MiR-10b-5p Impairs TET2-Mediated Inhibition of PD-L1 Transcription Thus Promoting Immune Evasion and Tumor Progression in Glioblastoma.

Glioblastoma (GBM) is a highly aggressive primary brain tumor that shows intratumoral heterogeneity at the cellular and molecular level. Activation of programmed death receptor 1 (PD-1) interaction with its ligand PD-L1 is a well-known mechanism requisite for immune evasion deployed by malignant tumors including GBM. Herein, we set out to dissect the mechanism explaining the regulation of PD-L1 gene expression in GBM. The clinical samples consisted of 37 GBM tissues and 18 normal brain tissues. GBM cell model was treated by microRNA (miRNA) inhibitor, DNA constructs, and siRNAs. Assays of CCK-8 and Transwell insert were employed to assess the survival, migratory and invasive ability of GBM cell model. The immunosuppressive factor production, T cell apoptosis, and T cell cytotoxicity to GBM cells were evaluated in the co-culture system. GBM exhibited more miR-10b-5p abundance than normal at both tissue and cellular level. Suppression of miR-10b-5p weakened the ability of GBM cell model to survive, migrate, and invade, decreased the release of immunosuppressive factors, reduced T cell apoptosis, and strengthened the T cell cytotoxicity to GBM cell model. MiR-10b-5p conferred a negative control of Ten-eleven translocation 2 (TET2) that was downregulated in GBM. The functions of miR-10b-5p on GBM cell aggressiveness and immune evasion were mediated by TET2. TET2 recruited histone deacetylases HDAC1 and HDAC2 into the PD-L1 promoter region thus inhibiting its transcription. The study demonstrated the importance of miR-10b-5p-mediated repression of TET2 in PD-L1-driven immune evasion and their potential for immunotherapeutic targeting in GBM.

LncRNA SEMA3B-AS1 inhibits breast cancer progression by targeting miR-3940/KLLN axis.

Long noncoding RNAs (lncRNAs) play crucial regulatory roles in the progression of various cancers. However, the functional roles of lncRNAs in breast cancer remain unclear. In this study, we investigated the functional role of a novel long noncoding RNA SEMA3B-AS1 (lncRNA SEAS1) in breast cancer progression and the underlying mechanisms. SEAS1 was downregulated in the triple-negative breast cancer (TNBC) tissues compared with the para-carcinoma tissues, which was associated with poor prognosis of TNBC patients. We demonstrated that SEAS1 knockdown significantly increased the proliferation, migration, and invasion of TNBC cell lines, whereas SEAS1 overexpression reversed these effects. Bioinformatics analysis demonstrated that microRNA (miR)-3940-3p was a potential target of SEAS1. Mechanistically, RNA immunoprecipitation (RIP) and luciferase reporter assays confirmed that lncRNA SEMA3B-AS1 acted as sponge for miR-3940-3p, preventing the degradation of its target gene KLLN, which acts as a tumor-inhibiter in TNBC. Moreover, RNA pulldown, mass spectrometry, ChIP, and luciferase reporter assays confirmed that SMAD3 directly interacted with the promoter of SEAS1 and suppressed its transcription, thereby promoting TNBC progression. The clinical samples of TNBC confirmed SEAS1 was correlated inversely with lymphatic and distant metastasis. In conclusion, our findings reveal a novel pathway for TNBC progression via SMAD3/lncRNA SEAS1/miR-3940-3p/KLLN axis, and suggest that SEAS1 may serve as a potential biomarker and therapeutic target for TNBC.

YTHDF1 promotes breast cancer progression by facilitating FOXM1 translation in an m6A-dependent manner.

BACKGROUND: N6-methyladenosine (m6A) is the most common post-transcriptional modification at the RNA level. However, the exact molecular mechanisms of m6A epigenetic regulation in breast cancer remain largely unknown and need to be fully elucidated. METHODS:  The integrating bioinformatics analyses were used to screen clinical relevance and dysregulated m6A "reader" protein YTHDF1 in breast cancer from TCGA databases, which was further validated in a cohort of clinical specimens. Furthermore, functional experiments such as the CCK-8 assay, EdU assay, wound healing assay, transwell invasion assay and cell cycle assay were used to determine the biological role of YTHDF1 in breast cancer. RIP, m6A-IP, and CLIP assays were used to find the target of YTHDF1 and further verification by RT-qPCR, western blot, polysome profiling assay. The protein-protein interaction between YTHDF1 and FOXM1 was detected via co-immunoprecipitation. RESULTS: Our study showed that YTHDF1 was overexpressed in breast cancer cells and clinical tissues specimens. At the same time, the high expression level of YTHDF1 was positively correlated with tumor size, lymph node invasion, and distant metastasis in breast cancer patients. YTHDF1 depletion repressed the proliferation, invasion and epithelial-mesenchymal transformation (EMT) and induced G0/G1 phase cell cycle arrest of breast cancer cells in vitro and in vivo. We also demonstrated that FOXM1 is a target of YTHDF1. Through recognizing and binding to the m6A-modified mRNA of FOXM1, YTHDF1 accelerated the translation process of FOXM1 and promoted breast cancer metastasis. Whereas overexpression of FOXM1 in breast cancer cells partially counteracted the tumor suppressed effects caused by YTHDF1 silence, which further verified the regulatory relationship between YTHDF1 and FOXM1. CONCLUSION: Our study reveals a novel YTHDF1/FOXM1 regulatory pathway that contributes to metastasis and progression of breast cancer, suggesting that YTHDF1 might be applied as a potential biomarker and therapeutic target. That also advances our understanding of the tumorigenesis for breast cancer from m6A epigenetic regulation.

Impact of General Factors on Glioma Immunotherapy.

Glioma remains the most common malignant tumor in the brain and is also the most difficult to treat. Immunotherapy achieving long-lasting tumor remission in multiple cancer types has received considerable attention due to its potential to improve the treatment outcomes of patients with glioma. However, clinical trials have not yet demonstrated major improvements in prognoses, which might be attributable to the extrinsic components and intrinsic mechanisms involved in the tumor microenvironment and immune system. It is particularly noteworthy that there is emerging evidence that current routine treatment modalities and the physical and psychological characteristics of patients have different impacts on the efficacy of glioma immunotherapy. This article addresses how these factors interact with the host immune system and tumor microenvironment, and highlights their potential roles in glioma immunotherapy, with the ultimate goal of developing better immunotherapy-based personalized medicine strategies.

Anterior Dorsal Root Entry Zone Approach in the Treatment of Spinal Intramedullary Glioma.

Surgical removal of lateral or ventrolateral spinal intramedullary gliomas remains a challenge. For lateral or ventrolateral tumors, the dorsal root entry zone (DREZ) myelotomy (equivalent to dorsolateral sulcus approach) and the posterior midline myelotomy would require dissection of the posterolateral tract or posterior column tracts and cause neurologic dysfunction. In Video 1, we introduce a novel approach in which myelotomy was performed anterior to DREZ. The spinal cord was entered between the DREZ and dorsal spinocerebellar tracts, and the surgical path was posterior to the lateral corticospinal tract. Thus no important spinal cord tracts were damaged. The patients with intramedullary glioma depicted in this video had no new neurologic dysfunction postoperatively. This approach has also been reported in treating intramedullary cavernous malformations.1 Compared with the DREZ approach, myelotomy anterior to the DREZ has 2 advantages. First, the blood vessels anterior to DREZ are always sparser than the posterolateral sulcus. Second, the injury of the somatosensory tract and posterior horn of the spinal cord caused by the dorsolateral sulcus approach can be avoided. Special technique details for this approach are as follows: 1) Myelotomy anterior to DREZ can be optional for selective cases of lateral or ventrolateral intramedullary tumor. 2) It is difficult for cervical intramedullary tumors because the cervical dorsal roots always cover the area of the anterior DREZ. 3) It is useful for a multisegment tumor to cut the dentate ligament. 4) Hemilaminectomy can be used in selective cases for this approach.

Evidence for residual SARS-CoV-2 in glioblastoma tissue of a convalescent patient.

Since coronavirus disease 2019 (COVID-19) swept all over the world, several studies have shown the susceptibility of a patient with cancer to COVID-19. In this case, the removed glioblastoma multiforme (GBM)-adjacent (GBM-A), GBM-peritumor and GBM-central (GBM-C) tissues from a convalescent patient of COVID-19, who also suffered from glioblastoma meanwhile, together with GBM-A and GBM tissues from a patient without COVID-19 history as negative controls, were used for RNA ISH, electron microscopy observing and immunohistochemical staining of ACE2 and the virus antigen (N protein). The results of RNA ISH, electron microscopy observing showed that SARS-CoV-2 directly infects some cells within human GBM tissues and SARS-CoV-2 in GBM-C tissue still exists even when it is cleared elsewhere. Immunohistochemical staining of ACE2 and N protein showed that the expressions of ACE2 are significantly higher in specimens, including GBM-C tissue from COVID-19 patient than other types of tissue. The unique phenomenon suggests that the surgical protection level should be upgraded even if the patient is in a convalescent period and the pharyngeal swab tests show negative results. Furthermore, more attention should be paid to confirm whether the shelter-like phenomenon happens in other malignancies due to the similar microenvironment and high expression of ACE2 in some malignancies.

[Neuronavigation-assisted microanatomical study of the facial nerve canal through the transpetrosal approach].

OBJECTIVE: To study the value of neuronavigation in the transpetroal approach, and to provide anatomic data for the protection of the nerves in the facial nerve canal (FNC) during surgeries. METHODS: Simulated surgery through the transpetroal approach was performed on 16 sides of 8 adult cadaver heads with the assistance by neuronavigation. The anatomy of the facial nerve and the relationship of related structures were observed and the distances from the utmost external edge of the mastoid to different segments of the FNC were measured. RESULTS: Neuronavigation was successful with all the FNC, with the mean error of less than 0.9 mm. The FNC could be divided into 3 segments, the labyrinthine, the tympanic and the mastoid segments, stretching 3.6+/-1.2 mm, 11.2+/-2.5 mm and 16.1+/-3.6 mm respectively and with diameters of 1.2+/-0.3 mm, 1.4+/-0.1 mm and 1.7+/-0.2 mm, respectively. CONCLUSION: Neuronavigation may help protect the FNC during surgical procedures, and a thorough knowledge of the anatomic features of the FNC can be significant for preservation of the facial nerves.

Early diagnosis of cerebral infarction with near-infrared spectroscopy: an experimental study.

OBJECTIVE: To monitor the changes in the blood flow and blood-oxygen content in rat cerebral tissue with focal cerebral infarction using near-infrared spectroscopy (NIRS), so as to verify the value of NIRS in early diagnosis of cerebral infarction. METHODS: Focal cerebral infarction models were established in 16 rats by injecting silk threads into the internal carotid artery. The bilateral blood flow and blood-oxygen content were monitored with NIRS in the models and also in 16 normal rats receiving saline injection to serve as blank control group. RESULTS: Focal cerebral infarction in rats caused the decrement in blood-oxygen content and the increase in blood flow. No changes were observed in the control group after saline injection (P >0.05). CONCLUSION: In the earlier stages of focal cerebral infarction, blood-oxygen decreases while blood flow increases in the infarcted area. NIRS provides real-time, non-invasive monitoring of blood volume and blood-oxygen content in the cerebral tissue.

Microanatomical and neuroendoscopic studies of the internal auditory meatus and its surrounding structures.

OBJECTIVE: To observe the morphology of the internal auditory meatus in relation with its surrounding structures in Chinese people, for the purpose of providing microanatomical reference for surgeries adopting retro-sigmoid approach. METHODS: The retro-sigmoid surgical approach was simulated on 5 fresh specimens of human head, in which the internal auditory meatus and its surrounding structures were observed through a neuroendoscope and a surgical microscope. The distances from the posterior inferior edge of the internal auditory meatus to the central point of the posterior edge of the sigmoid sinus and to the posterior edge of the posterior semicircular canal were measured. RESULTS: The internal auditory meatus was located at the center of the medial surface of the petrous bone, and the cranial nerve VII ran through its anterior-superior part while the cranial nerve VIII through its posterior-inferior part. After forming an arterial loop at the internal auditory meatus, the anterior-inferior cerebellar artery branched into 1 to 3 internal auditory arteries. The distance from the posterior-inferior edge of the internal auditory meatus to the central point of the posterior edge of the sigmoid sinus was 32.15+/-1.76 mm on the left side, and 33.34+/-1.57 mm on the right, and the distance to the posterior edge of the posterior semicircular canal was 12.51+/-2.15 mm on the left side, and 13.26+/-2.44 mm on the right. CONCLUSION: Thorough knowledge of the microanatomy of the internal auditory meatus and its surrounding structures is of crucial importance to preserve the functions of the cranial nerves VII and VIII in the surgical removal of acoustic neuroma.

[Intravertebral canals vascular malformations treated by superselective embolization].

OBJECTIVE: To assess the feasibility superselective embolization using microcatheters in treatment of intravertebral canal vascular malformation. METHODS: In 128 patients with intravertebral canals vascular malformation, their AVMS or fistulae were treated with silk thread, Ivalon microspheres or tungsten microcoils. RESULTS: In the 128 patients, 120 fistulae disappeared completely, but 8 were embolized 60% - 80%. Symptoms were improved in 113 patients. Improved muscular strength from grade I to IV was obtained in 8 patients, from grade II to III in 32, from grade III to IV in 32, and from grade IV to V in 41. The symptoms did not change in 15 patients. CONCLUSION: Superselective embolization through microcatheter is effective in the treatment of intraspinal canal vascular malformations.