The Association Between Thymidylate Synthase Gene Polymorphisms and the Risk of Ischemic Stroke in Chinese Han Population.

Family history of hypertension, smoking, diabetes and alcohol consumption and atherosclerotic plaque were identified as common risk factors in IS. We aimed at investigating the relationship between Thymidylate Synthase (TS) gene polymorphisms and ischemic stroke (IS).This case-control research selected and genotyped three single nucleotide polymorphisms (SNPs)of TS( rs699517, rs2790, and rs151264360) with Sanger sequencing in Chinese Han population. We also adopted logistic regression analysis in genetic models for calculating odds ratios and 95% confidence intervals. Genotype-Tissue Expression(GTEx) database analyzed the tissue-specific expression and TS polymorphisms. The ischemic stroke patients showed higher low-density lipoprotein cholesterol and total homocysteine (tHcy). It was found that patients with the TT genotype of rs699517 and GG genotype of rs2790 had larger degrees of tHcy than those with CC + CT genotypes and AA + AG genotypes, respectively. The genotype distribution of the three SNPs did not deviate from Hardy-Weinberg equilibrium (HWE). Haplotype analysis showed that T-G-del was the major haplotype in IS, and C-A-ins was the major haplotype in controls. GTEx database indicated that the rs699517 and rs2790 increased the expression of TS in healthy human and associated with TS expression level in a single tissue. In conclusion: This study has shown that TS rs699517 and rs2790 were significantly related to ischemic stroke patients.

Effects of dietary supplementation with tea polyphenols and probiotics on laying performance, biochemical parameters intestinal morphology and microflora of laying hens.

This study was conducted to investigate the effects of tea polyphenols (TP) and probiotics (PB) on the production performance, biochemical indices, and gut health of laying hens. A total of 400 Hy-line Brown layers (45 weeks old) were randomly assigned to 8 diet groups for 8-week feeding trial. Compared with the control basal diet (CT), dietary high dosage of TP and PB (HTP-PB) increased egg mass (P < 0.05). Supplementation with HTP-PB improved the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased the malonic dialdehyde (MDA) content (P < 0.05) without affecting the contents of immunoglobulins in the serum. The combination of HTP and PB supplementation promoted the secretion of estradiol (E2) and progesterone (PROG) compared with treatment with TP or PB alone (P < 0.05). The combined use of HTP and PB induced higher jejunal villus height (VH) than the CT group (P < 0.05). Dietary TP and PB could optimize the functional network of intestinal microflora and the interactions between the intestinal microflora and the host. Therefore, the combined use of the high dosage of TP and PB affected laying performance, improved antioxidant capacity, and promoted intestinal health, which may be associated with regulation of the intestinal microbiota.

Prognostic model for predicting overall survival in patients with glioblastoma: an analysis based on the SEER database.

Predicting the prognosis of glioblastoma (GBM) has always been important for improving survival. An understanding of the prognostic factors for patients with GBM can help guide treatment. Herein, we aimed to construct a prognostic model for predicting overall survival (OS) for patients with GBM. We identified 11,375 patients with pathologically confirmed GBM from the Surveillance, Epidemiology, and End Results database between 2004 and 2015. The 1-, 2-, and 3-year survival probabilities were 48.8%, 22.5%, and 13.1%, respectively. The patients were randomly divided into the training cohort (n = 8531) and the validation cohort (n = 2844). A Cox proportional risk regression model was used to analyze the prognostic factors of patients in the training cohort, and a nomogram was constructed. Then concordance indexes (C-indexes), calibration curves, and receiver operating characteristic (ROC) curves were used to assess the performance of the nomograms by internal (training cohort) and external validation (validation cohort). Log-rank test and univariate analysis showed that age, race, marital status, extent of surgical resection, chemotherapy, and radiation were the prognostic factors for patients with GBM (p < 0.05), which were used to construct nomogram. The C-index of the nomogram was 0.717 (95% confidence interval (CI), 0.710-0.724) in the training cohort, and 0.724 (95% CI, 0.713-0.735) in the validation cohort. The nomogram had a higher areas under the ROC curve value. The nomogram was well validated, which can effectively predict the OS of patients with GBM. Thus, this nomogram could be applied in clinical practice.

A Retrospective Comparative Study of Endoscopic Treatment of Gastrocnemius Contracture using the Modified Soft Tissue Release Kit.

Background and Objectives: This study aimed to evaluate the effectiveness and safety of endoscopic gastrocnemius recession using the self-developed Modified Soft Tissue Release Kit. Materials and Methods: This retrospective review followed up 22 patients (34 feet) who underwent endoscopic surgery and 20 patients (30 feet) who received open surgery between January 2020 and January 2022. The American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot score and the maximum ankle dorsiflexion angle were evaluated preoperatively and at the last follow-up. Postoperative complications were recorded. Patient satisfaction was surveyed at the last follow-up. The comparison between quantitative data was analyzed with the Wilcoxon signed-rank test. The comparison between qualitative data was analyzed with the chi-square test. Results: There was no significant difference in the baseline characteristics between the two groups. The AOFAS score in the endoscopic group increased from 50 (18) points preoperatively to 90 (13) points at the last follow-up; the maximum ankle dorsiflexion angle increased from -7.7 (2.8) degrees to 10.6 (3.6) degrees. The AOFAS score in the open group improved from 47 (15) points preoperatively to 90 (18) points at the last follow-up; the maximum ankle dorsiflexion angle increased from -7.6 (4.0) degrees to 10.7 (3.3) degrees. The change values of the AOFAS scores in the endoscopic and open groups were 39 (15) and 40.5 (11) points, respectively, and there was no significant difference between them. The change values of the maximum ankle dorsiflexion angles in the endoscopic and open groups were 19.5 (4.3) and 19.1 (4.9) degrees, respectively, and there was no significant difference between them. There were no complications, such as sural nerve injury, in both groups. There was no significant difference between the two groups in satisfaction with the surgical outcome. Conclusions: Endoscopic gastrocnemius recession using the Modified Soft Tissue Release Kit can significantly improve the foot function with significant mid-term efficacy and high safety.

Polydopamine-coated 3D-printed ß-tricalcium phosphate scaffolds to promote the adhesion and osteogenesis of BMSCs for bone-defect repair: mRNA transcriptomic sequencing analysis.

Cellular bioactivity and tissue regeneration can be affected by coatings on tissue-engineered scaffolds. Using mussel-inspired polydopamine (PDA) is a convenient and effective approach to surface modification. Therefore, 3D-printed ß-tricalcium phosphate (ß-TCP) scaffolds were coated with PDA in this study. The effects of the scaffolds on the adhesion and osteogenic differentiation of seeded bone marrow mesenchymal stem cells (BMSCs) in vitro and on new-bone formation in vivo were investigated. The potential mechanisms and related differential genes were assessed using mRNA sequencing. It was seen that PDA coating increased the surface roughness of the 3D-printed ß-TCP scaffolds. Furthermore, it prompted the adhesion and osteogenic differentiation of seeded BMSCs. mRNA sequencing analysis revealed that PDA coating might affect the osteogenic differentiation of BMSCs through the calcium signaling pathway, Wnt signaling pathway, TGF-beta signaling pathway, etc. Moreover, the expression of osteogenesis-related genes, such as R-spondin 1 and chemokine c-c-motif ligand 2, was increased. Finally, both the 3D-printed ß-TCP scaffolds and PDA-coated scaffolds could significantly accelerate the formation of new bone in critical-size calvarial defects in rats compared with the control group; and the new bone formation was obviously higher in the PDA-coated scaffolds than in ß-TCP scaffolds. In summary, 3D-printed ß-TCP scaffolds with a PDA coating can improve the physicochemical characteristics and cellular bioactivity of the scaffold surface for bone regeneration. Potential differential genes were identified, which can be used as a foundation for further research.

Extracellular Vesicles as Delivery Shippers for Noncoding RNA-Based Modulation of Angiogenesis: Insights from Ischemic Stroke and Cancer.

Ischemic stroke and systemic cancer are two of the leading causes of mortality. Hypoxia is a central pathophysiological component in ischemic stroke and cancer, representing a joint medical function. This function includes angiogenesis regulation. Vascular remodeling coupled with axonal outgrowth following cerebral ischemia is critical in improving poststroke neurological functional recovery. Antiangiogenic strategies can inhibit cancer vascularization and play a vital role in impeding cancer growth, invasion, and metastasis. Although there are significant differences in the cause of angiogenesis across both pathophysiological conditions, emerging evidence states that common signaling structures, such as extracellular vesicles (EVs) and noncoding RNAs (ncRNAs), are involved in this context. EVs, heterogeneous membrane vesicles encapsulating proteomic genetic information from parental cells, act as multifunctional regulators of intercellular communication. Among the multifaceted roles in modulating biological responses, exhaustive evidence shows that ncRNAs are selectively sorted into EVs, modulating common specific aspects of cancer development and stroke prognosis, namely, angiogenesis. This review will discuss recent advancements in the EV-facilitated/inhibited progression of specific elements of angiogenesis with a particular concern about ncRNAs within these vesicles. The review is concluded by underlining the clinical opportunities of EV-derived ncRNAs as diagnostic, prognostic, and therapeutic agents.

A Retrospective Clinical Study of Endoscopic Treatment of Carpal Tunnel Syndrome using the Modified Soft Tissue Release kit.

OBJECTIVE: Carpal tunnel syndrome (CTS) is the most common peripheral entrapment neuropathy, and endoscopic carpal tunnel release (ECTR) is one of the minimally invasive procedures for the treatment of CTS. Based on the shortcomings of ECTR, we designed the "Modified Soft Tissue Release Kit" to assist the endoscopic operation. This study aimed to evaluate the effectiveness and safety of endoscopic treatment of CTS using this kit. METHODS: This retrospective review included 57 patients (86 wrists) who underwent ECTR using the "Modified Soft Tissue Release Kit" at our department between January 2017 and August 2019. Three scale scores (i.e., Quick-Disabilities of the Arm, Shoulder, and Hand [QDASH]; Boston Carpal Tunnel Syndrome Questionnaire [BCTSQ]: symptom severity [BCTSQ-SS] and functional status [BCTSQ-FS]) were recorded to assess hand function and symptoms preoperatively, 1 month postoperatively, 3 months postoperatively, and at the last follow-up. We also asked patients to answer a satisfaction question during follow-up. Pre- and post-operation scores were compared using paired Wilcoxon signed-rank test. Spearman's rank-order correlation was used to evaluate the relationship between scale scores and patient satisfaction. RESULTS: A total of 55 patients (83 wrists) were followed up, with an average follow-up of 27.2 ± 9.3 months. The median preoperative QDASH score was 45.5; the scores at 1 month postoperatively, 3 months postoperatively, and the last follow-up were 4.5, 0, and 0, respectively, with a significant decrease noted compared with the preoperative scores (P < 0.001). The median preoperative BCTSQ-SS and BCTSQ-FS scores were 3.3 and 2.8, respectively; the scores at 1 month postoperatively, 3 months postoperatively, and the last follow-up were 1.2, 1.0, and 1.0, and 1.1, 1.0, and 1.0, respectively, all of which decreased significantly compared with the preoperative scores (P < 0.001). The incidence of nerve injury was 0. The incidence of pillar pain was 0 at the last follow-up. One patient showed no improvement in hand symptoms and function postoperatively, and two patients showed long-term recurrence despite postoperative symptom remission. Approximately 94.5% (52/55) of the patients were satisfied or very satisfied with the outcome. CONCLUSIONS: ECTR with the "Modified Soft Tissue Release Kit" can significantly relieve symptoms and improve function in patients with CTS, with significant short- and mid-term efficacy and high safety.

A clinical application study of a stent placement assessment.

BACKGROUND: Atherosclerotic acute carotid occlusion is a specific type of stroke, and controversy exists regarding the surgical strategy, that is, whether an internal carotid artery stent should be placed immediately after opening the occluded vessel. There is no objective evaluation system for this procedure. In a previous study, we summarized an evaluation decision system Emergent Carotid Artery Stent placement decision Evaluation System (ECASES) for emergency stent placement. STUDY DESIGN: This is a prospective, single-center, randomized controlled trial. Patients with acute ischemic stroke caused by atherosclerotic carotid artery occlusion confirmed by imaging (computed tomography/magnetic resonance angiography/digital subtraction angiography) will be randomly divided into the study and control groups, with 101 patients in each group. The study group will undergo surgery according to the ECASES system and the control group will undergo surgery according to the operator's experience. The postoperative outcomes of the 2 groups will be compared. STUDY OUTCOMES: Primary outcome: Neurological functional status (modified Rankin Scale and National Institutes of Health Stroke Scale scores) of patients 90 days postoperatively. Secondary outcomes: neurological function changes, hemorrhage events, cerebral edema, postoperative modified treatment in cerebral infarction grade, new cerebral infarction, and reocclusion of responsible vessels. DISCUSSION: Currently, no prospective controlled data exist regarding the efficacy and safety of carotid stenting in the acute phase. Previously, we had developed an ECASES stent placement system for acute carotid artery occlusion. The present study will evaluate the efficacy and safety of ECASES in a randomized, double-blind prospective study and clarify its guiding significance in acute atherosclerotic carotid artery occlusion surgery.

The Immunomodulatory Functions of BTK Inhibition in the Central Nervous System.

Bruton's tyrosine kinase (BTK) is a central signaling node in B cells. BTK inhibition has witnessed great success in the treatment of B-cell malignancies. Additionally, in the immune system, BTK is also a prominent component linking a wide variety of immune-related pathways. Therefore, more and more studies attempting to dissect the role of BTK in autoimmune and inflammation progression have emerged in recent years. In particular, BTK expression was also found to be elevated within the central nervous system (CNS) during neuroinflammation. BTK inhibitors are capable of crossing the blood-brain barrier rapidly to modulate B cell functions, attenuate microglial activities and affect NLRP3 inflammasome pathways within the CNS to improve the outcome of diseases. Thus, BTK inhibition appears to be a promising approach to modulate dysregulated inflammation in the CNS and alleviate destruction caused by excessive inflammatory responses. This review will summarize the immunomodulatory mechanisms in which BTK is involved in the development of neurological diseases and discuss the therapeutic potential of BTK inhibition for the treatment of neuroinflammatory pathology.

Outcomes of V-cut Osteotomy on the First Metatarsal Head Combined with Fixation in Mortise-shaped Bone Groove-Plasty and Akin Osteotomy on the First Toe for Hallux Valgus Correction.

OBJECTIVE: Hallux valgus (HV) is a common foot deformity, and recurrence is one of the most serious complications after HV correction. As a result, the surgical technique with a lower recurrence rate is a dream. The purpose of the article should be to observe the correction effect of hallux valgus using a novel "V-cut" osteotomy on the first metatarsal head combined with fixation in mortise-shaped bone groove-plasty technique. METHODS: Twenty-three consecutive patients (40 feet) with HV were included from March 2019 to May 2020, who were all treated using single screw fixation with V-cut osteotomy on the first metatarsal head combined with mortise-shaped metatarsal bone groove-plasty and Akin osteotomy on the first toe for hallux valgus correction. With a mean follow-up time of 21.7 months, the visual analogue scale (VAS) score and American Orthopedic Foot and Ankle Society (AOFAS) forefoot score and the changes of the hallux valgus angle (HVA), intermetatarsal angle (IMA) and distal metatarsal articular angle (DMAA) were evaluated during the clinical follow-up. The paired t test was used for analytical statistics. RESULTS: The VAS score improved from 6.78 ± 1.74 to 1.87 ± 1.45 and the AOFAS score improved from 53.9 ± 12.3 preoperatively to 94.7 ± 6.8 in the latest follow-up postoperatively (P < 0.01). Besides, the HVA improved from 30.0 ± 6.1° to 5.7 ± 2.8° (P < 0.01); the IMA changed from 13.1 ± 2.8° into 3.3 ± 1.6° (P < 0.01); and the DMAA ameliorated from 27.0 ± 8.4° to 5.9 ± 3.5° (P < 0.01). Only five toes had slight numbness and stiffness in early postoperative period, and these symptoms disappeared completely at 6 months after the surgery. Only one foot was corrected to excess. One screw stern protruding beneath the skin happened, which needed secondary screw removal under local anesthesia. CONCLUSIONS: Single screw fixation with V-cut osteotomy on the first metatarsal head combined with fixation in mortise-shaped metatarsal bone groove-plasty and Akin osteotomy on the first toe is an effective way with low recurrence rate for HV correction.

Stereotactic Surgery of Parkinson's Disease with Magnetic Resonance Imaging under Three-Dimensional Mark Point Positioning Algorithm.

This research aimed to study the application of magnetic resonance imaging (MRI) under three-dimensional mark point positioning algorithm in stereotactic surgery for Parkinson's disease (PD) and improve clinical treatment effect. Eighty patients with PD in Tianjin Medical University General Hospital were selected as the research objects and randomly divided into two groups. The three-dimensional mark point positioning algorithm was applied to perform feature positioning on the MRI images of PD patients, and the international unified Parkinson's disease rating scale (UPDRS) was assessed before and after single-target surgery of the two groups. There was a significant difference in the postoperative treatment effect between the two groups compared with the preoperative one (P < 0.05). Among the patients in the observation group, 37 cases were marked as markedly effective, accounting for 92.5% of the total group; 1 case was ineffective and 2 cases were improved, accounting for 2.5% and 5%, respectively. In the control group, 35, 2, and 3 cases were assessed as markedly effective, ineffective, and improved, accounting for 87.5%, 5%, and 7.5%, respectively. The overall curative effect of the observation group was better than that of the control group, and the difference was significant (P < 0.05). The MRI manifestations of PD patients were diversified. MRI under the three-dimensional mark point positioning algorithm had a high value for the stereotactic treatment of PD patients, which was beneficial to the clinical surgery.

Peripheral Monocyte Percentage as a Potential Indicator of Prognosis in Patients with Chronic Subdural Hematoma Receiving Conservative Therapy.

BACKGROUND: Studies have confirmed active and abnormal inflammation in the hematoma cavity of chronic subdural hematoma (CSDH). However, a relationship between the peripheral blood status and the prognosis of CSDH patients has not been demonstrated. METHODS: We retrospectively analyzed 245 CSDH patients who received conservative therapy (67 under close follow-up observation, 103 treated with atorvastatin, and 75 treated with atorvastatin combined with dexamethasone) from 2014 to 2021 to evaluate the role of major inflammation-associated cells in the prognostic assessment of patients. Univariate and multivariate analyses were performed to assess the potential factors that could indicate the prognosis among the 103 patients who underwent observation only or atorvastatin therapy. Changes in peripheral blood inflammation-associated cells at different time points were compared between patients with good and poor outcomes. Furthermore, the changes in inflammatory cells in 75 patients who received atorvastatin combined with dexamethasone were analyzed. RESULTS: The monocyte percentage was the only independent influencing factor in subsequent follow-up assessments. Patients with good outcomes had obviously lower circulating monocyte percentages in their peripheral blood counts throughout the treatment period. The monocyte percentage was also significantly decreased in the patients who responded well to atorvastatin combined with dexamethasone. The peripheral monocyte percentage was significantly higher in patients who transitioned to surgery because of a poor response to pharmacotherapy. CONCLUSIONS: The peripheral monocyte percentage may be a convenient and effective indicator for predicting the outcome of CSDH for patients receiving conservative treatment. A higher percentage of monocytes could be a risk factor for a poor response.

3D-Printed ß-Tricalcium Phosphate Scaffolds Promote Osteogenic Differentiation of Bone Marrow-Deprived Mesenchymal Stem Cells in an N6-methyladenosine-Dependent Manner.

Bone defect is a serious orthopedic disease which has been studied for a long time. Alternative degradable biomaterials are required for bone repairing and regeneration to address the limitation of autogenous bone. ß-tricalcium phosphate (ß-TCP) is an alternative material with good cytocompatibility and has been used in bone defect treatment. However, whether ß-TCP contributes to osteogenesis of bone marrow stem cells (BMSCs) through N6-methyladenosine (m6A) modification remains unknown. To address this issue, we verified the effects of ß-TCP on osteogenesis of BMSCs. We also studied the expression of m6A-related enzymes in BMSCs after ß-TCP treatment. Furthermore, the m6A level and stability of Runt-related transcription factor 2 (RUNX2) mRNA were investigated after ß-TCP treatment. Finally, rat calvarial defect models were performed to detect expression level of osteogenic factors and m6A-related enzymes after the stimulation of three-dimension (3D)-printed ß-TCP scaffolds. We found that ß-TCP showed good biocompatibility and was osteoinductive. Meanwhile, methyltransferase-like 3 (METTL3) increased, causing the elevation of m6A level of RUNX2, results in stabler RUNX2 mRNA level. At last, based on the animal experiments, we demonstrated that the increase of RUNX2 and METTL3 levels was induced by ß-TCP. These findings suggest that METTL3 increases the m6A level of RUNX2 mRNA after ß-TCP induction, contributing to its stability, and the results in vivo also confirmed the osteogenic and bone-repair properties of ß-TCP.

A Protective Role of Tumor Necrosis Factor Superfamily-15 in Intracerebral Hemorrhage-Induced Secondary Brain Injury.

Destabilization of blood vessels by the activities of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) following intracerebral hemorrhage (ICH) has been considered the main causes of aggravated secondary brain injury. Here, we show that tumor necrosis factor superfamily-15 (TNFSF15; also known as vascular endothelial growth inhibitor), an inhibitor of VEGF-induced vascular hyper-permeability, when overexpressed in transgenic mice, exhibits a neuroprotective function post-ICH. In this study, we set-up a collagenase-induced ICH model with TNFSF15-transgenic mice and their transgene-negative littermates. We observed less lesion volume and neural function perturbations, together with less severe secondary injuries in the acute phase that are associated with brain edema and inflammation, including vascular permeability, oxidative stress, microglia/macrophage activation and neutrophil infiltration, and neuron degeneration, in the TNFSF15 group compared with the littermate group. Additionally, we show that there is an inhibition of VEGF-induced elevation of MMP-9 in the perihematomal blood vessels of the TNFSF15 mice following ICH, concomitant with enhanced pericyte coverage of the perihematomal blood vessels. These findings are consistent with the view that TNFSF15 may have a potential as a therapeutic agent for the treatment of secondary injuries in the early phase of ICH.

Synergistic neuroprotective effects of hyperbaric oxygen and N-acetylcysteine against traumatic spinal cord injury in rat.

BACKGROUND: The mitochondrial dysfunction and following oxidative stress, as well as the spread of inflammation plays major roles in the failure to regenerate following severe spinal cord injury (SCI). In this regard, we investigated the neuroprotective effects of hyperbaric oxygen (HBO), as an anti-apoptotic and anti-inflammatory agent, and N-acetylcysteine (NAC), as a mitochondrial enhancer, in SCI. MATERIAL AND METHODS: Seventy-five female adult Wistar rats divided into five groups (n = 15): laminectomy alone (Sham) group, SCI group, HBO group (underwent SCI and received HBO), NAC group (underwent SCI and received NAC), and HBO+NAC group (underwent SCI and simultaneously received NAC and HBO). At the end of study, spinal cord tissue samples were taken for evaluation of biochemical profiles including malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD) and glutathione (GSH) levels, immunohistochemistry for caspase-3 as well as gene expressions of interleukin (IL)-10, tumor necrosis factor alpha (TNF-α), and IL-1ß. Stereological assessments were performed to determine the total volumes, central cavity volumes and as well as numerical density of the neural and glial cells in traumatic area. Moreover, neurological functions were evaluated by the Basso-Beattie-Bresnehan (BBB) and electromyography (EMG). RESULTS: Our results showed that the stereological parameters, biochemical profiles (except MDA) and neurological function were significantly higher in each HBO, NAC and HBO+NAC groups compared to the SCI group, and were highest in HBO+NAC ones. The transcript for IL-10 gene was significantly upregulated in all treatment regimens compared to SCI group, and was highest in HBO+NAC ones. While expression of TNF-α and IL-1ß, latency, as well as density of apoptosis cells in caspase-3 evaluation significantly more decreased in HBO+NAC group compared to other groups. CONCLUSION: Overall, using combined therapy with HBO and NAC has synergistic neuroprotective effects in SCI treatment.

Amlexanox Enhances Temozolomide-Induced Antitumor Effects in Human Glioblastoma Cells by Inhibiting IKBKE and the Akt-mTOR Signaling Pathway.

Temozolomide (TMZ), as the first-line chemotherapeutic agent for the treatment of glioblastoma multiforme (GBM), often fails to improve the prognosis of GBM patients due to the quick development of resistance. The need for more effective management of GBM is urgent. The aim of this study is to evaluate the efficacy of combined therapy with TMZ and amlexanox, a selective inhibitor of IKBKE, for GBM. We found that the combined treatment resulted in significant induction of cellular apoptosis and the inhibition of cell viability, migration, and invasion in primary glioma cells and in the human glioma cell line, U87 MG. As expected, TMZ enhanced the expression of p-AMPK and amlexanox led to the reduction of IKBKE, with no impact on p-AMPK. Furthermore, we demonstrated that compared to other groups treated with each component alone, TMZ combined with amlexanox effectively reversed the TMZ-induced activation of Akt and inhibited the phosphorylation of mTOR. In addition, the combination treatment also clearly reduced in vivo tumor volume and prolonged median survival time in the xenograft mouse model. These results suggest that amlexanox sensitized the primary glioma cells and U87 MG cells to TMZ at least partially through the suppression of IKBKE activation and the attenuation of TMZ-induced Akt activation. Overall, combined treatment with TMZ and amlexanox may provide a promising possibility for improving the prognosis of glioblastoma patients in clinical practice.

Long non-coding RNA AWPPH enhances malignant phenotypes in nasopharyngeal carcinoma via silencing PTEN through interacting with LSD1 and EZH2.

Evidence has emerged identifying long noncoding RNAs (lncRNAs) as important regulators of various cancers including nasopharyngeal carcinoma (NPC). LncRNA AWPPH is an oncogene recently identified in several cancers. However, the underlying role of AWPPH in NPC is still unclear and thus worth exploring. In this study, AWPPH expression was markedly upregulated in NPC cells. Further, loss- and gain-of-function assays indicated that AWPPH facilitates cell proliferation and migration and hinders apoptosis in NPC cells. Moreover, cytoplasmic AWPPH was predicted to share a common RNA-binding protein, IGF2BP1, with LSD1. The interaction between IGF2BP1 and both AWPPH and LSD1 mRNA was verified in NPC cells, and AWPPH stabilized LSD1 mRNA to enhance the expression of LSD1 in NPC through such interactions. Furthermore, nuclear AWPPH repressed PTEN expression through recruiting EZH2 and LSD1 to the PTEN promoter in NPC cells. Final rescue assays demonstrated that silenced PTEN could reverse the suppressive influence of AWPPH depletion on the progression of NPC. Collectively, our study shows that AWPPH inhibits PTEN expression to drive NPC progression through interacting with LSD1 and EZH2, providing potential biomarkers for NPC treatment.

Risk factors involved in the formation of multiple intracranial aneurysms.

BACKGROUND: Although several risk factors of the multiple intracranial aneurysms (MIAs) formation has been reported, the results are controversial. We aimed to find out the risk factors of MIAs formation by analyzing our clinic data combined with a meta-analysis. MATERIAL AND METHODS: A retrospective review work of medical records for the patients with aneurysms was undertaken. Univariate analysis was used to examine all mentioned variables. Binary logistic regression analysis was used to identify the risk factors of MIAs formation. RESULTS: In the retrospective review work, a total of 565 patients with aneurysm were included in this study. Of these 565 participants, 449 patients suffered SIAs and 116 patients suffered MIAs. Univariate analysis showed a significant difference in terms of female, cigarette smoking, family history of hypertension, and primary hypertension between the SIAs and MIAs group. The binary logistic regression analysis showed that the female (OR = 1.624), primary hypertension (OR = 1.563), and family history of hypertension (OR = 2.496) were independent risk factors of the formation of MIAs (for each P < 0.05). With regard to the meta-analysis results, it revealed that there was significant difference in the rates of female (P < 0.001), cigarette smoking (P < 0.001), primary hypertension (P = 0.001), and higher age (P = 0.011) among the MIAs patients. CONCLUSIONS: A higher rate of the formation of MIAs is closely associated with the elder and female. Patients with hypertension history, cigarette smoking, and family primary hypertension history also affected the formation of MIAs, these risk factors should be a guard against.

Fingolimod administration improves neurological functions of mice with subarachnoid hemorrhage.

PURPOSE: To investigate the brain protective effects of fingolimod on inflammatory response of SAH mice. METHODS: We utilized an endovascular mouse perforation model of SAH. Mice were divided into three groups: sham group, SAH group and SAH + Fingolimod group. Mice received either saline or fingolimod (1 mg/kg) intraperitoneally 2 h after sham surgery or SAH. The modified neurological severity score (mNSS) and Morris water maze were respectively used to evaluate the influence of nerve function. Evens blue (EB) extravasation was used to detect the permeability of blood-brain barrier, and water content in brain tissue was also detected. Flow cytometry, ELISA kits and western blotting were used to detect inflammatory factors in brain tissue. RESULTS: The results showed that compared with SAH group, after treatment, the delay time of locating the hidden platform was shorter. The mNSS results showed that fingolimod improved the behavior of SAH mice. In addition, fingolimod could reduce the water content in brain. Flow cytometry results showed that after 3 d of treatment, fingolimod significantly increased Treg cells and down-regulated NK cells. Western blotting results showed fingolimod inhibited the expression of inflammatory cytokines in brain tissue. ELISA kit results showed that fingolimod could down-regulate IL-6 and TNF-α and up-regulate IL-10 and TGF-ß1 in serum. CONCLUSIONS: Fingolimod could regulate the inflammatory response to alleviate SAH-induced brain damage and promote neurological recovery, which provides a new therapeutic strategy for SAH treatment.