The miR-29 family members induce glioblastoma cell apoptosis by targeting cell division cycle 42 in a p53-dependent manner.

BACKGROUND: Emerging evidence has shown that miR-29 is a promising biomarker and therapeutic target for malignancies. The roles of miR-29a/b/c in glioma pathogenesis remain need further investigation. METHODS: The expression levels of miR-29a/b/c and CDC42 were systematically analysed, and prognostic significance was evaluated by Kaplan-Meier survival and Cox regression analyses. The roles of miR-29a/b/c in apoptosis and the underlying mechanisms were explored via an alkaline single-cell gel electrophoresis assay, caspase 3/7 activity assays and Western blotting. RESULTS: miR-29a/b/c expression decreased progressively with the elevation of the WHO grade in our 147 human glioma specimens, compared with 20 non-tumour control brain tissues, and decreased miR-29a/b/c expression was associated with more aggressive phenotypes. Kaplan-Meier and Cox regression analyses demonstrated that lower miR-29a/b/c expression was correlated with worse prognosis, which was confirmed by analysis of 198 glioma patients from the CGGA cohort. These all indicate that miR-29a/b/c were independent predictors of prognosis in glioma patients. miR-29a/b/c induced apoptosis in GBM cells by silencing CDC42. Further detailed mechanistic investigation revealed that miR-29a/b/c promoted apoptosis in a p53-dependent manner by suppressing the CDC42/PAK/AKT/MDM2 pathway. CONCLUSIONS: miR-29a/b/c are independent predictors of prognosis in glioma patients. They induce glioblastoma cell apoptosis via silencing of CDC42 and suppression of downstream PAK/AKT/MDM2 signalling in a p53-dependent manner.

MRI Assessment of the Relationship Between Cortical Morphological Features and Hemiparetic Motor-Related Outcomes in Chronic Subcortical Stroke Patients.

BACKGROUND: It is unclear which cortical regions are specific to or commonly associated with the impairments of the upper/lower limbs and the activities of daily life (ADL) in stroke patients. PURPOSE: To investigate the relationships between MRI-assessed surface-based morphometry (SBM) features and motor function as well as ADL in participants with chronic stroke. STUDY TYPE: Prospective. SUBJECTS: Thirty-five participants with subcortical stroke more than 3 months from the first-onset (age: 56.44 ± 9.56 years; 32 male). FIELD STRENGTH/SEQUENCE: T1 -weighted images, 3.0 T, three-dimensional fast field-echo sequence. ASSESSMENT: FreeSurfer (6.0) was used to parcellate each hemisphere into 34 regions based on the Desikan-Killiany atlas and to extract the surface area, volume, thickness, and curvature. The motor function and ADL were assessed by the Fugl-Meyer Assessment for the Upper/Lower Extremity (FMA-UE/FMA-LE) and the Chinese version of the Modified Barthel Index (MBI-C), respectively. STATISTICAL TESTS: A linear mixed-effect model was applied to evaluate the relationship between the morphological features and the FMA-UE, FMA-LE, and MBI-C. A false discovery rate corrected P value < 0.05 was considered statistically significant. RESULTS: Correlations between the size of stroke lesion and MRI measurements did not pass the FDR correction (adjusted P > 0.05). SBM features in motor-related and high-order cognitive cortical regions showed significant correlations with FMA-UE and FMA-LE, respectively. Moreover, the thickness in the prefrontal cortex significantly positively correlated, while the surface area in the right supramarginal gyrus significantly negatively correlated, with both FMA-UE, FMA-LE, and MBI-C. The thickness in the left frontal lobe significantly positively correlated with both FMA-UE and MBI-C. DATA CONCLUSION: This study's findings suggest that different hemiparetic motor-related outcomes in participants with subcortical stroke which suffered a corticospinal tract-related injury show specific, but also share common, associations with several cortical regions. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Effectiveness of kinesiology taping on the functions of upper limbs in patients with stroke: a meta-analysis of randomized trial.

BACKGROUND: Kinesiology tape (KT), a water-resistant and elastic tape which is well known measure for preventing musculoskeletal injuries, has recently gained popularity in neurological rehabilitation. This is a systematic and meta-analysis study, useful both to evaluate the efficacy of kinesiology taping on the functions of upper limbs in patients with stroke and to collect the main outcomes evaluated in the analyzed studies. METHODS: A comprehensive literature search of electronic databases including Medline, Web of science, Embase, Cochrane Central Register of Controlled Trials, Physiotherapy Evidence Database (PEDro), WANFANG, and the China National Knowledge Infrastructure (CNKI). Additional articles were obtained by scanning reference lists of included studies and previous reviews. Keywords were "kinesiology taping," "kinesio," "kinesio taping," "tape" and "stroke," "hemiplegia," "hemiplegic paralysis," "apoplexy," "hemiparesis," "upper extremity," "upper limb." All the RCTs were included. Quality assessment was performed using Cochrane criteria. Upper extremity function and pain intensity was pooled as the primary outcome, and shoulder subluxation, muscle spasticity, general disability, PROM of abduction, and adverse effects as secondary outcomes. RESULTS: Twelve articles were included. Pooled data provided evidence that there was significance between kinesiology taping groups and control groups in pain intensity (standardized mean difference - 0.79, 95% CI - 1.39 to - 0.19), shoulder subluxation (standardized mean difference - 0.50, 95%CI - 0.80 to - 0.20), general disability (standardized mean difference 0.35, 95%CI 0.10 to 0.59), upper extremity function (standardized mean difference 0.61, 95%CI 0.18 to 1.04), and the PROM of flexion (standardized mean difference 0.63, 95%CI 0.28 to 0.98). CONCLUSION: Current evidence suggested that kinesiology taping could be recommended to improve upper limb function in patients with stroke in pain intensity, shoulder subluxation, general disability, upper extremity function, and the PROM of flexion. ETHICS AND DISSEMINATION: Ethical approval requirements are not necessary for this review. This systematic review and meta-analysis will be disseminated online and on paper to help guide the clinical practice better. PROSPERO REGISTRATION NUMBER: CRD42020179762.

miR-135a-5p Functions as a Glioma Proliferation Suppressor by Targeting Tumor Necrosis Factor Receptor-Associated Factor 5 and Predicts Patients' Prognosis.

miR-135a-5p has been reported as a tumor suppressor in several extracranial tumors. However, its exact roles in gliomagenesis and relevance to the patients' prognoses are largely unknown. Herein, we detected the miR-135a-5p and tumor necrosis factor receptor-associated factor 5 (TRAF5) levels in 120 human glioma specimens and 20 nontumoral brain tissues; we found the miR-135a-5p level decreased, whereas the TRAF5 level increased, with the elevation of glioma grade. Their labeling indexes were inversely correlated with each other and showed strong negative (miR-135a-5p) and positive (TRAF5) correlation with the Ki-67 index. Cox regression demonstrated that both of their expression levels were independent survival predictors, whereas Kaplan-Meier analysis showed that subgrouping the glioma patients according to their levels could perfectly reflect the patients' prognoses regardless of the similarities in pathologic, molecular, and clinical features. In the following in vitro and in vivo studies, it was demonstrated that miR-135a-5p induced G1 arrest and inhibited the proliferation of glioma cells by targeting TRAF5 and subsequently blocking AKT phosphorylation as well as c-Myc and cyclin D1 expression. These effects could be reversed by TRAF5 overexpression and simulated by specific TRAF5 silencing. This study highlights the importance of miR-135a-5p and TRAF5 in gliomagenesis and progression and implies their potential prognostic and therapeutic values in malignant glioma.

miR-29a/b/c function as invasion suppressors for gliomas by targeting CDC42 and predict the prognosis of patients.

BACKGROUND: The lethality and poor outcome of high-grade gliomas result from the tumour relentless invasion. miR-29a/b/c downexpressions contribute to several human tumourigenesis. However, their relevance to prognosis and invasion in gliomas remains unclear. METHODS: Relationships of miR-29a/b/c and CDC42 expressions to grade and survival-time in 147 human gliomas were analysed by in situ hybridisation and immunohistochemistry. Dual-luciferase reporter assay was used to identify CDC42 as a target of miR-29a/b/c. Underlining mechanisms by which miR-29a/b/c inhibited glioma cell migration and invasion were studied by in vitro and in vivo assays. RESULTS: miR-29a/b/c expressions were inversely correlated with glioma grades, but positively correlated with patients' survival. Two distinct subgroups of grade I-IV glioma patients with different prognoses were identified according to miR-29a/b/c expressions. miR-29a/b/c overexpressions suppressed glioma cell migration and invasion through targeting CDC42 and subsequently decreasing phosphorylated PAK1/2/3, LIMK1/2 and cofilin, the pivotal downstream effectors of CDC42. Moreover, CDC42 expression was positively correlated with glioma grades, but inversely correlated with miR-29a/b/c expressions and patients' survival. In glioblastoma cell lines, CDC42-knockdown could mimic the anti-tumour effects of miR-29a/b/c. CONCLUSIONS: miR-29a/b/c are important tumour suppressors and novel prognostic biomarkers of gliomas, and miR-29a/b/c and CDC42 are potential therapeutic candidates for malignant gliomas.

Identification of SRSF10 as a promising prognostic biomarker with functional significance among SRSFs for glioma.

AIMS: The serine/arginine-rich splicing factor (SRSF) protein family members are essential mediators of the alternative splicing (AS) regulatory network, which is tightly implicated in cancer progression. However, the expression, clinical correlation, immune infiltration, and prognostic value of SRSFs in gliomas remain unclear. MATERIALS AND METHODS: Glioma samples were extracted from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets. Several databases, such as HPA, DAVID, UALCAN were used to comprehensively explore the roles of SRSFs. In addition, experimental validation of SRSF10 was also conducted. KEY FINDINGS: Here, we found the expression alterations of the SRSF family in glioma samples using data from the TCGA and CGGA_325 datasets. Among the 12 genes, most were found to be closely associated with glioma clinical features, which linked to poor prognosis in glioma patients. Interestingly, survival analysis identified only SRSF10 as a potential independent risk prognostic biomarker for glioma patients. Immune analysis indicated that glioma patients with high SRSF10 expression may respond well to immunotherapies targeting immune checkpoint (ICP) genes. Finally, knocking down SRSF10 reduced glioma cell viability, induced G1 cell cycle arrest, and induced the exclusion of bcl-2-associated transcription factor 1 (BCLAF1) exon 5a. SIGNIFICANCE: Overall, this study uncovers the oncogenic roles of most SRSF family members in glioma, with the exception of SRSF5, while highlighting SRSF10 as a potential novel independent prognostic biomarker for glioma.

Supratentorial Collision Tumor of Hemangioblastoma and Metastatic Clear Cell Renal Cell Carcinoma in a Patient with von Hippel-Lindau Disease.

Collision tumors are rarely reported in patients with von Hippel-Lindau (VHL) disease, even though VHL patients often present with multi-organ tumor syndromes, like hemangioblastoma and renal cell carcinoma (RCC). Hemangioblastoma is rarely located in a supratentorial location, and intracranial lateral ventricular is also not a common site of metastasis for RCC. It is extremely rare for the two tumors to collide in the supratentorial area. We report a 64-year-old man with a history of clear cell RCC who presented with a sudden headache. The brain magnetic resonance imaging revealed that there was a cystic-solid mass in the intracranial lateral ventricular trigone. Histopathologically, the tumor consisted of two distinct components, most of which showed the typical morphology of hemangioblastoma. However, there were a few acinar structures composed of clear cells scattered in hemangioblastoma, and these acinar structures were subsequently confirmed as clear cell RCC. The genetic testing confirmed that the patient had VHL disease with de novo somatic mutation. Based on our case report, we systematically reviewed the characteristics of collision tumor composed of hemangioblastoma and metastatic RCC in VHL patients. The special growth site of our case is the first report of this kind of collision tumor, and can also help enrich our understanding of VHL disease and collision tumor.

Case report: Bilateral carotid body tumors with a concomitant skull-base paraganglioma.

Background: Bilateral carotid body tumors with a concomitant skull-base paraganglioma are extremely rare, of which only one case has been reported in the literature to date. Case presentation: We present the case of a 35-year-old male with 1 year of hypertension and high levels of dopamine and 3-methoxytyramine. Magnetic resonance imaging (MRI) scans demonstrated three separate masses at the left middle cranial fossa floor and bilateral carotid bifurcation. Genetic testing showed succinate dehydrogenase complex subunit D mutation. The patient underwent the resection of the left skull base mass. Histopathology and immunohistochemistry confirmed the presence of a skull-base paraganglioma. Conclusions: Succinate dehydrogenase complex subunit D mutation-associated bilateral carotid body tumors with a concomitant skull-base paraganglioma accompanied by abnormal dopamine and hypertension are extremely rare, which not only provides ideas for considering the association of gene mutations, biochemical abnormalities and clinical symptoms but also provides an expanded diagnostic spectrum for paraganglioma in atypical locations.

Ultra high b-value diffusion weighted imaging enables better molecular grading stratification over histological grading in adult-type diffuse glioma.

PURPOSE: Accurate preoperative radiological staging of adult-type diffuse glioma is crucial for effective prognostic stratification and selection of appropriate therapeutic interventions. The purpose of this study was to compare the effectiveness of apparent diffusion coefficient (ADC) maps generated from ultrahigh b-value diffusion-weighted imaging (DWI) for molecular grading with that for histological grading of adult-type diffuse glioma, and to evaluate the correlation between these ADC maps and molecular and histological biomarkers. METHODS: This study retrospectively enrolled forty adult-type diffuse glioma patients, diagnosed using the 2021 WHO classification criteria. Preoperative imaging data, including multiple b-value DWI and conventional magnetic resonance imaging, were collected. Tumors were graded using both histological and molecular criteria. Histogram analysis was conducted to generate 14 parameters for each tumor. Receiver operating characteristic curves and the area under the curve (AUC) were used to evaluate tumor grading and molecular status differentiation. Analysis of histological biomarkers was performed by calculating the Pearson and Spearman correlation coefficients of continuous and hierarchical variables, respectively. RESULTS: The intensity-related parameters for molecular grading were found to be superior to those for histological grading for the identification of WHO grade 4 (WHO4) adult-type diffuse glioma. The AUC of both grading systems increased with increasing b-values, with ADC8000-based histogram parameters showing the best results (molecular grading, square root: AUC = 0.897; histological grading, median: AUC = 0.737). The intensity-related parameters could also differentiate molecular WHO4 gliomas from histologically lower-grade gliomas (ADC8000-based square root: AUC = 0.919), and different ADC8000-based kurtosis was observed between molecular and histological WHO4 gliomas (AUC = 0.833). Significant correlations between the Ki-67 index and molecular status prediction for IDH, CDKN2A, and EGFR were also demonstrated. CONCLUSION: The histogram parameters derived from high b-value ADC maps were found to be more effective for differentiating molecular grades of WHO4 adult-type diffuse glioma than for differentiating histological grades.

A novel dual-task paradigm with story recall shows significant differences in the gait kinematics in older adults with cognitive impairment: A cross-sectional study.

Objective: Cognitive and motor dysfunctions in older people become more evident while dual-tasking. Several dual-task paradigms have been used to identify older individuals at the risk of developing Alzheimer's disease and dementia. This study evaluated gait kinematic parameters for dual-task (DT) conditions in older adults with mild cognitive impairment (MCI), subjective cognitive decline (SCD), and normal cognition (NC). Method: This is a cross-sectional, clinical-based study carried out at the Zhongshan Rehabilitation Branch of First Affiliated Hospital of Nanjing Medical University, China. Participants: We recruited 83 community-dwelling participants and sorted them into MCI (n = 24), SCD (n = 33), and NC (n = 26) groups based on neuropsychological tests. Their mean age was 72.0 (5.55) years, and male-female ratio was 42/41 (p = 0.112). Each participant performed one single-task walk and four DT walks: DT calculation with subtracting serial sevens; DT naming animals; DT story recall; and DT words recall. Outcome and measures: Kinematic gait parameters of speed, knee peak extension angle, and dual-task cost (DTC) were obtained using the Vicon Nexus motion capture system and calculated by Visual 3D software. A mixed-effect linear regression model was used to analyze the data. Results: The difference in gait speed under DT story recall and DT calculation was -0.099 m/s and - 0.119 m/s (p = 0.04, p = 0.013) between MCI and SCD, respectively. Knee peak extension angle under DT story recall, words recall, and single task was bigger in the MCI group compared to the NC group, respectively (p = 0.001, p = 0.001, p = 0.004). DTC was higher in the DT story recall test than all other DT conditions (p < 0.001). Conclusion: Kinematic gait parameters of knee peak extension angle for the DT story recall were found to be sensitive enough to discriminate MCI individuals from NC group. DTC under DT story recall was higher than the other DT conditions.

Recruitment of LEF1 by Pontin chromatin modifier amplifies TGFBR2 transcription and activates TGFß/SMAD signalling during gliomagenesis.

Synergies of transcription factors, chromatin modifiers and their target genes are vital for cell fate determination in human cancer. Although the importance of numerous epigenetic machinery for regulating gliomagenesis has been previously recognized, how chromatin modifiers collaborate with specific transcription factors remains largely elusive. Herein we report that Pontin chromatin remodelling factor acts as a coactivator for LEF1 to activate TGFß/SMAD signalling, thereby contributing to gliomagenesis. Pontin is highly expressed in gliomas, and its overexpression paralleled the grade elevation and poor prognosis of patients. Functional studies verified its oncogenic roles in GBM cells by facilitating cell proliferation, survival and invasion both in vitro and in vivo. RNA sequencing results revealed that Pontin regulated multiple target genes involved in TGFß/SMAD signalling. Intriguingly, we found that Pontin amplified TGFßR2 gene transcription by recruiting LEF1, thereby activating TGFß/SMAD signalling and facilitating gliomagenesis. Furthermore, higher TGFßR2 expression conferred worse patient outcomes in glioma. To conclude, our study revealed that the Pontin-LEF1 module plays a crucial role in driving TGFßR2 gene transcription, which could be exploited to target TGFß/SMAD signalling for anti-glioma therapy.

Effect of 3-Month Aerobic Dance on Hippocampal Volume and Cognition in Elderly People With Amnestic Mild Cognitive Impairment: A Randomized Controlled Trial.

As an intermediate state between normal aging and dementia, mild cognitive impairment (MCI), especially amnestic MCI (aMCI), is a key stage in the prevention and intervention of Alzheimer's disease (AD). Whether dancing could increase the hippocampal volume of seniors with aMCI remains debatable. The aim of this study was to investigate the influence of aerobic dance on hippocampal volume and cognition after 3 months of aerobic dance in older adults with aMCI. In this randomized controlled trial, 68 elderly people with aMCI were randomized to either the aerobic dance group or the control group using a 1:1 allocation ratio. Ultimately, 62 of 68 participants completed this study, and the MRI data of 54 participants were included. A specially designed aerobic dance routine was performed by the dance group three times per week for 3 months, and all participants received monthly healthcare education after inclusion. MRI with a 3.0T MRI scanner and cognitive assessments were performed before and after intervention. High-resolution three-dimensional (3D) T1-weighted anatomical images were acquired for the analysis of hippocampal volume. A total of 35 participants (mean age: 71.51 ± 6.62 years) were randomized into the aerobic dance group and 33 participants (mean age: 69.82 ± 7.74 years) into the control group. A multiple linear regression model was used to detect the association between intervention and the difference of hippocampal volumes as well as the change of cognitive scores at baseline and after 3 months. The intervention group showed greater right hippocampal volume (ß [95% CI]: 0.379 [0.117, 0.488], p = 0.002) and total hippocampal volume (ß [95% CI]: 0.344 [0.082, 0.446], p = 0.005) compared to the control group. No significant association of age or gender was found with unilateral or global hippocampal volume. There was a correlation between episodic memory and intervention, as the intervention group showed a higher Wechsler Memory Scale-Revised Logical Memory (WMS-RLM) score (ß [95% CI]: 0.326 [1.005, 6.773], p = 0.009). Furthermore, an increase in age may cause a decrease in the Mini-Mental State Examination (MMSE) score (ß [95% CI]: -0.366 [-0.151, -0.034], p = 0.002). In conclusion, 3 months of aerobic dance could increase the right and total hippocampal volumes and improve episodic memory in elderly persons with aMCI. Clinical Trial Registration: This study was registered on the Chinese Clinical Trial Registry [www.chictr.org.cn], identifier [ChiCTR-INR-15007420].

[Relationship between miR-218 and CDK6 expression and their biological impact on glioma cell proliferation and apoptosis].

OBJECTIVES: To investigate the relationship between the expression of miR-218 and CDK6 in glioma cells, and their biological impacts on the tumor cell proliferation and apoptosis. METHODS: Expression levels of miR-218 as well as CDK6 and Ki-67 proteins were analyzed in 60 cases of gliomas with various grades and 10 control brain tissue samples by tissue microarray, locked oligonucleotide probe in situ hybridization and immunohistochemistry. Glioblastoma multiform cell line (U87MG) was transfected with miR-218 mimics (mimics group) and a control sequence (control group), followed by qRT-PCR detection of miR-218 and immunocytochemical stain of CDK6 and Ki-67, respectively. Single cell gel electrophoresis was used to detect the presence of apoptotic cell. RESULTS: The miR-218 labeling indexes (LI) were statistically different (P<0.05) among all groups including control (22.45 +/- 0.59) and various glioma groups (grades I - II 4.00 +/- 1.07, grade III 1.87 +/- 1.06 and grade IV 0.94 +/- 0.78, respectively). The CDK6 LI of the four groups was 7.25 +/- 1.20, 16.71 +/- 0.80, 24.43 +/- 0.62 and 32.05 +/- 0.43, respectively. Significant differences existed between the control group and the glioma groups, and between grade IV and grades I - II glioma groups (P<0.01). Ki-67 positive cell densities of the above four groups (0.00 +/- 0.00, 9.30 +/- 3.48, 31.15 +/- 9.44 and 60.15 +/- 13.60) were significantly different from one and another (P<0.01). The expression of miR-218 negatively correlated with CDK-6 LI (r = -0.480, P<0. 01) and Ki-67 positive cell density (r = - 0.534, P<0.01), while the latter two positively correlated with each other (r = 0.530, P<0.01). U87MG transfection experiment showed that the miR-218 level of the mimics group was significantly higher than that of the control group (P<0.01). CDK6 and Ki-67 LI of the mimics group (14.74 +/- 1.19 and 30.88 +/- 3.31) were significantly lower than those of the control group (79.06 +/- 2.07 and 64.94 +/- 3.96, P<0.01), whilst its apoptotic index (AI) (68.44 +/- 7.05) was significantly higher than that of the control group (13.04 +/- 0.97, P<0.01). CONCLUSIONS: The expression level of miR-218 is an important reference indicator for the assessment of the grade of gliomas. An aberrant decrease of its expression may lead to an increase of the CDK6 expression and proliferative activity of giloma cells. Introducing exogenous miR-218 may effectively down-regulate the CDK6 expression, inhibit cell proliferation and induce apoptosis of malignant giloma cells. These findings imply that miR-218 may serve as a therapeutic agent against malignant glioma.

The surgical resection of dysplastic cerebellar gangliocytoma assisted by intraoperative sonography: illustrative case.

BACKGROUND: Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease) is an extremely rare, slow-growing hereditary mass lesion that is mainly characterized by both specific neuroradiological features and secondary hydrocephalus. Patients may present with symptoms of cerebellar mass lesion and increased intracranial pressure. As an important part of Cowden syndrome, Lhermitte-Duclos disease in adults is typically marked by PTEN gene mutation. OBSERVATIONS: The clinical management of a 31-year-old woman who suffered Lhermitte-Duclos disease was introduced in this case report. Subtotal resection was performed with the assistance of intraoperative sonography to relieve obstructive hydrocephalus, and prophylactic C1 laminectomy was performed to prevent possible postoperative progression of the residual lesion. Perioperative care and surgical process were clearly revealed in an accompanying video. Intraoperative sonography of Lhermitte-Duclos disease presents hyperechoic distorted thickening cortices surrounded by hypoechoic edema belt. The patient did not report any significant neurological complications or sequelae after the lesion resection. LESSONS: The authors first reported the use of intraoperative sonography in resection of adult-onset Lhermitte-Duclos disease. Hopefully, the educative case report can provide a feasible experience in the diagnosis and treatment of Lhermitte-Duclos disease.

Gait Kinematic and Kinetic Characteristics of Older Adults With Mild Cognitive Impairment and Subjective Cognitive Decline: A Cross-Sectional Study.

BACKGROUND: Older adults with mild cognitive impairment (MCI) have slower gait speed and poor gait performance under dual-task conditions. However, gait kinematic and kinetic characteristics in older adults with MCI or subjective cognitive decline (SCD) remain unknown. This study was designed to explore the difference in gait kinematics and kinetics during level walking among older people with MCI, SCD, and normal cognition (NC). METHODS: This cross-sectional study recruited 181 participants from July to December 2019; only 82 met the inclusion criteria and consented to participate and only 79 completed gait analysis. Kinematic and kinetic data were obtained using three-dimensional motion capture system during level walking, and joint movements of the lower limbs in the sagittal plane were analyzed by Visual 3D software. Differences in gait kinematics and kinetics among the groups were analyzed using multivariate analysis of covariance (MANCOVA) with Bonferroni post-hoc analysis. After adjusting for multiple comparisons, the significance level was p < 0.002 for MANCOVA and p < 0.0008 for post-hoc analysis. RESULTS: Twenty-two participants were MCI [mean ± standard deviation (SD) age, 71.23 ± 6.65 years], 33 were SCD (age, 72.73 ± 5.25 years), and 24 were NC (age, 71.96 ± 5.30 years). MANCOVA adjusted for age, gender, body mass index (BMI), gait speed, years of education, diabetes mellitus, and Geriatric Depression Scale (GDS) revealed a significant multivariate effect of group in knee peak extension angle (F = 8.77, p < 0.0001) and knee heel strike angle (F = 8.07, p = 0.001) on the right side. Post-hoc comparisons with Bonferroni correction showed a significant increase of 5.91° in knee peak extension angle (p < 0.0001) and a noticeable decrease of 6.21°in knee heel strike angle (p = 0.001) in MCI compared with NC on the right side. However, no significant intergroup difference was found in gait kinetics, including dorsiflexion, plantar flexion, knee flexion, knee extension, hip flexion, and hip extension(p > 0.002). CONCLUSION: An increase of right knee peak extension angle and a decrease of right knee heel strike angle during level walking were found among older adults with MCI compared to those with NC.

Improved Antiglioblastoma Activity and BBB Permeability by Conjugation of Paclitaxel to a Cell-Penetrative MMP-2-Cleavable Peptide.

In order to solve the problems of receptor promiscuity and poor blood-brain barrier (BBB) penetration in the treatment of glioblastomas (GBM), a novel dual-functional nanocomplex drug delivery system is developed based on the strategy of peptide-drug conjugates. In this study, SynB3-PVGLIG-PTX is designed and screened out by matrix metalloproteinase-2 (MMP-2), to which it exhibits the best affinity. The MMP-2-sensitive peptide (PVGLIG) and a cell-penetration peptide (SynB3) are combined to form a dual-functional peptide. Moreover, as a drug-peptide nanocomplex, SynB3-PVGLIG-PTX exhibited a high potential to form an aggregation with good solubility that can release paclitaxel (PTX) through the cleavage of MMP-2. From a functional perspective, it is found that SynB3-PVGLIG-PTX can specifically inhibit the proliferation, migration, and invasion of GBM cells in vitro in the presence of MMP-2, in contrast to that observed in MMP-2 siRNA transfected cells. Further investigation in vivo shows that SynB3-PVGLIG-PTX easily enters the brain of U87MG xenograft nude mice and can generate a better suppressive effect on GBM through a controlled release of PTX from SynB3-PVGLIG-PTX compared with PTX and temozolomide. Thus, it is proposed that SynB3-PVGLIG-PTX can be used as a novel drug-loading delivery system to treat GBM due to its specificity and BBB permeability.

The ATPase Pontin is a key cell cycle regulator by amplifying E2F1 transcription response in glioma.

Pontin (RUVBL1) is a highly conserved ATPase of the AAA + (ATPases Associated with various cellular Activities) superfamily and is implicated in various biological processes crucial for oncogenesis. Its overexpression is observed in multiple human cancers, whereas the relevance of Pontin to gliomagenesis remains obscure. To gain insights into Pontin involvement in glioma, we performed bioinformatics analyses of Pontin co-expressed genes, Pontin-affected genes, and carried out experimental studies. The results verified that Pontin was upregulated in gliomas. Its higher levels might predict the worse prognosis of glioma patients. The Pontin co-expressed genes were functionally enriched in cell cycle progression and RNA processing. In the nucleus, Pontin promoted cell growth via facilitating cell cycle progression. Using RNA-seq, we found that Pontin knockdown resulted in altered expression of multiple genes, among which the E2F1 targets accounted for a large proportion. Mechanistic studies found that Pontin interacted with E2F1 and markedly amplified the E2F1 transcription response in an ATPase domain-dependent manner. By analyzing the RNA-seq data, we also found that Pontin could impact on the alternative splicing (AS). Both differential expressed genes and AS events affected by Pontin were associated with cell cycle regulation. Taken together, our findings provide novel insights of the importance of Pontin in gliomagenesis by regulating cell cycle and AS, and shed light on the possible application of Pontin as an antineoplastic target in glioma.

Eucalyptal A inhibits glioma by rectifying oncogenic splicing of MYO1B mRNA via suppressing SRSF1 expression.

Glioma is the most common primary intracranial tumor, in which glioblastoma (GBM) is the most malignant and lethal. However, the current chemotherapy drugs are still unsatisfactory for GBM therapy. As the natural products mainly extracted from Eucalyptus species, phloroglucinol-terpene adducts have the potential to be anti-cancer lead compounds that attracted increasing attention. In order to discover the new lead compounds with the anti-GBM ability, we isolated Eucalyptal A with a phloroglucinol-terpene skeleton from the fruit of E. globulus and investigated its anti-GBM activity in vitro and in vivo. Functionally, we verified that Eucalyptal A could inhibit the proliferation, growth and invasiveness of GBM cells in vitro. Moreover, Eucalyptal A had the same anti-GBM activity in tumor-bearing mice as in vitro and prolonged the overall survival time by maintaining mice body weight. Further mechanism research revealed that Eucalyptal A downregulated SRSF1 expression and rectified SRSF1-guided abnormal alternative splicing of MYO1B mRNA, which led to anti-GBM activity through the PDK1/AKT/c-Myc and PAK/Cofilin axes. Taken together, we identified Eucalyptal A as an important anti-GBM lead compound, which represents a novel direction for glioma therapy.

[Detection of chromosomal DNA imbalance in medulloblastoma by comparative genomic hybridization].

OBJECTIVE: To investigate the relationship between chromosomal genomic DNA imbalance in medulloblastoma (MB), and the age and gender. METHODS: The gains and losses of chromosomal genomic DNA in 16 MBs were analyzed using comparative genomic hybridization. RESULTS: The gains and(or) losses were found in 15 of the 16 cases. There was not significant difference (P > 0.05) between the total gains (10/16) and losses (11/16). Both of their differences had also no significance between different age and gender groups (P > 0.05). In 15 cases with gains and(or) losses, single-, two-, three- and multi-chromosome genomic DNA imbalances were 3/15, 4/15, 1/15 and 7/15 respectively. Eleven gain zones (+5q, +6q, +7q, +11q, +15q, +17p, +17q, +19q, +20q, +21q, +Xp) and twenty-five loss zones (-1p, -1q, -2p, -2q, -3q, -4p, -6p, -6q, -8p, -8q, -10p, -10q, -11p, -14q, -16p, -16q, -17p, -18p, -18q, -19p, -19q, -20p, -20q, -Xp, -Xq) were detected in those tumors. +7q (6/16), +17q (6/16), -14q (5/16) and -10q (3/16) were the most frequent, but -14q only occurred in the cases of > 10-year-old. CONCLUSIONS: Most MBs have chromosomal genomic DNA imbalances. The frequent imbalance zones are mainly at the long arms of some chromosomes. +7q, +17q, -14q and -10q correlate closely to development of the tumors. -14q is important factor to result in MBs of > 10-year-old group. MB has possibly different molecular genetics subtype.

[Effects of azidothymidine on p33ING1b expression, apoptosis and senescence of TJ905 human glioblastoma cell line].

OBJECTIVES: To investigate the pharmacological effects of azidothymidine (AZT) on p33ING1b expression, senescence and apoptosis of TJ905 glioblastoma cells. METHODS: TJ905 cells were treated with AZT at a serial concentrations of 50, 100 and 200 µmol/L. Semi-quantitative RT-PCR and cytochemical staining of senescence related-galactosidase (sß-Gal) were used to evaluate the expression of p33ING1b mRNA and to label the senescent cells at the 1st, 3rd and 6th generations, respectively. In situ cell death detection and single cell gel electrophoresis were used to detect the apoptosis at the 3rd and 6th generations. RESULTS: AZT induced the expression of p33ING1b mRNA and senescence of the tumor cells of the 1st generation in a dosage and time dependent manner. At the 6th generation, the relative amount of p33ING1b RT-PCR product (1.44±0.23) and sß-Gal labeling index of 200 µmol/L group (45.62±6.74) were significantly higher than those of the 1st (0.95±0.13 and 7.82±2.40) and the 3rd generation cells (1.35±0.23, 26.27±7.17) of the same group, and cells of the same generation in the 50 µmol/L (0.85±0.24, 27.37±6.41) and 100 µmol/L groups (1.23±0.34, 35.49±5.12, P<0.01). There was a significant positive correlation between the p33ING1b mRNA expression and the labeling index of sß-Gal. Pro-apoptotic effects of AZT became obvious at the 6th generation. CONCLUSION: AZT upregulates the expression of p33ING1b, a possible mechanism in regulating senescence and apoptosis of the TJ905 cells.