Search

Bispecific T cell engagers (BiTEs) are bispecific antibodies that redirect T cells to target antigen-expressing tumors. We hypothesized that BiTE-secreting T cells could be a valuable therapy in solid tumors, with distinct properties in mono- or multi-valent strategies incorporating chimeric antigen receptor (CAR) T cells. Glioblastomas represent a good model for solid tumor heterogeneity, representing a significant therapeutic challenge. We detected expression of tumor-associated epidermal growth factor receptor (EGFR), EGFR variant III, and interleukin-13 receptor alpha 2 (IL13Rα2) on glioma tissues and cancer stem cells. These antigens formed the basis of a multivalent approach, using a conformation-specific tumor-related EGFR targeting antibody (806) and Hu08, an IL13Rα2-targeting antibody, as the single chain variable fragments to generate new BiTE molecules. Compared with CAR T cells, BiTE T cells demonstrated prominent activation, cytokine production, and cytotoxicity in response to target-positive gliomas. Superior response activity was also demonstrated in BiTE-secreting bivalent T cells compared with bivalent CAR T cells in a glioma mouse model at early phase, but not in the long term. In summary, BiTEs secreted by mono- or multi-valent T cells have potent anti-tumor activity in vitro and in vivo with significant sensitivity and specificity, demonstrating a promising strategy in solid tumor therapy.

Glioblastoma (GBM) is identified to share common signal pathways between glioma and immune cells. Here, we find that T cell immunoglobulin domain and mucin domain protein 3 (TIM-3) is one of the most common co-inhibitory immune checkpoints in GBM shared by tumor and non-tumor cells. Glioma cell-intrinsic TIM-3 is involved in not only regulating malignant behaviors of glioma cells but also inducing macrophage migration and transition to anti-inflammatory/pro-tumorigenic phenotype by a TIM-3/interleukin 6 (IL6) signal. In mechanism, as one of the major regulators of IL6, TIM-3 regulates its expression through activating NF-κB. Blocking this feedback loop by Tocilizumab, an IL6R inhibitor, inhibited the above effects and repressed the tumorigenicity of GBM

Objective Studies have shown that microRNAs play a role in the development of epilepsy by regulating downstream target messenger (m)RNA. The present study aims to determine the changes associated with microRNA-21-5p (miR-21-5p) during epileptogenesis in a kainic acid rat model, and to assess whether the PTEN-mTOR pathway is a target of miR-21-5p. Method Reverse transcription polymerase chain reaction (RT-PCR) was used to examine the quantitative expressions of miR-21-5p and PTEN, and Western blotting was used to test the activity of mTOR in the acute, latent, and chronic stages of epileptogenesis. The antagomir of miR-21-5p was injected into the intracerebroventricular space using a microsyringe. Neuronal death and epilepsy discharge were assessed by Nissl staining and electroencephalography (EEG), respectively. The Morris water maze (MWM) was used to assess the cognitive impairment in rats after status epilepticus (SE). Results Both miR-21-5p and mTOR were upregulated and PTEN was downregulated in rats during acute, latent, and chronic stages of epileptogenesis when compared with those of the control. After using antagomir miR-21-5p in vivo, miR-21-5p and mTOR decreased and the expression of PTEN increased compared with that in the SE model. The silencing of miR-21-5p diminished the number of abnormal spikes on EEG and decreased the number of neuron deletions on Nissl staining. The cognitive and memory impairment caused by epilepsy could also be improved after miR-21-5p knockdown in vivo. Conclusion The results of the present study demonstrate that PTEN-mTOR is the target of miR-21-5p in a kainic acid model of epilepsy. The knockout of miR-21-5p decreases the neuronal damage in stages of epileptogenesis. The miR-21-5p/PTEN/mTOR axis may be a potential target for preventing and treating seizures and epileptic damage.

In order to facilitate recovery and enhance phosphate adsorption capacity of lanthanum (La)-based materials, magnetic Fe3O4@MgAl-LDH@La(OH)3 (MMAL) composites with a hierarchical core-shell structure were synthesized. In the preparation process, citric acid played a vital role in the morphology control of La(OH)3, deciding the La content and phosphate adsorption capacity of materials. MMAL composites with a citric acid-to-La molar ratio of 0.375 (MMAL-0.375) exhibited a high adsorption capacity of 66.5 mg P/g, fast adsorption kinetics of 30 min, widely applicable pH range of 4.0–10.0, outstanding selective adsorption performance, and superior reusability in batch adsorption experiments. Moreover, the phosphate in the desorption solution could be concentrated by repeated use of desorption solution and recovered by using CaCl2. When the obtained composites were used for the sedimentary phosphorus sequestration and recovery, the results showed that the addition of MMAL-0.375 effectively reduced the concentration of soluble reactive phosphorus (SRP) in the overlying water. Accompanied by an evident increase in HCl-extractable phosphorus (HCl–P), mobile phosphorus (Pmob) in sediments was effectively reduced. This work indicates that the MMAL-0.375 composites can serve as an effective tool for the removal of phosphate from wastewater and the control of sedimentary phosphorus.

Background In minimally invasive endoscopic port surgery, the medium is air, and the image is clearer than in fluid. The most commonly used port is a single-channel port, which accommodates the rod lens of the endoscope and 2 microsurgical instruments. This setup decreases the freedom of movement of the 3 instruments, making the bimanual procedure difficult. We describe a novel “dual-channel” endoscopic port to facilitate a bimanual refinement procedure for removing deep-seated spontaneous intracerebral hematomas, and we demonstrate the feasibility of this method. Methods The small channel accommodates a 0° endoscope lens, and the large channel accommodates 2 microsurgical instruments. This method was used in 8 patients with deep-seated spontaneous intracerebral hematomas with obstructive hydrocephalus. It was necessary to evacuate the deep-seated hematomas in these patients as soon as possible to recover the circulation of cerebrospinal fluid. Results Dual-channel port surgery was performed in 8 patients with an average age of 55 years (range, 44–79 years). The time from ictus to surgery ranged from 4 hours to 12 days. The duration of drainage tube placement was 2–5 days. The hematomas in all patients, in the third ventricle or thalamus, were evacuated thoroughly. In each patient, improvements in Glasgow Coma Scale scores were observed from admission to discharge. Conclusions The dual-channel endoscopic port facilitated bimanual refinement microsurgery during the evacuation of deep-seated intracerebral hematomas, and it prevented the disturbance of the 3 instruments without restraining the scope of the operation during the microsurgical procedure.

We aimed to explore the pathogenesis of monocyte chemoattractant protein-1 (MCP1) and CC chemokine receptor 2 (CCR2) in brain tissue of patients with intractable epilepsy (IE). Hippocampi or temporal lobe tissues were obtained from 40 patients with IE and five patients without IE who had undergone surgical decompression and debridement. The levels of MCP1 and CCR2 were evaluated using immunohistochemistry. Pearson correlation analysis was employed to evaluate the correlation between levels of MCP1 and CCR2 in IE with or without hippocampal sclerosis (HS) and the disease duration, along with age. Higher levels of MCP1 (11.68±4.68% versus 1.72±1.54%) and CCR2 (11.54±4.65% versus 1.52±1.29%; P

Shakedown theory is often used to analyze the plastic behaviors of structures subjected to variable complex loads. It is an effective way to predict the maximum load under which the failure due to plastic collapse or excessive permanent deformation of pavement will not occur. Based on Melan's lower-bound shakedown theory, this work has proposed a numerical method for estimating the shakedown limit involving the effect of traffic moving speed. The dynamic response of elastic stress to traffic moving speed is computed using combined Finite Element-Infinite Element (FE-IE) method. The shakedown limits for a two-layered pavement system have been investigated at various traffic moving speeds. It shows that the shakedown limit early reduces and subsequently turns to grow as the moving speed increases. The shakedown limit decreases to the minimum when the traffic speed reaches the Rayleigh wave speed of subsoil. In order to provide an optimized design of the pavement system, the dependence of shakedown limits on the material properties of pavement system has also been estimated. Eventually, the characteristic distribution of critical residual stress is discussed.

Purpose Surgery is regarded as a common treatment option for patients with mesial temporal lobe epilepsy (MTLE) as a result of hippocampal sclerosis (HS). However, approximately one-third of patients with intractable epilepsy did not become seizure-free after tailored resection strategies. It would be compelling to identify predictive factors of postoperative seizure outcomes. Our aim was to assess the correlation between HS classification and long-term postoperative seizure outcome in patients with MTLE due to HS. Methods To investigate HS classification, semi-quantitative analysis and immunohistochemical staining of neuronal nuclei (NeuN) were performed on 100 postoperative hippocampal specimens. All patients had a 1–7 year postoperative follow-up. The postoperative seizure outcome was evaluated using International League Against Epilepsy (ILAE) outcome classification. Results Three types of HS were recognized. The highest incidence of initial precipitating injury (IPI) was noted in the HS ILAE type 1 group (53.1%). The most favorable long-term seizure outcome was also noted in the HS ILAE type 1 group. The shortest epilepsy duration was recorded in the HS ILAE type 2 group (mean epilepsy duration=6.64±5.83 years). The completely seizure free rate of patients in all groups declined with an increase in time. Conclusions Our study for the first time demonstrated a significant correlation between HS ILAE types and long-term postoperative seizure outcome in patients with MTLE due to HS. Therefore, HS ILAE types have predictive value in long-term seizure outcome following epilepsy surgery.

We evaluated the long-term outcome of epilepsy surgery in drug-resistant epilepsy patients, and investigated preoperative factors associated with postoperative long-term surgical outcome. We performed a retrospective study of 379 patients who received epilepsy surgeries from 2000 to 2010. Patients had completed a minimum of 2-year and up to 12-year follow-up. Preoperative evaluations, surgical outcomes and clinical data of patients were collected and analyzed. We found that the epilepsy surgery was effective in drug-resistant patients and the long-term outcome of epilepsy surgery was satisfactory. The bipolar electro-coagulation could improve the surgical outcome when the epileptogenic focus was on the functional cortex. Results of the 2-year follow-up showed that preoperative seizure characteristics including the history of febrile seizure, seizure frequency, and location, quantity and range of seizure foci were significantly associated with the surgical outcome. The surgery procedure including the surgery type and the extent of resection also affected outcome. Abnormal head or hippocampus MRI, inconsistent results of preoperative investigations, seizure types, and pathology type might also be predictors of long-term surgical outcome.

Rationale and Objectives Magnetic resonance imaging (MRI) studies reveal that atrophy of the corpus callosum (CC) is involved in early Alzheimer’s disease (AD). The aim of this study was to investigate when and how callosal changes occur in the early course of AD. Materials and Methods The Open Access Series of Imaging Studies data sets were used in this study to investigate callosal change. High-resolution structural MRI was performed in 196 older patients. Subjects were characterized using the Clinical Dementia Rating (CDR); 98 healthy controls were not demented (CDR 0), and 98 patients had clinical diagnosis of AD in the very mild dementia stage (CDR 0.5; n = 70) and the mild dementia stage (CDR 1; n = 28). A semiautomatic segmentation method was used to extract the CC in the midsagittal plane. The total and regional areas of the CC were measured. Results The results indicated that callosal atrophy occurred in when subjects’ CDRs were 0.5. The area of the genu and rostral body of the CC in the healthy controls (CDR 0) was significantly different from that of the subjects with very mild dementia (CDR 0.5) ( P P Conclusions Callosal atrophy can be detected in subjects with CDRs of 0.5. The change in the CC in the early stage of AD indicates an anterior-to-posterior atrophic process as the degree of dementia assessed by the CDR (from 0 to 0.5 to 1) increases.

Rationale and Objectives Anterior/posterior commissure reference system (AC/PC reference system) and the fastigium/ventricular floor plane reference system (FFL/VFL reference system) are two reference systems used in the stereotactic localization of the invisible nuclei of the brainstem in magnetic resonance (MR) images. This study investigated the variation of the midsagittal brainstem in relation to the AC/PC and VFL/FFL reference systems with respect to age and gender. Materials and Methods High-resolution T1-weighted structural MR images were acquired from 64 adults (age range 21–60 years, 32 males and 32 females). The AC/PC and VFL/FFL reference systems were identified automatically. A set of landmarks of the midsagittal brainstem were defined and localized interactively. Results Results illustrated that there was significant difference between the variance of the anteroposterior coordinate of the landmarks in relation to the AC/PC reference system and that in relation to the FFL/VFL reference system (P Conclusion Either the FFL/VFL reference system or the AC/PC reference system has its own advantage in the stereotactic localization of the structure in the brainstem.