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The regeneration of brain tissue poses a great challenge because of the limited self-regenerative capabilities of neurons after traumatic brain injury (TBI). For this purpose, 3D-printed collagen/silk fibroin/secretome derived from human umbilical cord blood mesenchymal stem cells (HUCMSCs) pretreated with bFGF scaffolds (3D-CS-bFGF-ST) at a low temperature were prepared in this study. From an in vitro perspective, 3D-CS-bFGF-ST showed good biodegradation, appropriate mechanical properties, and good biocompatibility. In regard to vivo, during the tissue remodelling processes of TBI, the regeneration of brain tissues was obviously faster in the 3D-CS-bFGF-ST group than in the other two groups (3D-printed collagen/silk fibroin/secretome derived from human umbilical cord blood mesenchymal stem cells (3D-CS-ST) group and TBI group) by motor assay, histological analysis, and immunofluorescence assay. Satisfactory regeneration was achieved in the two 3D-printed scaffold-based groups at 6 months postsurgery, while the 3D-CS-bFGF-ST group showed a better outcome than the 3D-CS-ST group., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Zhang, Wei, Hao, Zhong, Zhong, Liu, Liu, Feng, Wang, Zhang, Tian and Zhou.)

Spontaneous recovery after spinal cord injury (SCI) is extremely limited since the severe inflammatory responses lead to secondary damage, and the diseased extracellular matrix (ECM) fails to provide inductive cues for nerve regeneration. To address these dilemmas, herein, we propose a biomaterial-based strategy combining neuroprotection and neuroinduction for SCI repair. Taking advantage of a microfluidic chip, we constructed imine-crosslinked aldehyde-methacrylate-hyaluronan/collagen hybrid hydrogel microfibers incorporating interleukin 4 (IL-4)-loaded ZIF-8 nanoparticles (IL4@ZIF-8 NPs). The hybrid hydrogel microfibers possess pivotal traits mimicking the natural ECM and hold neuroinductive nanoalignment and viscoelasticity, as well as the acidic microenvironment-responsive release of neuroprotective IL-4. Then, we elucidated the role of the tailored hydrogel microfibers in promoting the structural and functional recovery of SCI rats. The implanted hydrogel microfibers incorporating IL4@ZIF-8 NPs protected endogenous neural cells by promoting M2 polarization of recruited macrophages and suppressing inflammation. Additionally, the hydrogel microfibers enhanced neuronal differentiation, accelerated axonal regrowth, synapse formation and remyelination, resulting from their ECM-mimicking oriented nano-topography and viscoelasticity. Moreover, the locomotor function was also improved by the implanted microfibers combining neuroprotective cues and neuroinductive cues. This work not only paves the steps for the development of a novel class of multifunctional hydrogels that manipulate tissue behavior by modifying the cellular microenvironment but also provides intriguing insights for the repair of SCI and even other central nervous system (CNS) injuries via tissue engineering approaches.

A flexible non-transient electrical platform that can realize bidirectional neural communication from living tissues is of great interest in neuroscience to better understand basic neuroscience and the nondrug therapy of diseases or disorders. The development of soft, biocompatible, and conductive neural interface with mechanical coupling and efficient electrical exchange is a new trend but remains a challenge. Herein, we designed a multifunctional neural electrical communication platform in the form of a mechanically compliant, electrically conductive, and biocompatible hydrogel electrode. Silk fibroin (SF) obtained from Bombyx Mori cocoons was compounded with aldehyde-hyaluronic acid (HA-CHO) with a dynamic network to delay or interrupt the β-sheet-induced hardening of SF chains, resulting in the fabrication of a hydrogel matrix that is mechanically matched to biological tissues. Moreover, the incorporation of functionalized carbon nanotubes (CNTs) facilitated interaction and dispersion and enabled the formation of a hydrogel electrode with a high-current percolation network, thus contributing toward improving the electrical properties in terms of conductivity, impedance, and charge storage capabilities. These advances allow high-efficiency stimulation and the recording of neural signals during in vivo implantation. Overall, a wide range of animal experiments demonstrate that the platform exhibits minimal foreign body responses, thus showing it to be a promising electrophysiology interface for potential applications in neuroscience.

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Currently, the standard treatment of glioblastoma includes surgery, radiotherapy, and chemotherapy. Despite aggressive treatment, the median survival is only 15 months. GBM progression and therapeutic resistance are the results of the complex interactions between tumor cells and tumor microenvironment (TME). TME consists of several different cell types, such as stromal cells, endothelial cells and immune cells. Although GBM has the immunologically "cold" characteristic with very little lymphocyte infiltration, the TME of GBM can contain more than 30% of tumor-associated microglia and macrophages (TAMs). TAMs can release cytokines and growth factors to promote tumor proliferation, survival and metastasis progression as well as inhibit the function of immune cells. Thus, TAMs are logical therapeutic targets for GBM. In this review, we discussed the characteristics and functions of the TAMs and evaluated the state of the art of TAMs-targeting strategies in GBM. This review helps to understand how TAMs promote GBM progression and summarizes the present therapeutic interventions to target TAMs. It will possibly pave the way for new immune therapeutic avenues for GBM patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Zhong, Wang, Zhang, Tang, Tong and Zhou.)

Background: Blood blister aneurysm (BBA) is a complex and rare aneurysm that presents significant treatment challenges. The application of pipeline embolization device (PED)-assisted coiling in the treatment of ruptured BBA remains controversial. This study aimed to report on our experience and assess the safety and efficacy of this strategy., Methods: Between February 2019 and February 2021, 12 patients with ruptured BBAs underwent PED-assisted coil embolization. We collected detailed data about each patient, including demographic information, aneurysmal data, technical details, antiplatelet strategy, operation-related complications, and follow-up outcomes., Results: A total of 12 BBA patients were treated with single PED-assisted coil embolization. One patient experienced intraoperative rupture that was controlled by rapid coiling without clinical consequences. All the patients demonstrated complete occlusion on postoperative angiography. A total of three patients had postoperative complications: left hemiparesis, Broca's aphasia, and right hemiplegia due to vasospasm, and transient hemiparesis. Follow-up angiography revealed that all BBAs were completely occluded, except one with neck residue. All patients had favorable outcomes at discharge and the most recent clinical follow-up (mRS score ≤ 2)., Conclusion: Endovascular treatment of BBAs of the internal carotid artery using PED-assisted coil embolization is a safe and effective strategy. This has contributed to the understanding of BBA therapy and provides a potentially optimal treatment option for this intractable lesion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Liu, Zhang, Lin, Wang, Xie, Zhou and Wang.)

Background: Despite advances in B7 homolog 3 protein (B7-H3) based immunotherapy, the development of drug resistance remains a major clinical concern. The heterogeneity and emerging loss of B7-H3 expression are the main causes of drug resistance and treatment failure in targeted therapies, which reveals an urgent need to elucidate the mechanism underlying the regulation of B7-H3 expression. In this study, we identified and explored the crucial role of the transcription factor SPT20 homolog (SP20H) in B7-H3 expression and tumor progression., Methods: Here, we performed CRISPR/Cas9-based genome scale loss-of-function screening to identify regulators of B7-H3 in human ovarian cancer cells. Signaling pathways altered by SP20H knockout were revealed by RNA sequencing. The regulatory role and mechanism of SP20H in B7-H3 expression were validated using loss-of-function and gain-of-function assays in vitro. The effects of inhibiting SP20H on tumor growth and efficacy of anti-B7-H3 treatment were evaluated in tumor-bearing mice., Results: We identified SUPT20H (SP20H) as negative and eIF4E as positive regulators of B7-H3 expression in various cancer cells. Furthermore, we provided evidence that either SP20H loss or TNF-α stimulation in tumor cells constitutively activates p38 MAPK-eIF4E signaling, thereby upregulating B7-H3 expression. Loss of SP20H upregulated B7-H3 expression both in vitro and in vivo. Additionally, deletion of SP20H significantly suppressed tumor growth and increased immune cells infiltration in tumor microenvironment. More importantly, antibody-drug conjugates targeting B7-H3 exhibited superior antitumor performance against SP20H-deficient tumors relative to control groups., Conclusions: Activation of p38 MAPK-eIF4E signaling serves as a key event in the transcription initiation and B7-H3 protein expression in tumor cells. Genetically targeting SP20H upregulates target antigen expression and sensitizes tumors to anti-B7-H3 treatment. Collectively, our findings provide new insight into the mechanisms underlying B7-H3 expression and introduce a potential synergistic target for existing antibody-based targeted therapy against B7-H3., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: It is hard to distinguish cerebral aneurysms from overlapping vessels in 2D digital subtraction angiography (DSA) images due to these images' lack of spatial information., Objective: The aims of this study were to (1) construct a deep learning diagnostic system to improve the ability to detect posterior communicating artery aneurysms on 2D DSA images and (2) validate the efficiency of the deep learning diagnostic system in 2D DSA aneurysm detection., Methods: We proposed a 2-stage detection system. First, we established the region localization stage to automatically locate specific detection regions of raw 2D DSA sequences. Second, in the intracranial aneurysm detection stage, we constructed a bi-input+RetinaNet+convolutional long short-term memory (C-LSTM) framework to compare its performance for aneurysm detection with that of 3 existing frameworks. Each of the frameworks had a 5-fold cross-validation scheme. The receiver operating characteristic curve, the area under the curve (AUC) value, mean average precision, sensitivity, specificity, and accuracy were used to assess the abilities of different frameworks., Results: A total of 255 patients with posterior communicating artery aneurysms and 20 patients without aneurysms were included in this study. The best AUC values of the RetinaNet, RetinaNet+C-LSTM, bi-input+RetinaNet, and bi-input+RetinaNet+C-LSTM frameworks were 0.95, 0.96, 0.92, and 0.97, respectively. The mean sensitivities of the RetinaNet, RetinaNet+C-LSTM, bi-input+RetinaNet, and bi-input+RetinaNet+C-LSTM frameworks and human experts were 89% (range 67.02%-98.43%), 88% (range 65.76%-98.06%), 87% (range 64.53%-97.66%), 89% (range 67.02%-98.43%), and 90% (range 68.30%-98.77%), respectively. The mean specificities of the RetinaNet, RetinaNet+C-LSTM, bi-input+RetinaNet, and bi-input+RetinaNet+C-LSTM frameworks and human experts were 80% (range 56.34%-94.27%), 89% (range 67.02%-98.43%), 86% (range 63.31%-97.24%), 93% (range 72.30%-99.56%), and 90% (range 68.30%-98.77%), respectively. The mean accuracies of the RetinaNet, RetinaNet+C-LSTM, bi-input+RetinaNet, and bi-input+RetinaNet+C-LSTM frameworks and human experts were 84.50% (range 69.57%-93.97%), 88.50% (range 74.44%-96.39%), 86.50% (range 71.97%-95.22%), 91% (range 77.63%-97.72%), and 90% (range 76.34%-97.21%), respectively., Conclusions: According to our results, more spatial and temporal information can help improve the performance of the frameworks. Therefore, the bi-input+RetinaNet+C-LSTM framework had the best performance when compared to that of the other frameworks. Our study demonstrates that our system can assist physicians in detecting intracranial aneurysms on 2D DSA images., (©JunHua Liao, LunXin Liu, HaiHan Duan, YunZhi Huang, LiangXue Zhou, LiangYin Chen, ChaoHua Wang. Originally published in JMIR Medical Informatics (https://medinform.jmir.org), 16.03.2022.)

Following spinal cord injury (SCI), the transmission of electrical signals is interrupted, and an oxidative microenvironment is generated, hindering nerve regeneration and functional recovery. The strategies of regulating oxidative pathological microenvironment while restoring endogenous electrical signal transmission hold promise for SCI treatment. However, challenges are still faced in simply fabricating bioactive scaffolds with both antioxidation and conductivity. Herein, aiming to construct an antioxidative and conductive microenvironment for nerve regeneration, the difunctional polypyrrole (PPy) nanoparticles were developed and incorporated into bioactive collagen/hyaluronan hydrogel. Owing to the embedded PPy in hydrogel, the encapsulated bone marrow mesenchymal stem cells (BMSCs) can be protected from oxidative damage, and their neuronal differentiation was promoted by the synergy between conductivity and electrical stimulation, which is proved to be related to PI3K/Akt and the mitogen-activated protein kinase (MAPK) pathway. In SCI rats, the BMSC-laden difunctional hydrogel restored the transmission of bioelectric signals and inhibited secondary damage, thereby facilitating neurogenesis, resulting in prominent nerve regeneration and functional recovery. Overall, taking advantage of a difunctional nanomaterial to meet two essential requirements in SCI repair, this work provides intriguing insights into the design of biomaterials for nerve regeneration and tissue engineering.

A 57-year-old female presented with headache and dizziness for 3 months. Preoperative MRI revealed a lesion located at the pineal region and back side of the third ventricle, accompanied by hydrocephalus. The infratentorial supracerebellar approach may cause visuomotor, acousticomotor, and hearing disturbances. With the patient in a supine position, the authors used a frontal linear incision that was 3 cm anterior to the coronal suture and 2 cm away from the midline and an anterior endoscopic transcortical approach, which could achieve endoscopic third ventriculostomy, alleviating and preventing hydrocephalus due to postoperative adhesion and resection of the lesion at the same time. The pathological diagnosis was cavernous hemangioma. The video can be found here: https://stream.cadmore.media/r10.3171/2021.4.FOCVID215., Competing Interests: Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this publication., (© 2021, The Authors.)

Knowledge on high-grade meningiomas in octogenarian and elderly patients is limited. We aimed to analyze the outcomes and identify factors that influence overall survival (OS) in this population, using data from the Surveillance, Epidemiology, and End Results (SEER) database.Patients (≥80 years old) diagnosed with high-grade meningiomas between 1990 and 2016 were retrieved from the SEER database. According to treatments received, patients were classified into three groups: observation, radiation only, and surgery (with or without radiation). A Cox proportional hazards regression model was used for univariate and multivariate analyses. Based on the inclusion criteria, 678 patients with high-grade meningiomas were included.Surgery was the most common treatment modality. The median OS was 32 months for patients who received surgery, compared with 20 months for observation (p = 0.001).The factors significantly associated with OS on multivariate analysis included increasing age (hazard ratio [HR] 1.353, p < 0.001), diagnosis after 2008 (HR 0.693, p = 0.022), and surgical treatment (HR 0.807, p = 0.028). Further analysis revealed increasing age (HR 1.451, p = 0.003), and subtotal resection (HR 1.275, p = 0.043) were significantly associated with worse OS following surgery. This is the largest clinical study of high-grade meningiomas in octogenarian and elderly patients conducted thus far. Age, treatment modality, and year of diagnosis were associated with OS in octogenarian and elderly patients with high-grade meningiomas. Patients who received subtotal resection had a worse prognosis than gross total resection., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In decades, the efficiency of glioma therapy is far from satisfaction due to the inability of most therapeutics to accumulate at the glioblastoma (GBM) site. Therefore, it is urgent to develop novel tumor-targeted delivery systems for more optimized and effective glioma treatment. In this study, hyaluronic acid modified MPEG-PDLLA polymer (HAML) nanoparticles were used to encapsulate the cabazitaxel (Cab), creating Cab loaded HAML nanoparticles (Cab/HAML NPs) for glioma therapy both in vitro and in vivo. MTT assay and apoptotic study indicated Cab/HAML NPs induced a significant cell growth inhibition and more apoptosis of C6 cells than free Cab in vitro. In vivo study showed that Cab/HAML NPs could significantly improve chemotherapeutic effect to C6 tumor-bearing rats compared with free Cab. The median survival rate of Cab/HAML NPs-treated groups (30 days) was remarkably longer than the other groups treated with control (20 days), free Cab (19 days) and Cab/ML NPs (26 days). Immunohistochemical analysis revealed that Cab/HAML NPs improved Cab's anti-tumor effect via improvement of tumor cell apoptosis, inhibition of tumor cell proliferation and a significant decrease in tumor angiogenesis. Together, our study suggested that Cab/HAML NPs might show promise for application to glioma therapy.

Recently, B7-H3 was frequently reported to be overexpressed in various cancer types and has been suggested to be a promising target for cancer immunotherapy. In the present study, we analyzed the mRNA expression of B7-H3 in The Cancer Genome Atlas (TCGA) database and validated its expression across multiple cancer types. We then generated a novel B7-H3-targeted chimeric antigen receptor (CAR) and tested its antitumor activity both in vitro and in vivo . The B7-H3 expression heterogeneity and variation were frequent. Moderate or even high expression levels of B7-H3 were also observed in some tumor-adjacent tissues, but the staining intensity was weaker than that in tumor tissues. B7-H3 expression was absent or very low in normal tissues and organs. Flow cytometry indicated that the mean expression level of B7-H3 in eight bone marrow specimens from patients with acute myeloid leukemia (AML) was 57.2% (range 38.8-80.4). Furthermore, we showed that the B7-H3-targeted CAR-T cells exhibited significant antitumor activity against AML and melanoma in vitro and in xenograft mouse models. In conclusion, although B7-H3 represents a promising pan-cancer target, and B7-H3-redirected CAR-T cells can effectively control tumor growth, the expression heterogeneity and variation have to be carefully considered in translating B7-H3-targeted CAR-T cell therapy into clinical practice., (© 2020 The Author(s).)

Rationale: Hemangiopericytoma (HPC) is a rare pediatric neoplasm with a high risk of bleeding, aggressive growth and high early relapse rates. Surgical excision remains the mainstream treatment, while the functions of chemotherapy and radiotherapy remain controversial. In particular, an infantile giant extracranial HPC located in the forehead has never been reported., Patient Concerns: A 3-day-old girl was delivered normally with a giant tumor localized mainly in the right frontal region. The surface of the mass was filled with vascularity., Diagnosis: According to the results of imaging and pathological examinations, the diagnosis was HPC grade II., Interventions: Gross total resection of the tumor and the invading partial frontal bone followed by skin scalp reconstruction was carried out without any blood transfusion., Outcomes: No recurrence was identified during 5 years of follow-up. And better outcomes can be achieved without adjuvant therapy., Lessons: Multimodality imaging and a collaborative multidisciplinary approach are indispensable for the successful surgical management of infantile HPC, especially for giant tumors and their potential risk of life-threatening bleeding. Gross total resection is the optimal option for infantile HPC, and even without adjuvant therapy, it achieves better outcomes.

Glioblastoma (GBM) remains one of the most malignant primary tumors in adults, with a 5-year survival rate less than 10% because of lacking effective treatment. Here, we aimed to explore whether B7-H3 could serve as a novel therapeutic target for GBM in chimeric antigen receptor (CAR) T cell therapy. In this study, a CAR targeting B7-H3 was constructed and transduced into T cells by lentivirus. Antitumor effects of B7-H3-specific CAR-T cells were assessed with primary and GBM cell lines both in vitro and in vivo . Our results indicated that B7-H3 was positively stained in most of the clinical glioma samples, and its expression levels were correlated to the malignancy grade and poor survival in both low-grade glioma (LGG) and GBM patients. Specific antitumor functions of CAR-T cells were confirmed by cytotoxic and ELISA assay both in primary glioblastoma cells and GBM cell lines. In the orthotropic GBM models, the median survival of the CAR-T-cell-treated group was significantly longer than that of the control group. In conclusion, B7-H3 is frequently overexpressed in GBM patients and may serve as a therapeutic target in CAR-T therapy.

BRAF-V600E (1799T > A) is one of the most frequently reported driver mutations in multiple types of cancers, and patients with such mutations could benefit from selectively inactivating the mutant allele. Near this mutation site, there are two TTTN and one NGG protospacer-adjacent motifs (PAMs) for Cpf1 and Cas9 CRISPR nucleases, respectively. The 1799T > A substitution also leads to the occurrence of a novel NGNG PAM for the EQR variant of Cas9. We examined the editing efficacy and selectivity of Cpf1, Cas9, and EQR variant to this mutation site. Only Cpf1 demonstrated robust activity to induce specific disruption of only mutant BRAF, not wild-type sequence. Cas9 recognized and cut both normal and mutant alleles, and no obvious gene editing events were observed using EQR variant. Our results support the potential applicability of Cpf1 in precision medicine through highly specific inactivation of many other gain-of-function mutations., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Annexin A2 (AnxA2) is a highly conserved Ca2 + -regulated membrane binding protein, which affects cell mobility and tumor progression. Adamantinomatous craniopharyngioma (AdaCP) are a kind of epithelial tumors of the sellar region with high tendency to recur. Robust biomarkers are required to predict tumor behavior and to establish follow-up individualized treatment approaches. In this study, we firstly compared four surgical AdaCP samples with normal brain by two-dimensional gel electrophoresis (2DE) proteomic analysis. Potential prognostic biomarkers were further validated in a large cohort of 65 AdaCPs by immunohistochemistry. The effects of AnxA2 on AdaCP cells proliferation and migration were analyzed in vitro with isolated primary AdaCP cells as well as SV40T-immortalized cells. Finally, the gefitinib sensitivity of AdaCPs with differentially expressed AnxA2 and the potential molecular mechanisms were examined by flow cytometric analysis, Real-time PCR and immunoblot assays. Proteomic analysis indicated that AnxA2 was the protein spot with the most elevated expression in AdaCP samples. Immunohistochemistry assays indicated the expression level of AnxA2 was significantly higher in recurrent AdaCPs compared with primary ones. Moreover, AnxA2 + AdaCP cells exhibited enhanced proliferation and migration ability compared with AnxA2 - AdaCP cells in vitro. Further, we show that AnxA2 + AdaCP cells exhibited elevated expression of EGFR and downstream p-AKT (S308) and p-AKT (S473), and were more sensitive to tyrosine kinase inhibitor gefitinib. Our data suggest that AnxA2 may serve as a promising biomarker for AdaCP progression, recurrence and drug susceptibility. Our data support potential clinical implications for the follow-up treatment of AdaCP patients with high AnxA2 expression.

Wound healing is a complex multifactorial process that relies on coordinated signaling molecules to succeed. Epidermal growth factor (EGF) is a mitogenic polypeptide that stimulates wound repair; however, precise control over its application is necessary to reduce the side effects and achieve desired therapeutic benefits. Moreover, the extensive oxidative stress during the wound healing process generally inhibits repair of the injured tissues. Topical applications of antioxidants like curcumin (Cur) could protect tissues from oxidative damage and significantly improve tissue remodeling. To achieve much accelerated wound healing effects, we designed a novel dual drug co-loaded in situ gel-forming nanoparticle/hydrogel system (EGF-Cur-NP/H) which acted not only as a supportive matrix for the regenerative tissue, but also as a sustained drug depot for EGF and Cur. In the established excisional full-thickness wound model, EGF-Cur-NP/H treatment significantly enhanced wound closure through increasing granulation tissue formation, collagen deposition, and angiogenesis, relative to normal saline, nanoparticle/hydrogel (NP/H), Cur-NP/H, and EGF-NP/H treated groups. In conclusion, this study provides a biocompatible in situ gel-forming system for efficient topical application of EGF and Cur in the landscape of tissue repair.

The protease β-secretase plays a critical role in the synthesis of pathogenic amyloid-β in Alzheimer's disease. In this study, pharmacophore constructed from receptor-ligand complex was used to screen Chemdiv and Zinc database and the resulting hits were subjected to docking experiments using LiandFit and CDOCKER programs. Molecules with high consensus scores and good interaction patterns in docking programs were retained. Drug-likeness assay including Lipinski's rule of five and ADMET properties filters were further used to identify BACE1 inhibitor. Finally, 13 compounds with novel scaffolds were selected and, considering of the nature of relative high LogP value of many marketed AD drugs, three of them with top 3 predicted LogP value were evaluated for their IC50 values in vitro by BACE1 enzymatic activity study. We believe that compound 13 with an IC50 value of 136 µM can be a lead compound with great potential in BACE1 inhibition and increasing activity by subsequently structure modification or optimization. At the same time, we found that the interaction between the residues Asp228, Asp32 of BACE1 and ligands is significant through analyzing the binding mode of 13 candidate compounds.

Intraperitoneal chemotherapy was explored in clinical trials as a promising strategy to improve the therapeutic effects of chemotherapy. In this work, we developed a biodegradable and injectable drug-delivery system by coencapsulation of docetaxel (Doc) and LL37 peptide polymeric nanoparticles (Doc+LL37 NPs) in a thermosensitive hydrogel system for colorectal peritoneal carcinoma therapy. Firstly, polylactic acid (PLA)-Pluronic L35-PLA (PLA-L35-PLA) was explored to prepare the biodegradable Doc+LL37 NPs using a water-in-oil-in-water double-emulsion solvent-evaporation method. Then, biodegradable and injectable thermosensitive PLA-L64-PLA hydrogel with lower sol-gel transition temperature at around body temperature was also prepared. Transmission electron microscopy revealed that the Doc+LL37 NPs formed with the PLA-L35-PLA copolymer were spherical. Fourier-transform infrared spectra certified that Doc and LL37 were encapsulated successfully. X-ray diffraction diagrams indicated that Doc was encapsulated amorphously. Intraperitoneal administration of Doc+LL37 NPs-hydrogel significantly suppressed the growth of HCT116 peritoneal carcinomatosis in vivo and prolonged the survival of tumor-bearing mice. Our results suggested that Doc+LL37 NPs-hydrogel may have potential clinical applications.

This study investigated ageing-resistant properties of carboxyl-terminated polyester (polyethylene glycol terephthalate) composites modified with nanoscale titanium dioxide particles (nano-TiO2). The nano-TiO2 was pretreated by a dry coating method, with aluminate coupling agent as a functional grafting additive. The agglomeration resistance was evaluated, which exhibited significant improvement for the modified nanoparticles. Then, the effects of the modified nano-TiO2 on the crosslinking and ageing-resistant properties of the composites were studied. With a real-time Fourier transform infrared (FT-IR) measurement, the nano-TiO2 displayed promoting effect on the crosslinking of polyester resin with triglycidyl isocyanurate (TGIC) as crosslinking agent. Moreover, the gloss retention, colour aberration and the surface morphologies of the composites during accelerated UV ageing (1500 hours) were investigated. The results demonstrated much less degree of ageing degradation for the nanocomposites, indicating an important role of the nano-TiO2 in improving the ageing-resistant properties of synthetic polymer composites.

The aim of this study was to develop a kind of osteogenic biodegradable composite graft consisting of human placenta-derived mesenchymal stem cell (hPMSC) material for site-specific repair of bone defects and attenuation of clinical symptoms. The novel nano- to micro-structured biodegradable hybrid fibers were prepared by electrospinning. The characteristics of the hybrid membranes were investigated by a range of methods, including Fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry. Morphological study with scanning electron microscopy showed that the average fiber diameter and the number of nanoscale pores on each individual fiber surface decreased with increasing concentration of poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCEC). The prepared polylactide (PLA)/PCEC fibrous membranes favored hPMSC attachment and proliferation by providing an interconnected, porous, three-dimensional mimicked extracellular environment. What is more, hPMSCs cultured on the electrospun hybrid PLA/PCEC fibrous scaffolds could be effectively differentiated into bone-associated cells by positive alizarin red staining. Given the good cellular response and excellent osteogenic potential in vitro, the electrospun PLA/PCEC fibrous scaffolds could be one of the most promising candidates for bone tissue engineering.

In this study, L-lactide was used to modify the tricalcium phosphate (β-TCP) and tetracalcium phosphate (TTCP) surface which can form functionalized poly(l-lactic acid) (PLLA)-grafted β-TCP (g-β-TCP) and PLLA-grafted TTCP (g-TTCP) particles. The g-β-TCP and g-TTCP obtained were incorporated into a PEG-PCL-PEG (PECE) matrix to prepare injectable thermosensitive hydrogel composites. The morphology of the hydrogel composites showed that the g-β-TCP and g-TTCP particles dispersed homogeneously into the polymer matrix, and each hydrogel composite had a three-dimensional network structure. Rheologic analysis showed that the composite had good thermosensitivity. Changes in calcium concentration and pH in simulated body fluid solutions confirmed the feasibility of surface-functionalized calcium phosphate for controlled release of calcium. All the results indicate that g-β-TCP/PECE and g-TTCP/PECE hydrogels might be a promising protocol for tissue engineering.

The ratio between FABP5 and CRABPII determines cellular response to physiological level of retinoic acid; tumor cells undergo proliferation with high level of FABP5 and apoptosis with high level of CRABPII. We intended to study FABP5 and CRABPII expression in craniopharyngiomas, to establish craniopharyngioma cell model using explants method, and to study the effect of pharmacological dose of retinoic acid on craniopharyngioma cells. Expression of FABP5 and CRABPII in craniopharyngioma tissue from 20 patients was studied using immunohistochemistry. Primary craniopharyngioma cell cultures were established using tissue explants method. Craniopharyngioma cells were treated using various concentrations of all-trans retinoic acid, and cell growth curve, apoptosis, expression of FABP5, CRABPII and NF-κB were assayed in different groups. FABP5/CRABPII ratio was significantly higher in adamatinomatous group than that in papillary group. Cell cultures were established in 19 cases (95 %). Pharmacological level retinoic acid inhibited cell growth and induced cellular apoptosis in dose dependent manner, and apoptosis rate cells treated with 30 μM retinoic acid for 24 h was 43 %. Also, retinoic acid increased CRABPII, and decreased FABP5 and NF-κB expression in craniopharyngioma cells. High FABP5/CRABPII ratio is observed in adamatinomatous craniopharyngioma. Retinoic acid at pharmacological level induced craniopharyngioma cell apoptosis via increasing FABP5/CRABPII ratio and inhibiting NF-κB signaling pathway. Our study demonstrated that all-trans retinoic acid might be a candidate for craniopharyngioma adjuvant chemotherapy in future.

Numerous challenges remain in the successful clinical translation of cell-based therapeutic studies for skeletal tissue repair, including appropriate cell sources and viable cell delivery systems. Poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) amphiphilic block copolymers have been extensively explored in microspheres preparation. Due to the introduction of hydrophilic PEG segments into PCL backbones, these copolymers have shown much more potentials in carrying protein, lipophilic drugs or genes than commonly used poly (ε-caprolactone) (PCL) and poly (lactic acid). The aim of this study is to investigate the attachment and osteogenic differentiation of human placenta derived mesenchymal stem cells (PMSCs) on PEG-PCL triblock copolymers nanofiber scaffolds. Here we demonstrated that PMSCs proliferate robustly and can be effectively differentiated into osteogenic-like cells on nanofiber scaffolds. This study provides evidence for the use of nanofiber scaffolds as an ideal supporting material for in vitro PMSCs culture and an in vivo cell delivery vehicle for bone repair.

Poly(methyl methacrylate-butyl acrylate) [P(MMA-BA)]/nanosized titanium oxide (nano-TiO2) composite particles were prepared via insitu emulsion polymerization of MMA and BA in presence of nano-TiO2 particles. Before polymerization, the nano-TiO2 particles were modified by coupling agent. The structure and thermal properties of the obtained P(MMA-BA)/nano-TiO2 composite particles were characterized by Fourier transform infrared spectra (FTIR), wide-angle X-ray diffraction (WAXD) and thermogravimetric analysis (TGA). The results showed that there are covalent bond bindings between P(MMA-BA) and nano-TiO2 particles, meaning that P(MMA-BA) and nano-TiO2 particles were not simply blended or mixed up and that there is a strong interaction between P(MMA-BA) and nano-TiO2 particles. TGA and DSC measurements indicated an enhancement of thermal stability. Transmission electron microscopy (TEM) results showed that P(MMA-BA) enhanced the dispersibility of nano-TiO2 particles. The dispersion stabilization of modified nano-TiO2 particles in aqueous system was significantly improved due to the introduction of grafted polymer on the surface of nano-particles.

Rathke's cleft cyst (RCC) is a congenital, benign, epithelial tumor and mainly occurs in sellar region and occasionally in suprasellar region; ectopic RCC is exceedingly rare. We report an uncommon RCC in cerebellopontine angle (CPA) associated with RCC apoplexy and investigated the possible hypothesis of its origin. A 12-year-old female student was admitted to hospital for 3-month history of vertigo, headache, nausea, and vomiting and aggravated for 1 week. Magnetic resonance imaging (MRI) revealed a space-occupying lesion with short T1 and long T2 signals in the left CPA and an intracystic floating nodule with hypointensity on T1- and T2-weighted imaging. The patient underwent the total tumor removal via the retrosigmoid approach with a good recovery. Primary RCC was confirmed by pathology. Follow-up MRI showed no recurrence 3.5 years after craniotomy. Primary RCC can occur in CPA and present special neuroimaging features associated with RCC apoplexy. We presumed that a mimicking mechanism of ectopic craniopharyngioma in CPA leads to the formation in the present case. Microsurgical resection is the optimal strategy for management. Further research and longer follow-up are helpful to better understanding the pathogenesis and development history of RCC in CPA.

Craniopharyngioma (CP) is a pathologically benign tumor with high incidence of recurrence and poor prognosis. DNA ploidy, S-phase fraction (SPF), and G2 phase/mitosis phase + S phase (G2/M + S) measured by flow cytometry (FCM) have been shown to correlate with cell cycle characteristics and clinical prognosis of other tumors. By use of FCM and terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) peroxidase, we compared DNA content, SPF, G2/M + S, necrosis and apoptosis in non-recurrent and recurrent tumor cells of CP from 63 cases including 32 adamantine epitheliomas (AEs) and 31 squamous papillary tumors (SPTs), and the ultrastructure of the CP cell was observed by transmission electron microscopy. Although no obvious differences between DNA content and necrosis and apoptosis rate were observed in subgroups of CPs, SPF and G2/M + S for recurrent tumors were statistically higher than those for recurrence-free tumors, and the recurrence rate of AE tumors is higher than that of SPT. Therefore, CP cells are diploid, and SPF and G2/M + S are related to recurrence of CP.

Background and Purpose: Posterior fossa craniopharyngiomas (PFCP) constitute 1.6-4% of all craniopharyngiomas and have long been neglected. The purpose of our study was to investigate neuroimaging features of this unique modality in a cohort of 7 cases., Methods: CT and/or MR imaging features (with and without contrast enhancement) of 7 patients who underwent craniotomies for histologically proved PFCP were reviewed and analyzed retrospectively. Surgical management was also reviewed., Results: All PFCPs arised from sellar/suprasellar region and extended into unilateral cerebellopontine angle in 6 cases, and bilateral in 1 case. Seven tumors were of retrochiasmatic origin and 5 of 7 were of retrostalk growth pattern with location in the ventral area of brain stem. On CT scans, tumors were isodense in solid component and hypodense in cystic component with (4/7) or without calcification (3 /7) and destruction in sellae turcia (2/7). Tumors demonstrated cyst formation (7/7) with hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging in 5 cases, hyperintense both on T1- and T2-weighted imaging in 2 cases. The solid components and capsule revealed mild to moderate inhomogeneous enhancement after administration of contrast agents. Total tumor removal was accomplished in 5 cases, subtotal removal and partial removal in 1 case respectively., Conclusions: PFCPs are well demarcated, contrast-enhanced tumors, typically with cystic parts or purely cyst. Most of PFCPs demonstrate a retrostalk growth pattern and characteristic connection. Tumor with cystic component arises from sellar region and then extends to posterior fossa, which should be strongly suspected as a PFCP. The combined supra- and infratentorial approach is an ideal choice for surgical management of PFCP.

Human 14-3-3 proteins have isoform-specific expression and functions in different kinds of normal or tumor cells and tissues. However, the expression profiling of 14-3-3 proteins and isoform-specific biological functions are unclear in human glioma so far. In our study, the expression levels and characterization of 14-3-3 isoforms in human glioma tissues were investigated by a sensitive, accurate stable isotope labeling with amino acids in cell culture-based quantitative proteomic strategy. As a result, except unexpressed 14-3-3σ, the other six isoforms, with different expression levels, were existed in glioma tissues and para-cancerous brain tissues (PBTs). 14-3-3β and η were upregulated, whereas 14-3-3ζ was downregulated in glioma tissues compared with that in PBTs. And the other three isoforms 14-3-3ε, θ, and γ had similar expression levels in human glioma tissues and PBTs. Western blot and immunohistochemistry analysis were both consistent with the quantitative proteomic data. The loss of expression of 14-3-3σ was further discovered due to DNA high methylation in its coding region in glioma by methylation-specific PCR analysis. These results indicated that the four isoforms, including 14-3-3β, η, ζ, and σ, may play important roles in tumorigenesis of human glioma, which is probably used as potential biomarkers for diagnosis and targets for treatment of human gliomas in future., (Copyright © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: To investigate the microsurgical management of cranionasal tumors and the method of the reconstruction of the skull base., Methods: From June 2005 to October 2007, 20 patients with cranionasal tumor were treated. There were 10 males and 10 females, aged between 13 and 77 years (median 49 years). The disease course was 2 months to 13 years. The cranionasal tumors, proved by MRI and CT scans, located in the anterior skull base, paranasal sinus, nasal and/or orbit cavity. And their clinical presentations were listed as follows: dysosphresia in 14 patients, headache in 11 patients, nasal obstruction in 9 patients, epistaxis in 8 patients, visual disorder in 4 patients, exophthalmos in 4 patients and conscious disturbance in 2 patients. All 20 patients underwent transnasal surgery combined with transnasal surgery, and tumors were resected by one-stage operation. The skull base was reconstructed by surgical technique "Pull Down Sandwich" with pedicle periosteum flap., Results: Tumors were resected by one-stage operation, and the anterior skull bases were reconstructed. Pathological examination showed 8 cases of malignant tumors and 12 cases of benign tumors. The total surgical excision was complete in 16 patients, and 4 patients with subtotal excision. There was no operative death. Eighteen patients were followed up 3 months to 2 years and 6 months. Transient cerebrospinal fluid rhinorrhea was found in 2 cases which were cured by lumbar drainage. And recurrence of tumor was observed in 5 patients 3 months to 2 years after operation., Conclusion: Microsurgical operation via subfrontal approach assisted by transnasal endoscopy is an effective method in management of cranionasal tumors, with the advantages of reconstruction of the skull base with pedicle periosteum flap or "Pull Down Sandwich" and low complication rate.