bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative Analysis of LGR5/6 Gene Variants, Gut Microbiota Composition and Osteoporosis Risk in Elderly Population
Authors: Di Dong-sheng , Li Can , Dai Yu , Wei Mu-hong , Wang Shan-shan , Song Wen-jing , Zhou Hao-long , Cui Yuan , Zhang Ru-yi , Huang Qin , Wang Qi 
Published: November 2021

Objective: This study aimed to explore the relationships between the common variants of R-spondin/Wnt signaling genes, gut microbiota composition, and osteoporosis (OP) risk in elderly Chinese Han population.Design: Dual-energy X-ray absorptiometry was used to obtain the OP-associated measurements at multiple skeleton sites among all 1,168 participants. Genotyping data was obtained by using the next-generation sequencing in the discovery stage (n = 400, 228 OP patients) and SNPscan technology in the replication stage (n = 768, 356 OP patients). Bioinformatic analysis was performed to provide more evidence for the genotype-OP associations. The 16S ribosomal RNA gene high-throughput sequencing technology was adopted to explore OP-associated gut microbiota variations.Results: The genetic variants of rs10920362 in the LGR6 gene (P-FDR = 1.19 × 10–6) and rs11178860 in the LGR5 gene (P-FDR = 1.51 × 10–4) were found to associate with OP risk significantly. Several microbial taxa were associated with the BMDs and T-scores at multiple skeleton sites. The associations between rs10920362 and BMD-associated microbiota maintained significance after adjusting confounders. The rs10920362 CT/TT genotype associated with a decreased relative abundance of Actinobacteria (β = −1.32, P &lt; 0.001), Bifidobacteriaceae (β = −1.70, P &lt; 0.001), and Bifidobacterium (β = −1.70, P &lt; 0.001) compared to the CC genotype.Conclusion: Our findings suggested that the variants loci of LGR6 may be associate with OP pathogenesis via gut microbiota modifications. The relationship between host genetics and gut microbiome provides new perspectives about OP prevention and treatment.
Eculizumab Pharmacokinetics and Pharmacodynamics in Patients With Generalized Myasthenia Gravis
Authors: Monteleone Jonathan P. R. , Gao Xiang , Kleijn Huub Jan , Bellanti Francesco , Pelto Ryan 
Published: November 2021

Objective: To investigate the pharmacokinetics, pharmacodynamics, and exposure–response of the approved 900/1,200 mg dosing regimen for the terminal complement component 5 (C5) inhibitor eculizumab in patients with generalized myasthenia gravis (gMG).Methods: The analysis used data from 62 patients aged ≥ 18 years with anti-acetylcholine receptor (AChR) antibody-positive refractory gMG who received eculizumab during the REGAIN study (ClinicalTrials.gov: NCT01997229). One- and two-compartment population-pharmacokinetic models were evaluated, and the impact of covariates on pharmacokinetic parameters was assessed. Relationships between eculizumab exposure and free C5 concentration, in vitro hemolytic activity, clinical response, and tolerability were characterized.Results: Steady-state serum eculizumab concentrations were achieved by Week 4 and were sustained throughout the 26-week treatment period. The eculizumab pharmacokinetic data were well-described by a two-compartment model with first-order elimination, including effects of body weight on pharmacokinetic parameters and plasma-exchange events on clearance. Complete inhibition of terminal complement was achieved in nearly all patients at the time of trough and peak eculizumab concentrations at all post-dose timepoints assessed (free C5 &lt; 0.5 μg/ml in 92% of patients; in vitro hemolysis &lt; 20% in 87% of patients). Serum eculizumab concentrations of ≥116 μg/ml achieved free C5 concentrations of &lt; 0.5 μg/ml. Clinical efficacy and tolerability were consistent across the eculizumab exposure range.Conclusions: Rigorous, quantitative, model-based exposure–response analysis of serum eculizumab concentration and response data demonstrated that the approved eculizumab dosing (900/1,200 mg) for adults with anti-AChR antibody-positive refractory gMG rapidly achieved complete inhibition of terminal complement activation and provided sustained clinical efficacy across the eculizumab exposure range.
Predictors of Comorbid Anxiety Symptoms After a New Diagnosis of Epilepsy: A Prospective 12-Month Follow-Up Observation
Authors: Zhong Rui , Lin Weihong , Chen Qingling , Zhang Xinyue , Li Guangjian 
Published: November 2021

Objectives:We aimed to identify the factors contributing to comorbid anxiety symptoms over a 12-month follow-up period in Chinese adults with newly diagnosed epilepsy.Methods:Adult patients with newly diagnosed epilepsy (PWNDE) were recruited from First Hospital, Jilin University. Anxiety symptoms were assessed using the Generalized Anxiety Disorder-7 questionnaire (GAD-7; Chinese version) at 12 months. Multivariate stepwise logistic regression analysis was employed to identify the predictors for anxiety symptoms at 12 months.Results:A total of 157 PWNDE completed the study and were included in the final analysis. The percentage of participants with anxiety symptoms significantly decreased from 31.2% at baseline to 23.6% at 12 months (p= 0.027). Multivariate stepwise logistic regression analysis indicated that depressive symptoms at baseline [odds ratio (OR) 3.877 (95% confidence interval (CI) 1.683–8.933);P= 0.001] and the number of antiseizure medications (ASMs) during the follow-up period [OR 2.814 (95% CI 1.365–5.803);P= 0.005] were independent factors contributing to comorbid anxiety symptoms at 12 months.Conclusion:Depressive symptoms at baseline and the number of ASMs during the follow-up period were significant predictors of comorbid anxiety symptoms 12 months after a diagnosis of epilepsy.
Vitamin D, Depressive Symptoms, and Covid-19 Pandemic
Authors: Ceolin Gilciane , Mano Giulia Pipolo Rodrigues , Hames Natália Schmitt , Antunes Luciana da Conceição , Brietzke Elisa , Rieger Débora Kurrle , Moreira Júlia Dubois 
Published: November 2021

Graphical AbstractRole of vitamin D in the development of depressive symptoms. The synthesis of vitamin D from sunlight is impaired by lockdown and social distance measures imposed by the governments around the world during COVID-10 pandemic. Endogenous vitamin D synthesis initiates in the skin when 7-dehydrocholesterol (7-DHC) is converted in pre-vitamin D3 and then vitamin D3 [25(OH)D3]. It is transported through blood circulation by the vitamin D binding protein (VDBP) to the liver, the kidney, and the brain, where can be converted in its the active form [1,25(OH)2D3]. In the brain, the biological effects of 1,25(OH)2D3 are largely mediated by vitamin D receptor (VDR) through genomic mechanisms, which influence several aspects of serotonin metabolism, such as increasing serotonin synthesis by induction of the tryptophan hydroxylase 2 (TPH2) gene expression; influencing the expression of serotonin reuptake transporter (SERT) and the levels of monoamine oxidase-A (MAO-A), responsible to serotonin catabolism; and indirectly may regulate the synthesis of melatonin that improve the circadian rhythm. This mechanism can be impaired during social isolation and consequent reduction of vitamin D due to low sun exposure during the pandemic, which could contribute to the development of depressive symptoms.
SPAG5 Is Involved in Human Gliomagenesis Through the Regulation of Cell Proliferation and Apoptosis
Authors: Wang Chunhong , Su Haiyang , Cheng Rui , Ji Hongming 
Published: November 2021

BackgroundGlioma is the most frequent malignant primary brain tumor in adults.ObjectiveTo explore the role of sperm-associated antigen 5 (SPAG5) in glioma.MethodsThe association between SPAG5 expression and clinical features was investigated based on The Cancer Genome Atlas (TCGA) datasets. The function of SPAG5 in glioma was analyzed using U87 and U251 cells. Knockdown glioma cells were constructed by shRNA interference. qRT-PCR and Western blotting were used to measure the expression of SPAG5 and Cadherin 2 (CDH2). Cell proliferation and apoptosis were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, caspase 3/7 assay, and high-content screening (HCS) proliferation analysis and colony formation assay. Transwell assays and wound-healing assays were used to investigate cell migration and invasion.ResultsThe increased expression of SPAG5 was correlated with poor outcomes in glioma patients. Knocking down SPAG5 could inhibit the proliferation and colony formation and promoted the apoptosis of glioma cells. Knocking down SPAG5 could also inhibit cell migration and invasion and the expression of CDH2. Overexpression of CDH2 with SPAG5 depletion could restore the proliferation and inhibit the apoptosis of glioma cells, which also promoted cell migration and invasion.ConclusionsSPAG5 is a promising prognostic factor and potential therapeutic target for clinical intervention in glioma.
Cancer of Pharyngoesophageal Junction: A Different Subtype From Hypopharyngeal and Cervical Esophageal Cancer?
Authors: Li Xiaoyu , Ai Dashan , Chen Yun , Liu Qi , Deng Jiaying , Zhu Hongcheng , Wang Ying , Wan Yue , Xie Yue , Chen Yanan , Chen Weiwei , Fan Jianhong , Wang Xiaoshen , Lu Xueguan , Ying Hongmei , He Xiayun , Hu Chaosu , Zhao Kuaile 
Published: November 2021

BackgroundSquamous cell cancers in the hypopharynx (HP) and cervical esophagus (CE) are different diseases with different staging systems and treatment approaches. Pharyngoesophageal junction (PEJ) tumor involves both the hypopharynx and the cervical esophagus simultaneously, but few reports focused on PEJ tumors. This study aimed to clarify clinical characteristics and the treatment approaches of PEJ tumors.Patients and MethodsA total of 222 patients with squamous cell carcinoma in the HP, PEJ, and CE were collected between January 2008 and June 2018 in Fudan University Shanghai Cancer Center. We compared different lymph node metastatic patterns of three diseases above and the survival of different tumor locations, different lymph node metastasis, and different radiotherapy approaches.ResultsFor HP, PEJ, and CE cancer, the upper and middle cervical lymph node metastatic rates were 85.7%, 47.1%, and 5.8%, respectively; the lower cervical lymph node metastatic rates were 36.7%, 42.9%, and 35.0%, respectively; and the mediastinal lymph node metastatic rates were 2.0%, 72.9%, and 80.6%, respectively. The 3-year overall survival rates were 69.5% in the HP group, 52.0% in the PEJ group, and 69.6% in the CE group (p = 0.024). No survival differences were found between the involved-field-irradiation and elective-node-irradiation subgroups among PEJ tumors (p = 0.717 for OS and p = 0.454 for PFS, respectively).ConclusionHP cancers had a high prevalence in all cervical lymph node metastases, while CE cancers had a lower prevalence in the cervical and mediastinal lymph node metastases. PEJ cancer had the combined metastatic patterns of both HP and CE cancers. Involved field irradiation was feasible in chemoradiotherapy for PEJ cancers.
Identification of Stage IIIC/IV EGFR-Mutated Non-Small Cell Lung Cancer Populations Sensitive to Targeted Therapy Based on a PET/CT Radiomics Risk Model
Authors: Shao Dan , Du Dongyang , Liu Haiping , Lv Jieqin , Cheng You , Zhang Hao , Lv Wenbing , Wang Shuxia , Lu Lijun 
Published: November 2021

ObjectivesThis project aimed to construct an individualized PET/CT prognostic biomarker to accurately quantify the progression risk of patients with stage IIIC-IV epidermal growth factor receptor (EGFR)-mutated Non-small cell lung cancer (NSCLC) after first-line first and second generation EGFR- tyrosine kinase inhibitor (TKI) drug therapy and identify the first and second generation EGFR-TKI treatment-sensitive population.MethodsA total of 250 patients with stage IIIC-IV EGFR-mutated NSCLC underwent first-line first and second generation EGFR-TKI drug therapy were included from two institutions (140 patients in training cohort; 60 patients in internal validation cohort, and 50 patients in external validation cohort). 1037 3D radiomics features were extracted to quantify the phenotypic characteristics of the tumor region in PET and CT images, respectively. A four-step feature selection method was performed to enable derivation of stable and effective signature in the training cohort. According to the median value of radiomics signature score (Rad-score), patients were divided into low- and high-risk groups. The progression-free survival (PFS) behaviors of the two subgroups were compared by Kaplan–Meier survival analysis.ResultsOur results shown that higher Rad-scores were significantly associated with worse PFS in the training (p &lt; 0.0001), internal validation (p = 0.0153), and external validation (p = 0.0006) cohorts. Rad-score can effectively identify patients with a high risk of rapid progression. The Kaplan–Meier survival curves of the three cohorts present significant differences in PFS between the stratified slow and rapid progression subgroups.ConclusionThe PET/CT-derived Rad-score can realize the precise quantitative stratification of progression risk after first-line first and second generation EGFR-TKI drug therapy for NSCLC and identify EGFR-mutated NSCLC populations sensitive to targeted therapy, which might help to provide precise treatment options for NSCLC.
Rivaroxaban Modulates TLR4/Myd88/NF-Kβ Signaling Pathway in a Dose-Dependent Manner With Suppression of Oxidative Stress and Inflammation in an Experimental Model of Depression
Authors: Abdelzaher Walaa Yehia , Mohammed Hanaa H. , Welson Nermeen N. , Batiha Gaber El-Saber , Baty Roua S. , Abdel-Aziz Asmaa Mohamed 
Published: November 2021

Depression is a common mental illness leading to upset or anxiety, with a high incidence rate in the world. Depression can lead to suicidal thoughts and behavior. The present study aimed to evaluate the effect of the direct oral anticoagulant rivaroxaban (RVX), in the model of depression induced by chronic unpredicted mild stress (CUMS) in rats. Fifty-six male Wister rats were randomly divided into seven experimental groups (8 rats/group); Group 1: Control group given vehicle per oral (p.o.), Group 2: RVXL-control group (received rivaroxaban 20 mg/kg/day, p.o..), Group 3: RVXH-control group (received rivaroxaban 30 mg/kg/day, p.o.), Group 4: chronic unpredictable mild stress (CUMS) group, Group 5: FLX-treated CUMS group (received fluoxetine 10 mg/kg/day, p.o..), Group 6: RVXL-treated CUMS group (received rivaroxaban 20 mg/kg/day, p.o.), and Group 7: RVXH-treated CUMS group (received rivaroxaban 30 mg/kg/day, p.o.). The rats received the drugs from the first day of the experiment and continued till 4 weeks—the duration of the study. The following were measured: monoamine neurotransmitters, malondialdehyde (MDA), total nitrite/nitrate (NOx), reduced glutathione (GSH), superoxide dismutase (SOD), Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor‐kappa B (NF‐κB), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor-A (VEGF-A). A forced swimming test (FST) was done. Furthermore, histological changes and glial fibrillary acidic protein (GFAP) immunoexpression were evaluated. CUMS showed a significant decrease in hypothalamic neurotransmitters, hippocampal GSH, SOD, BNDF, and VEGF-A with a significant increase in hippocampal MDA, NOx, NF-kβ, Myd88, TLR4, TNF-α, and GFAP immunoexpression. RVX showed significant improvement in all parameters (p-value &lt; 0.0001). In conclusion, RVX in a dose-dependent manner possesses potent ameliorative effects against depression by reducing the oxidative stress and inflammatory process, through the regulation of the TLR4/Myd88/NF-kβ signaling pathway.
Chinese Herbal Preparation SaiLuoTong Alleviates Brain Ischemia via Nrf2 Antioxidation Pathway–Dependent Cerebral Microvascular Protection
Authors: Fan Xiao-Di , Yao Ming-Jiang , Yang Bin , Han Xiao , Zhang Ye-Hao , Wang Guang-Rui , Li Peng , Xu Li , Liu Jian-Xun 
Published: November 2021

Stroke is one of the most devastating diseases worldwide. The Chinese herbal preparation SaiLuoTong (SLT) capsule showed outstanding therapeutic effects on stroke and its sequelae. The aim of this study was to further elucidate its therapeutic mechanism. We duplicated a permanent cerebral ischemia model in rats by MCAO and used SLT (33 and 16.5 mg/kg) to intervene. The results showed SLT dose dependently decreased infarction volumes, relieved neuron degeneration and loss, and ameliorated neurological functions, and the dose of 33 mg/kg had statistical significance (compared with the model group, p &lt; 0.05); SLT of 33 mg/kg also significantly inhibited the elevation in brain water content and the loss in claudin-1 and occludin expressions; additionally, it significantly increased nucleus translocation of Nrf2, elevated the expression of HO-1, and raised the activity of SOD and content of GSH (compared with the model group, p &lt; 0.05 or 0.01). These results testified SLT’s anti-brain ischemia effect and hint this effect may be related to the protection of brain microvascular endothelial cells (BMECs) that is dependent on the Nrf2 pathway. To further testify, we cultured hCMEC/D3 cells, duplicated OGD/R model to simulate ischemia, and used SLT (3.125, 6.25, and 12.5 mg/L) to treat. SLT dose dependently and significantly inhibited the drop in cell viabilities, and activated the Nrf2 pathway by facilitating Nrf2 nucleus translocation, and increasing HO-1 expression, SOD activity, and GSH content (compared with the model group, p &lt; 0.05 or 0.01); last, the anti-OGD/R effects of SLT, including raising cell viabilities, inhibiting the elevation in dextran permeability, and preserving expressions of claudin-1 and occludin, were all abolished by Nrf2 siRNA interference. The in vitro experiment undoubtedly confirmed the direct protective effect of SLT on BMECs and the obligatory role of the Nrf2 pathway in it. Collectively, data of this study suggest that SLT’s therapeutic effect on brain ischemia is related to its Nrf2-dependent BMECs protection.
The Impact of Expectation for Pain Relief on Orofacial Pain Treatment Outcomes
Authors: Haviv Yaron , Mazor Sigal , Shani Margolis , Yanko Robert , Aframian Doron J. , Zadik Yehuda , Ben-David Shiri , Wilensky Asaf , Sharav Yair 
Published: November 2021

Aims: To examine the effects of expectations for pain relief on the objective and subjective outcome of chronic orofacial pain (OFP) treatment.Materials and Methods: Sixty individuals referred to the Orofacial Pain Clinic at the Hebrew University-Hadassah School of Dental Medicine between 2015 and 2017 with OFP reported their expectation for pain relief upon initial consultation. They were also interviewed by telephone after treatment and asked to recall their expectations, referred to as “recalled expectations” (RE). Correlations between RE and treatment success were calculated from pain diaries, and from subjective pain improvement rates (PIR) reported by the patients.Results: 21 males (35.0%) and 39 females (65%), mean age of 46.90 ± 15.77 years and mean pain duration of 49.07 ± 51.95 months participated in the study. All participants rated their expectations as “10” on a 0 to 10 scale during their first visit. RE did not correlate with diary ratings, (P = 0.773) but inversely correlated (−0.3) with PIR (P = 0.020) treatment outcomes.Conclusions: Expectations for pain relief, reported as 10 on a 0–10 scale during the first appointment, may reflect the patient's desire for complete relief of their pain rather than their expectations. Clinicians should therefore be aware of the need for clear communication and wording when examining for expectations. Inverse correlation between recalled expectations and subjective outcome may be due to the nature of recalled expectations when patients already knew their treatment outcomes, and may be explained by the concept of cognitive dissonance.
Towards Raman-Based Screening of Acute Lymphoblastic Leukemia-Type B (B-ALL) Subtypes
Authors: Leszczenko Patrycja , Borek-Dorosz Aleksandra , Nowakowska Anna Maria , Adamczyk Adriana , Kashyrskaya Sviatlana , Jakubowska Justyna , Ząbczyńska Marta , Pastorczak Agata , Ostrowska Kinga , Baranska Malgorzata , Marzec Katarzyna Maria , Majzner Katarzyna 
Published: November 2021

Acute lymphoblastic leukemia (ALL) is the most common type of malignant neoplasms in the pediatric population. B-cell precursor ALLs (BCP-ALLs) are derived from the progenitors of B lymphocytes. Traditionally, risk factors stratifying therapy in ALL patients included age at diagnosis, initial leukocytosis, and the response to chemotherapy. Currently, treatment intensity is modified according to the presence of specific gene alterations in the leukemic genome. Raman imaging is a promising diagnostic tool, which enables the molecular characterization of cells and differentiation of subtypes of leukemia in clinical samples. This study aimed to characterize and distinguish cells isolated from the bone marrow of patients suffering from three subtypes of BCP-ALL, defined by gene rearrangements, i.e., BCR-ABL1 (Philadelphia-positive, t(9;22)), TEL-AML1 (t(12;21)) and TCF3-PBX1 (t(1;19)), using single-cell Raman imaging combined with multivariate statistical analysis. Spectra collected from clinical samples were compared with single-cell spectra of B-cells collected from healthy donors, constituting the control group. We demonstrated that Raman spectra of normal B cells strongly differ from spectra of their malignant counterparts, especially in the intensity of bands, which can be assigned to nucleic acids. We also showed that the identification of leukemia subtypes could be automated with the use of chemometric methods. Results prove the clinical suitability of Raman imaging for the identification of spectroscopic markers characterizing leukemia cells.
Cordyceps militaris: An Overview of Its Chemical Constituents in Relation to Biological Activity
Authors: Jędrejko Karol Jerzy , Lazur Jan , Muszyńska Bożena 
Published: November 2021

Cordyceps spp. mushrooms have a long tradition of use as a natural raw material in Asian ethnomedicine because of their adaptogenic, tonic effects and their ability to reduce fatigue and stimulate the immune system in humans. This review aims to present the chemical composition and medicinal properties of Cordyceps militaris fruiting bodies and mycelium, as well as mycelium from in vitro cultures. The analytical results of the composition of C. militaris grown in culture media show the bioactive components such as cordycepin, polysaccharides, γ-aminobutyric acid (GABA), ergothioneine and others described in the review. To summarize, based on the presence of several bioactive compounds that contribute to biological activity, C. militaris mushrooms definitely deserve to be considered as functional foods and also have great potential for medicinal use. Recent scientific reports indicate the potential of cordycepin in antiviral activity, particularly against COVID-19.