Gong Liang , Shi Min , Wang Jian , Xu Ronghua , Yu Siyi , Liu Duan , Ding Xin , Zhang Bei , Zhang Xingping , Xi Chunhua
Published: May 2021

Background

Mental syndromes such as anxiety and depression are common comorbidities in patients with chronic insomnia disorder (CID). The locus coeruleus noradrenergic (LC-NE) system is considered to be crucial for modulation of emotion and sleep/wake cycle. LC-NE system is also a critical mediator of the stress-induced anxiety. However, whether the LC-NE system contributes to the underlying mechanism linking insomnia and these comorbidities remain unclear. This study aimed to investigate the LC-NE system alterations in patients with insomnia and its relationship with depression and anxiety symptoms.

Materials and Methods

Seventy patients with CID and 63 matched good sleep control (GSC) subjects were recruited and underwent resting-state functional MRI scan. LC-NE functional network was constructed by using seed-based functional connectivity (FC) analysis. The alterations in LC-NE FC network in patients with CID and their clinical significance was explored.

Results

Compared with GSC group, the CID group showed decreased left LC-NE FC in the left inferior frontal gyrus, while they had increased LC-NE FC in the left supramarginal gyrus and the left middle occipital gyrus (MOG). For the right LC-NE FC network, decreased FC was found in left dorsal anterior cingulate cortex (dACC). Interesting, the increased LC-NE FC was located in sensory cortex, while decreased LC-NE FC was located in frontal control cortex. In addition, the FC between the left LC and left MOG was associated with the duration of the disease, while abnormal FC between right LC and left dACC was associated with the anxiety scores in patients with CID.

Conclusion

The present study found abnormal LC-NE functional network in patients with CID, and the altered LC-NE function in dACC was associated with anxiety symptoms in CID. The present study substantially extended our understanding of the neuropathological basis of CID and provided the potential treatment target for CID patients who also had anxiety.
Complete Correction of Brain and Spinal Cord Pathology in Metachromatic Leukodystrophy Mice
Authors: Audouard Emilie , Oger Valentin , Meha Béatrix , Cartier Nathalie , Sevin Caroline , Piguet Françoise
Published: May 2021

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder characterized by accumulation of sulfatides in both glial cells and neurons. MLD results from an inherited deficiency of arylsulfatase A (ARSA) and myelin degeneration in the central and peripheral nervous systems. Currently, no effective treatment is available for the most frequent late infantile (LI) form of MLD after symptom onset. The LI form results in rapid neurological degradation and early death. ARSA enzyme must be rapidly and efficiently delivered to brain and spinal cord oligodendrocytes of patients with LI MLD in order to potentially stop the progression of the disease. We previously showed that brain gene therapy with adeno-associated virus serotype rh10 (AAVrh10) driving the expression of human ARSA cDNA alleviated most long-term disease manifestations in MLD mice but was not sufficient in MLD patient to improve disease progression. Herein, we evaluated the short-term effects of intravenous AAVPHP.eB delivery driving the expression of human ARSA cDNA under the control of the cytomegalovirus/b-actin hybrid (CAG) promoter in 6-month-old MLD mice that already show marked sulfatide accumulation and brain pathology. Within 3 months, a single intravenous injection of AAVPHP.eB-hARSA-HA resulted in correction of brain and spinal cord sulfatide storage, and improvement of astrogliosis and microgliosis in brain and spinal cord of treated animals. These results strongly support to consider the use of AAVPHP.eB-hARSA vector for intravenous gene therapy in symptomatic rapidly progressing forms of MLD.
Long-Lasting Event-Related Beta Synchronizations of Electroencephalographic Activity in Response to Support-Surface Perturbations During Upright Stance: A Pilot Study Associating Beta Rebound and Active Monitoring in the Intermittent Postural Control
Authors: Nakamura Akihiro , Suzuki Yasuyuki , Milosevic Matija , Nomura Taishin
Published: May 2021

Movement related beta band cortical oscillations, including beta rebound after execution and/or suppression of movement, have drawn attention in upper extremity motor control literature. However, fewer studies focused on beta band oscillations during postural control in upright stance. In this preliminary study, we examined beta rebound and other components of electroencephalogram (EEG) activity during perturbed upright stance to investigate supraspinal contributions to postural stabilization. Particularly, we aimed to clarify the timing and duration of beta rebound within a non-sustained, but long-lasting postural recovery process that occurs more slowly compared to upper extremities. To this end, EEG signals were acquired from nine healthy young adults in response to a brief support-surface perturbation, together with the center of pressure, the center of mass and electromyogram (EMG) activities of ankle muscles. Event-related potentials (ERPs) and event-related spectral perturbations were computed from EEG data using the perturbation-onset as a triggering event. After short-latency (<0.3 s) ERPs, our results showed a decrease in high-beta band oscillations (event-related desynchronization), which was followed by a significant increase (event-related synchronization) in the same band, as well as a decrease in theta band oscillations. Unlike during upper extremity motor tasks, the beta rebound in this case was initiated before the postural recovery was completed, and sustained for as long as 3 s with small EMG responses for the first half period, followed by no excessive EMG activities for the second half period. We speculate that those novel characteristics of beta rebound might be caused by slow postural dynamics along a stable manifold of the unstable saddle-type upright equilibrium of the postural control system without active feedback control, but with active monitoring of the postural state, in the framework of the intermittent control.
Neutral Effect of Increased Dairy Product Intake, as Part of a Lifestyle Modification Program, on Cardiometabolic Health in Adolescent Girls With Overweight/Obesity: A Secondary Analysis From a Randomized Controlled Trial
Authors: Skelly Lauren E. , Barbour-Tuck Erin N. , Kurgan Nigel , Calleja Melissa , Klentrou Panagiota , Falk Bareket , Josse Andrea R.
Published: May 2021

Background:The presence of obesity and some cardiometabolic disease risk factors in childhood and adolescence track into adulthood. Intake of dairy products has been shown to be inversely related to adiposity and cardiometabolic variables in youth. However, limited research has examined cardiometabolic disease risk factors following increased dairy product consumption as part of a lifestyle modification intervention in youth with overweight/obesity. This secondary analysis aimed to determine whether 12 weeks of increased dairy consumption, as part of a lifestyle modification program, affects cardiometabolic variables in adolescent females (range: 10–18 years) with overweight/obesity (BMI > 85th centile).

Methods:Participants were randomized into two groups: higher dairy intake (RDa; four servings/day [to reflect previous Canada's Food Guide recommendations];n= 23) or low dairy intake (LDa; 0–2 servings/day;n= 23). Both RDa and LDa participated in a 12-week, eucaloric, lifestyle modification intervention consisting of exercise training, and nutritional counseling. Adiposity (percent body fat [%BF]), dietary intake, and measures of cardiometabolic health were measured pre- and post-intervention.

Results:There were no significant changes over time within groups or differences over time between groups for triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL), TC/HDL ratio, low-density lipoprotein cholesterol (LDL), glucose, insulin, homeostatic model assessment of insulin resistance, adiponectin, and tumor necrosis factor alpha (TNF-α) (main effects of time and interactions,p> 0.05). Leptin decreased over the 12-week lifestyle intervention in both groups (main effect of time,p= 0.02). After combining the groups (n= 46), significant correlations were found between change in %BF and change in some cardiometabolic variables (HDL [r= −0.40], TC/HDL ratio [r= 0.42], LDL [r= 0.36], and TNF-α [r= 0.35],p< 0.05). After controlling for change in dairy product intake, the correlations were unchanged.

Conclusion:Our findings demonstrate that increased dairy product consumption, as part of a lifestyle modification, weight management intervention, had a neutral effect on cardiometabolic disease risk factors in adolescent females with overweight/obesity. Change in dairy product intake did not influence the relationships between change in adiposity and change in cardiometabolic variables. Future research designed to primarily assess the effect of increased dairy product consumption on cardiometabolic disease risk factors in this population is warranted.

Clinical Trial Registration:Clinicaltrials.gov; NCT#02581813.
Intersecting Mechanisms of Hypoxia and Prostaglandin E2-Mediated Inflammation in the Comparative Biology of Oral Squamous Cell Carcinoma
Authors: Nasry Walaa Hamed Shaker , Martin Chelsea K.
Published: May 2021

The importance of inflammation in the pathogenesis of cancer was first proposed by Rudolph Virchow over 150 years ago, and our understanding of its significance has grown over decades of biomedical research. The arachidonic acid pathway of inflammation, including cyclooxygenase (COX) enzymes, PGE2 synthase enzymes, prostaglandin E2 (PGE2) and PGE2 receptors has been extensively studied and has been associated with different diseases and different types of cancers, including oral squamous cell carcinoma (OSCC). In addition to inflammation in the tumour microenvironment, low oxygen levels (hypoxia) within tumours have also been shown to contribute to tumour progression. Understandably, most of our OSCC knowledge comes from study of this aggressive cancer in human patients and in experimental rodent models. However, domestic animals develop OSCC spontaneously and this is an important, and difficult to treat, form of cancer in veterinary medicine. The primary goal of this review article is to explore the available evidence regarding interaction between hypoxia and the arachidonic acid pathway of inflammation during malignant behaviour of OSCC. Overlapping mechanisms in hypoxia and inflammation can contribute to tumour growth, angiogenesis, and, importantly, resistance to therapy. The benefits and controversies of anti-inflammatory and anti-angiogenic therapies for human and animal OSCC patients will be discussed, including conventional pharmaceutical agents as well as natural products.
p62 Overexpression Promotes Bone Metastasis of Lung Adenocarcinoma out of LC3-Dependent Autophagy
Authors: Li Dongqi , He Chuanchun , Ye Fan , Ye En , He Hao , Chen Gong , Zhang Jing
Published: May 2021

p62 protein has been implicated in bone metastasis and is a multifunctional adaptor protein usually correlated with autophagy. Herein, we investigated p62 expression and its prognostic significance in bone metastasis of lung adenocarcinoma, and analyzed whether the mechanism involved depends on autophagy. mRNA and protein expression of p62, LC3B and Beclin 1 were detected by reverse transcription-quantitative PCR and western blotting, respectively, in fresh bone metastasis tissues (n=6 cases) and normal cancellous bone tissues (n=3 cases). The association between p62 and LC3B expression and patient prognosis was subsequently analyzed in 62 paraffin-embedded bone metastasis specimens by immunohistochemistry assay. Small interfering RNA (siRNA) was employed to downregulate p62 expression in SPC-A-1 and A549 cells. Cell proliferation and migration ability were tested by CCK8, CCF and Transwell assays respectively. Autophagy was induced by Rapamycin or inhibited by Atg 7 knockout/Chloroquine in A549 cells and p62 and LC3II/I expression were analyzed. After subcutaneous inoculation or intracardial injection of A549 cells into nude mice, the effect of p62 downregulation in vivo was analyzed by histopathological examination. The results showed that p62, LC3B and Beclin 1 mRNA and protein were all overexpressed in bone metastasis tissues (all P<0.01). Patient samples with high p62 expression levels were significantly associated with more bone lesions (>3), shorter overall survival rates and shorter progression free survival rates compared with patients having lower p62 expression (P=0.014, P=0.003, P=0.048, respectively). Cox regression analysis identified p62 expression as an independent prognostic indicator of overall survival of patients with bone metastasis (P=0.007). In vitro p62 downregulation inhibited SPC-A-1 and A549 cells migration but had no effect on cell proliferation. After autophagy induction or inhibition, p62 expression involved in autophagy flux and changed inconsistently according to the switch of LC3I to LC3II in different autophagy conditions. In vivo p62 downregulation had no effect on growth of subcutaneous tumor. Lung or bone metastasis lesion was not found in all mice model. These findings suggested that p62 overexpression promotes tumor cell invasion out of LC3-dependent autophagy, which could be used a potential prognostic biomarker and therapeutic target for bone metastasis of lung adenocarcinoma.
Androgen Receptor, Although Not a Specific Marker For, Is a Novel Target to Suppress Glioma Stem Cells as a Therapeutic Strategy for Glioblastoma
Authors: Zhao Nan , Wang Fei , Ahmed Shaheen , Liu Kan , Zhang Chi , Cathcart Sahara J. , DiMaio Dominick J. , Punsoni Michael , Guan Bingjie , Zhou Ping , Wang Shuo , Batra Surinder K. , Bronich Tatiana , Hei Tom K. , Lin Chi , Zhang Chi
Published: May 2021

Targeting androgen receptor (AR) has been shown to be promising in treating glioblastoma (GBM) in cell culture and flank implant models but the mechanisms remain unclear. AR antagonists including enzalutamide are available for treating prostate cancer patients in clinic and can pass the blood–brain barrier, thus are potentially good candidates for GBM treatment but have not been tested in GBM orthotopically. Our current studies confirmed that in patients, a majority of GBM tumors overexpress AR in both genders. Enzalutamide inhibited the proliferation of GBM cells both in vitro and in vivo. Although confocal microscopy demonstrated that AR is expressed but not specifically in glioma cancer stem cells (CSCs) (CD133+), enzalutamide treatment significantly decreased CSC population in cultured monolayer cells and spheroids, suppressed tumor sphere-forming capacity of GBM cells, and downregulated CSC gene expression at mRNA and protein levels in a dose- and time-dependent manner. We have, for the first time, demonstrated that enzalutamide treatment decreased the density of CSCs in vivo and improved survival in an orthotopic GBM mouse model. We conclude that AR antagonists potently target glioma CSCs in addition to suppressing the overall proliferation of GBM cells as a mechanism supporting their repurposing for clinical applications treating GBM.
Sharp Downregulation of Hub Genes Associated With the Pathogenesis of Breast Cancer From Ductal Carcinoma In Situ to Invasive Ductal Carcinoma
Authors: Wang Yao , Liang Faqing , Zhou Yuting , Qiu Juanjuan , Lv Qing , Du Zhenggui
Published: May 2021

Introduction

Breast atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) are precursor stages of invasive ductal carcinoma (IDC). This study aimed to investigate the pathogenesis of breast cancer by dynamically analyzing expression changes of hub genes from normal mammary epithelium (NME) to simple ductal hyperplasia (SH), ADH, DCIS, and finally to IDC.

Methods

Laser-capture microdissection (LCM) data for NME, SH, ADH, DCIS, and IDC cells were obtained. Weighted gene co-expression network analysis (WGCNA) was performed to dynamically analyze the gene modules and hub genes associated with the pathogenesis of breast cancer. Tissue microarray, immunohistochemical, and western blot analyses were performed to determine the protein expression trends of hub genes.

Results

Two modules showed a trend of increasing expression during the development of breast disease from NME to DCIS, whereas a third module displayed a completely different trend. Interestingly, the three modules displayed inverse trends from DCIS to IDC compared with from NME to DCIS; that is, previously upregulated modules were subsequently downregulated and vice versa. We further analyzed the module that was most closely associated with DCIS (p=7e−07). Kyoto Gene and Genomic Gene Encyclopedia enrichment analysis revealed that the genes in this module were closely related to the cell cycle (p= 4.3e–12). WGCNA revealed eight hub genes in the module, namely, CDK1, NUSAP1, CEP55, TOP2A, MELK, PBK, RRM2, and MAD2L1. Subsequent analysis of these hub genes revealed that their expression levels were lower in IDC tissues than in DCIS tissues, consistent with the expression trend of the module. The protein expression levels of five of the hub genes gradually increased from NME to DCIS and then decreased in IDC. Survival analysis predicted poor survival among breast cancer patients if these hub genes were not downregulated from DCIS to IDC.

Conclusions

Five hub genes, RRM2, TOP2A, PBK, MELK, and NUSAP1, which are associated with breast cancer pathogenesis, are gradually upregulated from NME to DCIS and then downregulated in IDC. If these hub genes are not downregulated from DCIS to IDC, patient survival is compromised. However, the underlying mechanisms warrant further elucidation in future studies.
HOXA13, Negatively Regulated by miR-139-5p, Decreases the Sensitivity of Gastric Cancer to 5-Fluorouracil Possibly by Targeting ABCC4
Authors: Chen Zhengqian , Qin Zhiwei , Li Lei , Wo Qi , Chen Xia
Published: May 2021

Purpose

Chemoresistance remains a major challenge in the therapy of gastric cancer (GC). The homeobox (HOX) gene family has gained attention in carcinogenesis and chemoresistance. Here, this study aimed to explore the mechanism of HOXA13 in GC chemoresistance.

Methods

Quantitative real-time PCR (qRT-PCR) and Western blot were used to evaluate the expression of HOXA13 in GC tissues. The Kaplan–Meier plotter database was mined for prognosis analysis of GC patients with different HOXA13 expression receiving 5-Fluorouracil (5-FU) therapy. The effects of HOXA13 on sensitivity of GC cells to 5-FU were investigated by Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2’-deoxyuridine (EdU) incorporation, flow cytometry and experiment in vivo. RNA-Sequencing analysis was performed to explore the underlying mechanism of HOXA13-mediated 5-FU resistance in GC. Chromatin immunoprecipitation (ChIP) and rescue experiments were applied to determine the relationship between HOXA13 and ABCC4. Luciferase reporter assay was performed to assess interaction of miR-139-5p and HOXA13.

Results

HOXA13 was upregulated in GC and its high expression was associated with poor prognosis of GC patients with 5-FU treatment. Overexpression of HOXA13 impaired the inhibitory effects of 5-FU on GC cells proliferation in vitro and vivo, and knockdown of HOXA13 exacerbated 5-FU-induced GC cells apoptosis. Mechanistically, HOXA13, directly targeted by miR-139-5p in GC, might upregulate ABCC4 expression, thereby accentuating 5-FU resistance of GC cells.

Conclusion

Our study suggests that HOXA13 attenuates 5-FU sensitivity of GC possibly by upregulating ABCC4. Thus, targeting HOXA13 would provide a novel prospective into the potential therapeutic strategy for reversing chemoresistance.
A Phase 2 Randomised Clinical Trial Assessing the Tolerability of Two Different Ratios of Medicinal Cannabis in Patients With High Grade Gliomas
Authors: Schloss Janet , Lacey Judith , Sinclair Justin , Steel Amie , Sughrue Michael , Sibbritt David , Teo Charles
Published: May 2021

Background

Cannabis for cancer is very topical and, given the use of illicit cannabis preparations used in this vulnerable population, research investigating standardised, quality-assured medicinal cannabis is critical to inform clinicians and assist patient safety.

Methods

A randomized trial involving adult patients diagnosed with a high-grade glioma, no history of substance abuse, liver or kidney damage or myocardial infarction were eligible for inclusion in a tolerability study on two different ratios of medicinal cannabis. Baseline screening of brain morphology, blood pathology, functional status, and cognition was conducted. A retrospective control group was used for comparison for secondary outcomes.

Results

Participants (n=88) were on average 53.3 years old. A paired t-test assessed the Functional Assessment of Cancer Therapy for Brain Cancer (FACT-Br) between groups from baseline to week 12 found that the 1:1 ratio favoured both physical (p=0.025) and functional (p=0.014) capacity and improved sleep (p=0.009). Analysis of changes from baseline to week 12 also found 11% of 61 participants had a reduction in disease, 34% were stable, 16% had slight enhancement, and 10% had progressive disease. No serious adverse events occurred. Side effects included dry mouth, tiredness at night, dizziness, drowsiness.

Conclusion

This study demonstrated that a single nightly dose of THC-containing medicinal cannabis was safe, had no serious adverse effects and was well tolerated in patients. Medicinal cannabis significantly improved sleep, functional wellbeing, and quality of life.

Clinical Trial Registration

Australian New Zealand Clinical Trials Registry (ANZCTR) http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373556&isReview=true, identifier ACTRN12617001287325.
Induction Chemotherapy Combined With Intensity-Modulated Radiotherapy for 129 Nasopharyngeal Carcinoma Patients With Synchronous Metastases: A Retrospective Study
Authors: Ni Mengshan , Geng Lijun , Kong Fangfang , Du Chengrun , Zhai Ruiping , Lyu Yingchen , Hu Chaosu , Ying Hongmei
Published: May 2021

Objective

To analyze the therapeutic effect and prognostic factors of nasopharyngeal carcinoma (NPC) patients with distant metastases at initial diagnosis receiving induction chemotherapy with intensity-modulated radiotherapy (IMRT).

Methods

A total of 129 patients who underwent platinum-based induction chemotherapy followed by definitive IMRT with or without concurrent or adjuvant chemotherapy for newly diagnosed distant metastatic NPC in our center between March 2008 and November 2018 were retrospectively analyzed. 41 patients underwent local therapy for metastatic sites. Kaplan-Meier method was used to estimate survival rates, Log-rank test and Cox proportional hazards model were used to figure out independent prognostic factors of overall survival (OS).

Results

A total of 66 patients had been dead (median follow-up time, 51.5 months). The median overall survival (OS) time was 54.2 months (range, 7-136 months), and the 1-year, 2-year, 3-year, 5-year overall survival rates were 88.0%,71.0%,58.0%, and 47.0%. Multivariate analysis found that the factors correlated with poor overall survival were pre-treatment serum lactate dehydrogenase (SLDH) >180U/L, chemotherapy cycles<4, and M1 stage subdivision (M1b, single hepatic metastasis and/or multiple metastases excluding the liver; and M1c, multiple hepatic metastases). The 5-year OS rates for M1a, M1b and M1c were 62.6%,40.4% and 0%, respectively.

Conclusion

Platinum-containing induction chemotherapy combined with IMRT seemed to be advantageous to prolong survival for some NPC patients with synchronous metastases at initial diagnosis. The independent factors to prognosticate OS were pre-treatment SLDH, number of chemotherapy cycles, and M1 subcategories. Prospective clinical trials are needed to confirm the result.
Selenite Induces Cell Cycle Arrest and Apoptosis via Reactive Oxygen Species-Dependent Inhibition of the AKT/mTOR Pathway in Thyroid Cancer
Authors: Cheng Zhen , Yu Shuang , He Weiman , Li Jie , Xu Tianyi , Xue Junyu , Shi Peijie , Chen Shuwei , Li Yanbing , Hong Shubin , Xiao Haipeng
Published: May 2021

Thyroid cancer is the most common endocrine malignancy, and its incidence has increased in the past decades. Selenium has been shown to have therapeutic effects against several tumors. However, its role in thyroid cancer and its underlying molecular mechanism remains to be explored. In the present study, we demonstrated that sodium selenite significantly decreased cell viability and induced G0/G1 cell cycle arrest and apoptosis in thyroid cancer cells in a dose-dependent manner. Transcriptomics revealed that sodium selenite induced intracellular reactive oxygen species (ROS) by promoting oxidative phosphorylation. Increased intracellular ROS levels inhibited the AKT/mTOR signaling pathway and upregulated EIF4EBP3. Intracellular ROS inhibition by N-acetylcysteine (NAC) ameliorated the cellular effects of sodium selenite. The in vitro findings were reproduced in xenograft thyroid tumor models. Our data demonstrated that sodium selenite exhibits strong anticancer effects against thyroid cancer cells, which involved ROS-mediated inhibition of the AKT/mTOR pathway. This suggests that sodium selenite may serve as a therapeutic option for advanced thyroid cancer.
Preoperative nTMS and Intraoperative Neurophysiology - A Comparative Analysis in Patients With Motor-Eloquent Glioma
Authors: Rosenstock Tizian , Tuncer Mehmet Salih , Münch Max Richard , Vajkoczy Peter , Picht Thomas , Faust Katharina
Published: May 2021

Background

The resection of a motor-eloquent glioma should be guided by intraoperative neurophysiological monitoring (IOM) but its interpretation is often difficult and may (unnecessarily) lead to subtotal resection. Navigated transcranial magnetic stimulation (nTMS) combined with diffusion-tensor-imaging (DTI) is able to stratify patients with motor-eloquent lesion preoperatively into high- and low-risk cases with respect to a new motor deficit.

Objective

To analyze to what extent preoperative nTMS motor risk stratification can improve the interpretation of IOM phenomena.

Methods

In this monocentric observational study, nTMS motor mapping with DTI fiber tracking of the corticospinal tract was performed before IOM-guided surgery for motor-eloquent gliomas in a prospectively collected cohort from January 2017 to October 2020. Descriptive analyses were performed considering nTMS data (motor cortex infiltration, resting motor threshold (RMT), motor evoked potential (MEP) amplitude, latency) and IOM data (transcranial MEP monitoring, intensity of monopolar subcortical stimulation (SCS), somatosensory evoked potentials) to examine the association with the postoperative motor outcome (assessed at day of discharge and at 3 months).

Results

Thirty-seven (56.1%) of 66 patients (27 female) with a median age of 48 years had tumors located in the right hemisphere, with glioblastoma being the most common diagnosis with 39 cases (59.1%). Three patients (4.9%) had a new motor deficit that recovered partially within 3 months and 6 patients had a persistent deterioration (9.8%). The more risk factors of the nTMS risk stratification model (motor cortex infiltration, tumor-tract distance (TTD) ≤8mm, RMTratio <90%/>110%) were detected, the higher was the risk for developing a new postoperative motor deficit, whereas no patient with a TTD >8mm deteriorated. Irreversible MEP amplitude decrease >50% was associated with worse motor outcome in all patients, while a MEP amplitude decrease ≤50% or lower SCS intensities ≤4mA were particularly correlated with a postoperative worsened motor status in nTMS-stratified high-risk cases. No patient had postoperative deterioration of motor function (except one with partial recovery) when intraoperative MEPs remained stable or showed only reversible alterations.

Conclusions

The preoperative nTMS-based risk assessment can help to interpret ambiguous IOM phenomena (such as irreversible MEP amplitude decrease ≤50%) and adjustment of SCS stimulation intensity.
Treatment for Flexible Flatfoot in Children With Subtalar Arthroereisis and Soft Tissue Procedures
Authors: Li Bing , He Wenbao , Yu Guangrong , Zhou Haichao , Xia Jiang , Zhao Youguang , Zhu Hui , Yu Tao , Yang Yunfeng
Published: May 2021

Background: Children with flexible flatfoot is common in clinics and there is no unified conclusion on surgical treatment. And for some patients with severe deformities, the correction of the subtalar joint arthroereisis combine the release of the Achilles tendon or gastrocnemius muscle release is still not satisfactory. The main aim of the present study was to investigate the therapeutic outcomes of subtalar arthroereisis combined with Achilles tendon or gastrocnemius recession and medial soft tissue (spring ligament, talonavicular joint capsule, tibionavicular ligaments and tibiospring ligaments) tightening for treating flexible flatfoot with severe deformities.

Methods: Thirty patients (32 feet) with pediatric flexible flatfoot who underwent subtalar arthroereisis and soft tissue procedures during January 2016 to January 2018. There were 18 males (20 feet) and 12 females (12 feet) with an average age of 9.5 years (range, 8–12 years). We used the AOFAS scores and VAS scores combined with angles measure to evaluate the pre-operative and post-operative status.

Results: Thirty patients (32 feet) were followed up for 25.3 months on average (range, 18–36 months). There was no infection. Post-operative foot pain, arch collapse, and other symptoms improved. At last follow-up, the Meary angle was decreased from 17.5° ± 4.4° to 4.1° ± 1.2° (P < 0.05), the talar-first metatarsal (AP) was decreased from 15.3° ± 3.1° to 4.8° ± 1.3°(P < 0.05), The mean AOFAS score was rose from 66.6 ± 5.8 to 88.6 ± 7.9 (P < 0.05), the mean VAS score was decreased from 6.6 ± 0.6 to 1.7 ± 0.3 (P < 0.05).

Conclusion: The subtalar arthroereisis combined with soft tissue procedures can effectively correct flexible flatfoot in children and it is a significant method for severe forefoot abduction reconstruction.

Level of Evidence: IV
Efficacy of Chinese Herbal Injections for Elderly Patients With pneumonia—A Bayesian Network Meta-analysis of Randomized Control Trials
Authors: Yuan Yang , Zheng Quan , Si Zhilin , Liu Juhua , Li Zhi , Xiong Lian , Liu Pan , Li Xu , He Chengshi , Liang Jinghong
Published: May 2021

Background: Pneumonia is a prevalent and complicated disease among adults, elderly people in particular, and the debate on the optimal Chinese herbal injections (CHIs) is ongoing. Our objective is to investigate the comparative effectiveness of various CHIs strategies for elderly patients with pneumonia.

Methods: A comprehensive search strategy was executed to identify relevant randomized controlled trials (RCTs) by browsing through several databases from their inception to first, Feb 2020; All of the direct and indirect evidence included was rated by Network meta-analysis under a Bayesian framework.

Results: We ultimately identified 34 eligible randomized controlled trials that involved 3,111 elderly participants and investigated 4 CHIs combined with Western medicine (WM) (Xiyanping injection [XYP]+WM, Yanhuning injection [YHN]+WM, Tanreqing injection [TRQ]+WM, Reduning injection [RDN]+WM), contributing 34 direct comparisons between CHIs. Seen from the outcome of Clinical effective rate and time for defervescence, patients taking medicine added with CHIs [Clinical effective rate, XYP + WM(Odd ratio (OR): 0.74, 95%Credible intervals (CrIs):0.55–0.98), YHN + WM(OR: 0.66, 95%CrI: 0.45–0.95), TRQ + WM(OR: 0.65, 95%CrI: 0.50–0.83), RDN + WM(OR: 0.60, 95%CrI: 0.40–0.89); Time for defervescence, YHN + WM(Mean difference (MD): −2.11, 95%CrI: −3.26 to −0.98), XYP + WM(MD: −2.06, 95%CrI: −3.08 to −1.09), RDN + WM(MD: −1.97, 95%CrI: −3.61 to −0.35), TRQ + WM(MD: −1.69, 95%CrI: −2.27 to −1.04)] showed statistically better effect compared with participants in the Control group (CG) who only took WM. Meanwhile, based on the time for disappearance of cough, 3 out of 4 CHIs [TRQ + WM(MD: −2.56, 95%CrI: −3.38 to −1.54), YHN + WM(MD: −2.36, 95%CrI: −3.86 to −1.00) and XYP + WM(MD: −2.21, 95%CrI: −3.72 to −1.10)] strategies indicated improvement of clinical symptoms. Only XYP + WM(MD −1.78, 95%CrI: −3.29 to −0.27) and TRQ + WM (MD: −1.71, 95%CrI: −2.71 to −0.73) could significantly shorten the time for disappearance of pulmonary rales.

Conclusion: According to the statistical effect size (The surface under the cumulative ranking), we found that XYP + WM was presumably to be the preferable treatment for treating elderly patients with pneumonia compared with WM alone in terms of clinical effective rate. Our findings were based on very limited evidence and thus should be interpreted with caution. The application of the findings requires further research.
Dexmedetomidine Protects Human Cardiomyocytes Against Ischemia-Reperfusion Injury Through α2-Adrenergic Receptor/AMPK-Dependent Autophagy
Authors: Xiao Yingying , Li Junpeng , Qiu Lisheng , Jiang Chuan , Huang Yanhui , Liu Jinfen , Sun Qi , Hong Haifa , Ye Lincai
Published: May 2021

Background: Ischemia-reperfusion injury (I/R) strongly affects the prognosis of children with complicated congenital heart diseases (CHDs) who undergo long-term cardiac surgical processes. Recently, the α2-adrenergic receptor agonist Dexmedetomidine (Dex) has been reported to protect cardiomyocytes (CMs) from I/R in cellular models and adult rodent models. However, whether and how Dex may protect human CMs in young children remains largely unknown.

Methods and Results: Human ventricular tissue from tetralogy of Fallot (TOF) patients and CMs derived from human-induced pluripotent stem cells (iPSC-CMs) were used to assess whether and how Dex protects human CMs from I/R. The results showed that when pretreated with Dex, the apoptosis marker-TUNEL and cleaved caspase 3 in the ventricular tissue were significantly reduced. In addition, the autophagy marker LC3II was significantly increased compared with that of the control group. When exposed to the hypoxia/reoxygenation process, iPSC-CMs pretreated with Dex also showed reduced TUNEL and cleaved caspase 3 and increased LC3II. When the autophagy inhibitor (3-methyladenine, 3-MA) was applied to the iPSC-CMs, the protective effect of Dex on the CMs was largely blocked. In addition, when the fusion of autophagosomes with lysosomes was blocked by Bafilomycin A1, the degradation of p62 induced by Dex during the autophagy process was suspended. Moreover, when pretreated with Dex, both the human ventricle and the iPSC-CMs expressed more AMP-activated protein kinase (AMPK) and phospho AMPK (pAMPK) during the I/R process. After AMPK knockout or the use of an α2-adrenergic receptor antagonist-yohimbine, the protection of Dex and its enhancement of autophagy were inhibited.

Conclusion: Dex protects young human CMs from I/R injury, and α2-adrenergic receptor/AMPK-dependent autophagy plays an important role during this process. Dex may have a therapeutic effect for children with CHD who undergo long-term cardiac surgical processes.
Metformin Affects Gut Microbiota Composition and Diversity Associated with Amelioration of Dextran Sulfate Sodium-Induced Colitis in Mice
Authors: Liu Zhiyi , Liao Wangdi , Zhang Zihan , Sun Ruipu , Luo Yunfei , Chen Qiongfeng , Li Xin , Lu Ruiling , Ying Ying
Published: May 2021

Background: Inflammatory bowel disease (IBD) is an increasingly common and globally emergent immune-mediated disorder. The etiology of IBD is complex, involving multiple factors such as immune dysregulation, environmental factors, genetic mutations, and microbiota dysbiosis, exacerbated by a lack of effective clinical therapies. Recently, studies hypothesized that dysbiosis of intestinal flora might participate in the onset of IBD. Metformin is widely used to treat type 2 diabetes and has shown beneficial effects in mouse models of IBD, although its underlying mechanisms remain poorly understood. Accumulating studies found that metformin shows beneficial effects for diabetes by affecting microbiota composition. This study explores possible regulatory effects of metformin on intestinal microecology during treatment for IBD.

Methods: Inflammation was induced using 3% Dextran Sulfate Sodium (DSS) solution to generate mice models of IBD. Metformin treatments were assayed by measuring body weights and colon lengths of mice and H&E staining to observe histological effects on colon tissue structures. Changes in bacterial community composition and diversity-related to IBD and metformin treatment were assessed by high-throughput metagenomic sequencing analysis.

Results: Metformin administration significantly ameliorated body weight loss, inhibited colon shrinking, and contributed to preserving the integrity of colon histological structures. The gut microbiota profiles revealed that the biodiversity of intestinal flora lost during inflammation was restored under metformin treatment. Metformin administration was also associated with decreased pathogenic Escherichia shigella and increased abundance of Lactobacillus and Akkermansia.

Conclusion: Metformin appears to induce anti-inflammatory effects, thus ameliorating colitis symptoms, concurrent with enrichment for beneficial taxa and restored microbial diversity, suggesting a viable strategy against IBD.
Review on Biological Characteristics of Kv1.3 and Its Role in Liver Diseases
Authors: Liu Junda , Lv Xiong-Wen , Zhang Lei , Wang Hua , Li Jun , Wu Baoming
Published: May 2021

The liver accounts for the largest proportion of macrophages in all solid organs of the human body. Liver macrophages are mainly composed of cytolytic cells inherent in the liver and mononuclear macrophages recruited from the blood. Monocytes recruitment occurs mainly in the context of liver injury and inflammation and can be recruited into the liver and achieve a KC-like phenotype. During the immune response of the liver, macrophages/KC cells release inflammatory cytokines and infiltrate into the liver, which are considered to be the common mechanism of various liver diseases in the early stage. Meanwhile, macrophages/KC cells form an interaction network with other liver cells, which can affect the occurrence and progression of liver diseases. From the perspective of liver disease treatment, knowing the full spectrum of macrophage activation, the underlying molecular mechanisms, and their implication in either promoting liver disease progression or repairing injured liver tissue is highly relevant from a therapeutic point of view. Kv1.3 is a subtype of the voltage-dependent potassium channel, whose function is closely related to the regulation of immune cell function. At present, there are few studies on the relationship between Kv1.3 and liver diseases, and the application of its blockers as a potential treatment for liver diseases has not been reported. This manuscript reviewed the physiological characteristics of Kv1.3, the relationship between Kv1.3 and cell proliferation and apoptosis, and the role of Kv1.3 in a variety of liver diseases, so as to provide new ideas and strategies for the prevention and treatment of liver diseases. In short, by understanding the role of Kv1.3 in regulating the functions of immune cells such as macrophages, selective blockers of Kv1.3 or compounds with similar functions can be applied to alleviate the progression of liver diseases and provide new ideas for the prevention and treatment of liver diseases.
Multiple Molecular Mechanisms to Overcome Multidrug Resistance in Cancer by Natural Secondary Metabolites
Authors: El-Readi Mahmoud Zaki , Al-Abd Ahmed M. , Althubiti Mohammad A. , Almaimani Riyad A. , Al-Amoodi Hiba Saeed , Ashour Mohamed Lotfy , Wink Michael , Eid Safaa Yehia
Published: May 2021

Plant secondary metabolites (SMs) common natural occurrences and the significantly lower toxicities of many SM have led to the approaching development and use of these compounds as effective pharmaceutical agents; especially in cancer therapy. A combination of two or three of plant secondary metabolites together or of one SM with specific anticancer drugs, may synergistically decrease the doses needed, widen the chemotherapeutic window, mediate more effective cell growth inhibition, and avoid the side effects of high drug concentrations. In mixtures they can exert additive or even synergistic activities. Many SM can effectively increase the sensitivity of cancer cells to chemotherapy. In phytotherapy, secondary metabolites (SM) of medicinal plants can interact with single or multiple targets. The multi-molecular mechanisms of plant secondary metabolites to overcome multidrug resistance (MDR) are highlighted in this review. These mechanisms include interaction with membrane proteins such as P-glycoprotein (P-gp/MDR1); an ATP-binding cassette (ABC) transporter, nucleic acids (DNA, RNA), and induction of apoptosis. P-gp plays an important role in the development of MDR in cancer cells and is involved in potential chemotherapy failure. Therefore, the ingestion of dietary supplements, food or beverages containing secondary metabolites e.g., polyphenols or terpenoids may alter the bioavailability, therapeutic efficacy and safety of the drugs that are P-gp substrates.