NF-κB induces miR-148a to sustain TGF-ß/Smad signaling activation in glioblastoma.

BACKGROUND: Inflammatory cytokines and transforming growth factor-ß (TGF-ß) are mutually inhibitory. However, hyperactivation of nuclear factor-κB (NF-κB) and TGF-ß signaling both emerge in glioblastoma. Here, we report microRNA-148a (miR-148a) overexpression in glioblastoma and that miR-148a directly suppressed Quaking (QKI), a negative regulator of TGF-ß signaling. METHODS: We determined NF-κB and TGF-ß/Smad signaling activity using pNF-κB-luc, pSMAD-luc, and control plasmids. The association between an RNA-induced silencing complex and QKI, mitogen-inducible gene 6 (MIG6), S-phase kinase-associated protein 1 (SKP1), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was tested with microribonucleoprotein immunoprecipitation and real-time PCR. Xenograft tumors were established in the brains of nude mice. RESULTS: QKI suppression induced an aggressive phenotype of glioblastoma cells both in vitro and in vivo. Interestingly, we found that NF-κB induced miR-148a expression, leading to enhanced-strength and prolonged-duration TGF-ß/Smad signaling. Notably, these findings were consistent with the significant correlation between miR-148a levels with NF-κB hyperactivation and activated TGF-ß/Smad signaling in a cohort of human glioblastoma specimens. CONCLUSIONS: These findings uncover a plausible mechanism for NF-κB-sustained TGF-ß/Smad activation via miR-148a in glioblastoma, and may suggest a new target for clinical intervention in human cancer.

Microsurgical Resection of Cervical Spinal Cord Arteriovenous Malformations: Report of 6 Cases.

OBJECTIVE: To summarize the experience in microsurgical resection of cervical spinal cord arteriovenous malformation (AVM). METHODS: Six patients undergoing microsurgical resection of cervical intramedullary AVM in the Third Affiliated Hospital of Sun Yat-sen University, China, between March 2005 and March 2015 were reviewed retrospectively, and their clinical manifestations, imaging data, surgical treatment, and results of long-term follow-up were analyzed. RESULTS: Of the 6 patients who underwent AVM resection, 2 had compact AVMs and 4 had diffuse AVMs. All 6 patients were reexamined with spinal magnetic resonance imaging within 48 hours after surgery, and 1 patient was examined with digital subtraction angiography. The average patient age was 40.7 ± 10.4 years (range, 29-60 years). Three patients had chronic onset, of whom 2 developed sensory disturbances and 1 had muscle weakness. The other 3 patients had acute onset, including 1 with sudden quadriplegia, 1 with idiopathic severe headache and altered consciousness, and 1 with idiopathic neck pain. The average duration of follow-up was 48.5 ± 38.9 months (range, 15-119 months). One patient experienced complete recovery, and the other 5 patients showed improvement. No patient exhibited deterioration. CONCLUSION: Microsurgical resection of cervical intramedullary AVMs has obtained satisfactory clinical results. Preoperative magnetic resonance angiography, computed tomography angiography, and digital subtraction angiography are useful for evaluating the angioarchitecture, which is key to the success of surgery. Intraoperative indocyanine green fluorescence angiography is an important aid in the surgical treatment of spinal AVMs.

On clipping of anterior communicating artery aneurysm via eyebrow-lateral keyhole approach.

OBJECTIVE: To evaluate the application of eyebrow-lateral keyhole approach in clipping of anterior communicating artery aneurysm (ACAA) through observing the therapeutic effect of eyebrow-lateral keyhole approach on ACAA. METHODS: In 37 patients with ACAA, cisterns were exposed via the eyebrow-lateral keyhole approach to reveal ACAA complex followed by clipping of ACAA. Of the 37 patients, external ventricular drainage was performed on 5 patients before microsurgery. All patients underwent head CT angiography on the second day after operation. RESULTS: Clipping of ACAA was successful in all patients at the first time. In 3 patients, ruptured aneurysm occurred during operation. Three patients underwent ventriculoperitoneal shunt because of postoperative hydrocephalus. Two patients had one-sided anterior cerebral artery infarction after operation. No patient died during operation. Follow-up after the operation indicated that 26 patients returned to normal life and work, 6 patients were able to look after themselves, 4 patients required care in their daily life and one patient died. CONCLUSION: The eyebrow-lateral keyhole approach is a preferred choice for surgical treatment of ACAA because it can cope with brain swelling and intraoperative ruptured aneurysm. However, it has a certain range of application, so we must strictly follow its indications.

Intraoperative Ultrasonography Combined with Indocyanine Green Video-Angiography in Patients with Cerebral Arteriovenous Malformations.

BACKGROUND AND PURPOSE: During the operation, accurately identifying the boundary of cerebral arteriovenous malformation (AVM) and discriminating between feeding arteries and draining veins is the key to successful surgical treatment of cerebral AVM. We evaluated the application of intraoperative ultrasonography (IOU) combined with intraoperative indocyanine green video-angiography (IOICGA) in the patients with cerebral AVM. METHODS: The effects of IOU combined with IOICGA on AVM surgery were observed in 12 patients with cerebral AVM. RESULTS: The lesions of cerebral AVM were completely removed in the 12 patients. IOU could clearly visualize the boundary of AVM, so no patients had massive hemorrhage caused by rupture of malformed vessels. IOU also could detect the location of deep vessels and a total of 11 deep vessels were identified in the 12 patients. IOICGA was performed 41 times altogether in the 12 patients, and 31 feeding arteries and 10 draining veins were identified, so there was no massive hemorrhage caused by misjudgment of feeding arteries or draining veins. CONCLUSIONS: IOU combined with IOICGA can identify the boundary of AVM, detect deep vessels, and discriminate between feeding arteries and draining veins, reducing operation difficulty, decreasing mortality and disability rate, and increasing the rate of complete excision.

Glioma-derived ADAM10 induces regulatory B cells to suppress CD8+ T cells.

CD8+ T cells play an important role in the anti-tumor activities of the body. The dysfunction of CD8+ T cells in glioma is unclear. This study aims to elucidate the glioma cell-derived ADAM10 (A Disintegrin and metalloproteinase domain-containing protein 10) in the suppression of CD8+ effector T cells by the induction of regulatory B cells. In this study, glioma cells were isolated from surgically removed glioma tissue and stimulated by Phorbol myristate acetage (PMA) in the culture. The levels of ADAM10 in the culture were determined by enzyme-linked immunosorbent assay. Immune cells were assessed by flow cytometry. The results showed that the isolated glioma cells express ADAM10, which was markedly up regulated after stimulated with PMA. The glioma-derived ADAM10 induced activated B cells to differentiate into regulatory B cells, the later suppressed CD8+ T cell proliferation as well as the induced regulatory T cells, which also showed the immune suppressor effect on CD8+ effector T cell proliferation. In conclusion, glioma cells produce ADAM10 to induce Bregs; the latter suppresses CD8+ T cells and induces Tregs.

Correlation of MMP(1) and TIMP (1) expression with pituitary adenoma fibrosis.

OBJECTIVE: To explore the correlation of matrix metalloproteinase-1 (MMP(1)) and tissue inhibitor of metalloproteinase-1 (TIMP(1)) with pituitary adenoma fibrosis. METHODS: Thirty-eight pituitary adenoma specimens were divided into fibrous group (6 patients) and non-fibrous group (32 patients). MMP(1) and TIMP(1) expression was detected by RT-PCR and immunohistochemistry. The collagen content was determined by Sirius scarlet staining. RESULTS: In fibrous and non-fibrous group: (1) the collagen content was 20.95 +/- 8.42% and 7.98 +/- 5.18% respectively, and there was a statistical significance (P < 0.01). (2) The expression of MMP(1)mRNA was 0.47 +/- 0.40 and 0.59 +/- 0.54 respectively and its protein expression was 0.12 +/- 0.09 and 0.13 +/- 0.09 respectively, and there was no statistical significance (P > 0.05). Their expression was not related to collagen content (P > 0.05). (3) The expression of TIMP(1)mRNA was 1.61 +/- 1.09 and 0.79 +/- 0.59 respectively and its protein expression was 0.58 +/- 0.11 and 0.32 +/- 0.18 respectively, and there was a statistical significance (P < 0.01). Their expression was related to collagen content (P < 0.01). CONCLUSION: The pathological features of pituitary adenoma fibrosis are excessive collagen deposition. High expression of TIMP(1) may be an important cause.