PUMC-MB1 is a novel group 3 medulloblastoma preclinical model, sensitive to PI3K/mTOR dual inhibitor.

PURPOSE: Medulloblastoma (MB), a common and heterogeneous posterior fossa tumor in pediatric patients, presents diverse prognostic outcomes. To advance our understanding of MB's intricate biology, the development of novel patient tumor-derived culture MB models with necessary data is still an essential requirement. METHODS: We continuously passaged PUMC-MB1 in vitro in order to establish a continuous cell line. We examined the in vitro growth using Cell Counting Kit-8 (CCK-8) and in vivo growth with subcutaneous and intracranial xenograft models. The xenografts were investigated histopathologically with Hematoxylin and Eosin (HE) staining and immunohistochemistry (IHC). Concurrently, we explored its molecular features using Whole Genome Sequencing (WGS), targeted sequencing, and RNA sequecing. Guided by bioinformatics analysis, we validated PUMC-MB1's drug sensitivity in vitro and in vivo. RESULTS: PUMC-MB1, derived from a high-risk MB patient, displayed a population doubling time (PDT) of 48.18 h and achieved 100% tumor growth in SCID mice within 20 days. HE and Immunohistochemical examination of the original tumor and xenografts confirmed the classification of PUMC-MB1 as a classic MB. Genomic analysis via WGS revealed concurrent MYC and OTX2 amplifications. The RNA-seq data classified it within the Group 3 MB subgroup, while according to the WHO classification, it fell under the Non-WNT/Non-SHH MB. Comparative analysis with D283 and D341med identified 4065 differentially expressed genes, with notable enrichment in the PI3K-AKT pathway. Cisplatin, 4-hydroperoxy cyclophosphamide/cyclophosphamide, vincristine, and dactolisib (a selective PI3K/mTOR dual inhibitor) significantly inhibited PUMC-MB1 proliferation in vitro and in vivo. CONCLUSIONS: PUMC-MB1, a novel Group 3 (Non-WNT/Non-SHH) MB cell line, is comprehensively characterized for its growth, pathology, and molecular characteristics. Notably, dactolisib demonstrated potent anti-proliferative effects with minimal toxicity, promising a potential therapeutic avenue. PUMC-MB1 could serve as a valuable tool for unraveling MB mechanisms and innovative treatment strategies.

Risk factors for postoperative ventriculoperitoneal shunt requirement in pediatric patients with brain tumors invading or adjacent to CSF circulation pathways.

OBJECTIVE: Hydrocephalus is a common comorbidity of brain tumors in children that may persist following brain tumor resection. This study aimed to explore perioperative risk factors associated with postoperative ventriculoperitoneal shunt (VPS) placement for tumors located at or adjacent to the CSF circulation pathway. METHODS: Patients aged 0-18 years with tumors invading or adjacent to the CSF circulation pathways who underwent brain tumor resection between October 2015 and September 2021 were included in this study. The outcome metric was whether patients underwent VPS placement within 6 months of tumor resection. Patients were followed up every 3-6 months after surgery. Demographic and perioperative imaging characteristics, clinical variables, and long-term treatments, including radiotherapy or chemotherapy, were included in the analysis. RESULTS: Two hundred sixty-five children were included in this study. Of these patients, 38 (14.34%) underwent VPS placement within 6 months of tumor resection. One hundred thirty-two patients (49.81%) presented with preoperative hydrocephalus. Results from the multivariate analysis showed that medulloblastoma (OR 4.15, 95% CI 1.74-9.91, p = 0.001), lateral/third ventricle tumors (OR 4.07, 95% CI 1.33-12.30, p = 0.014), postoperative intraventricular hematoma (OR 3.36, 95% CI 1.53-7.38, p = 0.003), and presence of subdural hygroma in the nonoperated area within 48 hours after tumor resection (OR 2.78, 95% CI 1.15-6.74, p = 0.024) were independent risk factors for postoperative VPS placement. CONCLUSIONS: Postoperative lateral/third ventricle hematoma and subdural hygroma in the nonoperated area, anatomical location, and tumor histology may be potential risk factors for a postoperative VPS after brain tumor resection.

Beijing Children's Hospital guidelines on the design and conduction of the first standardized database for medulloblastoma.

Medulloblastoma (MB) is one of the most common malignant childhood brain tumors (WHO grade IV). Its high degree of malignancy leads to an unsatisfactory prognosis, requiring more precise and personalized treatment in the near future. Multi-omics and artificial intelligence have been playing a significant role in precise medical research, but their implementation needs a large amount of clinical information and biomaterials. For these reasons, it is urgent for current MB researchers to establish a large sample-size database of MB that contains complete clinical data and sufficient biomaterials such as blood, cerebrospinal fluid (CSF), cancer tissue, and urine. Unfortunately, there are few biobanks of pediatric central nervous system (CNS) tumors throughout the world for limited specimens, scarce funds, different standards collecting methods and et cl. Even though, China falls behind western countries in this area. The present research set up a standard workflow to construct the Beijing Children's Hospital Medulloblastoma (BCH-MB) biobank. Clinical data from children with MB and for collecting and storing biomaterials, along with regular follow-up has been collected and recorded in this database. In the future, the BCH-MB biobank could make it possible to validate the promising biomarkers already identified, discover unrevealed MB biomarkers, develop novel therapies, and establish personalized prognostic models for children with MB upon the support of its sufficient data and biomaterials, laying the foundation for individualized therapies of children with MB.

Long-term postoperative quality of life in childhood survivors with cerebellar mutism syndrome.

Background: To investigate the long-term quality of life (QoL) of children with cerebellar mutism syndrome (CMS) and explore the risk factors for a low QoL. Procedure: This cross-sectional study investigated children who underwent posterior fossa surgery using an online Pediatric Quality of Life Inventory questionnaire. CMS and non-CMS patients were included to identify QoL predictors. Results: Sixty-nine patients were included (male, 62.3%), 22 of whom had CMS. The mean follow-up time was 45.2 months. Children with CMS had a significantly lower mean QoL score (65.3 vs. 83.7, p < 0.001) and subdomain mean scores (physical; 57.8 vs. 85.3, p < 0.001; social: 69.5 vs. 85.1, p = 0.001; academic: p = 0.001) than those without CMS, except for the emotional domain (78.0 vs. 83.7, p = 0.062). Multivariable analysis revealed that CMS (coefficient = -14.748.61, p = 0.043), chemotherapy (coefficient = -7.629.82, p = 0.013), ventriculoperitoneal (VP) shunt placement (coefficient = -10.14, p = 0.024), and older age at surgery (coefficient = -1.1830, p = 0.007) were independent predictors of low total QoL scores. Physical scores were independently associated with CMS (coefficient = -27.4815.31, p = 0.005), VP shunt placement (coefficient = -12.86, p = 0.025), and radiotherapy (coefficient = -13.62, p = 0.007). Emotional score was negatively associated with age at surgery (coefficient = -1.92, p = 0.0337) and chemotherapy (coefficient = -9.11, p = 0.003). Social scores were negatively associated with male sex (coefficient = -13.68, p = 0.001) and VP shunt placement (coefficient = -1.36, p = 0.005), whereas academic scores were negatively correlated with chemotherapy (coefficient = -17.45, p < 0.001) and age at surgery (coefficient = -1.92, p = 0.002). Extent of resection (coefficient = 13.16, p = 0.021) was a good predictor of higher academic scores. Conclusion: CMS results in long-term neurological and neuropsychological deficits, negatively affecting QoL, and warranting early rehabilitation.

Epidemiological characteristics, clinical presentations, and prognoses of pediatric brain tumors: Experiences of national center for children's health.

Background: We aimed to describe the epidemiological characteristics, clinical presentations, and prognoses in a national health center for children. Methods: From January 2015 to December 2020, 484 patients aged 0-16 years, who were diagnosed with brain tumors and received neurosurgery treatment, were enrolled in the study. Pathology was based on the World Health Organization 2021 nervous system tumor classification, and tumor behaviors were classified according to the International Classification of Diseases for Oncology, third edition. Results: Among the 484 patients with brain tumors, the median age at diagnosis was 4.62 [2.19, 8.17] years (benign tumors 4.07 [1.64, 7.13] vs. malignant tumors 5.36 [2.78, 8.84], p=0.008). The overall male-to-female ratio was 1.33:1(benign 1.09:1 vs. malignant 1.62:1, p=0.029). Nausea, vomiting, and headache were the most frequent initial symptoms. The three most frequent tumor types were embryonal tumors (ET, 22.8%), circumscribed astrocytic gliomas (20.0%), and pediatric-type diffuse gliomas (11.0%). The most common tumor locations were the cerebellum and fourth ventricle (38.67%), the sellar region (22.9%) and ventricles (10.6%). Males took up a higher proportion than females in choroid plexus tumors (63.6%), ET (61.1%), ependymal tumors (68.6%), and germ cell tumors (GCTs, 78.1%). Patients were followed for 1 to 82 months. The overall 5-year survival rate was 77.5%, with survival rates of 91.0% for benign tumors and 64.6% for malignant tumors. Conclusion: Brain tumors presented particularly sex-, age-, and regional-dependent epidemiological characteristics. Our results were consistent with previous reports and might reflect the real epidemiological status in China.

Contribution of tumor characteristics and surgery-related factors to symptomatic hydrocephalus after posterior fossa tumor resection: a single-institution experience.

OBJECTIVE: Pediatric patients are at risk of persistent hydrocephalus after posterior fossa tumor resection. The relationship between surgery-related factors and postoperative symptomatic hydrocephalus has not been elucidated. The objective of this study was to analyze features influencing postoperative hydrocephalus in Chinese children. METHODS: The authors retrospectively evaluated 197 patients younger than 15 years of age who underwent posterior fossa tumor resection at their institution from January 2015 to June 2021. The outcome was whether children underwent CSF diversion within 6 months of resection. Preoperative characteristics, surgery-related factors, and postoperative features were included to identify independent prognosticators. A new logistic model containing independent prognosticators was developed and compared with the modified Canadian Preoperative Prediction Rule for Hydrocephalus (mCPPRH). RESULTS: In this study, 30 patients (15.2%) underwent CSF diversion within 6 months after tumor resection. Tumor location and consistency, intracranial or spinal tumor metastasis determined by perioperative cerebral and spinal MRI, intraoperative blood loss, ventricular blood as determined on postoperative CT, and pathology were statistically significant variables in the univariate analysis. The only two independent predictors of postoperative symptomatic hydrocephalus were tumor metastasis (OR 3.463, 95% CI 1.137-10.549; p = 0.029) and postoperative ventricular blood (OR 4.212, 95% CI 1.595-11.122; p = 0.004). The final logistic model comprising tumor metastasis and postoperative ventricular blood was found to have better discrimination than the mCPPRH. CONCLUSIONS: Tumor characteristics and surgery-related features were associated with postoperative symptomatic hydrocephalus. Tumor metastasis and postoperative ventricular blood were found to be important prognosticators of persistent hydrocephalus.

A presurgical voxel-wise predictive model for cerebellar mutism syndrome in children with posterior fossa tumors.

BACKGROUND: This study aimed to investigate cerebellar mutism syndrome (CMS)-related voxels and build a voxel-wise predictive model for CMS. METHODS: From July 2013 to January 2022, 188 pediatric patients diagnosed with posterior fossa tumor were included in this study, including 38 from a prospective cohort recruited between 2020 and January 2022, and the remaining from a retrospective cohort recruited in July 2013-Aug 2020. The retrospective cohort was divided into the training and validation sets; the prospective cohort served as a prospective validation set. Voxel-based lesion symptoms were assessed to identify voxels related to CMS, and a predictive model was constructed and tested in the validation and prospective validation sets. RESULTS: No significant differences were detected among these three data sets in CMS rate, gender, age, tumor size, tumor consistency, presence of hydrocephalus and paraventricular edema. Voxels related to CMS were mainly located in bilateral superior and inferior cerebellar peduncles and the superior part of the cerebellum. The areas under the curves for the model in the training, validation and prospective validation sets were 0.889, 0.784 and 0.791, respectively. CONCLUSIONS: Superior and inferior cerebellar peduncles and the superior part of the cerebellum were related to CMS, especially the right side, and voxel-based lesion-symptom analysis could provide valuable predictive information before surgery.

Male Predisposition in Cerebellar Mutism Syndrome: a Cohort Study.

The aim of this study was to explore the association between sex and cerebellar mutism syndrome and to examine other potential risk factors. This ambispective cohort study examined 218 pediatric patients (132 boys) with a posterior fossa tumor who underwent tumor resection from July 2013 to March 2021. The patients' demographics and tumor characteristics were examined and statistically analyzed to explore the associations among the variables. Multivariable and subgroup analyses were conducted to validate the independent risk factors for cerebellar mutism syndrome (CMS). The male and female patients did not differ significantly in terms of age, tumor size, tumor location, tumor consistency, VP shunt placement before resection, extent of resection, or surgeon, as well as with respect to the presence of hydrocephalus or paraventricular edema. The overall incidence of CMS was 32.6%. The incidence of CMS was significantly higher in male patients than that in female patients (41.7% vs. 18.6%; P = 0.001). In the multivariable analysis, male sex (adjusted odds ratio [OR], 3.27; P = 0.001), solid tumor consistency (adjusted OR, 5.61; P = 0.001), midline location (adjusted OR, 3.78; P = 0.004), and hydrocephalus (adjusted OR, 2.56; P = 0.047) were independent risk factors for the CMS. Chi-square analysis revealed that solid tumor consistency and midline location were associated with medulloblastoma (P < 0.001). Male patients had a higher risk of developing CMS after a posterior fossa tumor resection. Midline location, solid tumor consistency, and hydrocephalus were independent risk factors for CMS.

Postoperative MRI features of cerebellar mutism syndrome: a retrospective cohort study.

OBJECTIVE: In this study, the authors aimed to investigate the relationship between postoperative MRI features and cerebellar mutism syndrome. METHODS: A retrospective cohort of patients who underwent tumor resection from July 2013 to March 2021 for midline posterior fossa tumors was investigated. All patients were followed up at least once. Clinical data were extracted from medical records and follow-up databases. Two neuroradiologists independently reviewed preoperative and postoperative MRI. Univariable and multivariable analyses were performed to compare the postoperative cerebellar mutism syndrome (pCMS) and non-pCMS groups. Correlation analysis was performed using the Spearman correlation coefficient analysis. RESULTS: Of 124 patients, 47 (37.9%) developed pCMS. The median follow-up duration was 45.73 (Q1: 33.4, Q3: 64.0) months. The median duration of mutism was 45 days. The median tumor size was 48.8 (Q1: 42.1, Q3: 56.8) mm. In the univariable analysis, abnormal T2-weighted signal of the left dentate nucleus (DN) (74.5% in the pCMS group vs 36.4% in the non-pCMS group, p < 0.001), right DN (83.0% vs 40.3%, p < 0.001), left superior cerebellar peduncle (SCP) (74.5% vs 27.3%, p < 0.001), right SCP (63.8% vs 23.4%, p < 0.001), left middle cerebellar peduncle (MCP) (51.1% vs 26.0%, p = 0.008), and right MCP (61.7% vs 26.0%, p < 0.001); male sex (83.0% vs 45.5%, p < 0.001); vermis 3 impairment (49.4% vs 19.1%, p = 0.002); solid tumor (91.5% vs 72.7%, p = 0.022); and hydrocephalus (72.3% vs 45.5%, p = 0.006) were more frequent in the pCMS group than in the non-pCMS group. Multivariable logistic analysis showed that male sex (adjusted OR 4.08, p = 0.010) and the cerebro-cerebellar circuit score of T2-weighted images (adjusted OR 2.15, p < 0.001) were independent risk factors for pCMS. The cerebro-cerebellar circuit score positively correlated with the duration of mutism. In Cox regression analysis, the cerebro-cerebellar integrated circuit injury score of T2 (adjusted HR 0.790, 95% CI 0.637-0.980; p = 0.032) and injury of vermis 3 (adjusted HR 3.005, 95% CI 1.197-7.547; p = 0.019) were independently associated with the duration of mutism. CONCLUSIONS: Male sex and cerebro-cerebellar circuit damage are independent risk factors for pCMS. The cerebro-cerebellar circuit score indicates the duration of mutism.

GINS2 Is Downregulated in Peripheral Blood of Patients with Intervertebral Disk Degeneration and Promotes Proliferation and Migration of Nucleus Pulposus Cells.

GINS complex subunit 2 (GINS2) regulates the migration, invasion, and growth of cells in many malignant and chronic diseases. In the present study, we aimed to investigate the expression of GINS2 in the peripheral blood and nucleus pulposus (NP) cells of patients with intervertebral disk degeneration (IDD). GINS2 expression was detected using bioinformatics tools from the GEO public repository and validated using peripheral blood samples from IDD patients and healthy participants. GINS2 clinical significance was explored by the receiver operating curve (ROC) utilizing area under the curve (AUC). Moreover, the influences of GINS2 on cell viability, migration, and invasion were explored by MTT, wound healing, and transwell assays, whereas cell apoptosis was determined by flow cytometry. Expression levels of GINS2 in the peripheral blood were significantly lower in IDD patients than in healthy participants. Moreover, ROC obtained a significantly higher AUC of GINS2 in IDD patients. Further, overexpressed GINS2 increased the proliferation, migration, and invasion of NP cells while overexpressed GINS2 decreased the apoptotic property of cells compared to the NC plasmid and control groups. In conclusion, GINS2 might be a potential therapeutic target of IDD.

Identification of peptides in Qingke baijiu and evaluation of its angiotensin converting enzyme (ACE) inhibitory activity and stability.

The active peptides in Qingke baijiu fermented from Qingke (highland barley) are rarely reported. This work was designed to accurately identify peptides in Qingke baijiu and evaluate their angiotensin-converting enzyme inhibitory activities in vitro. Four novel peptides, Val-Val-Thr-Gly-Val-Gly-Gly-Gln (VVTGVGGQ), Leu-Pro-Val-Gly-Pro (LPVGP), Leu-Leu-Ser-Pro-Pro (LLSPP), and Phe-Pro-Leu-Gln-Pro-His-Gln-Pro (FPLQPHQP) were identified by Nano-UPLC-MS/MS. Molecular docking showed that LPVGP and FPLQPHQP had a high affinity with ACE (binding energy -8.78, -10.02 kcal mol-1), which matched its in vitro ACE inhibitory activity (IC50 9.05, 5.03 µM). This might be related to their high hydrophobicity. Moreover, three peptides have C-terminal proline, which may contribute to their anti-digestive activity. The content of LPVGP was over 91.23% after digestion, while the content of VVTGVGGQ dropped to 55.47%. Finally, the four peptides have no obvious toxicity to Caco-2 cells. This study clarifies the ACE inhibitory activity and the structure-activity relationship of the four peptides identified in Qingke baijiu.

Case Report: Congenital Intracranial Kaposiform Hemangioendothelioma Treated With Surgical Resection.

Background: Kaposiform hemangioendothelioma (KHE) is a locally aggressive but non-metastatic vascular neoplasm. Most studies have been restricted to small case series of limited generalizability. Intracranial KHE is extremely rare with only three cases reported in the literature. Here, we report a case of congenital intracranial KHE who underwent surgical resection, and no lesion recurrence was seen during the follow-up period of 13 months. Case Description: A 2-month-old boy initially presented with a left temporal mass following birth. Antenatal ultrasound at 36 weeks of gestation demonstrated a hyperechoic signal present in the left frontal lobe, with clear borders and irregular morphology. There were neither cutaneous abnormalities nor other neurologic examination abnormalities. No laboratory abnormality was identified. Computed tomography (CT) scans suggested that a massive hematoma was noted under the left frontal skull plate, with a little subdural hemorrhage in the adjacent temporal area. The adjacent meninges enhanced and thickened on contrasted T1 magnetic resonance (MR). After the multidisciplinary diagnostic assessment, the surgery was performed by the left frontotemporal craniotomy approach. The operation was extremely difficult. We completely removed the tumor, and the involved dura and brain tissue were resected with the lesion in a piecemeal fashion. On postoperative-day (POD) 3 and POD 14, the head CT re-examination revealed that cerebral perfusion improved gradually. The MRI of 6- and 12-month after operation showed no local recurrence or metastasis. Conclusions: Intracranial KHE is difficult to diagnose early and the prognosis has been uniformly poor. We supposed that meticulous intraoperative hemostasis is the key for a successful operation, and the radical resection of the tumor and involved structures are essential to reduce recurrence.

Case Report : Li-Fraumeni Syndrome with Central Nervous System Tumors in Two Siblings.

BACKGROUND: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome caused by germline TP53 gene mutations. It is characterized by high risk of early-onset cancer, and has been confirmed as associated with multiple tumors clinically. So pediatricians should be more alert to LFS in children with tumors. Choroid plexus carcinoma (CPC) is a rare, malignant tumor which account for less than 1% of all central nervous system (CNS) tumors. However, when such tumorigenesis occurs, it is important to be vigilant for the presence of LFS. CASE PRESENTATION: The first patient is a 32-month-old boy admitted for convulsions and then was found intracranial space-occupying lesion. Underwent operation, he was diagnosis as choroid plexus carcinoma (WHO Grade III). After 5 months, his elder sister, a 13-year-old girl, was brought to emergency department for confusion and intermittent convulsions. Surgery was performed immediately after head CT examination found the lesion. The pathology result indicated glioblastoma. Because the siblings of the same family have successively suffered from malignant tumors, we performed genetic testing on this family. TP53 gene mutation occurred in both children of these two cases from their father, and their other brother was not spared either. So the two siblings both met the diagnostic criteria of LFS. Then they all received systematic anti-tumor therapy, and follow-up hitherto. CONCLUSION: Here we reported a rare LFS case that two siblings were inherited the same TP53 germline mutations from their father. They suffered from choroid plexus carcinoma and glioblastoma and were finally diagnosed with LFS. In this LFS family, the primary tumors of the two children were both central nervous system tumors, which were not reported in the previous literature. It is suggested that clinicians should be alert to LFS related tumors, which is helpful for early diagnosis. Timely detection of TP53 gene is an important way for early diagnosis of LFS, especially in children with tumor. The incidence of secondary tumor in LFS patients is significantly higher, and other family members of the LFS patient also have an increased risk of suffering from the tumors. Therefore, early diagnosis and timely tumor surveillance can obtain better therapeutic effect and prognosis for both proband and their family.

Depletion of circRNA circ_CDK14 inhibits osteosarcoma progression by regulating the miR-520a-3p/GAB1 axis.

Osteosarcoma (OS) is a lethal bone malignancy. Circular RNAs (circRNAs) have emerged as important regulators of OS development. CircRNA cyclin dependent kinase 14 (circ_CDK14) was reported to be a potential oncogene in OS. However, the mechanistic pathway by which circ_CDK14 functions in OS is largely unknown. The relative expression of circ_CDK14, microRNA (miR)-520a-3p, and GRB2 Associated Binding Protein 1 (GAB1) was evaluated by quantitative real-time PCR and western blot assays. Flow cytometry was employed to monitor cell cycle distribution and apoptosis. Methyl thiazolyl tetrazolium (MTT) and colony formation assays were performed to assess cell viability and colony formation ability, respectively. Western blot assay was also used to detect the expression of apoptosis-related proteins. Transwell assay was carried out to monitor cell migration and invasion. Additionally, the target association between miR-520a-3p and circ_CDK14 or GAB1 was confirmed by a dual-luciferase reporter assay. Xenograft assay was applied to investigate the role of circ_CDK14 in vivo. Circ_CDK14 and GAB1 expression was upregulated, while miR-520a-3p was downregulated in OS tissues and cells. Circ_CDK14 depletion hindered OS cell proliferation, metastasis, and tumorigenesis while facilitated apoptosis, which were all ameliorated by miR-520a-3p inhibition. Circ_CDK14 could sponge miR-520a-3p. miR-520a-3p targeted GAB1 to repress OS cell proliferation and metastasis. Circ_CDK14 knockdown blocked OS tumor growth in vivo. Circ_CDK14 might positively affect OS development by modulating the miR-520a-3p/GAB1 axis.

Roles of miR-182 in Intervertebral Disc Degeneration and its Potential Prognostic Value.

BACKGROUND: MicroRNAs were reported to be involved in the progression of intervertebral disc degeneration (IDD). This study focused on the potential prognostic value and the underlying mechanism of miR-182 in IDD. METHODS: The expression level of miR-182 in plasma samples from 60 IDD patients and 60 healthy controls were examined in the present study. Then, the relationship between miR-182 expression and clinical features of IDD patients was analyzed. Moreover, the nucleus pulposus (NP) cells were cultured and transfected with either miR-182 inhibitor, mimics, or NC to explore the effects of miR-182 on cell proliferation and apoptosis. Furthermore, expression levels of proliferation and apoptosis-related proteins Bcl-2, Bax, and Caspase-3 were also evaluated. RESULTS: The expression level of miR-182 was dramatically increased in plasma samples of IDD patients compared with the controls. Moreover, ROC analysis indicated that miR-182 was a feasible diagnostic indicator for the diagnosis of IDD. According to the Japanese Orthopaedic Association (JOA) score, the prognosis of patients with the lower expression levels of miR-182 was better than for those with the higher expression levels of miR-182 in IDD. Furthermore, the miR-182 inhibitor significantly increased the proliferation, decreased the apoptosis of human NP cells, and altered the expression of proliferation and apoptosis-related proteins Bcl-2, Bax, and Caspase-3. On the contrary, miR-182 mimics notably inhibited proliferation but promoted apoptosis of human NP cells and increased Bax and Caspase-3 expressions while reducing the Bcl-2 level. CONCLUSIONS: miR-182 was negatively correlated with the prognosis of the IDD patients and affected the proliferation and apoptosis of NP cells in vitro.

An Immune-Related Gene Pairs Signature Predicts Prognosis and Immune Heterogeneity in Glioblastoma.

PURPOSE: Glioblastoma is one of the most aggressive nervous system neoplasms. Immunotherapy represents a hot spot and has not been included in standard treatments of glioblastoma. So in this study, we aim to filtrate an immune-related gene pairs (IRGPs) signature for predicting survival and immune heterogeneity. METHODS: We used gene expression profiles and clinical information of glioblastoma patients in the TCGA and CGGA datasets, dividing into discovery and validation cohorts. IRGPs significantly correlative with prognosis were selected to conduct an IRGPs signature. Low and high risk groups were separated by this IRGPs signature. Univariate and multivariate cox analysis were adopted to check whether risk can be a independent prognostic factor. Immune heterogeneity between different risk groups was analyzed via immune infiltration and gene set enrichment analysis (GSEA). Some different expressed genes between groups were selected to determine their relationship with immune cells and immune checkpoints. RESULTS: We found an IRGPs signature consisting of 5 IRGPs. Different risk based on IRGPs signature is a independent prognostic factor both in the discovery and validation cohorts. High risk group has some immune positive cells and more immune repressive cells than low risk group by means of immune infiltration. We discovered some pathways are more active in the high risk group, leading to immune suppression, drug resistance and tumor evasion. In two specific signaling, some genes are over expressed in high risk group and positive related to immune repressive cells and immune checkpoints, which indicate aggression and immunotherapy resistance. CONCLUSION: We identified a robust IRGPs signature to predict prognosis and immune heterogeneity in glioblastoma patients. Some potential targets and pathways need to be further researched to make different patients benefit from personalized immunotherapy.

Circ_0045714 alleviates TNF-α-induced chondrocyte injury and extracellular matrix degradation through miR-218-5p/HRAS axis.

Emerging evidence suggests that dysregulated circular RNAs (circRNAs) play a pivotal role in osteoarthritis (OA). Circ_0045714 is a functional circRNAs, and has been revealed to involve in the process of OA. However, the molecular mechanisms by which circ_0045714 regulates OA progression are not thoroughly elucidated. Circ_0045714 expression was decreased in OA and TNF-α-induced chondrocytes, ectopic overexpression of circ_0045714 abolished TNF-α-induced cell apoptosis, inflammation, extracellular matrix (ECM) degradation promotion and proliferation inhibition. In a mechanical study, circ_0045714 targeted miR-218-5p, and miR-218-5p overexpression reversed the effects of circ_0045714 on TNF-α-induced chondrocytes. Besides that, HRAS was a target of miR-218-5p, and HRAS knockdown attenuated the protective effects of miR-218-5p inhibition on TNF-α-induced chondrocyte dysfunction. Additionally, circ_0045714 could regulate HRAS expression via miR-218-5p in chondrocytes. Up-regulation of circ_0045714 suppressed TNF-α-induced chondrocyte growth inhibition, inflammation, and ECM degradation via miR-218-5p/HRAS axis, suggesting a novel insight into the pathogenesis of OA and the potential protective role of circ_0045714 in the occurrence and development of OA.

Ocular Dyskinesia and Hemifacial Spasm Secondary to Fourth Ventricular Tumor: Report of 4 Cases and Review of the Literature.

In clinical pediatric neurosurgery practice, fourth ventricle and cerebellar tumors are not rare. However, reports of secondary refractory hemifacial spasm are very rare. No report is currently available on the treatment of hemifacial spasm secondary to fourth ventricle and cerebellar tumors in China. Zamponi et al. [Childs Nerv Syst 2011 Jun;27(6):1001-5] reported that these lesions can occur in neonates and infants, and surgical resection is effective.

Upregulation of suppressor of cytokine signaling 3 ameliorates spinal degenerative disease in adolescents by mediating leptin and tumor necrosis factor-α levels.

Spinal degenerative changes may occur following the rapid growth observed in adolescents, causing a reduced quality of life. The suppressor of cytokine signaling (SOCS) is involved in various degenerative diseases. The current study recruited adolescents with spinal degenerative disease (SDD) to identify the effect of SOCS-3 on leptin and tumor necrosis factor-α (TNF-α) levels in this disorder. From January 2010 to January 2016, 120 adolescents (aged 14 to 25) were enrolled in the current study, with 68 diagnosed with SDD and the remaining 52 treated as controls. Nucleus pulposus cells (NPCs) were extracted and cultured in vitro. TNF-α levels in NPCs were determined using flow cytometry. Degenerative NPCs were then transfected with pCR3.1-SOCS-3 and ELISA was performed to determined TNF-α and leptin levels. RT-qPCR was performed to measure the mRNA level of SOCS-3 and leptin in NPCs and western blotting was utilized to detect the protein level of leptin and the extent of leptin receptor phosphorylation. The results revealed that TNF-α levels in degenerative NPCs were higher than those in normal NPCs. The overexpression of SOCS-3 reduced levels of TNF-α and leptin in degenerative NPCs. In addition, the upregulation of leptin increased SOCS-3 levels in a concentration-dependent manner. Furthermore, the expression of the leptin receptor and phosphorylated leptin receptor gradually decreased with increasing leptin concentrations and the level of phosphorylated leptin receptor negatively correlated with SOCS-3 expression. The inductive effect of leptin on the level of SOCS-3 and the inhibitory effect of SOCS-3 on the activity of leptin were identified. The current study demonstrated that SOCS-3 reduces leptin and TNF-α levels in degenerative NPCs from adolescents, indicating its potential role in the development of novel SDD therapies.