Endoscopic transorbital decompression for traumatic superior orbital fissure syndrome: from cadaveric study to clinical application.

PURPOSE: The endoscopic endonasal approach (EEA) is a minimally invasive and promising modality for treating traumatic superior orbital fissure (SOF) syndrome (tSOFS). Recently, the endoscopic transorbital approach (ETOA) has been considered an alternative method for reaching the anterolateral skull base. This study accessed the practicality of using the ETOA to treat SOF decompression using both cadaveric dissection and clinical application. METHODS: Bilateral anatomic dissections were performed on four adult cadaveric heads using the ETOA and EEA to address SOF decompression. The ETOA procedure for SOF decompression is described, and the extent of SOF decompression was compared between the ETOA and EEA. The clinical feasibility of the ETOA for treating SOF decompression was performed in two patients diagnosed with tSOFS. RESULTS: ETOA allowed for decompression over the lateral aspect of the SOF, from the meningo-orbital band superolaterally to the maxillary strut inferomedially. By contrast, the EEA allowed for decompression over the medial aspect of the SOF, from the lateral opticocarotid recess superiorly to the maxillary strut inferiorly. In both patients treated using the ETOA and SOF decompression, the severity of ophthalmoplegia got obvious improvement. CONCLUSIONS: Based on the cadaveric findings, ETOA provided a feasible access pathway for SOF decompression with reliable outcomes, and our patients confirmed the clinical efficacy of the ETOA for managing tSOFS.

Transorbital transposition of the temporoparietal fascia flap to reconstruct the skull base defects: A preclinical study with comparison to the transpterygoid transposition.

BACKGROUND: Transpterygoid transposition of the temporoparietal fascia flap (TPFF) is a feasible selection for ventral skull base defect (VSBD) reconstruction, but not anterior skull base defect (ASBD) reconstruction, after expanded endoscopic endonasal approach (EEEA). The goal of this study is to introduce the transorbital transposition of the TPFF for skull base defects reconstruction after EEEA, and make quantitative comparison between the transpterygoid transposition and transorbital transposition. METHODS: Cadaveric dissections were performed in five adult cadaveric heads with creating three transporting corridors bilaterally, encompassing superior transorbital corridor, inferior transorbital corridor, and transpterygoid corridor. For each transporting corridor, the minimum necessary length of the TPFF for skull base defects reconstruction was measured. RESULTS: The areas of ASBD and VSBD were 1019.63 ± 176.32 mm2 and 572.99 ± 126.21 mm2 . The length of the harvested TPFF was 149.38 ± 6.21 mm. In contrast to the transpterygoid transposition with incomplete coverage, transorbital transposition of the TPFF allowed full coverage of ASBD with a minimum necessary length of 109.75 ± 8.31 mm. For VSBD reconstruction, transorbital transposition of the TPFF needs shorter minimum necessary length (123.88 ± 4.49 mm) than transpterygoid transposition (138.00 ± 6.28 mm). CONCLUSIONS: Transorbital corridor is a novel pathway for transporting the TPFF into the sinonasal cavity for skull base defects reconstruction after EEEA. In comparison with transpterygoid transposition, transorbital transposition provides wider coverage of skull base defects with a fixed length of the TPFF.

Endoscopically assisted presigmoid retrolabyrinthine approach to the lateral mesencephalic sulcus: a cadaveric study with comparison to the variant supracerebellar infratentorial approaches.

The supracerebellar infratentorial (SCIT) approach is commonly used to gain access to the lateral mesencephalic sulcus (LMS), which has been established as a safe entry point into the posterolateral midbrain. This study describes a lateral variant of the SCIT approach, the supreme-lateral SCIT approach, for accessing the LMS through the presigmoid retrolabyrinthine craniectomy and quantitatively compares this approach with the paramedian and extreme-lateral SCIT approaches. Anatomical dissections were performed in four cadaveric heads. In each head, the supreme-lateral SCIT approach was established on one side, following a detailed description of each step, whereas the paramedian and supreme-lateral SCIT approaches were established on the other side. Quantitative measurements of the exposed posterolateral midbrain, the angles of LMS entry, and the depth of surgical corridors were recorded and compared between the three SCIT approach variants. The supreme-lateral (67.70 ± 23.14 mm2) and extreme-lateral (70.83 ± 24.99 mm2) SCIT approaches resulted in larger areas of exposure anterior to the LMS than the paramedian SCIT approach (38.61 ± 9.84 mm2); the supreme-lateral SCIT approach resulted in a significantly smaller area of exposure posterior to the LMS (65.24 ± 6.81 mm2) than the other two variants (paramedian = 162.75 ± 31.98 mm2; extreme-lateral = 143.10 ± 23.26 mm2; both P < .001). Moreover, the supreme-lateral SCIT approach resulted in a surgical corridor with a shallower depth and a smaller angle relative to the horizontal plane than the other two variants. The supreme-lateral SCIT approach is a more lateral approach than the extreme-lateral SCIT approach, providing a subtemporal approach with direct LMS visualization. The supreme-lateral SCIT offers the benefits of both subtemporal and SCIT approaches and represents a suitable option for the management of selected midbrain pathologies.

Asia-pacific consensus on osteoporotic fracture prevention in postmenopausal women with low bone mass or osteoporosis but no fragility fractures.

Postmenopausal women are at significant risk for osteoporotic fractures due to their rapid bone loss. Half of all postmenopausal women will get an osteoporosis-related fracture over their lifetime, with 25% developing a spine deformity and 15% developing a hip fracture. By 2050, more than half of all osteoporotic fractures will occur in Asia, with postmenopausal women being the most susceptible. Early management can halt or even reverse the progression of osteoporosis. Consequently, on October 31, 2020, the Taiwanese Osteoporosis Association hosted the Asia-Pacific (AP) Postmenopausal Osteoporotic Fracture Prevention (POFP) consensus meeting, which was supported by the Asian Federation of Osteoporosis Societies (AFOS) and the Asia Pacific Osteoporosis Foundation (APOF). International and domestic experts developed ten applicable statements for the prevention of osteoporotic fractures in postmenopausal women with low bone mass or osteoporosis but no fragility fractures in the AP region. The experts advocated, for example, that postmenopausal women with a high fracture risk be reimbursed for pharmaceutical therapy to prevent osteoporotic fractures. More clinical experience and data are required to modify intervention tactics.

Circular RNAs Modulate Cancer Hallmark and Molecular Pathways to Support Cancer Progression and Metastasis.

Circular RNAs (circRNAs) are noncoding products of backsplicing of pre-mRNAs which have been established to possess potent biological functions. Dysregulated circRNA expression has been linked to diseases including different types of cancer. Cancer progression is known to result from the dysregulation of several molecular mechanisms responsible for the maintenance of cellular and tissue homeostasis. The dysregulation of these processes is defined as cancer hallmarks, and the molecular pathways implicated in them are regarded as the targets of therapeutic interference. In this review, we summarize the literature on the investigation of circRNAs implicated in cancer hallmark molecular signaling. First, we present general information on the properties of circRNAs, such as their biogenesis and degradation mechanisms, as well as their basic molecular functions. Subsequently, we summarize the roles of circRNAs in the framework of each cancer hallmark and finally discuss the potential as therapeutic targets.

Interstitial Control-Released Polymer Carrying a Targeting Small-Molecule Drug Reduces PD-L1 and MGMT Expression in Recurrent High-Grade Gliomas with TMZ Resistance.

In recurrent glioblastoma, Gliadel wafer implantation after surgery has been shown to result in incomplete chemical removal of residual tumor and development of brain edema. Furthermore, temozolomide (TMZ) resistance caused by O6-methylguanine-DNA-methyltransferase (MGMT) activation and programmed cell death-ligand 1 (PD-L1) expression leads to immune-cold lesions that result in poorer prognosis. Cerebraca wafer, a biodegradable polymer containing (Z)-n-butylidenephthalide (BP), is designed to eliminate residual tumor after glioma resection. An open-label, one-arm study with four dose cohorts, involving a traditional 3 + 3 dose escalation clinical trial, of the Cerebraca wafer combined with TMZ on patients with recurrent high-grade glioma, was conducted. Of the 12 patients who receive implantation of Cerebraca wafer, there were no drug-related adverse events (AEs) or serious AEs (SAEs). The median overall survival (OS) of patients receiving low-dose Cerebraca wafer was 12 months in the group with >25% wafer coverage of the resected tumor, which is longer than OS duration in previously published studies (Gliadel wafer, 6.4 months). Patients who received high-dose Cerebraca wafer treatment had not yet died at the data cut-off date; a 100% progression-free survival (PFS) rate at six month was achieved, indicating the median OS of cohort IV was more than 17.4 months. In vitro study of the primary cells collected from the patients revealed that the IC50 of BP against tumor stem cells was four times lower than that of bis-chloroethylnitrosourea (BCNU). A synergistic effect between BP and TMZ was demonstrated by a reduction in MGMT expression. Furthermore, BP inhibited PD-L1 expression, thereby activating T-cell cytotoxicity and increasing interferon-gamma (IFN-γ) secretion. The better therapeutic effect of Cerebraca wafer on recurrent high-grade glioma could occur through re-sensitization of TMZ and reduction of PD-L1.

Strategic Decoy Peptides Interfere with MSI1/AGO2 Interaction to Elicit Tumor Suppression Effects.

Peptide drugs that target protein-protein interactions have attracted mounting research efforts towards clinical developments over the past decades. Increasing reports have indicated that expression of Musashi 1 (MSI1) is tightly correlated to high grade of cancers as well as enrichment of cancer stem cells. Treatment failure in malignant tumors glioblastoma multiform (GBM) had also been correlated to CSC-regulating properties of MSI1. It is thus imperative to develop new therapeutics that could effectively improve current regimens used in clinics. MSI1 and AGO2 are two emerging oncogenic molecules that both contribute to GBM tumorigenesis through mRNA regulation of targets involved in apoptosis and cell cycle. In this study, we designed peptide arrays covering the C-terminus of MSI1 and identified two peptides (Pep#11 and Pep#26) that could specifically interfere with the binding with AGO2. Our Biacore analyses ascertained binding between the identified peptides and AGO2. Recombinant reporter system Gaussian luciferase and fluorescent bioconjugate techniques were employed to determine biological functions and pharmacokinetic characteristics of these two peptides. Our data suggested that Pep#11 and Pep#26 could function as decoy peptides by mimicking the interaction function of MSI1 with its binding partner AGO2 in vitro and in vivo. Further experiments using GMB animal models corroborated the ability of Pep#11 and Pep#26 in disrupting MSI1/AGO2 interaction and consequently anti-tumorigenicity and prolonged survival rates. These striking therapeutic efficacies orchestrated by the synthetic peptides were attributed to the decoy function to C-terminal MSI1, especially in malignant brain tumors and glioblastoma.

Oncogenic circRNA C190 Promotes Non-Small Cell Lung Cancer via Modulation of the EGFR/ERK Pathway.

Lung cancers are the leading cause of cancer-related mortality worldwide, and the majority of lung cancers are non-small cell lung carcinoma (NSCLC). Overexpressed or activated EGFR has been associated with a poor prognosis in NSCLC. We previously identified a circular noncoding RNA, hsa_circ_0000190 (C190), as a negative prognostic biomarker of lung cancer. Here, we attempted to dissect the mechanistic function of C190 and test the potential of C190 as a therapeutic target in NSCLC. C190 was upregulated in both NSCLC clinical samples and cell lines. Activation of the EGFR pathway increased C190 expression through a MAPK/ERK-dependent mechanism. Transient and stable overexpression of C190 induced ERK1/2 phosphorylation, proliferation, and migration in vitro and xenograft tumor growth in vivo. RNA sequencing and Expression2Kinases (X2K) analysis indicated that kinases associated with cell-cycle and global translation are involved in C190-activated networks, including CDKs and p70S6K, which were further validated by immunoblotting. CRISPR/Cas13a-mediated knockdown of C190 decreased proliferation and migration of NSCLC cells in vitro and suppressed tumor growth in vivo. TargetScan and CircInteractome databases predicted that C190 targets CDKs by sponging miR-142-5p. Analysis of clinical lung cancer samples showed that C190, CDK1, and CDK6 expressions were significantly higher in advanced-stage lung cancer than in early-stage lung cancer. In summary, C190 is directly involved in EGFR-MAPK-ERK signaling and may serve as a potential therapeutic target for the treatment of NSCLC. SIGNIFICANCE: The circRNA C190 is identified as a mediator of multiple pro-oncogenic signaling pathways in lung cancer and can be targeted to suppress tumor progression.

Musashi-1 Regulates MIF1-Mediated M2 Macrophage Polarization in Promoting Glioblastoma Progression.

Glioblastoma (GBM) is the most malignant brain tumor which is characterized by high proliferation and migration capacity. The poor survival rate has been attributed to limitations of the current standard therapies. The search for novel biological targets that can effectively hamper tumor progression remains extremely challenging. Previous studies indicated that tumor-associated macrophages (TAMs) are the abundant elements in the tumor microenvironment that are closely implicated in glioma progression and tumor pathogenesis. M2 type TAMs are immunosuppressive and promote GBM proliferation. RNA-binding protein Musashi-1 (MSI1) has recently been identified as a marker of neural stem/progenitor cells, and its high expression has been shown to correlate with the growth of GBM. Nevertheless, the relationship between MSI1 and TAMs in GBM is still unknown. Thus, in our present study, we aimed to investigate the molecular interplay between MSI1 and TAMs in contributing to GBM tumorigenesis. Our data revealed that the secretion of macrophage inhibitory factor 1 (MIF1) is significantly upregulated by MSI1 overexpression in vitro. Importantly, M2 surface markers of THP-1-derived macrophages were induced by recombinant MIF1 and reduced by using MIF1 inhibitor (S,R)-3-(4-hHydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1). Furthermore, GBM tumor model data suggested that the tumor growth, MIF1 expression and M2 macrophage population were significantly downregulated when MSI1 expression was silenced in vivo. Collectively, our findings identified a novel role of MSI1 in the secretion of MIF1 and the consequent polarization of macrophages into the M2 phenotype in promoting GBM tumor progression.

Erratum: Chen, Y.-R., et al. Improvement of Impaired Motor Functions by Human Dental Exfoliated Deciduous Teeth Stem Cell-Derived Factors in a Rat Model of Parkinson's Disease. Int. J. Mol. Sci. 2020, 21, 3807.

The authors regret to have made a mistake in publishing this paper [...].

Endoscopic transcanal transpetrosal approach to the petroclival region: a cadaveric study with comparison to the Kawase approach.

This study introduces expanded application of the endoscopic transcanal approach with anterior petrosectomy (ETAP) in reaching the petroclival region, which was compared through a quantitative analysis to the middle fossa transpetrosal-transtentorial approach (Kawase approach). Anatomical dissections were performed in five cadaveric heads. For each head, the ETAP was performed on one side with a detailed description of each step, while the Kawase approach was performed on the contralateral side. Quantitative measurements of the exposed area over the ventrolateral surface of the brainstem, and of the angles of attack to the posterior margin of the trigeminal nerve root entry zone (CN V-REZ) and porus acusticus internus (PAI) were obtained for statistical comparison. The ETAP provided significantly larger exposure over the ventrolateral surface of the pons (93.03 ± 21.87 mm2) than did the Kawase approach (34.57 ± 11.78 mm2). In contrast to the ETAP, the Kawase approach afforded greater angles of attack to the CN V-REZ and PAI in the vertical and horizontal planes. The ETAP is a feasible and minimally invasive procedure for accessing the petroclival region. In comparison to the Kawase approach, the ETAP allows for fully anterior petrosectomy and larger exposure over the ventrolateral surface of the brainstem without passing through the cranial nerves or requiring traction of the temporal lobe.

Quantitative comparison of endoscopically assisted endonasal, sublabial and transorbital transmaxillary approaches to the anterolateral skull base.

OBJECTIVES: The aim of this anatomical study is to make quantitative comparison among three endoscopic approaches, encompassing contralateral endonasal transseptal transmaxillary transpterygoid approach (contralateral EEA), endoscopic sublabial transmaxillary transalisphenoid (Caldwell-Luc) approach and endoscopic transorbital transmaxillary approach through inferior orbital fissure (ETOA), to the anterolateral skull base for assisting preoperative planning. DESIGN & PARTICIPANTS: Anatomical dissections were performed in four adult cadaveric heads bilaterally using three endoscopic transmaxillary approaches described above. SETTING: Skull Base Laboratory at the National Defense Medical Center. MAIN OUTCOME MEASURES: The area of exposure, angles of attack and depth of surgical corridor of each approach were measured and obtained for statistical comparison. RESULTS: The ETOA had significantly larger exposure over middle cranial fossa (731.40 ± 80.08 mm2 ) than contralateral EEA (266.60 ± 46.74 mm2 ) and Caldwell-Luc approach (468.40 ± 59.67 mm2 ). In comparison with contralateral EEA and Caldwell-Luc approach, the ETOA offered significantly greater angles of attack and shorter depth of surgical corridor (P < .05 for all comparisons). CONCLUSIONS: The ETOA is the superior choice for target lesion occupying multiple compartments with its epicentre located in the middle cranial fossa or superior portion of infratemporal fossa.

Musashi-1 promotes cancer stem cell properties of glioblastoma cells via upregulation of YTHDF1.

BACKGROUND: Glioblastoma (GBM) is the most lethal brain tumor characterized by high morbidity and limited treatment options. Tumor malignancy is usually associated with the epigenetic marks, which coordinate gene expression to ascertain relevant phenotypes. One of such marks is m6A modification of RNA, whose functional effects are dependent on the YTH family m6A reader proteins. METHODS AND RESULTS: In this study, we investigated the expression of five YTH family proteins in different GBM microarray datasets from the Oncomine database, and identified YTHDF1 as the most highly overexpressed member of this family in GBM. By performing the knockdown of YTHDF1 in a GBM cell line, we found that it positively regulates proliferation, chemoresistance and cancer stem cell-like properties. Musashi-1 (MSI1) is a postranscriptional gene expression regulator associated with high oncogenicity in GBM. By knocking down and overexpressing MSI1, we found that it positively regulates YTHDF1 expression. The inhibitory effects imposed on the processes of proliferation and migration by YTHDF1 knockdown were shown to be partially rescued by concomitant overexpression of MSI1. MSI1 and YTHDF1 were shown to be positively correlated in clinical glioma samples, and their concomitant upregulation was associated with decreased survival of glioma patients. We identified the direct regulation of YTHDF1 by MSI1. CONCLUSIONS: Given the fact that both proteins are master regulators of gene expression, and both of them are unfavorable factors in GBM, we suggest that in any future studies aimed to uncover the prognostic value and therapy potential, these two proteins should be considered together.

Association of early vertebroplasty with risk of hip replacement: A nationwide population-based cohort study in Taiwan.

Studies show that vertebral fractures could predict the risk of hip fractures. We aimed to evaluate the potential benefits of whether the timing of vertebroplasty (VP) for vertebral fracture associated with the risk of hip fracture for hip replacement.We identified 142,782 patients from the Taiwan National Health Insurance Database with thoracolumbar vertebral fracture (International Classification of Diseases, Ninth Revision, Clinical Modification:805.2-805.9) who were followed up from 2000 to 2013. These patients were divided into those who underwent VP (VP group) (International Classification of Diseases, Ninth Revision, Clinical Modification : 78.49) within 3 months and those who did not (non-VP group). After adjusting for the confounding factors, the Cox proportional hazards analysis was used to estimate the effect of early VP on reducing the risk of hip fracture. The difference in the risk of hip replacement, between the VP group and non-VP group was estimated using the Kaplan-Meier method with the log-rank test.In the 14-year follow-up, the cumulative incidence rate of hip replacement in the VP group was lower than that in the non-VP group (0.362% and 0.533%, respectively, long-rank P < .001). There was a significant difference between the 2 groups since the first-year follow-up.Our study showed that early VP performed to avoid progression of the kyphotic changes following thoracolumbar vertebral fracture may reduce the risk of hip fracture. These results, obtained from retrospective data, indicate that a prospective study is warranted.

Improvement of Impaired Motor Functions by Human Dental Exfoliated Deciduous Teeth Stem Cell-Derived Factors in a Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is a long-term degenerative disease of the central nervous system (CNS) that primarily affects the motor system. So far there is no effective treatment for PD, only some drugs, surgery, and comprehensive treatment can alleviate the symptoms of PD. Stem cells derived from human exfoliated deciduous teeth (SHED), mesenchymal stem cells derived from dental pulp, may have promising potential in regenerative medicine. In this study, we examine the therapeutic effect of SHED-derived conditioned medium (SHED-CM) in a rotenone-induced PD rat model. Intravenous administration of SHED-CM generated by standardized procedures significantly improved the PD symptoms accompanied with increased tyrosine hydroxylase amounts in the striatum, and decreased α-synuclein levels in both the nigra and striatum, from rotenone-treated rats. In addition, this SHED-CM treatment decreased both Iba-1 and CD4 levels in these brain areas. Gene ontology analysis indicated that the biological process of genes affected by SHED-CM was primarily implicated in neurodevelopment and nerve regeneration. The major constituents of SHED-CM included insulin-like growth factor binding protein-6 (IGFBP-6), tissue inhibitor of metalloproteinase (TIMP)-2, TIMP-1, and transforming growth factor 1 (TGF-1). RNA-sequencing (RNA-seq) and Ingenuity Pathway Analysis (IPA) revealed that these factors may ameliorate PD symptoms through modulating the cholinergic synapses, calcium signaling pathways, serotoninergic synapses, and axon guidance. In conclusion, our data indicate that SHED-CM contains active constituents that may have promising efficacy to alleviate PD.

Musashi-1 promotes stress-induced tumor progression through recruitment of AGO2.

Carcinomatous progression and recurrence are the main therapeutic challenges frequently faced by patients with refractory tumors. However, the underlined molecular mechanism remains obscure. Methods: We found Musashi-1 (MSI1) transported into cytosol under stress condition by confocal microscopy and cell fractionation. Argonaute 2 (AGO2) was then identified as a cytosolic binding partner of MSI1 by Mass Spectrametry, immunoprecipitation, and recombinant protein pull-down assay. We used RNA-IP to determine the MSI1/AGO2 associated regions on downstream target mRNAs. Finally, we overexpressed C-terminus of MSI1 to disrupt endogenous MSI1/AGO2 interaction and confirm it effects on tmor progression. Results: Malignant tumors exhibit elevated level of cytosolic Musashi-1 (MSI1), which translocates into cytosol in response to stress and promote tumor progression. Cytosolic MSI1 forms a complex with AGO2 and stabilize or destabilize its target mRNAs by respectively binding to their 3´ untranslated region or coding domain sequence. Both MSI1 translocation and MSI1/AGO2 binding are essential for promoting tumor progression. Blocking MSI1 shuttling by either chemical inhibition or point mutation attenuates the growth of GBM-xenografts in mice. Importantly, overexpression of the C-terminus of MSI1 disrupts endogenous MSI1/AGO2 interaction and effectively reduces stress-induced tumor progression. Conclusion: Our findings highlight novel molecular functions of MSI1 during stress-induced carcinomatous recurrence, and suggest a new therapeutic strategy for refractory malignancies by targeting MSI1 translocation and its interaction with AGOs.

Endoscopic transorbital approach to anterolateral skull base through inferior orbital fissure: a cadaveric study.

BACKGROUND: Endoscopic transorbital approach (eTOA) has been announced as an alternative minimally invasive surgery to skull base. Owing to the inferior orbital fissure (IOF) connecting the orbit with surrounding pterygopalatine fossa (PPF), infratemporal fossa (ITF), and temporal fossa, the idea of eTOA to anterolateral skull base through IOF is postulated. The aim of this study is to access its practical feasibility. METHODS: Anatomical dissections were performed in five human cadaveric heads (10 sides) using 0-degree and 30-degree endoscopes. A stepwise description of eTOA to anterolateral skull base through IOF was documented. The anterosuperior corner of the maxillary sinus in the horizontal plane of the upper edge of zygomatic arch was defined as reference point (RP). The distances between the RP to the foramen rotundum (FR), foramen ovale (FO), and Gasserian ganglion (GG) were measured. The exposed area of anterolateral skull base in the coronal plane of the posterior wall of the maxillary sinus was quantified. RESULTS: The surgical procedure consisted of six steps: (1) lateral canthotomy with cantholysis and preseptal lower eyelid approach with periorbita dissection; (2) drilling of the ocular surface of greater sphenoid wing and lateral orbital rim osteotomy; (3) entry into the maxillary sinus and exposure of PPF and ITF; (4) mobilization of infraorbital nerve with drilling of the infratemporal surface of the greater sphenoid wing and pterygoid process; (5) exposure of middle cranial fossa, Meckel's cave, and lateral wall of cavernous sinus; and (6) reconstruction of orbital floor and lateral orbital rim. The distances measured were as follows: RP-FR = 45.0 ± 1.9 mm, RP-FO = 55.7 ± 0.5 mm, and RP-GG = 61.0 ± 1.6 mm. In comparison with the horizontal portion of greater sphenoid wing, the superior and inferior axes of the exposed area were 22.3 ± 2.1 mm and 20.5 ± 1.8 mm, respectively. With reference to the FR, the medial and lateral axes of the exposed area were 11.6 ± 1.1 mm and 15.8 ± 1.6 mm, respectively. CONCLUSIONS: The eTOA through IOF can be used as a minimally invasive surgery to access whole anterolateral skull base. It provides a possible resolution to target lesion involving multiple compartments of anterolateral skull base.

Tumor Mesenchymal Stromal Cells Regulate Cell Migration of Atypical Teratoid Rhabdoid Tumor through Exosome-Mediated miR155/SMARCA4 Pathway.

Atypical teratoid/rhabdoid tumor (ATRT) is a rare pediatric brain tumor with extremely high aggressiveness and poor prognosis. The tumor microenvironment is regulated by a complex interaction among distinct cell types, yet the crosstalk between tumor-associated mesenchymal stem cells (tMSCs) and naïve ATRT cells are unclear. In this study, we sought to identify the secretory factor(s) that is responsible for the tMSC-mediated regulation of ATRT migration. Comparing with ATRT cell alone, co-culture of tMSCs or addition of its conditioned medium (tMSC-CM) promoted the migration of ATRT, and this effect could be abrogated by exosome release inhibitor GW4869. The exosomes in tMSC-CM were detected by transmission electron microscope and flow cytometry. ATRT naïve cell-derived conditioned media (ATRT-CM) also enhanced the exosome secretion from tMSCs, indicating the interplay between ATRT cells and tMSCs. Microarray analysis revealed that, compared with that in bone marrow-derived MSCs, microRNA155 is the most upregulated microRNA in the tMSC-CM. Tracing the PK67-labeled exosomes secreted from tMSCs confirmed their incorporation into naïve ATRT cells. After entering ATRT cells, miR155 promoted ATRT cell migration by directly targeting SMARCA4. Knockdown of SMARCA4 mimicked the miR155-driven ATRT cell migration, whereas SMARCA4 overexpression or the delivery of exosomes with miR155 knockdown suppressed the migration. Furthermore, abrogation of exosome release with GW4869 reduced the tumorigenesis of the xenograft containing naïve ATRT cells and tMSCs in immunocompromised recipients. In conclusion, our data have demonstrated that tMSCs secreted miR155-enriched exosomes, and the exosome incorporation and miR155 delivery further promoted migration in ATRT cells via a SMARCA4-dependent mechanism.

Musashi-1 Enhances Glioblastoma Migration by Promoting ICAM1 Translation.

Glioblastoma multiforme (GBM) is a lethal brain tumor with a mean survival time of 1 year. One major reason for therapeutic failure is that GBM cells have an extraordinary capacity to invade normal brain tissue beyond the surgical margin, accounting for the lack of treatment efficacy. GBM cells that can infiltrate into the healthy brain possess tumor properties of stemness and invasion, and previous studies demonstrate that Musashi-1 (MSI1), a neural stem cell marker, plays an important role in the maintenance of stem cell status, cellular differentiation, and tumorigenesis in cancers. By analyzing neuronal progenitor cell markers and stemness genes, we predicted that MSI1 might be an important factor in GBM pathogenesis. Because inflammation aids in the proliferation and survival of malignant cells, the inflammatory microenvironment also promotes GBM invasion, and intercellular adhesion molecule-1 (ICAM1), a member of the immunoglobulin superfamily, is involved in inflammation. Our results indicate that the above phenomena are likely due to MSI1 upregulation, which occurred simultaneously with higher expression of ICAM1 in GBM cells. Indeed, MSI1 knockdown effectively suppressed ICAM1 expression and blocked GBM cell motility and invasion, whereas overexpressing ICAM1 reversed these effects. According to RNA immunoprecipitation assays, MSI1-mediated mRNA interactions promote ICAM1 translation. Finally, immunohistochemical analysis showed MSI1 and ICAM-1 to be coexpressed at high levels in GBM tissues. Thus, the MSI1/ICAM1 pathway plays an important role in oncogenic resistance, including increased tumor invasion, and MSI1/ICAM1 may be a target for GBM treatment.

Endoscopic transorbital transtentorial approach to middle incisural space: preclinical cadaveric study.

BACKGROUND: Endoscopic transorbital approach is a novel development of minimally invasive skull base surgery. Recently, anatomical studies have started to discuss the expanded utilization of endoscopic transorbital route for intracranial intradural lesions. The goal of this cadaveric study is to assess the feasibility of endoscopic transorbital transtentorial approach for exposure of middle incisural space. METHODS: Anatomical dissections were performed in four human cadaveric heads (8 sides) using 0- and 30-degree endoscopes. A stepwise description of endoscopic transorbital transtentorial approach to middle incisural space and related anatomy was provided. RESULTS: Orbital manipulation following superior eyelid crease incision with lateral canthotomy and cantholysis established space for bone drilling. Extradural stage consisted of extensive drilling of orbital roof of frontal bone, lessor, and greater wings of sphenoid bone. Intradural stage was composed of dissection of sphenoidal compartment of Sylvian fissure, lateral mobilization of mesial temporal lobe, and penetration of tentorium. A cross-shaped incision of tentorium provided direct visualization of crural cistern with anterolateral aspect of cerebral peduncle and upper pons. Interpeduncular cistern, prepontine cistern, and anterior portions of ambient and cerebellopontine cisterns were exposed by 30-degree endoscope. CONCLUSION: The endoscopic transorbital transtentorial approach can be used as a minimally invasive surgery for exposure of middle incisural space. Extensive drilling of sphenoid wing and lateral mobilization of mesial temporal lobe are the main determinants of successful dissection. Further studies are needed to confirm the clinical feasibility of this novel approach.