TRIM6: An Upregulated Biomarker with Prognostic Significance and Immune Correlations in Gliomas.

This study investigates the expression and prognostic value of TRIM6 in gliomas, the most prevalent primary brain and spinal cord tumors. Our results show that TRIM6 is predominantly overexpressed in glioma tissues and is associated with reduced overall survival, disease-specific survival, and progression-free interval. Furthermore, TRIM6 expression is correlated with WHO grade and primary treatment outcomes. Functional analysis indicates that interactions between cytokines and their receptors play a critical role in the prognosis of glioma patients. A protein-protein interaction network reveals 10 hub genes closely linked to cytokine-cytokine receptor interaction. In vitro experiments demonstrate that silencing TRIM6 impairs the proliferation, invasion, and migration of glioma cells, while overexpressing TRIM6 enhances these abilities. Additionally, TRIM6 expression is positively associated with the abundance of innate immune cells and negatively associated with the abundance of adaptive immune cells. In summary, TRIM6 is significantly upregulated in gliomas and linked to poor prognosis, making it a potential diagnostic and prognostic biomarker. TRIM6 plays a crucial role in promoting cell viability, clonogenic potential, migration, and invasion in glioma cells. It may regulate glioma progression by modulating cytokine-cytokine receptor interaction, leading to an inflammatory response and an imbalance in immunomodulation, thereby representing a potential therapeutic target.

Development of an MCL-1-related prognostic signature and inhibitors screening for glioblastoma.

Introduction: The effect of the conventional treatment methods of glioblastoma (GBM) is poor and the prognosis of patients is poor. The expression of MCL-1 in GBM is significantly increased, which shows a high application value in targeted therapy. In this study, we predicted the prognosis of glioblastoma patients, and therefore constructed MCL-1 related prognostic signature (MPS) and the development of MCL-1 small molecule inhibitors. Methods: In this study, RNA-seq and clinical data of 168 GBM samples were obtained from the TCGA website, and immunological analysis, differential gene expression analysis and functional enrichment analysis were performed. Subsequently, MCL-1-associated prognostic signature (MPS) was constructed and validated by LASSO Cox analysis, and a nomogram was constructed to predict the prognosis of patients. Finally, the 17931 small molecules downloaded from the ZINC15 database were screened by LibDock, ADME, TOPKAT and CDOCKER modules and molecular dynamics simulation in Discovery Studio2019 software, and two safer and more effective small molecule inhibitors were finally selected. Results: Immunological analysis showed immunosuppression in the MCL1_H group, and treatment with immune checkpoint inhibitors had a positive effect. Differential expression gene analysis identified 449 differentially expressed genes. Build and validate MPS using LASSO Cox analysis. Use the TSHR HIST3H2A, ARGE OSMR, ARHGEF25 build risk score, proved that low risk group of patients prognosis is better. Univariate and multivariate analysis proved that risk could be used as an independent predictor of patient prognosis. Construct a nomogram to predict the survival probability of patients at 1,2,3 years. Using a series of computer-aided techniques, two more reasonable lead compounds ZINC000013374322 and ZINC000001090002 were virtually selected. These compounds have potential inhibitory effects on MCL-1 and provide a basis for the design and further development of MCL-1 specific small molecule inhibitors. Discussion: This study analyzed the effect of MCL-1 on the prognosis of glioblastoma patients from the perspective of immunology, constructed a new prognostic model to evaluate the survival rate of patients, and further screened 2 MCL-1 small molecule inhibitors, which provides new ideas for the treatment and prognosis of glioblastoma.

Combining HbA1c and insulin resistance to assess the risk of gestational diabetes mellitus: A prospective cohort study.

OBJECTIVE: To investigate the association of glycated hemoglobin (HbA1c) and homeostasis model assessment insulin resistance (HOMA-IR) with gestational diabetes mellitus (GDM) risk. METHODS: Data for this study were from a prospective cohort in Hangzhou, China. We included pregnant women with HbA1c, fasting insulin, and fasting glucose (FG) measured at 15-20 weeks of gestation and underwent oral glucose tolerance test (OGTT) at 24-28 weeks. Based on HbA1c and HOMA-IR, participants were divided into four groups. We estimated the odds ratios (OR) with 95% confidence intervals (CI) to assess the associations of HbA1c and HOMA-IR with GDM occurrence. Finally, we the potential additive interaction between HbA1c and HOMA-IR by calculating relative excess risk due to interaction (RERI) and the attributable proportion due to interaction (AP). RESULT: 462 pregnant women were included, of whom 136 (29.44%) developed GDM. Based on HbA1c and HOMA-IR, the study population was divided into four groups, with the percentages of each group being 51.30%, 15.58%, 20.56%, and 12.55%, respectively. The incidence of GDM increased with the increase of HOMA-IR and HbA1c, respectively, and the risk of GDM was significantly increased when both HOMA-IR and HbA1c were elevated. However, no such risk was observed in pregnant women < 35 years. Finally, we found significantly higher FG at 24-28 weeks in the high HOMA-IR and HbA1c group among GDM-positive pregnant women. CONCLUSIONS: The incidence of GDM increased with increasing HbA1c and HOMA-IR, and the risk of GDM was significantly increased when both HbA1c and HOMA-IR were elevated. This finding may help to identify high-risk women for GDM early in pregnancy and provide timely interventions.

A simple method to isolate structurally and chemically intact brain vascular basement membrane for neural regeneration following traumatic brain injury.

BACKGROUND: The brain vascular basement membrane (brain-VBM) is an important component of the brain extracellular matrix, and the three-dimensional structure of the cerebrovascular network nested with many cell-adhesive proteins may provide guidance for brain tissue regeneration. However, the potential of ability of brain-VBM to promote neural tissue regeneration has not been examined due to the technical difficulty of isolating intact brain-VBM. METHODS: The present study developed a simple, effective method to isolate structurally and compositionally intact brain-VBM. Structural and component properties of the brain-VBM were characterized to confirm the technique. Seed cells were cocultured with brain-VBM in vitro to analyze biocompatibility and neurite extension. An experimental rat model of focal traumatic brain injury (TBI) induced by controlled cortical impact were conducted to further test the tissue regeneration ability of brain-VBM. RESULTS: Brain-VBM isolated using genipin showed significantly improved mechanical properties, was easy to handle, supported high cell viability, exhibited strong cell adhesive properties, and promoted neurite extension and outgrowth. Further testing of the isolated brain-VBM transplanted at lesion sites in an experimental rat model of focal TBI demonstrated considerable promise for reconstructing a complete blood vessel network that filled in the lesion cavity and promoting repopulation of neural progenitor cells and neurons. CONCLUSION: The technique allows isolation of intact brain-VBM as a 3D microvascular scaffold to support brain tissue regeneration following TBI and shows considerable promise for the production of naturally-derived biomaterials for neural tissue engineering.

Disruption of ß-catenin-mediated negative feedback reinforces cAMP-induced neuronal differentiation in glioma stem cells.

Accumulating evidence supports the existence of glioma stem cells (GSCs) and their critical role in the resistance to conventional treatments for glioblastoma multiforme (GBM). Differentiation therapy represents a promising alternative strategy against GBM by forcing GSCs to exit the cell cycle and reach terminal differentiation. In this study, we demonstrated that cAMP triggered neuronal differentiation and compromised the self-renewal capacity in GSCs. In addition, cAMP induced negative feedback to antagonize the differentiation process by activating ß-catenin pathway. Suppression of ß-catenin signaling synergized with cAMP activators to eliminate GSCs in vitro and extended the survival of animals in vivo. The cAMP/PKA pathway stabilized ß-catenin through direct phosphorylation of the molecule and inhibition of GSK-3ß. The activated ß-catenin translocated into the nucleus and promoted the transcription of APELA and CARD16, which were found to be responsible for the repression of cAMP-induced differentiation in GSCs. Overall, our findings identified a negative feedback mechanism for cAMP-induced differentiation in GSCs and provided potential targets for the reinforcement of differentiation therapy for GBM.

Surgical Techniques and the Choice of Operative Approach for Cranioorbital Lesions.

Objectives Cranioorbital lesions present a great challenge for neurosurgeons and ophthalmologists. There is no consensus on the choice of surgical approach. The aims of this study were to investigate 49 cases of cranioorbital lesions and evaluate surgical approaches and outcomes. Patients and Methods A retrospective study was done on 49 patients (51 operations) from 2009 to 2018. Information about the lesion was used to decide whether the supraorbital eyebrow approach (SEA) or pterional approach (PA) was performed. Results Twenty-eight patients had surgical resection using SEA, 21 patients received PA, each group included one case of recurrence, who underwent reoperation via the same approach. SEA provided better cosmetic satisfaction, and a shorter incision than PA ( p < 0.05). There was no significant difference in total resection rates, visual outcomes, recovery of ptosis, and other new surgical-related complications between SEA group and PA group ( p > 0.05). Forty-nine cases of proptosis (94.1%, 49/51) were improved. Thirty-three patients (33/37, 89.2%) who underwent follow-up for longer than 12 weeks had a modified Rankin Scale (mRS) score ≤ 3. Conclusion Surgery is the preferred treatment for cranioorbital lesions, but total resection is difficult. SEA may be a more minimally invasive option for some more limited lesions superior to optic nerve. PA may be more reasonable for the lesion with obvious hyperostosis and more extensive lesions.

Contralateral Approach Based on a Preoperative 3-Dimensional Virtual Osteotomy Technique for Anterior Circulation Aneurysms.

OBJECTIVE: Our objective was to review 15 consecutive patients with anterior circulation aneurysms managed through a contralateral approach. Individualized surgical simulation using three-dimensional (3D) imaging was adopted to enable safe performance of clipping surgery. METHODS: Five patients had multiple intracranial aneurysms, and 10 patients had a single aneurysm on the contralateral side of the craniotomy. Preoperatively, the unique architecture of aneurysms was fully understood in their 3-dimensionality reconstructed by Mimics software. The location of the cranial bone window and the patient's head position was individually optimized using a preoperative simulation system. RESULTS: In this cohort, 17 contralateral aneurysms showed no wall calcifications. Projections of the aneurysms were superomedial (3/17, 17.6%), medial (8/17, 47.1%), posterior (3/17, 17.6%), and superior (3/17, 17.6%). The visual similarity between the simulating scene and the operative view was excellent in 100% of the cases. Four patients were treated with a contralateral pterional approach, and the remaining 11 patients were treated with a contralateral supraorbital keyhole approach. All of them were well-clipped, except 1 blister-like aneurysm being wrapped. All 15 patients had good outcomes (mRS ≤ 3) after a mean 13 months follow-up. There were no recurrences after surgical treatment. CONCLUSIONS: The contralateral approach for the selected anterior circulation aneurysms is feasible in experienced hands with acceptable morbidity. This approach should be the choice only under judicious case-to-case planning based on a preoperative 3D virtual osteotomy technique.

Xenogeneic acellular nerve scaffolds supplemented with autologous bone marrow-derived stem cells promote axonal outgrowth and remyelination but not nerve function.

Autologous nerves, artificial scaffolds or acellular nerve scaffolds are commonly used in bridging treatment for peripheral nerve defects. Xenogeneic acellular nerve scaffolds and allogeneic cellular nerve scaffolds have the same structural characteristics. Due to the wider source of raw materials, these latter scaffolds have high-potential value for applications. However, whether their heterogeneity will affect nerve regeneration is unknown. The current study evaluated the efficiency of xenogeneic acellular nerve scaffolds (XANs) combined with 5-ethynyl-2'-deoxyuridine (EdU)-labeling of autologous bone marrow-derived stem cells (BMSCs) for repair of a 1.5 cm gap in rat sciatic nerves. XANs from rabbit tibial nerves were prepared, the structure and components of the scaffolds were evaluated after completely removing the cellular components. Animals were divided into four groups based on graft: the simple XAN group, the XAN + BMSC group, the XAN + Media (from BMSC culture) group, and the autograft group. Serological immune tests showed that XANs induce an immune response in the first 2 weeks after transplantation. Moreover, cell tracking revealed that the proportion of EdU+ cells decreased over time, as shown by the measures at 2 days (70%), 4 days (20%), and 8 days (even <3%) postoperatively. Nerve functional analyses revealed that in contrast to the autograft group results, the XAN-BMSC, XAN + Media, and XAN groups did not exhibit good restoration of the sciatic functional index (SFI) or electrophysiological results (the peak action potential amplitudes) 12 weeks, postoperatively. However, the XAN-BMSC and autograft groups demonstrated greater remyelination and increased axon numbers and myelin thickness than the XAN + Media and XAN groups 12 weeks, postoperatively (p < .05). In conclusion, in the early stage of transplantation, XANs induce a certain degree of inflammation. Although the combination of XANs with autologous BMSCs enhanced the number of regenerated axons and the remyelination, the combination did not effectively improve the recovery of nervous motor function. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3065-3078, 2018.

Endoscopic Transvestibular Transmandibular Approach for Trigeminal Schwannoma in Infratemporal Fossa and Parapharyngeal Space.

BACKGROUND: Schwannomas that involve the mandibular division of the trigeminal nerve and localize exclusively in the parapharyngeal space (PPS) and infratemporal fossa (ITF) are extremely rare, and a surgical approach to treat such tumors has not been well established. CASE DESCRIPTION: We present our experience in the treatment of a giant trigeminal schwannoma with wide extension in the ITF and PPS using an endoscopic transvestibular transmandibular approach. The clinical and radiologic findings, preoperative planning, advantages of the surgical approach, and clinical outcome are discussed. CONCLUSIONS: Schwannomas located in the ITF and PPS are rare benign neoplasms. They are usually detected late after considerable signs and symptoms appear. Preoperative planning is beneficial to individual surgical approach selection. Total surgical excision following careful evaluation of preoperative computed tomography and magnetic resonance images is the treatment of choice. Recurrence is rare after complete excision.