Glutamine Metabolism Heterogeneity in Glioblastoma Unveils an Innovative Combination Therapy Strategy.

Treatment of glioblastoma multiforme (GBM) remains challenging. Unraveling the orchestration of glutamine metabolism may provide a novel viewpoint on GBM therapy. The study presented a full and comprehensive comprehending of the glutamine metabolism atlas and heterogeneity in GBM for facilitating the development of a more effective therapeutic choice. Transcriptome data from large GBM cohorts were integrated in this study. A glutamine metabolism-based classification was established through consensus clustering approach, and a classifier by LASSO analysis was defined for differentiating the classification. Prognosis, signaling pathway activity, tumor microenvironment, and responses to immune checkpoint blockade (ICB) and small molecular drugs were characterized in each cluster. A combinational therapy of glutaminase inhibitor CB839 with dihydroartemisinin (DHA) was proposed, and the influence on glutamine metabolism, apoptosis, reactive oxygen species (ROS), and migration was measured in U251 and U373 cells. We discovered that GBM presented heterogeneous glutamine metabolism-based clusters, with unique survival outcomes, activity of signaling pathways, tumor microenvironment, and responses to ICB and small molecular compounds. In addition, the classifier could accurately differentiate the two clusters. Strikingly, the combinational therapy of CB839 with DHA synergistically attenuated glutamine metabolism, triggered apoptosis and ROS accumulation, and impaired migrative capacity in GBM cells, demonstrating the excellent preclinical efficacy. Altogether, our findings unveil the glutamine metabolism heterogeneity in GBM and propose an innovative combination therapy of CB839 with DHA for this malignant disease.

Identification of distinct tumor cell patterns with single-cell RNA sequencing integrating primary lung adenocarcinoma and brain metastasis tumor.

Background: Lung adenocarcinoma (LUAD) is the most common form of lung cancer and is often accompanied by brain metastasis (BM). The heterogeneity of the tumor renders all current conventional treatments less effective. This study aims to dissect tumor cell heterogeneity and identify potential therapeutic targets. Methods: We conducted single-cell RNA-sequencing (scRNA-seq) in 8 patients with treatment-naïve LUAD BM and included scRNA-seq data of 10 primary LUAD samples and their matched adjacent normal tissue from GSE131907 to determine the tumor cell heterogeneity. Results: Our analyses revealed tumor cells derived from brain metastases were more heterogeneous. Tumor cells from BM harbored significantly more copy number variants (CNVs), and cells of magnoid subtype were the critical source of malignant cells both in BM and the primary lung tumor. Pseudo-time trajectory analysis revealed that malignant cells had upregulated genes enriched for cell cycle and cell division. Integrated analysis of tumor cells revealed 2 distinct malignant cell clusters (cluster 4 and cluster 6) and their marker genes. The signatures identified in the single-cell profile had prognostic value in the bulk tumor profiles. Moreover, the signature of cluster 4 had significant prognostic value in predicting patients surviving longer than 3.5 years, while the signature of cluster 6 showed better predictive ability within 1 year. Magnoid-type cells are most likely to develop into the riskiest cell type and potentially promote tumor progression. Conclusions: scRNA profiling that integrates LUAD BM and primary LUAD can provide information on those malignant cells with BM potential, offering additional prognostic information at cellular level, and may serve as a foundational resource for further tumor cell dissection and therapeutic target exploration.

Effects of miRNA-130a on the proliferation and apoptosis of glioma cell lines.

Regulatory ability of micro-ribose nucleic acid-130a (miRNA-130a) in the proliferation and invasive growth of human brain glioma cells and its mechanism were investigated. RT-qPCR was used to analyze expression of miRNA-130a in U-87MG glioma specimens; lipidosome was used to mediate miRNA-130a mimic transfecting glioma cells and the expression of miRNA-130a was detected by using RT-qPCR after transfection; methyl thiazolyl tetrazolium (MTT) assay and flow cytometry (FCM) were adopted to evaluate the changes in biological characteristics of cell growth and proliferation; the migration and invasion abilities of tumor cells were measured through scratch assay and Transwell in vitro cell migration assay. In miRNA-130a mimic-transfected U-87MG cells, RT-qPCR showed that the expression of miRNA-130a was upregulated; MTT assay and FCM revealed that the cell growth was strengthened; scratch assay and Transwell in vitro cell migration assay verified that the migration and invasion abilities of cells were enhanced. In conclusion, the high expression of miRNA-130a can promote growth and invasion, indicating that miRNA-130a can be considered as a candidate target of gene therapy for glioma.

MicroRNA-221-3p Plays an Oncogenic Role in Gastric Carcinoma by Inhibiting PTEN Expression.

Gastric carcinoma is one of the most common malignancies in men, and microRNA plays a critical role in regulating the signaling networks of gastric carcinoma tumorigenesis and metastasis. We first report the functional characteristics of miR-221-3p in gastric carcinoma. Quantification in gastric carcinoma cell lines and tumor samples reveals significantly increasing miR-221-3p expression. Moreover, a high level of miR-221-3p is correlated with a poor prognosis for gastric carcinoma patients. Ectopic miR-221-3p expression significantly promotes gastric carcinoma cell proliferation, invasion, and sphere formation, while silencing miR-221-3p significantly inhibits these abilities in gastric carcinoma cells. Tests in vivo showed that miR-221-3p significantly promotes tumor growth in xenograft mouse models. In this study, we reveal that miR-221-3p targets PTEN mRNA and downregulates PTEN, which is the possible mechanism of miR-221-3p-induced oncogenic properties. Collectively, we reveal a critical role for miR-221-3p in gastric carcinoma development and progression.

[Characteristics of invasive damages of nerve system in sphenoid-sinus-o-tumoropathy and transnasal endoscopic surgery].

OBJECTIVE: To explore the relationships between the sphenoid-sinus-o-tumoropathy and local anatomy, as well as the characteristics of invasive damages of nerve system in sphenoid-sinus-o-tumoropathy, and emphasize that it is crucial of early diagnosis and surgery for sphenoid-sinus-o-tumoropathy. METHOD: Retrospective analysis of the characteristics of invasive damages of nerve system in 13 patients with sphenoid-sinus-o-tumoropathy, and follow-up the outcomes of nerve system after transnasal endoscopic surgery. RESULT: 1) The majority clinical manifestations of invasive damages in nerve system are cranial nerves, there are 9 cases optic nerve, 7 cases oculomotorius nerve, 4 cases trochlear nerve, 4 cases abducent nerve and 1 cases trigeminal nerve have been found damage at different levels in this group, and the secondly are 3 cases dysfunction of pituitary and 2 cases central nerve damage. 2) The improvement of invasive damages in nerve system after transnasal endoscopic surgery are as follow: at the day of operation or the next day, there are 4 cases to be reported that the symptoms of headache and eyes relieve very well; during 3 to 7 days after operation there are 9 cases to be reported that the symptoms of headache and eyes relieve or disappear significantly; 2 weeks after operation, there are 8 cases to be reported that the optical sights recovery at different levels, and there are many symptoms such as headache (9 cases), visual diplopia (1 cases), ptosis (2 cases), fixation of eyeball (1 cases), exophthalmoptosis (2 cases), face pain (2 cases), orbital paralysis (2 cases) disappeared completely. No complications of cerebrospinal fluid rhinorrhea, brain edema and hemorrhage to be found during the period of operation and follow-up. CONCLUSION: The majority clinical characteristics of invasive damage in nerve system with sphenoid-sinus-o-tumoropathy are cranial nerve manifestations, and the second manifestation is dysfunction of pituitary. Transnasal endoscopic surgery could inhibit the invasive damages in cranial nerves of sphenoid-sinus-o-tumoropathic patients effectively.

Surgical strategy for cerebrospinal fluid rhinorrhea repair.

OBJECTIVE: Cerebrospinal fluid (CSF) rhinorrhea is leakage of CSF from the nasal cavity caused by cranial base or meningeal defects. Surgical treatment of CSF rhinorrhea is still problematic. We evaluated the clinical outcomes of 132 consecutive cases of CSF rhinorrhea treated via transcranial or transnasal endoscopic approaches according to the patient's condition. The indications for the approaches are discussed. METHODS: Of 132 patients with CSF rhinorrhea, a transnasal endoscopic approach was used in 98 to repair cranial base defects in the ethmoid and sphenoid sinuses. A transcranial intradural approach was used in the remaining 34 patients for frontal sinus defects, multiple fractures of the cranial base, or combination nerve injury. RESULTS: CSF rhinorrhea resolved after initial surgery in 124 of 132 patients, giving a success rate of 94%. Of the 8 failures or recurrent cases, 4 were successfully repaired by repeat endoscopic surgery, 2 were cured by transcranial revision surgery, and 2 refused additional surgery (the condition subsequently resolved without treatment in these patients). Postoperative complications included intracranial infection (8 patients) and anosmia (1 patient). No neurological deficits were apparent over the 10-month mean follow-up period. CONCLUSION: Transnasal endoscopic repair is a reliable method for CSF rhinorrhea patients whose fistulae are located in the ethmoid and sphenoid sinuses. The transcranial procedure should be the treatment of choice for patients with frontal sinus fracture, multiple or complex anterior cranial base fractures, or nerve injury. A satisfactory surgical outcome depends on exact diagnosis, proper operative approach, and the surgeon's skill and experience.

Anterior and middle skull base reconstruction after tumor resection.

BACKGROUND: Surgical management of skull base tumors is still challenging today due to its sophisticated operation procedure. Surgeons who specialize in skull base surgery are making endeavor to promote the outcome of patients with skull base tumor. A reliable skull base reconstruction after tumor resection is of paramount importance in avoiding life-threatening complications, such as cerebrospinal fluid leakage and intracranial infection. This study aimed at investigating the indication, operation approach and operation technique of anterior and middle skull base reconstruction. METHODS: A retrospective analysis was carried out on 44 patients who underwent anterior and middle skull base reconstruction in the Department of Neurosurgery at Beijing Tiantan Hospital between March 2005 and March 2008. Different surgical approaches were selected according to the different regions involved by the tumor. Microsurgery was carried out for tumor resection and combined endoscopic surgery was performed in some cases. According to the different locations and sizes of various defects after tumor resection, an individualized skull base soft tissue reconstruction was carried out for each case with artificial materials, pedicled flaps, free autologous tissue, and free vascularized muscle flaps, separately. A skull base bone reconstruction was carried out in some cases simultaneously. RESULTS: Soft tissue reconstruction was performed in all 44 cases with a fascia lata repair in 9 cases, a free vascularized muscle flap in 1 case, a pedicled muscle flap in 14 cases, and a pedicled periosteal flap in 20 cases. Skull base bone reconstruction was performed on 10 cases simultaneously. The materials for bone reconstruction included titanium mesh, free autogenous bone, and a Medpor implant. The result of skull base reconstruction was satisfactory in all patients. Postoperative early-stage complications occurred in 10 cases with full recovery after conventional treatment. CONCLUSIONS: The specific characteristics of skull base defects in various regions require different reconstruction materials and methods. The individualized reconstruction based on different skull base defects can achieve satisfactory results.

[Endoscopic endonasal surgery for meningoencephalocele].

OBJECTIVE: To investigate the management experience with transnasal endoscopic technique for meningoencephalocele. METHODS: Nine patients with endonasal encephalomeningocele were managed by transnasal endoscopic surgery, and the skull base defect was repaired by fascia. RESULTS: Eight cases were successfully managed at the time of the first operation, and no relapse case was found during 1 to 4 years follow-up. Only one case of a two years old child relapsed with cerebrospinal fluid rhinorrhea one month after operation. During the second operation, titanium mesh uncovering was found, and replacement of titanium mesh by fascia via skull base defect was done, without relapse one and half years after the second operation. Another case of a one year old child got a fever one day after operation, but no white blood cell was found in the cerebrospinal fluid, and the temperature recovered to normal after release cerebrospinal fluid management. There were no complications of cranial infection, hemorrhage, edema and water retention in brain to be found in all cases. CONCLUSIONS: It is not only minimally invasive, safety and efficiency of transnasal endoscopic technique for meningoencephalocele, but also had a clear operating view for better recolonization of the position of leak and the structure of operating field, therefore, transnasal endoscopic technique is the first choice for the management of endonasal encephalomeningocele. The accurate localization of leak and selection of the appropriate repairing materials are the key point for the successful operation.