Prosaposin is a biomarker of mesenchymal glioblastoma and regulates mesenchymal transition through the TGF-ß1/Smad signaling pathway.

Mesenchymal glioblastoma (GBM) is the most aggressive subtype of GBM. Our previous study found that neurotrophic factor prosaposin (PSAP) is highly expressed and secreted in glioma and can promote the growth of glioma. The role of PSAP in mesenchymal GBM is still unclear. In this study, bioinformatic analysis, western blotting and RT-qPCR were used to detect the expression of PSAP in different GBM subtypes. Human glioma cell lines and patient-derived glioma stem cells were studied in vitro and in vivo, revealing that mesenchymal GBM expressed and secreted the highest level of PSAP among four subtypes of GBM, and PSAP could promote GBM invasion and epithelial-mesenchymal transition (EMT)-like processes in vivo and in vitro. Bioinformatic analysis and western blotting showed that PSAP mainly played a regulatory role in GBM invasion and EMT-like processes via the TGF-ß1/Smad signaling pathway. In conclusion, the overexpression and secretion of PSAP may be an important factor causing the high invasiveness of mesenchymal GBM. PSAP is therefore a potential target for the treatment of mesenchymal GBM. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A Low-Temperature Micro Hotplate Gas Sensor Based on AlN Ceramic for Effective Detection of Low Concentration NO2.

Air pollution is one of the major threats to human health. The monitoring of toxic NO2 gas in urban air emission pollution is becoming increasingly important. Thus, the development of an NO2 sensor with low power consumption, low cost, and high performance is urgent. In this paper, a planar structural micro hotplate gas sensor based on an AlN ceramic substrate with an annular Pt film heater was designed and prepared by micro-electro-mechanical system (MEMS) technology, in which Pt/Nb/In2O3 composite semiconductor oxide was used as the sensitive material with a molar ratio of In:Nb = 9:1. The annular thermal isolation groove was designed around the heater to reduce the power consumption and improve the thermal response rate. Furthermore, the finite element simulation analysis of the thermal isolation structure of the sensor was carried out by using ANSYS software. The results show that a low temperature of 94 °C, low power consumption of 150 mW, and low concentration detection of 1 to 10 ppm NO2 were simultaneously realized for the Nb-doped In2O3-based gas sensor. Our findings provide a promising strategy for the application of In2O3-based sensors in highly effective and low concentration NO2 detection.

Low preoperative prognostic nutritional index predicts poor survival in patients with newly diagnosed high-grade gliomas.

Preoperative prognostic nutritional index (PNI) has been widely demonstrated to predict survival of patients with malignant tumors. Its utility in predicting outcomes in patients with high-grade gliomas (HGG) remains undefined. A retrospective study of 188 HGG patients was conducted. An optimal PNI cut-off value was applied to stratify patients into high PNI (≥52.55, n = 78) and low PNI (<52.55, n = 110) groups. Univariate and multivariate analysis was performed to identify prognostic factors associated with overall survival (OS) and progression free survival (PFS). The resulting prognostic models were externally validated using a demographic-matched cohort of 130 HGG patients. In the training set, PNI value was negatively correlated with age (p = 0.027) and tumor grade (p = 0.048). Both PFS (8.27 vs. 20.77 months, p < 0.001) and OS (13.57 vs. 33.23 months, p < 0.001) were significantly worse in the low PNI group. Strikingly, patients in high PNI group had a 52% decrease in the risk of tumor progression and 55% decrease of death relative to low PNI. Multivariate analysis further demonstrated PNI as an independent predictor for PFS (HR = 0.62, 95% CI 0.43-0.87) and OS (HR = 0.56, 95% CI 0.38-0.80). The PNI retained independent prognostic value in the validation set for both PFS (p = 0.013) and OS (p = 0.003). On subgroup analysis by tumor grade and treatment modalities, both PFS and OS were better for the patients with high PNI. The PNI is a potentially valuable preoperative marker for the survival of patients following HGG resection.

Postoperative functional status in patients with supratentorial superficial low-grade glioma.

BACKGROUND: We investigated the functional status of adult supratentorial superficial low-grade glioma (ASS-LGG) after surgery and analyzed its relevant factors to guide the therapeutic strategy and improve the life quality of these patients. METHODS: Clinical materials from January 2008 to December 2010 in 104 adults with ASS-LGG were analyzed retrospectively. The follow-up period ranged from 6 months to 1.5 years. The logistic regression was used to evaluate the preoperative and postoperative variation of functional status in patients to disclose the relevant factors affecting postoperative functional status, such as age, gender, the duration of symptom, size and location of the tumor, hemisphere, resection degree, and tumor pathologic grade and preoperative Karnofsky performance status (Pre-KPS). RESULTS: Four out of nine candidate factors are related to the postoperative functional status. They are age less than 40 years, the size of tumor less than 5 cm in diameter, tumor located in the right hemisphere, and limited resection of tumor in the eloquent area. CONCLUSIONS: It seems more meaningful to evaluate the functional status of the patients with ASS-LGG on the basis of these clinical features, involving age, tumor size, location, and extent of resection.

A new aurone glycoside from Veratrum dahuricum (Turcz.) Loes. f.

To study the chemical constituents of Veratrum dahuricum (Turcz.) Loes. f., a new aurone glycoside named as (Z)-7, 4'-dimethoxy-6-hydroxyl-aurone-4-O-ß-glucopyranoside was isolated from the 95% ethanol extracts of the rhizomes and roots of Veratrum dahuricum (Turcz.) Loes. f. by repeated column chromatography on silica gel and recrystallization. Its structure was established by extensive spectroscopic analyses, and its cytotoxicities against HepG-2, MCF7 and A549 cell lines were measured in vitro.

MiR-181b sensitizes glioma cells to teniposide by targeting MDM2.

BACKGROUND: Although the incidence of glioma is relatively low, it is the most malignant tumor of the central nervous system. The prognosis of high-grade glioma patient is very poor due to the difficulties in complete resection and resistance to radio-/chemotherapy. Therefore, it is worth investigating the molecular mechanisms involved in glioma drug resistance. MicroRNAs have been found to play important roles in tumor progression and drug resistance. Our previous work showed that miR-181b is involved in the regulation of temozolomide resistance. In the current study, we investigated whether miR-181b also plays a role in antagonizing the effect of teniposide. METHODS: MiR-181b expression was measured in 90 glioma patient tissues and its relationship to prognosis of these patients was analyzed. Cell sensitivity to teniposide was tested in 48 primary cultured glioma samples. Then miR-181b stably overexpressed U87 cells were generated. The candidate genes of miR-181b from our previous study were reanalyzed, and the interaction between miR-181b and target gene MDM2 was confirmed by dual luciferase assay. Cell sensitivity to teniposide was detected on miR-181b over expressed and MDM2 down regulated cells. RESULTS: Our data confirmed the low expression levels of miR-181b in high-grade glioma tissues, which is related to teniposide resistance in primary cultured glioma cells. Overexpression of miR-181b increased glioma cell sensitivity to teniposide. Through target gene prediction, we found that MDM2 is a candidate target of miR-181b. MDM2 knockdown mimicked the sensitization effect of miR-181b. Further study revealed that miR-181b binds to the 3'-UTR region of MDM2 leading to the decrease in MDM2 levels and subsequent increase in teniposide sensitivity. Partial restoration of MDM2 attenuated the sensitivity enhancement by miR-181b. CONCLUSIONS: MiR-181b is an important positive regulator on glioma cell sensitivity to teniposide. It confers glioma cell sensitivity to teniposide through binding to the 3'-UTR region of MDM2 leading to its reduced expression. Our findings not only reveal the novel mechanism involved in teniposide resistance, but also shed light on the optimization of glioma treatment in the future.

Vasculogenic mimicry: a novel target for glioma therapy.

Anti-angiogenic therapy has shown promising but insufficient efficacy on gliomas. Recent studies suggest that vasculogenic mimicry (VM), or the formation of non-endothelial, tumor-cell-lined microvascular channels, occurs in aggressive tumors, including gliomas. There is also evidence of a physiological connection between the endothelial-lined vasculature and VM channels. Tumor cells, by virtue of their high plasticity, can form vessel-like structures themselves, which may function as blood supply networks. Our previous study on gliomas showed that microvessel density was comparably less in VM-positive tumors than in VM-negative tumors. Thus, VM may act as a complement to ensure tumor blood supply, especially in regions with less microvessel density. Patients with VM-positive gliomas survived a shorter period of time than did patients with VM-negative gliomas. Although the detailed molecular mechanisms for VM are not fully understood, glioma stem cells might play a key role, since they are involved in tumor tissue remodeling and contribute to neovascularization via transdifferentiation. In the future, successful treatment of gliomas should involve targeting both VM and angiogenesis. In this review, we summarize the progress and challenges of VM in gliomas.

Enhanced MGMT expression contributes to temozolomide resistance in glioma stem-like cells.

O6-methylguanine DNA methyltransferase (MGMT) can remove DNA alkylation adducts, thereby repairing damaged DNA and contributing to the drug resistance of gliomas to alkylating agents. In addition, glioma stem-like cells (GSCs) have been demonstrated to be involved in the recurrence and treatment resistance of gliomas. In this study, we aimed to investigate MGMT expression and regulatory mechanisms in GSCs and the association of MGMT with temozolomide (TMZ) sensitivity. GSCs were enriched from one MGMT-positive cell line (SF-767) and 7 MGMT-negative cell lines (U251, SKMG-4, SKMG-1, SF295, U87, MGR1, and MGR2) through serum-free clone culture. GSCs from the U251G, SKMG-4G, SF295G, and SKMG-1G cell lines became MGMT-positive, but those from the U87G, MGR1G, and MGR2G cell lines remained MGMT-negative. However, all the GSCs and their parental glioma cell lines were positive for nuclear factor-κB (NF-κB). In addition, GSCs were more resistant to TMZ than their parental glioma cell lines (P < 0.05). However, there was no significant difference in the 50% inhibition concentration (IC50) of TMZ between MGMT-positive and MGMT-negative GSCs (P > 0.05). When we treated the MGMT-positive GSCs with TMZ plus MG-132 (an NF-κB inhibitor), the antitumor activity was significantly enhanced compared to that of GSCs treated with TMZ alone (P <0.05). Furthermore, we found that MGMT expression decreased through the down-regulation of NF-κB expression by MG-132. Our results show that MG-132 may inhibit NF-κB expression and further decrease MGMT expression, resulting in a synergistic effect on MGMT-positive GSCs. These results indicate that enhanced MGMT expression contributes to TMZ resistance in MGMT-positive GSCs.

Clinical Oversight and Delayed Diagnosis of a Pathological Compression Fracture Causing Paraplegia.

While osteoporosis is the primary cause of vertebral compression fractures (VCFs), it's crucial to promptly recognize pathological fractures through comprehensive diagnostic tests, including vertebral biopsies, to determine the exact etiology. For instance, a 66-year-old male with osteoporosis experienced worsening lower limb weakness and back pain after an initial vertebroplasty for a T12 compression fracture. Subsequent MRI revealed severe circumferential extradural compression at T12, leading to further surgeries that eventually uncovered metastatic adenocarcinoma from a pancreatic tumor. This case highlights the importance of precise diagnosis through vertebral biopsy and the necessity of sufficient ventral decompression or corpectomy, coupled with extensive laminectomy, to address severe neurological impairments like paraplegia. Prompt and accurate interventions can significantly improve patient outcomes and quality of life.

Neurosurgical interventions for patients with nasopharyngeal carcinoma: a single institution experience.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a frequent head and neck cancer in southern China and Southeast Asia. The majority of NPC patients are managed by radiation oncologists, medical oncologists and head and neck surgeons. Actually, neurosurgical interventions are warranted under specific circumstances. In this article, we described our experience as neurosurgeons in the management of NPC patients. METHODS: Medical records of NPC patients who received neurosurgical procedure at Sun Yat-sen University Cancer Center were reviewed. RESULTS: Twenty-seven patients were identified. Among 27 cases, neurosurgical procedures were performed in 18 (66.7%) with radiation-induced temporal necrosis, 2 (7.4%) with radiation-induced sarcoma, 4 (14.8%) with synchronous NPC with primary brain tumors, 2 (7.4%) with recurrent NPC involving skull base, and 1 (3.7%) with metachronous skull eosinophilic granuloma, respectively. The diagnosis is challenging in specific cases and initial misdiagnoses were found in 6 (22.2%) patients. CONCLUSIONS: For NPC patients with intracranial or skull lesions, the initial diagnosis can be occasionally difficult because of the presence or a history of NPC and related treatment. Unawareness of these entities can result in misdiagnosis and subsequent improper treatment. Neurosurgical interventions are necessary for the diagnosis and treatment for these patients.

Radiomics-based survival risk stratification of glioblastoma is associated with different genome alteration.

BACKGROUND: Glioblastoma (GBM) is a remarkable heterogeneous tumor with few non-invasive, repeatable, and cost-effective prognostic biomarkers reported. In this study, we aim to explore the association between radiomic features and prognosis and genomic alterations in GBM. METHODS: A total of 180 GBM patients (training cohort: n = 119; validation cohort 1: n = 37; validation cohort 2: n = 24) were enrolled and underwent preoperative MRI scans. From the multiparametric (T1, T1-Gd, T2, and T2-FLAIR) MR images, the radscore was developed to predict overall survival (OS) in a multistep postprocessing workflow and validated in two external validation cohorts. The prognostic accuracy of the radscore was assessed with concordance index (C-index) and Brier scores. Furthermore, we used hierarchical clustering and enrichment analysis to explore the association between image features and genomic alterations. RESULTS: The MRI-based radscore was significantly correlated with OS in the training cohort (C-index: 0.70), validation cohort 1 (C-index: 0.66), and validation cohort 2 (C-index: 0.74). Multivariate analysis revealed that the radscore was an independent prognostic factor. Cluster analysis and enrichment analysis revealed that two distinct phenotypic clusters involved in distinct biological processes and pathways, including the VEGFA-VEGFR2 signaling pathway (q-value = 0.033), JAK-STAT signaling pathway (q-value = 0.049), and regulation of MAPK cascade (q-value = 0.0015/0.025). CONCLUSIONS: Radiomic features and radiomics-derived radscores provided important phenotypic and prognostic information with great potential for risk stratification in GBM.

[Part IV. Synthesis and antitumor evaluation of s-triazolothiadiazines and pyrazolo s-triazoles derived from ciproxacin].

An efficient modified route based on the targeting mechanism of antibacterial fluoroquinolones for the shift from the antibacterial activity to the antitumor one was further developed. Using a fused heterocyclic ring, s-triazolothiadiazine as a carboxyl bioisostere of ciprofloxacin, the title compounds, 1-cyclopropyl-6-fluoro-7-piperazin-1-yl-3-(6-substituted-phenyl-7H-[1, 2, 4]triazolo[3, 4-b][1, 3, 4]thiadiazin-3-yl)-quinolin-4(1H)-ones (5a-5e) and their corresponding N-acetyl products (6a-6e), were designed and synthesized, separately. Meaningfully, a ring-contraction of fused six-membered thiadiazine occurred by a sulfur extrusion reaction gave new tri-acetylated fused heterocycles related to pyrazolo[5, 1-c][1, 2, 4] triazoles (7a-7e). The in vitro antitumor activity against L1210, CHO and HL60 cell lines was also evaluated for the synthesized fifteen heterocycles compared to parent ciprofloxacin by methylthiazole trazolium (MTT) assay. Interestingly, the results displayed that fifteen fused heterocyclic compounds showed more significant growth inhibitory activity (IC50 < 25.0 micromo x L(-1)) than that of parent ciprofloxacin (IC50 > 150.0 micromol x L(-1)), and the active order decreased from 7a-7e to 5a-5e to 6a-6e, respective.

Longest survival with primary intracranial malignant melanoma: A case report and literature review.

BACKGROUND: Primary intracranial malignant melanoma (PIMM) is rare, and its prognosis is very poor. It is not clear what systematic treatment strategy can achieve long-term survival. This case study attempted to identify the optimal strategy for long-term survival outcomes by reviewing the PIMM patient with the longest survival following comprehensive treatment and by reviewing the related literature. CASE SUMMARY: The patient is a 47-year-old Chinese man who suffered from dizziness and gait disturbance. He underwent surgery for right cerebellum melanoma and was subsequently diagnosed by pathology in June 2000. After the surgery, the patient received three cycles of chemotherapy but relapsed locally within 4 mo. Following the second surgery for total tumor resection, the patient received an injection of Newcastle disease virus-modified tumor vaccine, interferon, and ß-elemene treatment. The patient was tumor-free with a normal life for 21 years before the onset of the recurrence of melanoma without any symptoms in July 2021. A third gross-total resection with adjuvant radiotherapy and temozolomide therapy was performed. Brain magnetic resonance imaging showed no residual tumor or recurrence 3 mo after the 3rd operation, and the patient recovered well without neurological dysfunction until the last follow-up in June 2022, which was 22 years following the initial treatment. CONCLUSION: It is important for patients with PIMM to receive comprehensive treatment to enable the application of the most appropriate treatment strategies. Long-term survival is not impossible in patients with these malignancies.

Predicting glioblastoma molecular subtypes and prognosis with a multimodal model integrating convolutional neural network, radiomics, and semantics.

OBJECTIVE: The aim of this study was to build a convolutional neural network (CNN)-based prediction model of glioblastoma (GBM) molecular subtype diagnosis and prognosis with multimodal features. METHODS: In total, 222 GBM patients were included in the training set from Sun Yat-sen University Cancer Center (SYSUCC) and 107 GBM patients were included in the validation set from SYSUCC, Xuanwu Hospital Capital Medical University, and the First Hospital of Jilin University. The multimodal model was trained with MR images (pre- and postcontrast T1-weighted images and T2-weighted images), corresponding MRI impression, and clinical patient information. First, the original images were segmented using the Multimodal Brain Tumor Image Segmentation Benchmark toolkit. Convolutional features were extracted using 3D residual deep neural network (ResNet50) and convolutional 3D (C3D). Radiomic features were extracted using pyradiomics. Report texts were converted to word embedding using word2vec. These three types of features were then integrated to train neural networks. Accuracy, precision, recall, and F1-score were used to evaluate the model performance. RESULTS: The C3D-based model yielded the highest accuracy of 91.11% in the prediction of IDH1 mutation status. Importantly, the addition of semantics improved precision by 11.21% and recall in MGMT promoter methylation status prediction by 14.28%. The areas under the receiver operating characteristic curves of the C3D-based model in the IDH1, ATRX, MGMT, and 1-year prognosis groups were 0.976, 0.953, 0.955, and 0.976, respectively. In external validation, the C3D-based model showed significant improvement in accuracy in the IDH1, ATRX, MGMT, and 1-year prognosis groups, which were 88.30%, 76.67%, 85.71%, and 85.71%, respectively (compared with 3D ResNet50: 83.51%, 66.67%, 82.14%, and 70.79%, respectively). CONCLUSIONS: The authors propose a novel multimodal model integrating C3D, radiomics, and semantics, which had a great performance in predicting IDH1, ATRX, and MGMT molecular subtypes and the 1-year prognosis of GBM.

Association between glioblastoma cell-derived vessels and poor prognosis of the patients.

BACKGROUND: Vessels with different microcirculation patterns are required for glioblastoma (GBM) growth. However, details of the microcirculation patterns in GBM remain unclear. Here, we examined the microcirculation patterns of GBM and analyzed their roles in patient prognosis together with two well-known GMB prognosis factors (O6 -methylguanine DNA methyltransferase [MGMT] promoter methylation status and isocitrate dehydrogenase [IDH] mutations). METHODS: Eighty GBM clinical specimens were collected from patients diagnosed between January 2000 and December 2012. The microcirculation patterns, including endothelium-dependent vessels (EDVs), extracellular matrix-dependent vessels (ECMDVs), GBM cell-derived vessels (GDVs), and mosaic vessels (MVs), were evaluated by immunohistochemistry (IHC) and immunofluorescence (IF) staining in both GBM clinical specimens and xenograft tissues. Vascular density assessments and three-dimensional reconstruction were performed. MGMT promoter methylation status was determined by methylation-specific PCR, and IDH1/2 mutations were detected by Sanger sequencing. The relationship between the microcirculation patterns and patient prognosis was analyzed by Kaplan-Meier method. RESULTS: All 4 microcirculation patterns were observed in both GBM clinical specimens and xenograft tissues. EDVs were detected in all tissue samples, while the other three patterns were observed in a small number of tissue samples (ECMDVs in 27.5%, GDVs in 43.8%, and MVs in 52.5% tissue samples). GDV-positive patients had a median survival of 9.56 months versus 13.60 months for GDV-negative patients (P = 0.015). In MGMT promoter-methylated cohort, GDV-positive patients had a median survival of 6.76 months versus 14.23 months for GDV-negative patients (P = 0.022). CONCLUSION: GDVs might be a negative predictor for the survival of GBM patients, even in those with MGMT promoter methylation.

Pretreatment neutrophil-to-lymphocyte ratio plus albumin-to-gamma-glutamyl transferase ratio predict the diagnosis of grade III glioma.

BACKGROUND: The present study explored the predictive value of systemic inflammatory indexes in diagnosing grade III gliomas of oligodendroglial origin. METHODS: A retrospective study of 154 patients with grade III gliomas was conducted. Systemic inflammatory indexes, including neutrophil-to-lymphocyte ratio (NLR), albumin-to-gamma-glutamyl transferase ratio (AGR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, prognostic nutritional index, and fibrinogen-to-albumin ratio, were reviewed. The resulting predictive model was externally validated using a demographic-matched cohort of 49 grade III glioma patients. RESULTS: In the training set, gliomas of oligodendroglial origin tended to have a lower NLR (P=0.018) and a higher AGR (P=0.036) than those with tumors of astrocytic origin. Moreover, both NLR and AGR had predictive value for oligodendroglial tumors, when compared with astrocytic tumors. The best diagnostic value was obtained using NLR + AGR (AUC =64.9%, 95% CI: 55.5-74.3%, P=0.005). In the validation set, NLR + AGR satisfactorily predicted the presence of oligodendroglial tumors (AUC =66.5%, 95% CI: 50.6-82.4%, P<0.05) and co-deletion of 1p/19q (AUC =73.7%, 95% CI: 59.2-88.1%, P=0.005). Multivariate analysis further demonstrated NLR + AGR as an independent predictor for overall survival. CONCLUSIONS: Pretreatment NLR and AGR aid in prognosis and diagnosing grade III oligodendroglial gliomas.

Tenascin-cmediated vasculogenic mimicry formation via regulation of MMP2/MMP9 in glioma.

Vasculogenic mimicry (VM), the formation of vessel-like structures by highly invasive tumor cells, has been considered one of several mechanisms responsible for the failure of anti-angiogenesis therapy in glioma patients. Therefore, inhibiting VM formation might be an effective therapeutic method to antagonize the angiogenesis resistance. This study aimed to show that an extracellular protein called Tenascin-c (TNC) is involved in VM formation and that TNC knockdown inhibits VM in glioma. TNC was upregulated with an increase in glioma grade. TNC and VM formation are potential independent predictors of survival of glioma patients. TNC upregulation was correlated with VM formation, and exogenous TNC stimulated VM formation. Furthermore, TNC knockdown significantly suppressed VM formation and proliferation in glioma cells in vitro and in vivo, with a reduction in cellular invasiveness and migration. Mechanistically, TNC knockdown decreased Akt phosphorylation at Ser473 and Thr308 and subsequently downregulated matrix metalloproteinase 2 and 9, both of which are important proteins associated with VM formation and migration. Our results indicate that TNC plays an important role in VM formation in glioma, suggesting that TNC is a potential therapeutic target for anti-angiogenesis therapy for glioma.

Prosaposin promotes the proliferation and tumorigenesis of glioma through toll-like receptor 4 (TLR4)-mediated NF-κB signaling pathway.

BACKGROUND: As a neurotrophic factor, prosaposin (PSAP) can exert neuroprotective and neurotrophic effects. It is involved in the occurrence and development of prostate and breast cancer. However, there is no research about the role of PSAP in glioma. METHODS: The PSAP overexpressed or silenced glioma cells or glioma stem cells were established based on Lentiviral vector transfection. Cell viability assay, Edu assay, neurosphere formation assay and xenograft experiments were used to detect the proliferative ability. Western blot, Elisa and luciferase reporter assays were used to detect the possible mechanism. FINDINGS: Our study firstly found that PSAP was highly expressed and secreted in clinical glioma specimens, glioma stem cells, and glioma cell lines. It was associated with poor prognosis. We found that PSAP significantly promoted the proliferation of glioma stem cells and cell lines. Moreover, PSAP promoted tumorigenesis in subcutaneous and orthotopic models of this disease. Furthermore, GSEA and KEGG analysis predicted that PSAP acts through the TLR4 and NF-κB signaling pathways, which was confirmed by western blot, immunoprecipitation, immunofluorescence, and use of the TLR4-specific inhibitor TAK-242. INTERPRETATION: The findings of this study suggest that PSAP can promote glioma cell proliferation via the TLR4/NF-κB signaling pathway and may be an important target for glioma treatment. FUND: This work was funded by National Natural Science Foundation of China (Nos. 81101917, 81270036, 81201802, 81673025), Program for Liaoning Excellent Talents in University (No. LR2014023), and Liaoning Province Natural Science Foundation (Nos. 20170541022, 20172250290). The funders did not play a role in manuscript design, data collection, data analysis, interpretation nor writing of the manuscript.

Glioblastoma stem cell differentiation into endothelial cells evidenced through live-cell imaging.

BACKGROUND: Glioblastoma cell-initiated vascularization is an alternative angiogenesis called vasculogenic mimicry. However, current knowledge on the mechanism of de novo vessel formation from glioblastoma stem cells (GSCs) is limited. METHODS: Sixty-four glioblastoma samples from patients and 10 fluorescent glioma xenograft samples were examined by immunofluorescence staining for endothelial marker (CD34 and CD31) and glial cell marker (glial fibrillary acidic protein [GFAP]) expression. GSCs were then isolated from human glioblastoma tissue and CD133+/Sox2+ red fluorescent protein-containing (RFP)-GSC-1 cells were established. The ability of these cells to form vascular structures was examined by live-cell imaging of 3D cultures. RESULTS: CD34-GFAP or CD31-GFAP coexpressing glioblastoma-derived endothelial cells (GDEC) were found in 30 of 64 (46.9%) of clinical glioblastoma samples. In those 30 samples, GDEC were found to form vessel structures in 21 (70%) samples. Among 21 samples with GDEC vessels, the CD34+ GDEC vessels and CD31+ GDEC vessels accounted for about 14.16% and 18.08% of total vessels, respectively. In the xenograft samples, CD34+ GDEC were found in 7 out of 10 mice, and 4 out of 7 mice had CD34+ GDEC vessels. CD31+ GDEC were also found in 7 mice, and 4 mice had CD31+ GDEC vessels (10 mice in total). Through live-cell imaging, we observed gradual CD34 expression when cultured with vascular endothelial growth factor in some glioma cells, and a dynamic increase in endothelial marker expression in RFP-GSC-1 in vitro was recorded. Cells expressed CD34 (9.46%) after 6 hours in culture. CONCLUSIONS: The results demonstrated that GSCs may differentiate into endothelial cells and promote angiogenesis in glioblastomas.

Langerhans cell histiocytosis of skull: a retrospective study of 18 cases.

BACKGROUND: The present study presents 18 cases of Chinese patients harboring a Langerhans cell histiocytosis (LCH) of the skull. METHODS: Eighteen consecutive patients were diagnosed as LCH of the skull and confirmed pathologically between March 2002 and February 2014. In the present study, the patients of LCH without skull involvement were excluded. According to disease extent at diagnosis, the 18 LCH patients with skull involvement were divided into three groups: (I) unifocal-monosystem group, including ten cases with solitary skull lesion; (II) multifocal-monosystem group, including two cases with multiple bone lesions and no extra-skeletal involvement; (III) multisystem group, including six cases with LCH lesions involving both skeletal and extra-skeletal system. In unifocal-monosystem group, excision of the skull lesion was performed in eight of ten cases, a low dosage of local radiotherapy and a purposeful observation was accept by the remaining two cases of this group after biopsy respectively. In multifocal-monosystem group, both of the two cases were received chemotherapy. In multi-system group, all the six cases were managed with systemic chemotherapy, after their diagnoses of LCH were confirmed. RESULTS: The mean age at the time of diagnosis was 9.4 years. There was a male predominance in this disease male/female ratio was 3.5:1. In our cases, a skull mass with or without tenderness was the most common chief complaint (13 cases, 72.2%), and frontal bone was the most frequent affected locations of skull (6 cases, 33.3%). In unifocal-monosystem group, nine of ten remained free from LCH, the remain one lesion recurred 22 months after his surgical excision. In multifocal-monosystem group, a complete response (CR) was obtained in one of them, and a stable disease (SD) of multiple osseous lesions was obtained in another one. In the multi-system group, a CR in four cases and a partial response (PR) in one case were obtained, and a progressive disease (PD) was observed in the remaining one. CONCLUSIONS: The unifocal-monosystem of LCH of the skull is a clinicopathological entity with a good outcome, and resection, irradiation or purposeful observation are also can be been utilized as the choice of treatment. For the multifocal bone lesions and multisystem lesions of LCH, chemotherapy is an effective treatment as a systemic therapy. There is no enough publication literature to determine guidelines or indications for managing this disease.