bluuebunny/crossref_metadata_2025 huggingface dataset:
Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit
Authors: Hayes Cellas A. , Ashmore Brandon G. , Vijayasankar Akshaya , Marshall Jessica P. , Ashpole Nicole M.
Published: November 2021

The age-related reduction in circulating levels of insulin-like growth factor-1 (IGF-1) is associated with increased risk of stroke and neurodegenerative diseases in advanced age. Numerous reports highlight behavioral and physiological deficits in blood-brain barrier function and neurovascular communication when IGF-1 levels are low. Administration of exogenous IGF-1 reduces the extent of tissue damage and sensorimotor deficits in animal models of ischemic stroke, highlighting the critical role of IGF-1 as a regulator of neurovascular health. The beneficial effects of IGF-1 in the nervous system are often attributed to direct actions on neurons; however, glial cells and the cerebrovasculature are also modulated by IGF-1, and systemic reductions in circulating IGF-1 likely influence the viability and function of the entire neuro-glio-vascular unit. We recently observed that reduced IGF-1 led to impaired glutamate handling in astrocytes. Considering glutamate excitotoxicity is one of the main drivers of neurodegeneration following ischemic stroke, the age-related loss of IGF-1 may also compromise neural function indirectly by altering the function of supporting glia and vasculature. In this study, we assess and compare the effects of IGF-1 signaling on glutamate-induced toxicity and reactive oxygen species (ROS)-produced oxidative stress in primary neuron, astrocyte, and brain microvascular endothelial cell cultures. Our findings verify that neurons are highly susceptible to excitotoxicity, in comparison to astrocytes or endothelial cells, and that a prolonged reduction in IGFR activation increases the extent of toxicity. Moreover, prolonged IGFR inhibition increased the susceptibility of astrocytes to glutamate-induced toxicity and lessened their ability to protect neurons from excitotoxicity. Thus, IGF-1 promotes neuronal survival by acting directly on neurons and indirectly on astrocytes. Despite increased resistance to excitotoxic death, both astrocytes and cerebrovascular endothelial cells exhibit acute increases in glutamate-induced ROS production and mitochondrial dysfunction when IGFR is inhibited at the time of glutamate stimulation. Together these data highlight that each cell type within the neuro-glio-vascular unit differentially responds to stress when IGF-1 signaling was impaired. Therefore, the reductions in circulating IGF-1 observed in advanced age are likely detrimental to the health and function of the entire neuro-glio-vascular unit.
Diffusion Tensor Imaging Study of Olfactory Identification Deficit in Patients With Mild Cognitive Impairment
Authors: Shao Yongjia , Wang Zijian , Ji Bin , Qi Hang , Hao Shangci , Li Gang , Zhang Yue , Xi Qian
Published: November 2021

Objective: To explore the relationship between white matter changes and olfactory ability among patients with mild cognitive impairment (MCI) and to develop a tool to predict the development of Alzheimer’s disease among patients with MCI.

Methods: The Montreal Cognitive Assessment (MoCA) was used for cognitive assessments, and the 70% isopropanol test paper was used to evaluate olfactory function. Tract-based spatial statistics, based on the diffusion tensor imaging technology, were used to obtain relevant parameters, and behavioral and imaging results were compared between patients with MCI (n = 36) and healthy older adults (n = 32).

Results: The olfactory ability of MCI patients was lower overall, which was positively correlated with the MoCA score. Fractional anisotropy (FA) changes significantly of all parameters. Lower FA regions were mainly located in the corpus callosum, the orbitofrontal gyrus, and the left occipital lobe. The olfactory score was significantly correlated with the FA value of the orbitofrontal gyrus. Fibrous connections in several brain regions, such as the entorhinal cortex, were stronger in patients with MCI.

Conclusion: The olfactory ability of MCI patients in our group was positively correlated with the neuropsychological scale results. Impairment in olfactory function was superior to memory deficits for predicting cognitive decline among cognitively intact participants. The fibrous connections in several brain regions, such as the entorhinal cortex, were higher in patients with MCI, which suggested that there may be a compensatory mechanism in the olfactory pathway in MCI patients. The decline in olfactory function may be a significant and useful indicator of neuropathological changes in MCI patients and an effective marker for the development of cognitive decline and dementia.
Boosting-GNN: Boosting Algorithm for Graph Networks on Imbalanced Node Classification
Authors: Shi Shuhao , Qiao Kai , Yang Shuai , Wang Linyuan , Chen Jian , Yan Bin
Published: November 2021

The graph neural network (GNN) has been widely used for graph data representation. However, the existing researches only consider the ideal balanced dataset, and the imbalanced dataset is rarely considered. Traditional methods such as resampling, reweighting, and synthetic samples that deal with imbalanced datasets are no longer applicable in GNN. This study proposes an ensemble model called Boosting-GNN, which uses GNNs as the base classifiers during boosting. In Boosting-GNN, higher weights are set for the training samples that are not correctly classified by the previous classifiers, thus achieving higher classification accuracy and better reliability. Besides, transfer learning is used to reduce computational cost and increase fitting ability. Experimental results indicate that the proposed Boosting-GNN model achieves better performance than graph convolutional network (GCN), GraphSAGE, graph attention network (GAT), simplifying graph convolutional networks (SGC), multi-scale graph convolution networks (N-GCN), and most advanced reweighting and resampling methods on synthetic imbalanced datasets, with an average performance improvement of 4.5%.
Successful Treatment of Noise-Induced Hearing Loss by Mesenchymal Stromal Cells: An RNAseq Analysis of Protective/Repair Pathways
Authors: Warnecke Athanasia , Harre Jennifer , Shew Matthew , Mellott Adam J. , Majewski Igor , Durisin Martin , Staecker Hinrich
Published: November 2021

Mesenchymal stromal cells (MSCs) are an adult derived stem cell-like population that has been shown to mediate repair in a wide range of degenerative disorders. The protective effects of MSCs are mainly mediated by the release of growth factors and cytokines thereby modulating the diseased environment and the immune system. Within the inner ear, MSCs have been shown protective against tissue damage induced by sound and a variety of ototoxins. To better understand the mechanism of action of MSCs in the inner ear, mice were exposed to narrow band noise. After exposure, MSCs derived from human umbilical cord Wharton’s jelly were injected into the perilymph. Controls consisted of mice exposed to sound trauma only. Forty-eight hours post-cell delivery, total RNA was extracted from the cochlea and RNAseq performed to evaluate the gene expression induced by the cell therapy. Changes in gene expression were grouped together based on gene ontology classification. A separate cohort of animals was treated in a similar fashion and allowed to survive for 2 weeks post-cell therapy and hearing outcomes determined. Treatment with MSCs after severe sound trauma induced a moderate hearing protective effect. MSC treatment resulted in an up-regulation of genes related to immune modulation, hypoxia response, mitochondrial function and regulation of apoptosis. There was a down-regulation of genes related to synaptic remodeling, calcium homeostasis and the extracellular matrix. Application of MSCs may provide a novel approach to treating sound trauma induced hearing loss and may aid in the identification of novel strategies to protect hearing.
Astroglial CB1 Cannabinoid Receptors Mediate CP 55,940-Induced Conditioned Place Aversion Through Cyclooxygenase-2 Signaling in Mice
Authors: Cong Jin , Lu Kangrong , Zou Wenjie , Li Ziming , Guo Zhipeng , Tong Xiangzhen , Zheng Jiawei , Zhu Jianping , Li Shuji , Zhang Wangming , Guo Yanwu , Gao Tian-Ming , Chen Rongqing
Published: November 2021

Cannabinoids (CBs), such as phytocannabinoids, synthetic CBs, and endogenous CBs, can be neuroprotective, rewarding, or aversive. The aversive effects of CBs may hinder their medical and recreational applications. It is unknown which type of CB receptors mediates the direct aversive effects of synthetic CB CP 55,940 which is an analog of Δ9-tetrahydrocannabinol, the major psychoactive component of marijuana. In this study, we address this question by taking the advantage of systematic type 1 CB receptor (CB1R) knockout mice and conditional reinstatement of this receptor only in astrocytes. We show that CP 55,940 at a concentration of 1 mg/kg induces conditioned place aversion (CPA) and the CPA effect of CP 55,940 is mediated by the astroglial CB1Rs. Inhibiting cyclooxygenase-2 (COX-2) eliminates CP 55,940-induced CPA in mice that only express CB1Rs in astrocytes. These findings conclude that CPA effect of CP 55,940 is mediated by the astroglial CB1Rs through COX-2 signaling, suggesting that selective COX-2 inhibition or precise isolation of astroglial CB1R activity may be the strategy for treating aversive response of medical and recreational administrations of marijuana.
Endovascular Biopsy of Vertebrobasilar Aneurysm in Patient With Polyarteritis Nodosa
Authors: Narsinh Kazim H. , Narsinh Kamileh , McCoy David B. , Sun Zhengda , Halabi Cathra , Meisel Karl , Tihan Tarik , Chaganti Krishna , Amans Matthew R. , Halbach Van V. , Higashida Randall T. , Hetts Steven W. , Dowd Christopher F. , Winkler Ethan A. , Abla Adib A. , Nowakowski Tomasz J. , Cooke Daniel L.
Published: November 2021

Background and Purpose: The management of unruptured intracranial aneurysms remains controversial. The decisions to treat are heavily informed by estimated risk of bleeding. However, these estimates are imprecise, and better methods for stratifying the risk or tailoring treatment strategy are badly needed. Here, we demonstrate an initial proof-of-principle concept for endovascular biopsy to identify the key molecular pathways and gene expression changes associated with aneurysm formation. We couple this technique with single cell RNA sequencing (scRNAseq) to develop a roadmap of the pathogenic changes of a dolichoectatic vertebrobasilar aneurysm in a patient with polyarteritis nodosa.

Methods: Endovascular biopsy and fluorescence activated cell sorting was used to isolate the viable endothelial cells (ECs) using the established techniques. A single cell RNA sequencing (scRNAseq) was then performed on 24 aneurysmal ECs and 23 patient-matched non-aneurysmal ECs. An integrated panel of bioinformatic tools was applied to determine the differential gene expression, enriched signaling pathways, and cell subpopulations hypothesized to drive disease pathogenesis.

Results: We identify a subset of 7 (29%) aneurysm-specific ECs with a distinct gene expression signature not found in the patient-matched control ECs. A gene set enrichment analysis identified these ECs to have increased the expression of genes regulating the leukocyte-endothelial cell adhesion, major histocompatibility complex (MHC) class I, T cell receptor recycling, tumor necrosis factor alpha (TNFα) response, and interferon gamma signaling. A histopathologic analysis of a different intracranial aneurysm that was later resected yielded a diagnosis of polyarteritis nodosa and positive staining for TNFα.

Conclusions: We demonstrate feasibility of applying scRNAseq to the endovascular biopsy samples and identify a subpopulation of ECs associated with cerebral aneurysm in polyarteritis nodosa. Endovascular biopsy may be a safe method for deriving insight into the disease pathogenesis and tailoring the personalized treatment approaches to intracranial aneurysms.
Association Between Glycemic Gap and In-hospital Outcomes in Aneurysmal Subarachnoid Hemorrhage
Authors: Sun Philip Y. , Poblete Roy A. , Nguyen Peggy L. , Bulic Sebina F. , Kim-Tenser May A. , Marehbian Jonathan , Cen Steven Y. , Emanuel Benjamin A.
Published: November 2021

Introduction: Glycemic gap (GG), as determined by the difference between glucose and the hemoglobin A1c (HbA1c)-derived estimated average glucose (eAG), is associated with poor outcomes in various clinical settings. There is a paucity of data describing GG and outcomes after aneurysmal subarachnoid hemorrhage (aSAH). Our main objectives were to evaluate the association of admission glycemic gap (aGG) with in-hospital mortality and with poor composite outcome and to compare aGG's predictive value to admission serum glucose. Secondary outcomes were the associations between aGG and neurologic complications including vasospasm and delayed cerebral ischemia following aSAH.

Methods: We retrospectively reviewed 119 adult patients with aSAH admitted to a single tertiary care neuroscience ICU. Spearman method was used for correlation for non-normality of data. Area under the curve (AUC) for Receiver Operating Characteristic (ROC) curve was used to estimate prediction accuracy of aGG and admission glucose on outcome measures. Multivariable analyses were conducted to assess the value of aGG in predicting in-hospital poor composite outcome and death.

Results: Elevated aGG at or above 30 mg/dL was identified in 79 (66.4%) of patients. Vasospasm was not associated with the elevated aGG. Admission GG correlated with admission serum glucose (r = 0.94, p < 0.01), lactate (r = 0.41, p < 0.01), procalcitonin (r = 0.38, p < 0.01), and Hunt and Hess score (r = 0.51, p < 0.01), but not with HbA1c (r = 0.02, p = 0.82). Compared to admission glucose, aGG had a statistically significantly improved accuracy in predicting inpatient mortality (AUC mean ± SEM: 0.77 ± 0.05 vs. 0.72 ± 0.06, p = 0.03) and trended toward statistically improved accuracy in predicting poor composite outcome (AUC: 0.69 ± 0.05 vs. 0.66 ± 0.05, p = 0.07). When controlling for aSAH severity, aGG was not independently associated with delayed cerebral ischemia, poor composite outcome, and in-hospital mortality.

Conclusion: Admission GG was not independently associated with in-hospital mortality or poor outcome in a population of aSAH. An aGG ≥30 mg/dL was common in our population, and further study is needed to fully understand the clinical importance of this biomarker.
Antiplatelet vs. Anticoagulation in Cervical Artery Dissection: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Liu Sihua , Zhang Xiao , Bai Xuesong , Yang Yutong , Wang Tao , Xu Xin , Xu Ran , Li Long , Feng Yao , Yang Kun , Wang Xue , Guo Xiaofan , Chen Jing , Ma Yan , Jiao Liqun
Published: November 2021

Objective: The optimal management for cervical artery dissection (CAD) is uncertain. This study aimed to summarize the current randomized controlled trials (RCTs) to compare the efficacy and safety of antiplatelet and anticoagulation therapies for CAD.

Methods: A literature search was conducted in the major databases, such as MEDLINE, Embase, and the Cochrane Library. Only the RCTs comparing the antiplatelet and anticoagulation therapies for the patients with CAD were included. Combined estimates of the relative risk (RR) of antiplatelet vs. anticoagulation were analyzed. Heterogeneity was measured using the I2 statistical analysis. The analyses were performed in the intention-to-treat (ITT) and per-protocol (PP) population, respectively.

Results: Two RCTs involving 444 patients in the ITT population and 370 patients in the PP population were included. The quality of studies was high overall. In the ITT population, compared with the patients in the anticoagulation group, the patients in the antiplatelet group showed a higher rate of ischemic stroke within 3 months (RR = 6.73 [95% CI, 1.22–37.15], I2 = 0%, P = 0.029). No difference between these two treatment groups was found for the outcomes of transient ischemic attack (RR = 0.37 [95% CI, 0.09–1.58], I2 = 0%, P = 0.181), intracranial hemorrhage (RR = 0.33 [95% CI, 0.01–7.98], I2 = 0%, P = 0.494), major extracranial bleeding (RR = 0.31 [95% CI, 0.01–7.60], I2 = 0%, P = 0.476), or the composite of these outcomes within 3 months. For the PP population, the results of the meta-analysis of outcomes between the antiplatelet and anticoagulation groups were consistent with the ITT population.

Conclusions: Compared with the antiplatelet group, the anticoagulation group has a lower risk of ischemic stroke without increasing bleeding risk when treating CAD. Anticoagulation seems to be superior over the antiplatelet in treating CAD but needs to be further tested by specifying several issues, such as location, initial symptom types, and treatment protocols.
Different Associated Factors of Subjective Cognitive Complaints in Patients With Early- and Late-Onset Parkinson's Disease
Authors: Xiao Yi , Ou Ruwei , Yang Tianmi , Liu Kuncheng , Wei Qianqian , Hou Yanbing , Zhang Lingyu , Lin Junyu , Shang Huifang
Published: November 2021

Background: Subjective cognitive complaints (SCCs), which are associated with a higher risk of cognitive decline, are widespread in the patients with Parkinson's disease (PD). The previous studies have reported inconsistent factors related to SCCs in the patients with late-onset PD (LOPD), and there is limited information on SCCs in the patients with early-onset PD (EOPD).

Objective: We aimed to investigate the factors associated with SCCs in the drug-naïve patients with EOPD and LOPD without cognitive impairment.

Methods: This cross-sectional study included 332 drug-naïve patients with PD, among whom 134 were EOPD and 198 were LOPD. Motor and non-motor symptoms, such as global objective cognitive status, depression, anxiety, apathy, fatigue, sleep, rapid eye movement sleep behavior disorder, orthostatic hypotension, and excessive daytime sleepiness, were assessed.

Results: Twenty-five (18.66%) patients with EOPD and 49 (24.74%) patients with LOPD reported SCCs. A multivariate binary logistic regression analysis revealed that older age at onset [odds ratio (OR) = 1.24, P = 0.002], higher apathy score (OR = 1.13, P = 0.003), and lower scores in the visuospatial/executive abilities (OR = 0.25, P < 0.001) and memory (OR = 0.50, P = 0.024) domains of the Montreal Cognitive Assessment were associated with a higher risk of SCCs in the EOPD group. Higher apathy (OR = 1.06, P = 0.011) and anxiety (OR = 1.14, P < 0.001) scores were associated with SCCs in the LOPD group.

Conclusion: Subjective cognitive complaints are only associated with mood disorders in patients with LOPD. In addition, SCCs may reflect subthreshold cognitive impairment in the patients with EOPD.
Altered Hippocampal Subfields Volumes Is Associated With Memory Function in Type 2 Diabetes Mellitus
Authors: Li Mingrui , Li Yifan , Liu Yujie , Huang Haoming , Leng Xi , Chen Yuna , Feng Yue , Ma Xiaomeng , Tan Xin , Liang Yi , Qiu Shijun
Published: November 2021

Objective: Cognitive impairment in type 2 diabetes mellitus (T2DM) patients is related to changes in hippocampal structure and function. However, the alternation of hippocampal subfields volumes and their relationship with cognitive function are unclear. This study explored morphological alterations in the hippocampus and its subfields in T2DM patients and their relationship with cognitive function.

Methods: Thirty T2DM patients and 20 healthy controls (HCs) were recruited and underwent 3-dimensional, high-resolution T1-weighted sequence (3D-T1) and a battery of cognitive tests. Freesurfer 6.0 was performed to segment the hippocampus into 12 subregions automatically. Then relationships between hippocampal subfield volumes and neurocognitive scale scores in the T2DM group were evaluated.

Results: Immediate memory scores on the auditory verbal learning test (AVLT) and Montreal Cognitive Assessment (MoCA) scores in T2DM patients were lower than in the HCs. T2DM patients showed that volumes of the bilateral hippocampus were significantly reduced, mainly in the bilateral molecular layer, granule cell and molecular layer of the dentate gyrus (GC-ML-DG), cornu ammonis 4 (CA4), fimbria, and left subiculum and the right hippocampus amygdala transition area (HATA) compared to HCs. In addition, T2DM patients showed the FINS was negatively correlated with volume of left GC-ML-DG (r = −0.415, P = 0.035) and left CA4 (r = −0.489, P = 0.011); the FBG was negatively correlated with volume of right fimbria (r = −0.460, P = 0.018); the HOMA-IR was negatively correlated with volume of left GC-ML-DG (r = −0.367, P = 0.046) and left CA4(r = 0.462, P = 0.010). Partial correlation analysis found that the volume of right HATA in T2DM group was positively correlated with AVLT (immediate) scores (r = 0.427, P = 0.03).

Conclusion: This study showed the volumes of multiple hippocampal subfields decreased and they were correlated with FINS, FBG and HOMA-IR in T2DM patients. We hypothesized that decreased hippocampal subfields volumes in T2DM patients was related to insulin resistance and impaired vascular function. In addition, we also found that abnormal hippocampal subfields volumes were related to memory function in T2DM patients, suggesting that reduced volumes in specific hippocampal subfields may be the potential mechanism of memory dysfunction in these patients.
Anti-ganglioside Antibodies in Guillain-Barre Syndrome: A Novel Immunoblotting-Panel Assay
Authors: Zhu Jiting , Zhang Yuanyuan , Li Runyun , Lin Yi , Fu Ying , Yan Yaping , Zhu Wenli , Wang Ning , Zhang Zaiqiang , Xu Guorong
Published: November 2021

Objective: This study aimed to determine the diagnostic efficiency of a novel immunoblotting detection assay for anti-ganglioside antibodies (AGAs) in the Guillain–Barre syndrome (GBS).

Method: Serum immunoglobulin (IgG and IgM) of AGAs were measured in 121 participants from a registered cohort study of immune-mediated neuropathies and 29 healthy controls by immunoblotting panel assay. Sensitivity, specificity, and positive predictive value (PPV) of the assay were compared to calculate the diagnostic accuracy.

Result: In our cohort, any of the AGAs were positive in 42.4% of the GBS patients. The sensitivity and specificity of AGAs (both IgG and IgM) in the diagnosis of GSB were 42 and 76% while for IgG-AGAs were 35 and 87%. AGAs positivity had a significant association with the AMAN subtype (P = 0.0004), and the sensitivity, specificity of AGAs in AMAN were 86, 69%, respectively with high (AUC = 0.78, p = 0.002) discriminative powers. GM1-IgG AGA was more common and specific to AMAN patients than other GBS forms (p = 0.008).

Conclusion: Our novel immunoblotting detection assay could complement GBS diagnosis. IgG-AGAs were more likely to be detected in GBS, and GM1-IgG AGA could assist AMAN diagnosis.
Assessing Lumbar Plexus and Sciatic Nerve Damage in Relapsing-Remitting Multiple Sclerosis Using Magnetisation Transfer Ratio
Authors: Boonsuth Ratthaporn , Samson Rebecca S. , Tur Carmen , Battiston Marco , Grussu Francesco , Schneider Torben , Yoneyama Masami , Prados Ferran , Ttofalla Antrea , Collorone Sara , Cortese Rosa , Ciccarelli Olga , Gandini Wheeler-Kingshott Claudia A. M. , Yiannakas Marios C.
Published: November 2021

Background: Multiple sclerosis (MS) has traditionally been regarded as a disease confined to the central nervous system (CNS). However, neuropathological, electrophysiological, and imaging studies have demonstrated that the peripheral nervous system (PNS) is also involved, with demyelination and, to a lesser extent, axonal degeneration representing the main pathophysiological mechanisms.

Aim: The purpose of this study was to assess PNS damage at the lumbar plexus and sciatic nerve anatomical locations in people with relapsing-remitting MS (RRMS) and healthy controls (HCs) in vivo using magnetisation transfer ratio (MTR), which is a known imaging biomarker sensitive to alterations in myelin content in neural tissue, and not previously explored in the context of PNS damage in MS.

Method: Eleven HCs (7 female, mean age 33.6 years, range 24-50) and 15 people with RRMS (12 female, mean age 38.5 years, range 30-56) were recruited for this study and underwent magnetic resonance imaging (MRI) investigations together with clinical assessments using the expanded disability status scale (EDSS). Magnetic resonance neurography (MRN) was first used for visualisation and identification of the lumbar plexus and the sciatic nerve and MTR imaging was subsequently performed using identical scan geometry to MRN, enabling straightforward co-registration of all data to obtain global and regional mean MTR measurements. Linear regression models were used to identify differences in MTR values between HCs and people with RRMS and to identify an association between MTR measures and EDSS.

Results: MTR values in the sciatic nerve of people with RRMS were found to be significantly lower compared to HCs, but no significant MTR changes were identified in the lumbar plexus of people with RRMS. The median EDSS in people with RRMS was 2.0 (range, 0-3). No relationship between the MTR measures in the PNS and EDSS were identified at any of the anatomical locations studied in this cohort of people with RRMS.

Conclusion: The results from this study demonstrate the presence of PNS damage in people with RRMS and support the notion that these changes, suggestive of demyelination, maybe occurring independently at different anatomical locations within the PNS. Further investigations to confirm these findings and to clarify the pathophysiological basis of these alterations are warranted.
Treating Metastatic Brain Cancers With Stem Cells
Authors: Sadanandan Nadia , Shear Alex , Brooks Beverly , Saft Madeline , Cabantan Dorothy Anne Galang , Kingsbury Chase , Zhang Henry , Anthony Stefan , Wang Zhen-Jie , Salazar Felipe Esparza , Lezama Toledo Alma R. , Rivera Monroy Germán , Vega Gonzales-Portillo Joaquin , Moscatello Alexa , Lee Jea-Young , Borlongan Cesario V.
Published: November 2021

Stem cell therapy may present an effective treatment for metastatic brain cancer and glioblastoma. Here we posit the critical role of a leaky blood-brain barrier (BBB) as a key element for the development of brain metastases, specifically melanoma. By reviewing the immunological and inflammatory responses associated with BBB damage secondary to tumoral activity, we identify the involvement of this pathological process in the growth and formation of metastatic brain cancers. Likewise, we evaluate the hypothesis of regenerating impaired endothelial cells of the BBB and alleviating the damaged neurovascular unit to attenuate brain metastasis, using the endothelial progenitor cell (EPC) phenotype of bone marrow-derived mesenchymal stem cells. Specifically, there is a need to evaluate the efficacy for stem cell therapy to repair disruptions in the BBB and reduce inflammation in the brain, thereby causing attenuation of metastatic brain cancers. To establish the viability of stem cell therapy for the prevention and treatment of metastatic brain tumors, it is crucial to demonstrate BBB repair through augmentation of vasculogenesis and angiogenesis. BBB disruption is strongly linked to metastatic melanoma, worsens neuroinflammation during metastasis, and negatively influences the prognosis of metastatic brain cancer. Using stem cell therapy to interrupt inflammation secondary to this leaky BBB represents a paradigm-shifting approach for brain cancer treatment. In this review article, we critically assess the advantages and disadvantages of using stem cell therapy for brain metastases and glioblastoma.
Roles of Long Non-coding RNAs in the Development of Chronic Pain
Authors: Li Zheng , Li Xiongjuan , Jian Wenling , Xue Qingsheng , Liu Zhiheng
Published: November 2021

Chronic pain, a severe public health issue, affects the quality of life of patients and results in a major socioeconomic burden. Only limited drug treatments for chronic pain are available, and they have insufficient efficacy. Recent studies have found that the expression of long non-coding RNAs (lncRNAs) is dysregulated in various chronic pain models, including chronic neuropathic pain, chronic inflammatory pain, and chronic cancer-related pain. Studies have also explored the effect of these dysregulated lncRNAs on the activation of microRNAs, inflammatory cytokines, and so on. These mechanisms have been widely demonstrated to play a critical role in the development of chronic pain. The findings of these studies indicate the significant roles of dysregulated lncRNAs in chronic pain in the dorsal root ganglion and spinal cord, following peripheral or central nerve lesions. This review summarizes the mechanism underlying the abnormal expression of lncRNAs in the development of chronic pain induced by peripheral nerve injury, diabetic neuropathy, inflammatory response, trigeminal neuralgia, spinal cord injury, cancer metastasis, and other conditions. Understanding the effect of lncRNAs may provide a novel insight that targeting lncRNAs could be a potential candidate for therapeutic intervention in chronic pain.
Assessing Dietary Intake Patterns Through Cluster Analysis Among Adolescents in Selected Districts of Bihar and Assam From India: A Cross-Sectional Survey
Authors: Sharma Shantanu , Maheshwari Sonali , Kuwatada Jitesh , Chandrashekhar  , Mehra Sunil
Published: November 2021

Background: In the recent decade, dietary pattern assessment has evolved as a promising tool to describe the whole diet and represent inter-correlations between different dietary components. We aimed to derive the dietary patterns of adolescents (10–19 years) using cluster analysis on food groups and evaluate these patterns according to their socio-demographic profile.

Methods: This community-based cross-sectional study was conducted in two districts, each from Bihar and Assam in India. Adolescents (10–19 years) were enrolled from both rural and urban areas. The dietary intake was assessed through a pre-validated single food frequency questionnaire. Cluster analysis was performed by a 2-step procedure to explore dietary patterns, pre-fixed at 2 clusters. Clusters were analyzed with respect to socio-demographic characteristics using binomial logistic regression.

Results: A total of 826 girls and 811 boys were enrolled in the study. We found two major dietary patterns, namely a low- and high-mixed diet. The low-mixed diet (76.5% prevalence) had daily consumption of green vegetables, including leafy vegetables, with less frequent consumption of other foods. The high-mixed diet (23.5% prevalence) had more frequent consumption of chicken, meat, egg, and milk/curd apart from green vegetables. Adolescent boys had 3.6 times higher odds of consuming a low-mixed diet compared to girls. Similarly, adolescents with lower education grades and from marginalized social classes had two times higher odds of taking a low-mixed diet than their respective counterparts.

Conclusions: The high consumption of a low-mixed diet and relatively less milk consumption limit the comprehensive growth of adolescents. Improvement in dietary intake of adolescents from marginalized sections of society can prove to be an important deterrent in mitigating India's nutritional challenges.
Tropical Oral Disease: Analysing Barriers, Burden, Nutrition, Economic Impact, and Inequalities
Authors: Rajendra Santosh Arvind Babu , Jones Thaon
Published: November 2021

Traditionally, a healthy mouth is a good indicator of good general health. Poor oral hygiene reflects the health of the oral cavity and is a risk factor for overall health. Although oral diseases like dental decay and periodontitis are prevalent, awareness of oral diseases is still limited. Oral disorders include a wide range of diseases that may not be confined to the oral anatomical structures but may be manifestations of systemic diseases. Identification of the risk factors of dental and oral diseases, including socio-economic determinants, plays a major role in the type of oral health care, and in the promotion of dental health awareness. This article reviews oral diseases in the Caribbean and aims to raise awareness of this subject while suggesting a research agenda for the region.
Different Effects of Soy and Whey on Linear Bone Growth and Growth Pattern in Young Male Sprague-Dawley Rats
Authors: Bar-Maisels Meytal , Menahem Chen , Gabet Yankel , Hiram-Bab Sahar , Phillip Moshe , Gat-Yablonski Galia
Published: November 2021

The aim of this investigation was to determine the better protein for supporting optimal linear growth, as the exact composition and benefits of specific dietary proteins in supporting linear growth is unknown. In the current study, we compared the effect of soy and whey proteins, both proteins contain all essential amino acids and are considered the best proteins in their categories. Young male rats were subjected to multiple feeding protocols using iso-energetic diets containing soy or whey as the sole protein source. The rats were allowed to eat ad libitum for 11, 24, or 74 days in the first set of experiments, and the soy group was pair-fed to the whey group in the second set. The differences in weight gain, food consumption, and humeri length of the soy group that were greater at the beginning of the ad libitum experiments lessened over time. Pair-fed experiments revealed that the increased weight and humeri length resulted from the differences in food consumption. However, other parameters were protein specific. Bone quality, which was better in the soy group at 24 days, was matched by the whey group and even surpassed that of the soy group in the long-term experiment, with a significantly greater bone mineral density, cortical thickness, and growth plate. Although in the short term the levels of insulin like growth factor (IGF)-I were similar between the groups, IGF-I increased with age in the whey group, and the levels at the long-term experiment were significantly higher compared to the soy group. Furthermore, using the pair fed setup made it clear that when the difference in food consumption were no longer playing part, whey was more efficient in increasing IGF-I. There were no indications of metabolic sequelae. Although the use of soy is gaining in popularity as a sustainable protein, our findings indicate a better effect of whey on linear growth by leading to slower growth with better-organized epiphyseal growth plates and bone quality.
Regulation of Key Genes for Milk Fat Synthesis in Ruminants
Authors: Mu Tong , Hu Honghong , Ma Yanfen , Feng Xiaofang , Zhang Juan , Gu Yaling
Published: November 2021

Milk fat is the most important and energy-rich substance in milk and plays an important role in the metabolism of nutrients during human growth and development. It is mainly used in the production of butter and yogurt. Milk fat not only affects the flavor and nutritional value of milk, but also is the main target trait of ruminant breeding. There are many key genes involve in ruminant milk fat synthesis, including ACSS2, FASN, ACACA, CD36, ACSL, SLC27A, FABP3, SCD, GPAM, AGPAT, LPIN, DGAT1, PLIN2, XDH, and BTN1A1. Taking the de novo synthesis of fatty acids (FA) and intaking of long-chain fatty acids (LCFA) in blood to the end of lipid droplet secretion as the mainline, this manuscript elucidates the complex regulation model of key genes in mammary epithelial cells (MECs) in ruminant milk fat synthesis, and constructs the whole regulatory network of milk fat synthesis, to provide valuable theoretical basis and research ideas for the study of milk fat regulation mechanism of ruminants.
Dietary Amylose/Amylopectin Ratio Modulates Cecal Microbiota and Metabolites in Weaned Goats
Authors: Gebeyew Kefyalew , Chen Kai , Wassie Teketay , Azad Md. Abul Kalam , He Jianhua , Jiang Weimin , Song Wu , He Zhixiong , Tan Zhiliang
Published: November 2021

Increasing the ratio of amylose in the diet can increase the quantity of starch that flows to the large intestine for microbial fermentation. This leads to the alteration of microbiota and metabolite of the hindgut, where the underlying mechanism is not clearly understood. The present study used a combination of 16S amplicon sequencing technology and metabolomics technique to reveal the effects of increasing ratios of amylose/amylopectin on cecal mucosa- and digesta-associated microbiota and their metabolites in young goats. Twenty-seven Xiangdong black female goats with average body weights (9.00 ± 1.12 kg) were used in this study. The goats were randomly allocated to one of the three diets containing starch with 0% amylose corn (T1), 50% high amylose corn (T2), and 100% high amylose corn (T3) for 35 days. Results showed that cecal valerate concentration was higher (P < 0.05) in the T2 group than those in the T1 and T3 groups. The levels of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 were decreased (P < 0.05) in cecal tissue while IL-10 was increased (P < 0.05) in the T2 group when compared with T1 or T3 groups. At the phylum level, the proportion of mucosa-associated Spirochaetes was increased (P < 0.05), while Proteobacteria was deceased by feeding high amylose ratios (P < 0.05). The abundance of Verrucomicrobia was decreased (P < 0.05) in the T3 group compared with the T1 and T2 groups. The abundance of digesta-associated Firmicutes was increased (P < 0.05) while Verrucomicrobia and Tenericutes were deceased (P < 0.05) with the increment of amylose/amylopectin ratios. The LEfSe analysis showed that a diet with 50% high amylose enriched the abundance of beneficial bacteria such as Faecalibacterium and Lactobacillus in the digesta and Akkermansia in the mucosa compared with the T1 diet. The metabolomics results revealed that feeding a diet containing 50% high amylose decreased the concentration of fatty acyls-related metabolites, including dodecanedioic acid, heptadecanoic acid, and stearidonic acid ethyl ester compared with the T1 diet. The results suggested that a diet consisting of 50% high amylose could maintain a better cecal microbiota composition and host immune function.
Extracellular Vesicles Derived From Citrus sinensis Modulate Inflammatory Genes and Tight Junctions in a Human Model of Intestinal Epithelium
Authors: Bruno Stefania Paola , Paolini Alessandro , D'Oria Valentina , Sarra Angelo , Sennato Simona , Bordi Federico , Masotti Andrea
Published: November 2021

It is widely acknowledged that mammalian exosomes (or extracellular vesicles), have a key role in intercellular communication, owing to the presence of various bioactive molecules such as lipids, proteins, and microRNAs within their inner compartment. Most recently, the discovery of extracellular vesicles isolated from edible plants (such as vegetables and fruits) and their similarity in terms of size and content with exosomes has opened new perspectives on possible intercellular communication and regulation of important biological processes in which these vesicles are involved. It is also well-known that a balanced diet rich of fruits and vegetables (i.e., the Mediterranean diet) can contribute to maintain a “healthy gut” by preserving the intestinal epithelial barrier integrity and avoid that inflammatory stimuli that can alter homeostasis. In our study, we optimized a method to isolate extracellular vesicles from the orange juice (Citrus sinensis) (CS-EVs), and we characterized their morphology and behavior when in contact with the intestinal epithelium. We showed that CS-EVs are stable in a simulated gastrointestinal environment and are absorbed by intestinal cells without toxic effects, as expected. Furthermore, we demonstrated that CS-EVs can alter the gene expression of several genes involved in inflammation (i.e., ICAM1 and HMOX-1) and tight junctions (i.e., OCLN, CLDN1, and MLCK), contributing to limit inflammatory stimuli and restore a functional barrier by increasing the tight junction OCLN protein. Therefore, our study emphasizes the relevant role of fruit-derived extracellular vesicles in modulating important biological processes and maintaining a healthy intestinal epithelium, ultimately promoting human health and well-being.
A Prognostic Nomogram for T3N0 Rectal Cancer After Total Mesorectal Excision to Help Select Patients for Adjuvant Therapy
Authors: Zhang Chao , Zhao Shutao , Wang Xudong
Published: November 2021

Background

The recurrence rate of T3N0 rectal cancer after total mesorectal excision (TME) is relatively low, meaning that not all patients need adjuvant therapy (AT) (radiotherapy, chemotherapy, or chemoradiotherapy).

Methods

Patients diagnosed with pT3N0M0 rectal cancer after TME were analyzed using the SEER database, of which 4367 did not receive AT and 2794 received AT. Propensity score matching was used to balance the two groups in terms of confounding factors. Cox proportional hazards regression analysis was used to screen independent prognostic factors, which were then used to establish a nomogram. The patients were then divided into three groups with X-tile software according to their risk scores. We enrolled 334 patients as external validation.

Results

The C-index of the model was 0.725 (95% confidence interval: 0.694–0.756). We divided the patients into three different risk layers based on the nomogram prediction scores, and found that AT did not improve the prognosis of low- and moderate-risk patients, while high-risk patients benefited from AT. External validation data also support the above conclusions.

Conclusion

This study developed a nomogram that effectively and comprehensively evaluates the prognosis of T3N0 rectal cancer patients after TME. After using the nomogram, we recommend AT for high-risk patients, but not for low- and moderate-risk patients.
Immune Checkpoints OX40 and OX40L in Small-Cell Lung Cancer: Predict Prognosis and Modulate Immune Microenvironment
Authors: Chen Peixin , Wang Hao , Zhao Lishu , Guo Haoyue , Zhang Liping , Zhang Wei , Sun Chenglong , Zhao Sha , Li Wei , Zhu Jun , Yu Jia , Wu Chunyan , He Yayi
Published: November 2021

Background

OX40 and OX40 ligand (OX40L), as essential immune checkpoint (IC) modulators, are highly correlated with cancer immunity regulation as well as tumor microenvironment (TME). Immunotherapy showed outstanding advantages in small-cell lung cancer (SCLC) therapy. However, functions and clinical significance of OX40 and OX40L in SCLC were not clear yet.

Materials and Methods

SCLC samples of 143 patients were collected for immunohistochemistry (IHC) or whole-exome sequencing (WES). We comprehensively explored the expression and mutation of OX40/OX40L in SCLC, and systematically linked OX40/OX40L with TME.

Results

The expression of OX40/OX40L on tumor cells and tumor-infiltrating lymphocytes (TILs) was found in the IHC cohort and verified in other cohorts with SCLC tissues and cell lines. The results showed co-expression patterns among OX40/OX40L, other ICs, and T-cell markers. The WES data suggested that OX40/OX40L mutation is rare in SCLC (<5%). Patients with positive OX40 protein expression on TILs showed substantially higher recurrence-free survival than those with negative expression (p=0.009). The external dataset also indicated that high OX40/OX40L expression was correlated with better prognosis [overall survival: OX40, p<0.001; OX40L, p=0.019]. Importantly, activation of immunity and high infiltration of CD4(+) and CD8(+) T cells were observed in the high OX40/OX40L expression group.

Conclusions

Collectively, this work highlighted the significance of OX40 and OX40L in prognosis and TME cell infiltration characterization of SCLC. Evaluating the OX40/OX40L-expression levels of individual patients with SCLC might contribute to guiding more precise therapy.
Biological Adaptations of Tumor Cells to Radiation Therapy
Authors: Carlos-Reyes Angeles , Muñiz-Lino Marcos A. , Romero-Garcia Susana , López-Camarillo César , Hernández-de la Cruz Olga N.
Published: November 2021

Radiation therapy has been used worldwide for many decades as a therapeutic regimen for the treatment of different types of cancer. Just over 50% of cancer patients are treated with radiotherapy alone or with other types of antitumor therapy. Radiation can induce different types of cell damage: directly, it can induce DNA single- and double-strand breaks; indirectly, it can induce the formation of free radicals, which can interact with different components of cells, including the genome, promoting structural alterations. During treatment, radiosensitive tumor cells decrease their rate of cell proliferation through cell cycle arrest stimulated by DNA damage. Then, DNA repair mechanisms are turned on to alleviate the damage, but cell death mechanisms are activated if damage persists and cannot be repaired. Interestingly, some cells can evade apoptosis because genome damage triggers the cellular overactivation of some DNA repair pathways. Additionally, some surviving cells exposed to radiation may have alterations in the expression of tumor suppressor genes and oncogenes, enhancing different hallmarks of cancer, such as migration, invasion, and metastasis. The activation of these genetic pathways and other epigenetic and structural cellular changes in the irradiated cells and extracellular factors, such as the tumor microenvironment, is crucial in developing tumor radioresistance. The tumor microenvironment is largely responsible for the poor efficacy of antitumor therapy, tumor relapse, and poor prognosis observed in some patients. In this review, we describe strategies that tumor cells use to respond to radiation stress, adapt, and proliferate after radiotherapy, promoting the appearance of tumor radioresistance. Also, we discuss the clinical impact of radioresistance in patient outcomes. Knowledge of such cellular strategies could help the development of new clinical interventions, increasing the radiosensitization of tumor cells, improving the effectiveness of these therapies, and increasing the survival of patients.
SPAK Deficiency Attenuates Chemotherapy-Induced Intestinal Mucositis
Authors: Huang Tien-Yu , Yang Sung-Sen , Liao Ching-Len , Lin Ming-Hong , Lin Hsuan-Hwai , Lin Jung-Chun , Chen Peng-Jen , Shih Yu-Lueng , Chang Wei-Kuo , Hsieh Tsai-Yuan
Published: November 2021

Introduction

Ste20-related protein proline/alanine-rich kinase (SPAK) affects cell proliferation, differentiation, and transformation, and sodium and chloride transport in the gut. However, its role in gut injury pathogenesis is unclear.

Objective

We determined the role of SPAK in chemotherapy-induced intestinal mucositis using in vivo and in vitro models.

Methods

Using SPAK-knockout (KO) mice, we evaluated the severity of intestinal mucositis induced by 5-fluorouracil (5-FU) by assessing body weight loss, histological changes in the intestinal mucosa, length of villi in the small intestine, pro-inflammatory cytokine levels, proliferative indices, and apoptotic indices. We also evaluated changes in gut permeability and tight junction-associated protein expression. Changes in cell permeability, proliferation, and apoptosis were assessed in SPAK siRNA-transfected 5FU-treated IEC-6 cells.

Results

5-FU-treated SPAK-KO mice exhibited milder intestinal mucositis, reduced pro-inflammatory cytokine expression, increased villus length, good maintenance of proliferative indices of villus cells, decreased apoptotic index of enterocytes, reduced gut permeability, and restoration of tight junction protein expression (vs. 5-FU-treated wild-type mice). Under in vitro conditions, siRNA-mediated SPAK-knockdown in IEC-6 cells decreased cell permeability and maintained homeostasis following 5-FU treatment.

Conclusion

SPAK deficiency attenuated chemotherapy-induced intestinal mucositis by modulating gut permeability and tight junction-associated protein expression and maintaining gut homeostasis in murine small intestinal tissues following gut injury. The expression of SPAK may influence the pathogenesis of chemotherapy-induced intestinal mucositis.