NDUFA4L2 promotes glioblastoma progression, is associated with poor survival, and can be effectively targeted by apatinib.

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2 (NDUFA4L2) is a subunit of Complex I of the mitochondrial respiratory chain, which is important in metabolic reprogramming and oxidative stress in multiple cancers. However, the biological role and molecular regulation of NDUFA4L2 in glioblastoma (GBM) are poorly understood. Here, we found that NDUFA4L2 was significantly upregulated in GBM; the elevated levels were correlated with reduced patient survival. Gene knockdown of NDUFA4L2 inhibited tumor cell proliferation and enhanced apoptosis, while tumor cells initiated protective mitophagy in vitro and in vivo. We used lentivirus to reduce expression levels of NDUFA4L2 protein in GBM cells exposed to mitophagy blockers, which led to a significant enhancement of tumor cell apoptosis in vitro and inhibited the development of xenografted tumors in vivo. In contrast to other tumor types, NDUFA4L2 expression in GBM may not be directly regulated by hypoxia-inducible factor (HIF)-1α, because HIF-1α inhibitors failed to inhibit NDUFA4L2 in GBM. Apatinib was able to effectively target NDUFA4L2 in GBM, presenting an alternative to the use of lentiviruses, which currently cannot be used in humans. Taken together, our data suggest the use of NDUFA4L2 as a potential therapeutic target in GBM and demonstrate a practical treatment approach.

NF-kappa B interacting long noncoding RNA enhances the Warburg effect and angiogenesis and is associated with decreased survival of patients with gliomas.

In various malignant tumors, NF-kappa B interacting long noncoding RNA (NKILA) displays antitumor activity by inhibiting the NF-kappa B pathway. However, the role of NKILA in gliomas remains unclear. Surprisingly, this study showed that NKILA is significantly upregulated in gliomas, and the increased levels of NKILA were correlated with a decrease in patient survival time. NKILA increased the expression level of hypoxia-inducible factor-1α, and the activity of the hypoxia pathway in gliomas. Furthermore, we demonstrated that NKILA enhances the Warburg effect and angiogenesis in gliomas both in vitro and in vivo. Therefore, NKILA is a potential therapeutic target in gliomas. In addition, we showed that a 20(S)-Rg3 monomer suppresses NKILA accumulation and reverses its stimulation of the Warburg effect and angiogenesis in gliomas, both in vitro and in vivo. Therefore, this study not only identified NKILA as a potential therapeutic target in gliomas, but also demonstrated a practical approach to treatment.

Giant Tarlov Cysts with Rare Pelvic Extension: Report of 3 Cases and Literature Review.

BACKGROUND: Giant presacral Tarlov cysts (TCs) with pelvic extension are extremely rare and have many special features that differ from normal TCs in examination, diagnosis, symptoms, and treatment. We report 3 rare cases of giant presacral TCs with pelvic extension and review the pertinent literature. CASE DESCRIPTION: We report 3 cases of giant presacral TCs with rare pelvic extension and analyzed the symptoms, diagnoses, and surgical procedures. Operations with the key point of blocking the inlet of the fistula from inside the dural sac were performed in all 3 cases. All 3 patients revealed alleviation of previous symptoms with no serious complications. Postoperative magnetic resonance imaging showed all the cysts were well blocked with no cyst recurrence. CONCLUSIONS: Giant TC with pelvic extension is extremely rare and often is discovered on gynecological ultrasound, where it might be misdiagnosed as adnexal mass. Different from patients with normal TCs, these patients also may present with abdominal symptoms like hydronephrosis, abdominal, or pelvic pain due to the cyst's ventral mass effect. Thus, patients with abdominal and back symptoms at the same time should be paid particular attention for lumbosacral magnetic resonance imaging examination to avoid misdiagnosis. Surgical procedures are recommended for symptomatic cases. However, cyst resection by laparotomy is doomed to postoperative recurrence because the fistula still exists. We describe a simple procedure with the key point of blocking the inlet of cyst fistula, which is more applicable and minimizes the probability of cyst recurrence.

Long Noncoding RNA LINC-PINT Suppresses Cell Proliferation, Invasion, and EMT by Blocking Wnt/ß-Catenin Signaling in Glioblastoma.

Background: Glioblastoma (GBM) represents the most aggressive glioma with high invasive potential. Recent studies proved the involvement of epithelial-mesenchymal transition (EMT) process in increasing the malignancy and invasiveness of GBM. LncRNAs have been verified to play pivotal roles in human disease including GBM. However, the molecular mechanisms of lncRNA-mediated EMT in GBM remain largely unknown. LINC-PINT, a LncRNA which has never been studied in GBM before, was predicted to be negatively associated with EMT in GBM. This study aimed to explore the biological function and the EMT relevance of LINC-PINT in GBM and further explore the molecular mechanism. Methods: The bioinformatic prediction data of LINC-PINT in GBM was derived from The Cancer Genome Atlas (TCGA) database by R software and GEPIA website. qRT-PCR assay was performed to detect the expression level of LINC-PINT in GBM cell lines. Cell counting kit-8 (CCK8), clone formation, transwell, and wound healing assays were performed to determine the biological function of LINC-PINT in vivo. Tumor xenograft experiment and tumor peritoneal metastasis experiments were performed to verify the in vivo function. Western blot and immunofluorescence staining assays were carried out to detect the relevance of LINC-PINT with EMT and Wnt/ß-catenin signaling. Rescue assays were performed to check the regulation mechanism of LINC-PINT/Wnt signaling/EMT axis in GBM. Results: LINC-PINT was downregulated in GBM cell lines. LINC-PINT suppressed cell progression, invasion, and EMT in GBM. LINC-PINT blocked Wnt/ß-catenin signaling in GBM. Conclusion: LINC-PINT suppressed cell proliferation, invasion, and EMT by blocking Wnt/ß-catenin signaling in GBM.

Treatment of Venous Hemorrhage Between Vestibulocochlear Nerve and Hypertrophic Flocculus During Microvascular Decompression Procedure for Hemifacial Spasm.

Hemifacial spasm is a kind of painless, intermittent, involuntary, and irregular unilateral facial muscles convulsion. Microvascular decompression has become the standard surgical procedure for hemifacial spasm after years of popularization and development. In the article, the authors described in detail a therapeutic strategy for rapid intracranial venous bleeding between vestibulocochlear nerve and hypertrophic flocculus. When simple compression hemostasis failed, the authors applied fibrin glue and gelatin sponges for hemostasis and finally successfully controlled venous bleeding. The patient's symptoms were completely relieved after operation. Routine postoperative examination of head computed tomography revealed no intracranial hemorrhage. The combination of fibrin glue and gelatin sponges may be a possible solution for complicated and intractable venous hemorrhage during microvascular decompression procedure in some patients with hemifacial spasm.

20(S)-ginsenoside-Rg3 reverses temozolomide resistance and restrains epithelial-mesenchymal transition progression in glioblastoma.

Glioblastoma multiforme (GBM) is one of the most malignant human intracranial tumors. Temozolomide (TMZ) is the primary alkylating agent for GBM patients. However, many GBM patients are resistant to TMZ. Therefore, patients with GBM urgently need more effective therapeutic options. 20(S)-ginsenoside-Rg3 (20(S)-Rg3) is a natural chemical with anti-tumor effects, but at present there is little understanding of its functional mechanism. Several research reports have demonstrated that O6 -methylguanine DNA-methyltransferase (MGMT) repairs damaged DNA and contributes to TMZ resistance in gliomas. In addition, recent studies have shown that MGMT gene expression could be regulated by the Wnt/ß-catenin pathway. However, whether 20(S)-Rg3 inhibits MGMT expression and augments chemosensitivity to Temozolomide (TMZ) in glioma cells remains unclear. In this study, we explored the modulating effects of 20(S)-Rg3 on MGMT. We used glioma cell lines, primary cell strain (including T98G, U118 and GBM-XX; all of them are MGMT-positive glioma cell lines) and xenograft glioma models to examine whether 20(S)-Rg3 increased the sensitivity to TMZ and to reveal the underlying mechanisms. We found that the MGMT expression was effectively downregulated by 20(S)-Rg3 via the Wnt/ß-catenin pathway in glioma cell lines, and TMZ resistance was significantly reversed by 20(S)-Rg3. Meanwhile, 20(S)-Rg3 shows no obvious cytotoxicity at its effective dose and is well tolerated in vivo. In addition, we found that 20(S)-Rg3 significantly restrains the epithelial-mesenchymal transition (EMT) progression of glioma cells. Taken together, these results indicate that 20(S)-Rg3 may be a novel agent to use in treatment of GBM, especially in TMZ-resistant GBM with high MGMT expression.

Epigallocatechin Gallate Preferentially Inhibits O6-Methylguanine DNA-Methyltransferase Expression in Glioblastoma Cells Rather than in Nontumor Glial Cells.

OBJECTIVE: O6-methylguanine (O6-meG) DNA-methyltransferase (MGMT) is a main regulator of temozolomide (TMZ) resistance in glioblastomas. Some MGMT inhibitors have been studied in clinical trials but with very little success, because their inhibiting effects were not tumor-selective, and often cause severe toxicity in normal tissues in the presence of TMZ. The goal of this study is to explore whether Epigallocatechin gallate (EGCG), a natural small molecule, could preferentially modulate MGMT in glioblastoma cells. METHODS: Two MGMT-positive glioblastoma cell lines (GBM-XD and T98G) and one nontumor glial cell culture (GliaX) were included in this study. The MGMT promoter methylation status, mRNA abundance, and protein levels were determined before and after EGCG treatment. The mechanisms were characterized. RESULTS: EGCG substantially suppressed mRNA and protein expression of MGMT, and reversed TMZ resistance in MGMT-positive GBM-XD and T98G cells via the WNT/ß-catenin pathway. EGCG prevented ß-catenin translocation into the nucleus and might directly inhibit the transcription factors TCF1 and LEF1. Meanwhile, EGCG enhanced the MGMT expression in the nontumor glial cells, through inhibition of the DNMT1 and demethylation of MGMT promoter. CONCLUSIONS: EGCG preferentially inhibits MGMT and enhances TMZ cytotoxicity in glioblastoma cells rather than in nontumor glial cells.

FM19G11 inhibits O6 -methylguanine DNA-methyltransferase expression under both hypoxic and normoxic conditions.

FM19G11 is a small molecular agent that inhibits hypoxia-inducible factor-1-alpha (HIF-1α) and other signaling pathways. In this study, we characterized the modulating effects of FM19G11 on O6 -methylguanine DNA-methyltransferase (MGMT), the main regulator of temozolomide (TMZ) resistance in glioblastomas. This study included 2 MGMT-positive cell lines (GBM-XD and T98G). MGMT promoter methylation status, mRNA abundance, and protein levels were determined before and after FM19G11 treatment, and the roles of various signaling pathways were characterized. Under hypoxic conditions, MGMT mRNA and protein levels were significantly downregulated by FM19G11 via the HIF-1α pathway in both GBM-XD and T98G cells. In normoxic culture, T98G cells were strongly positive for MGMT, and MGMT expression was substantially downregulated by FM19G11 via the NF-κB pathway. In addition, TMZ resistance was reversed by treatment with FM19G11. Meanwhile, FM19G11 has no cytotoxicity at its effective dose. FM19G11 could potentially be used to counteract TMZ resistance in MGMT-positive glioblastomas.

Postoperative pneumocephalus increases the recurrence rate of chronic subdural hematoma.

OBJECTIVES: Pneumocephalus is a common operative complication of chronic subdural hematoma. This study is to analyze the relationship between postoperative pneumocephalus and the recurrence and surgical outcomes. PATIENTS AND METHODS: This is a retrospective case-cohort study, including a pneumocephalus group (n = 46) and a control group (n = 181). Their recurrence rates, CT attenuation values, hospital stay, healing time and the neurological status were recorded and analyzed. RESULTS: The pneumocephalus group had a recurrence rate of 32.6%, significantly higher than the control (17.7%). In addition, the pneumocephalus group had a higher rate of postoperative epilepsy (21.7% vs 3.3%), longer hospital stay (11.5 ±â€¯2.8 vs 7.8 ±â€¯1.2 days), longer healing time (10.8 ±â€¯5.4 vs 6.5 ±â€¯2.3 months), and worse neurological scores than the control. CONCLUSION: Pneumocephalus increases the recurrence rate of chronic subdural hematoma, and it not only prolongs the hospital stay and healing time, but also leads to deterioration of the neurological status.

Treatment of Posterior Inferior Cerebellar Artery Adhesion on Petrous Bone During Microvascular Decompression Procedure for Hemifacial Spasm: Technique Note.

Hemifacial spasm is a hyperactive cranial nerve disease mainly characterized by unilateral facial muscles paroxysmal, involuntary, irregular and clonic convulsion. Standard microvascular decompression is currently the most effective solution. During operation, it is pivotal to conduct a sharp dissection of arachnoid membrane around the caudal cranial nerves and facial, auditory nerves for fully exposure of pontomedullary sulcus, and lateral pontine region. In this article, the authors demonstrate a hemifacial spasm patient who underwent microvascular decompression successfully in their department. But the authors encountered a serious barrier to the exploration of facial nerve and its offending vessels before decompression and found that posterior inferior cerebellar artery tightly adhered to petrous bone and closely attached to a petrosal vein on cerebellar surface at the same time. The petrosal vein was also seriously stuck to petrous bone. To solve this practical difficulty, the authors employed sharp point knife blade and microsurgical scissors boldly to separate posterior inferior cerebellar artery from the dura mater of petrous bone bidirectionally and bipolar coagulation for effective hemostasis. And then the authors moderately dealt with the surface adhesion of cerebellum for smooth exploration instead of processing the petrosal vein attached to petrous bone because the authors did not want to sacrifice this vein. Relative to the routine microvascular decompression for hemifacial spasm, treatments of the adhensions before decompression were the key technology of this operation.

Tarlov Cyst Is Correlated with a Short Broad Terminal of the Thecal Sac.

Background In clinical practice, we noted that the end section of the thecal sac is apparently different in patients with Tarlov cyst compared with that of the normal population. We conducted this clinical study based on magnetic resonance imaging (MRI). Methods Our study included 30 patients with Tarlov cyst and 30 healthy volunteers as the control. The L4, L5 cross-section areas, the L4, L5 anteroposterior diameters, and the terminal length of the thecal sac were measured from the lumbosacral spine MRI. Results The L4, L5 cross-section areas and the L4, L5 anteroposterior diameters are larger for the Tarlov cyst patients than the controls, but the terminal length of the thecal sac is shorter. Conclusion The Tarlov cyst is correlated with a short broad end of the thecal sac. Possibly, this anatomical variant is a causative factor of Tarlov cyst.

Association of MSH6 mutation with glioma susceptibility, drug resistance and progression.

MutS homolog 6 (MSH6) is one of the mismatch repair proteins and is encoded by the MSH6 gene, which is located on chromosome 2 and is 23,806 bp in length, including 10 exons and 83 untranslated regions. The MSH6 protein consists of 1,358 amino acid residues and forms a heterodimer with another mismatch repair protein, MSH2. The MSH2-MSH6 heterodimeric complex is able to recognize base-base substitution and single-base insertion/deletion mismatches. Germline mutations of MSH6 lead to high susceptibility to glioma, as well as a number of benign or malignant tumors in other organs. However, somatic MSH6 mutations are not associated with susceptibility to glioma. Somatic MSH6 mutations usually follow temozolomide treatment and result in resistance to temozolomide. Subsequently, MSH6 mutations cause a hypermutation in the glioma cell genome, which may accelerate tumor progression.

Good Surgical Outcomes of Hemifacial Spasm Patients with Obvious Facial Nerve Indentation and Color Change.

OBJECTIVES: Hemifacial spasm results from vascular compression of the facial nerve. It remains controversial whether severe compression and subsequent nerve indentation predict a good or a poor surgical outcome. Here, to illustrate the relationship between the degree of neurovascular compression and surgical outcome, we conducted a retrospective case-cohort study focused on patients whose facial nerve was seriously compressed. METHODS: This study included 2 groups. The nerve-indentation group included 48 patients with hemifacial spasm whose facial nerves had obvious indentation and color change at the site of neurovascular conflict. The control group included 48 randomly selected patients with hemifacial spasm without facial nerve indentation or color change who were surgically treated by the same team during the same period. The surgical findings, intraoperative lateral spread response results, and clinical outcomes were compared. RESULTS: Single-vessel compression was found more frequently in the nerve-indentation group (87.5%) than in the control group (60.4%, P < 0.05). The lateral spread response (LSR) resolution rate of the nerve-indentation group was 91.7%, and that of the control group was 87.5% (P > 0.05). The rates at which the microvascular decompression procedure was successful were equal in the nerve-indentation and the control groups (93.8% vs. 91.7%, P > 0.05). CONCLUSIONS: Severe vascular compression and subsequent nerve indentation were correlated with a greater possibility of single compression and a lower incidence of multiple neurovascular conflicts in patients with hemifacial spasm, making the microvascular decompression procedure more accurate and easier. Therefore nerve indentation might predict good surgical outcomes.

Balloon-Assisted Fistula Sealing Procedure for Symptomatic Tarlov Cysts.

OBJECTIVE: Tarlov cyst is an abnormal expansion of the spinal nerve sleeve, and it communicates with the subarachnoid cavity via a perineural fistula. This study presents our experience of a balloon-assisted fistula sealing procedure in treating Tarlov cyst. METHODS: Twenty-two patients with symptomatic Tarlov cysts were surgically treated. An emulsion balloon was placed into the lumbar subarachnoid cistern through a trocar, so as to temporarily block cerebrospinal fluid flow, then the thecal sac was opened and the inlet of the fistula was sealed by suture of a muscular patch and reinforced by fibrin glue. Finally, the cyst wall was imbricated and the bony cavity was filled with pedicled muscle flaps. RESULTS: Comparing the preoperative and postoperative pain scores according to visual analog scale, 2 patients were slightly improved and 18 patients were substantially improved, including 3 completely pain-free cases. Only 2 patients were unchanged in pain, and both of them had multiple cysts. As a whole, the postoperative pain score was much better than the preoperative score (2.4 vs. 7.5; P < 0.01). Bladder weakness was slightly improved, and bowel dysfunction was almost unchanged after operation. During follow-up, cyst recurrence was found in 1 patient. CONCLUSIONS: The balloon-assisted fistula sealing procedure is safe and effective for Tarlov cyst, especially for the single cyst. It is a good complement to the cyst wall imbricating procedure.

Microvascular Decompression for Trigeminal Neuralgia: Zone Exploration and Decompression Techniques.

OBJECTIVE: The aim of this study is to introduce zone exploration of the trigeminal nerve and decompression techniques for different types of vasculars. METHODS: The trigeminal nerve was sectioned into 5 zones. Zone 1, 2, 3, 4 was located at the rostral, caudal, ventral, and dorsal part of the nerve root entry zone (REZ) respectively, and zone 5 was located at the distal of the nerve root. This study contained 86 patients with trigeminal neuralgia underwent microvascular decompression. Every zone was exposed through preoperative imaging. During the operation, offending vessels were explored from zone 1 to zone 5, and different decompression techniques were used for different types of vessels. RESULTS: Through zone exploration, the sensitivity of preoperative imaging was 96.5% and specificity was 100%. Location of the neurovascular conflict was in the zone 1 in 53.5% of the patients, zone 2 in 32.6%, zone 3 in 45.3%, zone 4 in 29.1%, and zone 5 in 34.9%. In total, 2 zones were both involved in 59.3%, and 3 zones were involved in 18.6%. All offending arteries were moved away and interposed with Teflon sponge. Offending veins of 11 patients were too small to interpose, and coagulated and cut was adopted. The other offending veins were interposed with wet gelatin and Teflon sponge, respectively. CONCLUSIONS: Zone exploration is helpful in finding offending vessels and adequate decompression can be achieved by choosing different methods according to different types of offending vessels.

Management of vessels passing through the facial nerve in the treatment of hemifacial spasm.

BACKGROUND: In hemifacial spasm, it is extremely rare to find a vessel passing through the facial nerve. In this study, we present our experience of the surgical treatment of four such patients. METHODS: From January 2010 to Match 2015, we treated 2,576 hemifacial spasm patients with microvascular decompression in our department. Of these, four had an intraneural vessel. Intraoperative findings and treatment were recorded, and postoperative outcomes were analyzed. RESULTS: In three patients, the intraneural vessel was the anterior inferior cerebellar artery, which we wrapped with small pieces of wet gelatin and Teflon sponge. A small vein found in the fourth patient was treated with facial nerve combing. Complete decompression was achieved and abnormal muscle response disappeared. Three patients got an excellent result and one patient got a good result. One patient had postoperative facial paralysis, which improved over 10 months of follow-up. CONCLUSION: If an artery passes through the facial nerve, it can be decompressed by wrapping the vessel with wet gelatin and Teflon sponge. If a vein passes through the facial nerve, combing can be used. Intraoperative abnormal muscle response monitoring is very helpful in achieving complete decompression.

Nimodipine-mediated re-myelination after facial nerve crush injury in rats.

This study aimed to investigate the mechanism of nimodipine-mediated neural repair after facial nerve crush injury in rats. Adult Sprague-Dawley rats were divided into three groups: healthy controls, surgery alone, and surgery plus nimodipine. A facial nerve crush injury model was constructed. Immediately after surgery, the rats in the surgery plus nimodipine group were administered nimodipine, 6 mg/kg/day, for a variable numbers of days. The animals underwent electromyography (EMG) before surgery and at 3, 10, or 20 days after surgery. After sacrifice, nerve samples were stained with hematoxylin and eosin (H&E) and luxol fast blue. The EMG at 20 days revealed an apparent recovery of eletroconductivity, with the surgery plus nimodipine group having a higher amplitude and shorter latency time than the surgery only group. H&E staining showed that at 20 days, the rats treated with nimodipine had an obvious recovery of myelination and reduction in the number of infiltrating cells, suggesting less inflammation, compared with the rats in the surgery only group. Luxol fast blue staining was relatively even in the surgery plus nimodipine group, indicating a protective effect against injury-induced demyelination. Staining for S100 calcium-binding protein B (S-100ß) was not evident in the surgery alone group, but was evident in the surgery plus nimodipine group, indicating that nimodipine reversed the damage of the crush injury. After a facial nerve crush injury, treatment with nimodipine for 20 days reduced the nerve injury by mediating remyelination by Schwann cells. The protective effect of nimodipine may include a reduction of inflammation and an increase in calcium-binding S-100ß protein.

Management of different kinds of veins during microvascular decompression for trigeminal neuralgia: technique notes.

OBJECTIVE: During microvascular decompression surgery for trigeminal neuralgia, surgeons will encounter various kinds of veins that block the approach to or compress the trigeminal nerve. The aim of this study was to present our experience in managing different kinds of veins. METHODS: This was a retrospective study of 21 patients with trigeminal neuralgia, in whom one or more veins were encountered during surgery. The techniques used in treating 4 types of veins during microvascular decompression were assessed, and the surgical outcomes and operative complications were analysed. RESULTS: For the first type, large veins blocking the approach towards the root entry zone (REZ) of the trigeminal nerve were bypassed via cerebellar fissure approach. Second, veins lying on the brainstem surface and compressing the REZ were detached using a gelatin-assisted dissecting technique and then interposed. Third, veins rising from the surface of the brainstem and crossing the cisternal portion of the trigeminal nerve were interposed. Fourth, intraneural veins, which were generally small, were coagulated and cut. In this series, there was no intentional sacrifice or unintentional rupture of large veins, and the sacrifice rate of medium and small veins was only 19.0%. Thirteen patients (61.9%) gained complete pain relief immediately after surgery (i.e. "excellent" result), while the remaining eight patients (38.1%) achieved "good" pain relief. CONCLUSION: Different surgical techniques were used based on the different kinds of veins encountered. This allowed preservation of almost all the large veins. There were no serious complications postoperatively.

The mechanism of hemifacial spasm: a new understanding of the offending artery.

Although neurovascular confliction was believed to be the cause of hemifacial spasm (HFS), the mechanism of the disorder remains unclear to date. Current theories, merely focusing on the facial nerve, have failed to explain the clinical phenomenon of immediate relief following a successful microvascular decompression surgery (MVD). With the experience of thousands of microvascular decompression surgeries and preliminary investigations, we have learned that the offending artery may play a more important role than the effect of merely mechanical compression in the pathogenesis of the disease. We believe that the attrition of neurovascular interface is the essence of the etiology, and the substance of the disease is emersion of ectopic action potentials from the demyelinated facial nerve fibers, which were triggered by the sympathetic endings from the offending artery wall. In this paper, we put forward evidence to support this hypothesis, both logically and theoretically.