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.

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.

Epigenetic regulation of the miR142-3p/interleukin-6 circuit in glioblastoma.

Epigenetic regulation plays a critical role in glioblastoma (GBM) tumorigenesis. However, how microRNAs (miRNAs) and cytokines cooperate to regulate GBM tumor progression is still unclear. Here, we show that interleukin-6 (IL-6) inhibits miR142-3p expression and promotes GBM propagation by inducing DNA methyltransferase 1-mediated hypermethylation of the miR142-3p promoter. Interestingly, miR142-3p also suppresses IL-6 secretion by targeting the 3' UTR of IL-6. In addition, miR142-3p also targets the 3' UTR and suppresses the expression of high-mobility group AT-hook 2 (HMGA2), leading to inhibition of Sox2-related stemness. We further show that HMGA2 enhances Sox2 expression by directly binding to the Sox2 promoter. Clinically, GBM patients whose tumors present upregulated IL-6, HMGA2, and Sox2 protein expressions and hypermethylated miR142-3p promoter also demonstrate poor survival outcome. Orthotopic delivery of miR142-3p blocks IL-6/HMGA2/Sox2 expression and suppresses stem-like properties in GBM-xenotransplanted mice. Collectively, we discovered an IL-6/miR142-3p feedback-loop-dependent regulation of GBM malignancy that could be a potential therapeutic target.

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.

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 [...].

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.

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.

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.

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.

Musashi-1 promotes chemoresistant granule formation by PKR/eIF2α signalling cascade in refractory glioblastoma.

Musashi-1 (MSI1), one of the RNA-binding proteins, is abundantly found not only in neural stem cells but also in several cancer tissues and has been reported to act as a positive regulator of cancer progression. Growing evidence indicates that PKR and eIF2α play pivotal roles in the stimulation of stress granule formation as well as in the subsequent translation modulation in response to stressful conditions; however, little is known about whether MSI1 is involved in this PKR/eIF2α cancer stem cell-enhancing machinery. In this study, we demonstrated that MSI1 promotes human glioblastoma multiforme (GBM) stem cells and enhances chemoresistance when exposed to sublethal stress. The overexpression of MSI1 leads to a protective effect in mitigating drug-induced cell death, thus facilitating the formation of chemoresistant stress granules (SGs) in response to arsenic trioxide (ATO) treatment. SG components, such as PKR and eIF2α, were dominantly activated and assembled, while ATO was engaged. The activated PKR and eIF2α contribute to the downstream enhancement of stem cell genes, thereby promoting the progression of GBM. The silencing of MSI1 or PKR both obviously withdrew the phenomena. Taken together, our findings indicate that MSI1 plays a leading role in stress granule formation that grants cancer stem cell properties and chemoresistant stress granules in GBM, in response to stressful conditions via the PKR/eIF2α signalling cascade.

Changes in sensorimotor-related thalamic diffusion properties and cerebrospinal fluid hydrodynamics predict gait responses to tap test in idiopathic normal-pressure hydrocephalus.

OBJECTIVES: To compare diffusion tensor (DT)-derived indices from the thalamic nuclei and cerebrospinal fluid (CSF) hydrodynamic parameters for the prediction of gait responsiveness to the CSF tap test in early iNPH patients. METHODS: In this study, 22 patients with iNPH and 16 normal controls were enrolled with the approval of an institutional review board. DT imaging and phase-contrast magnetic resonance imaging were performed in patients and controls to determine DT-related indices of the sensorimotor-related thalamic nuclei and CSF hydrodynamics. Gait performance was assessed in patients using gait scale before and after the tap test. The Mann-Whitney U test and receiver operating characteristic (ROC) curve analysis were applied to compare group differences between patients and controls and assess the predictive performance of gait responsiveness to the tap test in the patients. RESULTS: Fractional anisotropy (FA) and axial diffusivity showed significant increases in the ventrolateral (VL) and ventroposterolateral (VPL) nuclei of the iNPH group compared with those of the control group (p < 0.05). The predictions of gait responsiveness of ventral thalamic FA alone (area under the ROC curve [AUC] < 0.8) significantly outperformed those of CSF hydrodynamics alone (AUC < 0.6). The AUC curve was elevated to 0.812 when the CSF peak systolic velocity and FA value were combined for the VPL nucleus, yielding the highest sensitivity (0.769) and specificity (0.778) to predict gait responses. CONCLUSIONS: Combined measurements of sensorimotor-related thalamic FA and CSF hydrodynamics can provide potential biomarkers for gait response to the CSF tap test in patients with iNPH. KEY POINTS: • Ventrolateral and ventroposterolateral thalamic FA may predict gait responsiveness to tap test. • Thalamic neuroplasticity can be assessed through DTI in idiopathic normal-pressure hydrocephalus. • Changes in the CST associated with gait control could trigger thalamic neuroplasticity. • Activities of sensorimotor-related circuits could alter in patients with gait disturbance. • Management of patients with iNPH could be more appropriate.

Notch prevents transforming growth factor-beta-assisted epithelial-mesenchymal transition in cultured limbal progenitor cells through the induction of Smad7.

PURPOSE: Continuous culture of limbal epithelial stem cells (LSCs) slows down proliferation, which inevitably results in differentiation. Transforming growth factor-beta (TGFß)-assisted epithelial-mesenchymal transition (EMT) is often found in the late stage of LSC culture. Thus, EMT is proposed to be part of the mechanism responsible for the loss of LSCs in culture. To explore the regulation mechanism of EMT, we investigated the early stage culture for factor(s) that may potentially prevent EMT. METHODS: LSCs from the corneal limbus region of rabbits were isolated and expanded to confluence in culture (P0), and then serial passage of these LSCs (P1 to P3) was performed. EMT in LSCs was induced with TGFß1, and the corresponding EMT signaling was confirmed with Smad2/3 phosphorylation. The expression of mesenchymal markers, including alpha-smooth muscle actin (α-SMA) and vimentin, was determined with western blot analysis. Proteins extracted from different passaged cells were also subjected to western blot analysis of TGFß signaling components, including TGFß1, TGFß receptor I/II, and Smad2/3 as well as Smad7, the main negative regulator of TGFß signaling. The mitogenic response was measured with the bromodeoxyuridine (BrdU) labeling index and real-time PCR using primers for Ki67. N-(N-[3,5-difluorophenacetyl]-l-alanyl)-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor, and Jagged-1 Notch ligand were used to block and activate Notch signaling, respectively, and their efficacy was evaluated by determining the expression of Hes1, a Notch signaling target. RESULTS: Mesenchymal marker induction and growth arrest were found in the TGFß1-treated P1 cells, and the changes were less significant in the TGFß1-treated P0 cells. Western blot analysis confirmed that the expressed levels of TGFß signaling components, including TGFß1, TGFß receptor I/II, and Smad2/3, were relatively stable with passages. In contrast, the expression of Hes1 and Smad7 markedly decreased after the first passage, and with each passage, the levels diminished even further. Hes1 and Smad7 were expressed only in the limbal epithelium and not in the corneal epithelium. DAPT effectively blocked the expression of Hes1. DAPT also dose-dependently suppressed Smad7 expression in P0 cells, which was associated with the susceptibility of P0 cells to TGFß1-induced Smad2/3 phosphorylation, EMT formation, and growth arrest. Reciprocally, Jagged-1 upregulated Smad7 expression in LSCs against TGFß signaling. CONCLUSIONS: These findings indicate that Smad7 plays a crucial role in antagonizing EMT induced by TGFß signaling and support our proposition that Smad7 is a Notch signaling target in LSCs, and may mediate the Notch function in preventing the occurrence of EMT.

Celecoxib suppresses the phosphorylation of STAT3 protein and can enhance the radiosensitivity of medulloblastoma-derived cancer stem-like cells.

Medulloblastoma (MB) is a malignant primary brain tumor with poor prognosis. MB-derived CD133/Nestin double-positive cells (MB-DPs) exhibit cancer stem-like cell (CSC)-like properties that may contribute to chemoradioresistance, tumorigenesis and recurrence. In various tumors, signal transducer and activator of transcription 3 (STAT3) upregulation including MB which can regulate the expression of Nestin. Celecoxib, a selective COX-2 inhibitor, has been shown to potentially reduce STAT3 phosphorylation. The aim of the present study was to investigate the role of celecoxib in enhancing the effects of ionizing radiotherapy (IR) on MB-DP. MB-DPs and MB-derived CD133/Nestin double-negative cells (MB-DNs) were isolated from medulloblastoma cell line Daoy. Then, both of them were treated with celecoxib in different concentrations, and cell viability was assessed. The assays of cell survival, sphere formation, radiosensitivity, colony formation, apoptotic activity and mouse xenografting experiments in MB-DPs and MB-DNs treated with celecoxib alone, radiation alone, or celecoxib combined with radiation were further evaluated. We isolated MB-DPs from MB cell line Daoy, which exhibited typical CSC-like characteristics. Microarray analysis and Western blotting both indicated the upregulation of Janus kinase (JAK)-STAT cascade and STAT3 phosphorylation. Incubation with celecoxib dose-dependently suppressed the CSC-like properties and enhanced the IR effect on the induction of apoptosis, as detected by TUNEL assay and staining for Caspase 3 and Annexin V. Finally, celecoxib also enhanced the IR effect to suppress tumorigenesis and synergistically improve the recipient survival in orthotopic MB-derived CD133/Nestin double-positive cells (MB-DP cells) bearing mice.

Nanomedicine-based neuroprotective strategies in patient specific-iPSC and personalized medicine.

In recent decades, nanotechnology has attracted major interests in view of drug delivery systems and therapies against diseases, such as cancer, neurodegenerative diseases, and many others. Nanotechnology provides the opportunity for nanoscale particles or molecules (so called "Nanomedicine") to be delivered to the targeted sites, thereby, reducing toxicity (or side effects) and improving drug bioavailability. Nowadays, a great deal of nano-structured particles/vehicles has been discovered, including polymeric nanoparticles, lipid-based nanoparticles, and mesoporous silica nanoparticles. Nanomedical utilizations have already been well developed in many different aspects, including disease treatment, diagnostic, medical devices designing, and visualization (i.e., cell trafficking). However, while quite a few successful progressions on chemotherapy using nanotechnology have been developed, the implementations of nanoparticles on stem cell research are still sparsely populated. Stem cell applications and therapies are being considered to offer an outstanding potential in the treatment for numbers of maladies. Human induced pluripotent stem cells (iPSCs) are adult cells that have been genetically reprogrammed to an embryonic stem cell-like state. Although the exact mechanisms underlying are still unclear, iPSCs are already being considered as useful tools for drug development/screening and modeling of diseases. Recently, personalized medicines have drawn great attentions in biological and pharmaceutical studies. Generally speaking, personalized medicine is a therapeutic model that offers a customized healthcare/cure being tailored to a specific patient based on his own genetic information. Consequently, the combination of nanomedicine and iPSCs could actually be the potent arms for remedies in transplantation medicine and personalized medicine. This review will focus on current use of nanoparticles on therapeutical applications, nanomedicine-based neuroprotective manipulations in patient specific-iPSCs and personalized medicine.

Intratumoral decorin gene delivery by AAV vector inhibits brain glioblastomas and prolongs survival of animals by inducing cell differentiation.

Glioblastoma multiforme (GBM) is the most malignant cancer in the central nervous system with poor clinical prognosis. In this study, we investigated the therapeutic effect of an anti-cancer protein, decorin, by delivering it into a xenograft U87MG glioma tumor in the brain of nude mice through an adeno-associated viral (AAV2) gene delivery system. Decorin expression from the AAV vector in vitro inhibited cultured U87MG cell growth by induction of cell differentiation. Intracranial injection of AAV-decorin vector to the glioma-bearing nude mice in vivo significantly suppressed brain tumor growth and prolonged survival when compared to control non-treated mice bearing the same U87MG tumors. Proteomics analysis on protein expression profiles in the U87MG glioma cells after AAV-mediated decorin gene transfer revealed up- and down-regulation of important proteins. Differentially expressed proteins between control and AAV-decorin-transduced cells were identified through MALDI-TOF MS and database mining. We found that a number of important proteins that are involved in apoptosis, transcription, chemotherapy resistance, mitosis, and fatty acid metabolism have been altered as a result of decorin overexpression. These findings offer valuable insight into the mechanisms of the anti-glioblastoma effects of decorin. In addition, AAV-mediated decorin gene delivery warrants further investigation as a potential therapeutic approach for brain tumors.

Hyperglycemia exacerbates intracerebral hemorrhage via the downregulation of aquaporin-4: temporal assessment with magnetic resonance imaging.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is associated with high mortality and neurological deficits, and concurrent hyperglycemia usually worsens clinical outcomes. Aquaporin-4 (AQP-4) is important in cerebral water movement. Our aim was to investigate the role of AQP-4 in hyperglycemic ICH. METHODS: Hyperglycemia was induced by intraperitoneal injection of streptozotocin (STZ; 60 mg/kg) in adult Sprague-Dawley male rats. ICH was induced by stereotaxic infusion of collagenase/heparin into the right striatum. One set of rats was repeatedly monitored by MRI at 1, 4, and 7 days after ICH induction so as to acquire information on the formation of hematoma and edema. Another set of rats was killed and brains were examined for differences in the degree of hemorrhage and edema, water content, blood-brain barrier destruction, and AQP-4 expression. RESULTS: Hyperglycemia ICH rats exhibited increased brain water content, more severe blood-brain barrier destruction, and greater vasogenic edema as seen on diffusion-weighted MRI. Significant downregulation of AQP-4 was observed in STZ-treated rats after ICH as compared with non-STZ-treated rats. Apoptosis was greater on day 1 after ICH in STZ-treated rats. CONCLUSIONS: The expression of AQP-4 in the brain is downregulated in hyperglycemic rats as compared with normoglycemic rats after ICH. This change is accompanied by increased vasogenic brain edema and more severe blood-brain barrier destruction.

Disrupting the CXCL12/CXCR4 axis disturbs the characteristics of glioblastoma stem-like cells of rat RG2 glioblastoma.

BACKGROUND: Glioblastoma stem-like cells (GSC) have been shown to promote tumor growth, tumor-associated neovascularization, therapeutic resistance, and metastasis. CXCR4 receptors have been found involved in the proliferation, metastasis, angiogenesis, and drug-resistant characteristics of glioblastoma. However, the role of CXCR4 in modulating the stem-like cell properties of rat glioblastoma remains ambiguous. METHODS: To explore the role of the CXCL12/CXCR4 axis in maintaining rat GSC properties, we disrupted the CXCR4 signaling by using small hairpin interfering RNA (shRNA). To investigate the role of the CXCL12/CXCR4 axis in maintaining rat GSC properties, we used a spheroid formation assay to assess the stem cell self-renewal properties. A western blot analysis and PCR arrays were used to examine the genes involved in proliferation, self-renewal, and cancer drug resistance. Finally, DNA content and flow cytometry, an immunohistochemical analysis, and methylcellulose colony formation, in vitro invasive and intracranial injection xenograft assays were employed to examine the disruptive effect of CXCR4 on the characteristics of GSCs of the RG2 cell line. RESULTS: Disrupting CXCR4 inhibited the proliferation of RG2 cells both in vitro and in vivo. The spheroid formation assay indicated that CXCR4 was vital for the self-renewal of RG2 GSCs. Disrupting the CXCL12/CXCR4 pathway also reduced the expression of GSC cell markers, including Nestin, ABCG2, and musashi (Msi), and the expression of genes involved in regulating stem cell properties, including Oct4, Nanog, maternal embryonic leucine zipper kinase (MELK), MGMT, VEGF, MMP2, and MMP9. CONCLUSION: The chemokine receptor CXCR4 is crucial for maintaining the self-renewal, proliferation, therapeutic resistance, and angiogenesis of GSCs of rat RG2 glioblastoma.

EMMPRIN expression positively correlates with WHO grades of astrocytomas and meningiomas.

High-grade primary brain tumors possessed poor outcome due to invasiveness. Extracellular matrix metalloproteinase inducer (EMMPRIN) stimulates peri-tumoral fibroblasts to secrete matrix metalloproteinase and promote invasiveness. This study hypothesized that high-grade brain tumors overexpress EMMPRIN. Analyzing the public delinked database from the Gene Expression Omnibus profile, the results showed that the EMMPRIN mRNA level was higher in WHO grade IV (n = 81) than in grade III (n = 19, p < 0.0005) astrocytomas and non-tumor brain tissue controls (n = 23, p < 0.00001). The results of tissue microarray-based immunohistochemical (IHC) staining revealed that EMMPRIN levels positively correlated with WHO grades for astrocytomas (p = 0.008) and meningiomas (p = 0.048). EMMPRIN mRNA levels in conventional glioma cell lines (n = 36) was not less than those in glioma primary culture cells (n = 27) and glioblastoma stem-like cells (n = 12). The GBM8401, U87MG, and LN229 human glioma cell lines also overexpressed EMMPRIN. Hematoxylin and eosin, IHC, and immunofluorescence staining of xenografts confirmed that high-grade brain tumors overexpressed EMMPRIN. Lastly, Kaplan-Meier analysis revealed poorer survival in WHO grade IV (n = 56) than in grade III astrocytomas (n = 21, by log-rank test; p = 0.0001, 95 % CI: 1.842-3.053). However, in high-grade astrocytomas, there was no difference in survival between high and low EMMPRIN mRNA levels. Thus, this study identified that high-grade brain tumors overexpress EMMPRIN, which positively correlates with WHO grades in human astrocytomas and meningiomas, and suggests that EMMPRIN may be a therapeutic target of brain tumor.