Establishment of tumor microenvironment-preserving organoid model from patients with intracranial meningioma.

BACKGROUND: Although meningioma is the most common primary brain tumor, treatments rely on surgery and radiotherapy, and recurrent meningiomas have no standard therapeutic options due to a lack of clinically relevant research models. Current meningioma cell lines or organoids cannot reflect biological features of patient tumors since they undergo transformation along culture and consist of only tumor cells without microenvironment. We aim to establish patient-derived meningioma organoids (MNOs) preserving diverse cell types representative of the tumor microenvironment. METHODS: The biological features of MNOs were evaluated using WST, LDH, and collagen-based 3D invasion assays. Cellular identities in MNOs were confirmed by immunohistochemistry (IHC). Genetic alteration profiles of MNOs and their corresponding parental tumors were obtained by whole-exome sequencing. RESULTS: MNOs were established from four patients with meningioma (two grade 1 and two grade 2) at a 100% succession rate. Exclusion of enzymatic dissociation-reaggregation steps endowed MNOs with original histology and tumor microenvironment. In addition, we used a liquid media culture system instead of embedding samples into Matrigel, resulting in an easy-to-handle, cost-efficient, and time-saving system. MNOs maintained their functionality and morphology after long-term culture (> 9 wk) and repeated cryopreserving-recovery cycles. The similarities between MNOs and their corresponding parental tumors were confirmed by both IHC and whole-exome sequencing. As a representative application, we utilized MNOs in drug screening, and mifepristone, an antagonist of progesterone receptor, showed prominent antitumor efficacy with respect to viability, invasiveness, and protein expression. CONCLUSION: Taken together, our MNO model overcame limitations of previous meningioma models and showed superior resemblance to parental tumors. Thus, our model could facilitate translational research identifying and selecting drugs for meningioma in the era of precision medicine.

Clinicopathological analysis of non-functioning pituitary adenomas (PAs) according to the 2022 WHO classification.

PURPOSE: For asymptomatic non-functioning pituitary adenomas (NFPAs), conservative approaches such as observation are preferred. However, some NFPAs exhibit poor prognoses. Thus, the purpose of this study was to investigate clinicopathological characteristics of tumors for identifying those with unfavorable prognoses. METHODS: A total of 125 patients with NFPAs who underwent surgery between November 2017 and December 2022 at our institution were retrospectively analyzed. Clinical, radiological, and pathological data, including hormone profiles, tumor size, presence of cavernous sinus invasion, and Ki-67 index levels, were reviewed. High-risk PAs were identified according to 2022 WHO criteria. Statistical analyses including Kaplan-Meier survival analysis and Cox regression were performed to evaluate factors associated with tumor progression or recurrence. RESULTS: A high-risk group demonstrated a significantly higher rate of tumor progression/recurrence than a low-risk group (p-value = 0.004). In multivariate analysis, the high-risk group at the time of diagnosis remained as an independent prognostic factor for NFPAs (p-value = 0.0148). The high-risk group also had a higher percentage of younger patients (80.0% in the high-risk group vs. 62.2% in the low-risk group, p-value = 0.016) and female patients (91.4% vs. 34.4%, p< 0.001). The presence of cavernous sinus invasion and higher Ki-67 index levels were more commonly observed in the high-risk group, although these factors did not significantly impact the overall prognosis. CONCLUSION: Our findings indicate that patients with high-risk NFPAs have a more aggressive disease course and a higher rate of progression or recurrence. This high-risk group has higher prevalence of younger and female patients. They may benefit from closer monitoring and possibly more aggressive treatment approaches.

Is reduced-dose whole-brain radiotherapy also feasible in primary CNS lymphoma for curative or salvage purpose?

PURPOSE: Recently, reduced-dose whole-brain radiotherapy (WBRT) has been used to treat primary central nervous system lymphoma (PCNSL). However, whether reduced-dose WBRT is also an acceptable option for curative or salvage purposes has not yet been reported. We analyzed the clinical outcomes of patients with PCNSL who received radiotherapy for curative or salvage purposes and compared the clinical outcomes according to the WBRT dose. METHODS: A total of 66 patients were divided into two groups: those treated with 30 Gy (2 Gy per fraction) or less WBRT (low-dose WBRT, n = 34) and those treated with more than 30 Gy WBRT (high-dose WBRT, n = 32). The median WBRT dose was 25.2 and 49.6 Gy in low-dose and high-dose WBRT groups, respectively. The median total radiotherapy dose, including the boost dose, was 50 Gy (range, 36.0-55.8 Gy). RESULTS: The 3-year overall survival and progression-free survival were 77.8% and 29.8%, respectively. Intracranial relapse occurred in 31 patients (47.0%) at a median of 27 months after RT. Overall survival and progression-free survival did not differ between the two groups. The 3-year intracranial disease control rate did not differ between the two groups (35.2% vs. 41.6%, p = 0.300). Grade 3 or higher neurological toxicities were observed in six patients, of whom five were in the high-dose WBRT group. CONCLUSION: Reduced-dose WBRT in curative and salvage treatments for PCNSL had no significant negative effect on the intracranial disease control rate or survival. Therefore, without impaired efficacy, use of reduced-dose WBRT appears promising for reduction of neurotoxicity.

Potential impact of high-density lipoprotein cholesterol in the postoperative outcomes of chronic subdural hematoma patients: multi-institutional study in Korea.

BACKGROUND: Chronic subdural hematoma (CSDH) is a common clinical situation in neurosurgical practice, but the optimal treatment option is controversial. This study aimed to evaluate the effect of cholesterol-lowering medications on and how they affected the prognoses of CSDH patients. METHODS: In this multi-institutional observational study performed in Korea, data from recently treated CSDH patients were gathered from 5 hospitals. A total of 462 patients were collected from March 2010 to June 2021. Patient clinical characteristics, history of underlying diseases and their treatments, radiologic features, and surgical outcomes were analyzed. RESULTS: Seventy-five patients experienced recurrences, and 62 had reoperations after the initial burr hole surgery. Among these, 15 patients with recurrences and 12 with reoperations were taking cholesterol-lowering medications. However, the use of medications did not significantly affect recurrence or reoperation rates (P = 0.350, P = 0.336, respectively). When analyzed by type of medication, no clinically relevant differences in total cholesterol (TC), triglyceride (TG), or low-density lipoprotein cholesterol (LDL-C) levels were identified. The combination of a statin drug and ezetimibe significantly elevated high-density lipoprotein cholesterol (HDL-C) levels (P = 0.004). TC, LDL-C, and TG levels did not significantly affect patient prognoses. However, HDL-C levels and recurrence (odds ratio (OR) = 0.96; 95% confidence interval (CI): 0.94-0.99; p = 0.010) were negatively correlated. An HDL-C level of 42.50 mg/dL was identified as the threshold for recurrence and reoperation. CONCLUSIONS: In this study, using cholesterol-lowering medications did not significantly impact the prognosis of patients who underwent surgical management for a chronic subdural hematoma. However, the findings showed that the higher the HDL-C level, the lower the probability of recurrence and reoperation.

Efficacy of Mesenchymal-Stromal-Cell-Derived Extracellular Vesicles in Ameliorating Cisplatin Nephrotoxicity, as Modeled Using Three-Dimensional, Gravity-Driven, Two-Layer Tubule-on-a-Chip (3D-MOTIVE Chip).

Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) are known to have a therapeutic effect on nephrotoxicity. As animal models require significant time and resources to evaluate drug effects, there is a need for a new experimental technique that can accurately predict drug effects in humans. We evaluated the therapeutic effect of MSC-derived EVs in cisplatin nephrotoxicity using a three-dimensional, gravity-driven, two-layer tubule-on-a-chip (3D-MOTIVE chip). In the 3D-MOTIVE chip, 10 µM cisplatin decreased the number of attached cells compared to the vehicle. Conversely, annexin V and reactive oxygen species (ROS) were increased. Cell viability was increased 2.8-fold and 2.5-fold after treatment with EVs at 4 and 8 µg/mL, respectively, compared to the cisplatin-induced nephrotoxicity group. Cell attachment was increased 2.25-fold by treatment with 4 µg/mL EVs and 2.02-fold by 8 µg/mL EVs. Annexin V and ROS levels were decreased compared to those in the cisplatin-induced nephrotoxicity group. There were no significant differences in annexin V and ROS levels according to EV concentration. In sum, we created a cisplatin-induced nephrotoxicity model on a 3D-MOTIVE chip and found that MSC-derived EVs could restore cell viability. Thus, MSC-derived EVs may have the potential to ameliorate cisplatin-induced nephrotoxicity.

Predictors of ideal outcomes after reconstructive surgery for chronic Monteggia fracture in children.

BACKGROUND: We aimed to analyze surgical outcomes of reconstructive surgery for chronic Monteggia fracture, which is one of the most challenging problems for orthopaedic surgeons. METHODS: Twenty-eight patients were followed during 55.6 ± 32.0 months after open reduction of the radial head combined with ulnar osteotomy and annular ligament reconstruction. The mean interval from trauma was 15.1 ± 19.6 months, and the mean age at the surgery was 9.1 ± 3.5 years. In addition to the chronological age, elbow maturity was assessed using the Sauvegrain score. Surgical outcomes were primarily evaluated using the Kim's score. In addition, we newly defined more successful criteria for the ideal surgical outcomes, equivalent to preinjury status. RESULTS: There were 19 excellent, 3 good, 4 fair, and 2 poor outcomes based on the Kim's scoring system. Among the 19 patients with excellent outcomes, 14 met our criteria for the ideal outcomes. The age (p < 0.001) and the Sauvegrain score (p < 0.001) were lower, and the interval (p = 0.004) was shorter in 14 patients with ideal outcomes. There were 9 patients with preoperative deformation of the radial head, and all of them showed non-ideal outcomes. In regression analyses, lower Sauvegrain score (p = 0.004) and shorter interval (p = 0.012) were associated with higher postoperative Kim's score, and lower Sauvegrain score (p = 0.031) was related to the achievement of the ideal outcomes. With the Sauvegrain score of >21.5, all patients had postoperative re-dislocation or osteoarthritic changes regardless of the interval. With the Sauvegrain score of <21.5 and an interval of ≤7 months, the ideal outcomes were achieved in 85.7%, and no patients had postoperative re-dislocation or osteoarthritic changes. CONCLUSION: Over the skeletal ages of 14 years in boys and 11.5 years in girls, reconstructive surgery must be cautiously indicated. Under these skeletal ages with an interval of ≤7 months and undeformed radial head, it appears to be ideal. STUDY DESIGN: Level III, Retrospective comparative study.

Comparison of Anatomical Conformity between TomoFix Anatomical Plate and TomoFix Conventional Plate in Open-Wedge High Tibial Osteotomy.

Background and Objectives: The TomoFix anatomical plate was developed to improve plate position, proximal screw direction, and post-correction tibial contouring. The purpose of this study was to compare postoperative configurations between the TomoFix anatomical plate and the TomoFix conventional plate. It was hypothesized that the new modified plate provides a better fixative coaptation than the conventional plate. Materials and Methods: A total of 116 cases (112 patients) were enrolled in this study from March 2015 to February 2021. Among them, 63 patients underwent surgery using the TomoFix conventional plate, and 53 underwent surgery using the TomoFix anatomical plate. The radiographic outcomes, including the hip−knee−ankle (HKA) angle, medial proximal tibial angle (MPTA), tibial slope, plate angle, proximal screw angles, and plate-to-cortex distance at #1 hole (just below the osteotomy site) were compared between the two groups. Results: Patients with the TomoFix anatomical plate showed similar results in terms of the pre- and postoperative HKA angle, MPTA, and tibial slope. The TomoFix anatomical group showed a significantly greater plate angle (39.2° ± 8.1° vs. 31.7° ± 7.0°, p < 0.001) and less screw angles, indicating that the TomoFix anatomical plates allowed a more posterior plate position than the conventional plate. The plate-to-cortex distance was significantly less in the TomoFix anatomical group than in the TomoFix conventional group (p < 0.001). Conclusion: The TomoFix anatomical plate showed a more posteromedial plating position, better proximal screw direction to the lateral hinge, and improved post-correction tibial contour compared to the TomoFix conventional plate.

Radiomics may increase the prognostic value for survival in glioblastoma patients when combined with conventional clinical and genetic prognostic models.

OBJECTIVES: To evaluate the additional prognostic value of multiparametric MR-based radiomics in patients with glioblastoma when combined with conventional clinical and genetic prognostic factors. METHODS: In this single-center study, patients diagnosed with glioblastoma between October 2007 and December 2019 were retrospectively screened and grouped into training and test sets with a 7:3 distribution. Segmentations of glioblastoma using multiparametric MRI were performed automatically via a convolutional-neural network. Prognostic factors in the clinical model included age, sex, type of surgery/post-operative treatment, and tumor location; those in the genetic model included statuses of isocitrate dehydrogenase-1 mutation and O-6-methylguanine-DNA-methyltransferase promoter methylation. Univariate and multivariate Cox proportional hazards analyses were performed for overall survival (OS) and progression-free survival (PFS). Integrated time-dependent area under the curve (iAUC) for survival was calculated and compared between prognostic models via the bootstrapping method (performances were validated with prediction error curves). RESULTS: Overall, 120 patients were included (training set, 85; test set, 35). The mean OS and PFS were 25.5 and 18.6 months, respectively. The prognostic performances of multivariate models improved when radiomics was added to the clinical model (iAUC: OS, 0.62 to 0.73; PFS, 0.58 to 0.66), genetic model (iAUC: OS, 0.59 to 0.67; PFS, 0.59 to 0.65), and combined model (iAUC: OS, 0.65 to 0.73; PFS, 0.62 to 0.67). In the test set, the combined model (clinical, genetic, and radiomics) demonstrated robust validation for risk prediction of OS and PFS. CONCLUSIONS: Radiomics increased the prognostic value when combined with conventional clinical and genetic prognostic models for OS and PFS in glioblastoma patients. KEY POINTS: • CNN-based automatic segmentation of glioblastoma on multiparametric MRI was useful in extracting radiomic features. • Patients with glioblastoma with high-risk radiomics scores had poor overall survival (hazards ratio 8.33, p < 0.001) and progression-free survival (hazards ratio 3.76, p < 0.001). • MR-based radiomics improved the survival prediction when combined with clinical and genetic factors (overall and progression-free survival iAUC from 0.65 to 0.73 and 0.62 to 0.67, respectively; both p < 0.001).

Sortase A-Inhibitory Coumarins from the Folk Medicinal Plant Poncirus trifoliata.

Thirteen coumarins (1-13), including five new compounds (1-5), were isolated from the folk medicinal plant Poncirus trifoliata. Combined spectroscopic analyses revealed that coumarins 1-4 are bis-isoprenylated coumarins with diverse oxidation patterns, while 5 is an enantiomeric di-isoprenylated coumarin. The absolute configurations of the stereogenic centers in the isoprenyl chains were assigned through MTPA and MPA methods, and those of the known compounds triphasiol (6) and ponciol (7) were also assigned using similar methods. These coumarins inhibited significantly Staphylococcus aureus-derived sortase A (SrtA), a transpeptidase responsible for anchoring surface proteins to the peptidoglycan cell wall in Gram-positive bacteria. The present results obtained indicated that the bioactivity and underlying mechanism of action of these coumarins are associated with the inhibition of SrtA-mediated S. aureus adhesion to eukaryotic cell matrix proteins including fibrinogen and fibronectin, thus potentially serving as SrtA inhibitors.

Virtual Reality Haptic Simulator for Endoscopic Sinus and Skull Base Surgeries.

OBJECTIVE: This paper proposes a virtual reality (VR) haptic simulator with realistic instruments, an exchangeable patient-specific three-dimensional (3D)-printed external nostril and a caudal septum model to facilitate real surgical motion for training in endoscopic sinus and skull-base surgery. STUDY DESIGN AND SETTING: industry-academy cooperation development model METHODS:: The VR simulator consists of the main simulator body, a monitor, an endoscope device, 2 haptic devices, an endoscope holder support fixture, and a pair of pedals. The location of the endoscope device is determined by an electromagnetic sensor. Two haptic devices are located so as to prevent mutual interference during application of the two-nostrils/four-hands technique for endoscopic skull-base surgery. The pedals were used for select surgical instrument and endoscopes, and operate microdebriders or microdrill. An exchangeable patient-specific external nostril and caudal septum model was created using material that mimics the texture of human tissue and a 3D printer. Graphics were rendered using Unity 3D, to which the Simulation Open Framework Architecture (SOFA) physics engine can be bolted on using the Unity3d plug-in. RESULTS: This VR haptic simulator enables performance of basic endoscopic sinus surgeries (eg, maxillary sinus antrostomy, ethmoidectomy, and frontostomy), as well as endoscopic endonasal transsphenoidal (including sphenoidotomy) and transclival approaches. CONCLUSION: VR haptic simulators can improve the skill and confidence of surgical trainees by allowing them to accrue experience in various tasks under different conditions. The simulator introduced here comprises novel technologies and provides a realistic training environment for endoscopic sinus and skull-base surgery.

Development of Willow Tree Yield-Mapping Technology.

With today's environmental challenges, developing sustainable energy sources is crucial. From this perspective, woody biomass has been, and continues to be, a significant research interest. The goal of this research was to develop new technology for mapping willow tree yield grown in a short-rotation forestry (SRF) system. The system gathered the physical characteristics of willow trees on-the-go, while the trees were being harvested. Features assessed include the number of trees harvested and their diameter. To complete this task, a machine-vision system featuring an RGB-D stereovision camera was built. The system tagged these data with the corresponding geographical coordinates using a Global Navigation Satellite System (GNSS) receiver. The proposed yield-mapping system showed promising detection results considering the complex background and variable light conditions encountered in the outdoors. Of the 40 randomly selected and manually observed trees in a row, 36 were successfully detected, yielding a 90% detection rate. The correctly detected tree rate of all trees within the scenes was actually 71.8% since the system tended to be sensitive to branches, thus, falsely detecting them as trees. Manual validation of the diameter estimation function showed a poor coefficient of determination and a root mean square error (RMSE) of 10.7 mm.

Microstructural engineering in interface-type synapse device for enhancing linear and symmetric conductance changes.

The origins of the nonlinear and asymmetric synaptic characteristics of TiO x -based synapse devices were investigated. Based on the origins, a microstructural electrode was utilized to improve the synaptic characteristics. Under an identical pulse bias, a TiO x -based synapse device exhibited saturated conductance changes, which led to nonlinear and asymmetric synaptic characteristics. The formation of an interfacial layer between the electrode and TiO x layer, which can limit consecutive oxygen migration and chemical reactions, was considered as the main origin of the conductance saturation behavior. To achieve consecutive oxygen migration and chemical reactions, structural engineering was utilized. The resultant microstructural electrode noticeably improved the synaptic characteristics, including the unsaturated, linear, and symmetric conductance changes. These synaptic characteristics resulted in the recognition accuracy significantly increasing from 38% to 90% in a neural network-based pattern recognition simulation.

Control of intracranial disease is associated with improved survival in patients with brain metastasis from hepatocellular carcinoma.

BACKGROUND: Brain metastasis is a rare event in patients with hepatocellular carcinoma (HCC). This retrospective study aimed to identify the prognostic factors and determine the outcomes of patients with brain metastases from HCC. METHODS: About 86 patients with brain metastases (0.6%) from HCC were identified from two institutions; of them, 32 underwent tumor-removing surgery or stereotactic radiosurgery (SRS) with or without adjuvant whole brain radiotherapy (WBRT) (group 1), 30 had WBRT alone (group 2), and 24 received conservative treatment (group 3). Estimates for overall survival (OS) after brain metastases were determined, and clinical prognostic factors were identified. RESULTS: The median OS after development of brain metastases was 50 days. About 75 (87.2%) patients had lung metastases at the time of brain metastasis diagnosis. Group 1 showed better OS, followed by group 2 and group 3, sequentially (p < 0.001). Univariate analyses showed that treatment with curative intent (surgery or SRS), Child-Pugh class A, alpha-fetoprotein level < 400 ng/ml, and recursive partitioning analysis classification I or II were associated with improved survival (p < 0.001, 0.002, 0.029, and 0.012, respectively). Multivariate analysis showed that treatment with curative intent and Child-Pugh class A was associated with improved OS (p < 0.001 and 0.009, respectively). CONCLUSION: Although the overall prognosis of patients with brain metastases from HCC is extremely poor, patients actively treated with surgery or radiosurgery have prolonged survival, suggesting that interventions to control intracranial disease are important in these patients.

Effects of Heat Treatment on Interfacial Behavior and Bonding Strength of Surface Activated Bonding Ti-Al Laminate.

The surface activated bonding (SAB) method generally has the advantage of high bonding strength, low contact resistance, and high microstructural stability at room temperature. In this study, Ti-Al laminates were produced by surface activated bonding with aluminum and titanium foils. Heat treatment was conducted at the temperature range from 200 to 550 °C in vacuum. The bonding strength Ti-Al laminates was measured by a peel test, and the interfacial characteristics were investigated microstructural observation. The results showed that the bonding strength was the highest with heat treatment at 400 °C, microstructure observation revealed that the bonding strength of the Ti-Al laminate was influenced by the interfacial characteristics.

Is Coincidental Rhinosinusitis a Predisposing Factor for Postoperative Central Nervous System Infection After Endoscopic Endonasal Transsphenoidal Surgery?

BACKGROUND: To investigate the effect of rhinosinusitis in patients who undergo surgery via the endoscopic endonasal transsphenoidal approach (EETSA). METHODS: The authors retrospectively reviewed the medical records of patients who underwent surgery via the EETSA between February 2009 and November 2016. In total, 505 patients were included in the study. Preoperative paranasal sinus computed tomography, sellar magnetic resonance imaging, and nasal endoscopy were performed for all the patients. RESULTS: Fifteen patients without sphenoid sinusitis underwent surgery with the concomitant transsphenoidal approach and functional endoscopic sinus surgery, and showed no central nervous system (CNS) complication. During surgery via the EETSA, the presence of rhinosinusitis did not significantly affect the incidence of postoperative CNS infection (P = 0.051), except for sphenoid sinusitis (P = 0.003). Conversely, the incidence of postoperative CNS infection was not related significantly to the Lund-Mackay score or tumor size. The risk of CNS infection was 12.151-fold higher in patients with sphenoid sinusitis (95% confidence interval, 3.153-46.827; P ≤ 0.001). CONCLUSION: Surgery via the EETSA and functional endoscopic sinus surgery can be safely performed together in most patients with rhinosinusitis. However, sphenoid sinus infection appears to be a predisposing factor for postoperative CNS infection. Therefore, a separate surgical procedure for sphenoid lesions should be considered in these patients before the use of the EETSA.

Can Tumor Size Be a Predictive Factor of Olfactory Dysfunction After Endoscopic Endonasal Trans-Sphenoidal Approach?

BACKGROUND AND OBJECTIVE: The aim of this study is to investigate the relationships between tumor size, nasal symptoms including olfactory function, and posoperative atrophic mucosal changes after the endoscopic endonasal transsphenoidal approach (EETSA). METHODS: This was a retrospective review of the medical records of 112 patients who underwent the 2 nostrils/4 hands EETSA with bilateral modified nasoseptal rescue flaps between February 2009 and January 2016. Pre- and postoperative paranasal sinus computed tomography, nasal cavity endoscopic images, the Connecticut Chemosensory Clinical Research Center (CCCRC) test, Cross-Cultural Smell Identification Test (CCSIT), the Nasal Obstruction Symptoms Evaluation, and the Sino-Nasal Outcome Test-20 were conducted. Nasal mucosal changes as determined by endoscopy were divided into 4 groups: normal to normal, Group A; atrophy to atrophy, Group B; normal to atrophy, Group C; and atrophy to more atrophy, Group D. The Mimics program was used to calculate nasal cavity volume changes after surgery. RESULTS: There were significant differences between pre- and postoperative olfactory function as reflected by the CCCRC (P < 0.001) and CCSIT (P < 0.001) scores. There was also a correlation between tumor size and olfactory function scores such as the CCCRC (P = 0.012) or CCSIT (P = 0.015). Moreover, nasal mucosal atrophic changes were related to tumor size and olfactory function tests. CONCLUSION: The tumor size was related to olfactory function and atrophic mucosal changes. Therefore, patients with large tumors should be informed that, after the EETSA, their olfaction may be altered and that nasal symptoms related to mucosal atrophy could occur.

Direct Probing of the Electronic Structures of Single-Layer and Bilayer Graphene with a Hexagonal Boron Nitride Tunneling Barrier.

The chemical and mechanical stability of hexagonal boron nitride (h-BN) thin films and their compatibility with other free-standing two-dimensional (2D) crystals to form van der Waals heterostructures make the h-BN-2D tunnel junction an intriguing experimental platform not only for the engineering of specific device functionalities but also for the promotion of quantum measurement capabilities. Here, we exploit the h-BN-graphene tunnel junction to directly probe the electronic structures of single-layer and bilayer graphene in the presence and the absence of external magnetic fields with unprecedented high signal-to-noise ratios. At a zero magnetic field, we identify the tunneling spectra related to the charge neutrality point and the opening of the electric-field-induced bilayer energy gap. In the quantum Hall regime, the quantization of 2D electron gas into Landau levels (LL) is seen as early as 0.2 T, and as many as 30 well-separated LL tunneling conductance oscillations are observed for both electron- and hole-doped regions. Our device simulations successfully reproduce the experimental observations. Additionally, we extract the relative permittivity of three-to-five layer h-BN and find that the screening capability of thin h-BN films is as much as 60% weaker than bulk h-BN.

Gram-negative and Gram-positive bacterial extracellular vesicles.

Like mammalian cells, Gram-negative and Gram-positive bacteria release nano-sized membrane vesicles into the extracellular environment either in a constitutive manner or in a regulated manner. These bacterial extracellular vesicles are spherical bilayered proteolipids enriched with bioactive proteins, lipids, nucleic acids, and virulence factors. Recent progress in this field supports the critical pathophysiological functions of these vesicles in both bacteria-bacteria and bacteria-host interactions. This review provides an overview of the current understanding on Gram-negative and Gram-positive bacterial extracellular vesicles, especially regarding the biogenesis, components, and functions in poly-species communities. We hope that this review will stimulate additional research in this emerging field of bacterial extracellular vesicles and contribute to the development of extracellular vesicle-based diagnostic tools and effective vaccines against pathogenic Gram-negative and Gram-positive bacteria.

Endoscopic Endonasal Transsphenoidal Approach From the Surgeon Point of View.

OBJECTIVE: In February 2009, the authors' center formed a team of neurosurgeons, otolaryngologists, endocrinologists, and radiologists to perform pituitary surgery using the endoscopic endonasal transsphenoidal approach (EETSA). This paper reviews the authors' experience with the technique, pathological outcomes, hormone profiles, and postoperative complications. METHODS: Between February 2009 and December 2015, 535 patients underwent the EETSA with 2-nostrils/4-hands surgery. All of the patients had preoperative neurophthalmological and endocrinological assessments and neuroimaging. Patients were followed for at least 6 months with otolaryngological evaluations. RESULTS: The most common pathology treated was pituitary adenomas, with 390 (72.9%) patients. Of these, 287 (73.6%) were nonfunctioning adenomas. As the surgical method, the conventional 2-nostrils/4-hands technique was performed in 77 patients (14.4%), a right conventional nasoseptal flap and left modified nasoseptal rescue flap technique was used in 135 patients (25.2%), and bilateral modified nasoseptal rescue flaps were used in 323 patients (60.4%). Postoperative complications occurred in 46 patients (8.6%). The most common complications were vascular injury or hematoma (10 patients, 1.9%), and the most common postoperative sinonasal complaints were hyposmia or anosmia. Olfactory function was significantly decreased according to the Connecticut Chemosensory Clinical Research Center test (P <0.001) and Cross-Cultural Smell Identification Test scores (P <0.001) evaluated 6 months postoperatively. CONCLUSIONS: Skull-base tumor surgery via an EETSA with a team approach was performed for various extended tumors. It is important to consider postoperative sinonasal dysfunction, such as hyposmia or anosmia, and to have this followed by an otolaryngologist.

Novel LRRK2 GTP-binding inhibitors reduced degeneration in Parkinson's disease cell and mouse models.

Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant Parkinson's disease (PD) and contribute to sporadic PD. LRRK2 contains Guanosine-5'-triphosphate (GTP) binding, GTPase and kinase activities that have been implicated in the neuronal degeneration of PD pathogenesis, making LRRK2, a potential drug target. To date, there is no disease-modifying drug to slow the neuronal degeneration of PD and no published LRRK2 GTP domain inhibitor. Here, the biological functions of two novel GTP-binding inhibitors of LRRK2 were examined in PD cell and mouse models. Through a combination of computer-aided drug design (CADD) and LRRK2 bio-functional screens, two novel compounds, 68: and 70: , were shown to reduce LRRK2 GTP binding and to inhibit LRRK2 kinase activity in vitro and in cultured cell assays. Moreover, these two compounds attenuated neuronal degeneration in human SH-SY5Y neuroblastoma cells and mouse primary neurons expressing mutant LRRK2 variants. Although both compounds inhibited LRRK2 kinase activity and reduced neuronal degeneration, solubility problems with 70: prevented further testing in mice. Thus, only 68: was tested in a LRRK2-based lipopolysaccharide (LPS)-induced pre-inflammatory mouse model. 68: reduced LRRK2 GTP-binding activity and kinase activity in brains of LRRK2 transgenic mice after intraperitoneal injection. Moreover, LPS induced LRRK2 upregulation and microglia activation in mouse brains. These findings suggest that disruption of GTP binding to LRRK2 represents a potential novel therapeutic approach for PD intervention and that these novel GTP-binding inhibitors provide both tools and lead compounds for future drug development.