Role of STAT3-FOXO3 Signaling in the Modulation of Neuroplasticity by PD-L1-HGF-Decorated Mesenchymal Stem Cell-Derived Exosomes in a Murine Stroke Model.

The limited therapeutic strategies available for stroke leave many patients disabled for life. This study assessed the potential of programmed death-ligand 1 (PD-L1) and hepatocyte growth factor (HGF)-engineered mesenchymal stem cell-derived exosomes (EXO-PD-L1-HGF) in enhancing neurological recovery post-stroke. EXO-PD-L1-HGF, which efficiently endocytosed into target cells, significantly diminishes the H2O2-induced neurotoxicity and increased the antiapoptotic proteins in vitro. EXO-PD-L1-HGF attenuates inflammation by inhibiting T-cell proliferation and increasing the number of CD8+CD122+IL-10+ regulatory T cells. Intravenous injection of EXO-PD-L1-HGF could target stromal cell-derived factor-1α (SDF-1α+) cells over the peri-infarcted area of the ischemic brain through CXCR4 upregulation and accumulation in neuroglial cells post-stroke. EXO-PD-L1-HGF facilitates endogenous nestin+ neural progenitor cell (NPC)-induced neurogenesis via STAT3-FOXO3 signaling cascade, which plays a pivotal role in cell survival and neuroprotection, thereby mitigating infarct size and enhancing neurological recovery in a murine stroke model. Moreover, increasing populations of the immune-regulatory CD19+IL-10+ and CD8+CD122+IL-10+ cells, together with reducing populations of proinflammatory cells, created an anti-inflammatory microenvironment in the ischemic brain. Thus, innovative approaches employing EXO-PD-L1-HGF intervention, which targets SDF-1α+ expression, modulates the immune system, and enhances the activation of resident nestin+ NPCs, might significantly alter the brain microenvironment and create a niche conducive to inducing neuroplastic regeneration post-stroke.

Differentiation Induction of Mesenchymal Stem Cells by a Au Delivery Platform.

Au decorated with type I collagen (Col) was used as a core material to cross-link with stromal cell-derived factor 1α (SDF1α) in order to investigate biological performance. The Au-based nanoparticles were subjected to physicochemical determination using scanning electron microscopy (SEM), dynamic light scattering (DLS) and ultraviolet-visible (UV-Vis) and Fourier-transform infrared spectroscopy (FTIR). Mesenchymal stem cells (MSCs) were used to evaluate the biocompatibility of this nanoparticle using the MTT assay and measuring reactive oxygen species (ROS) production. Also, the biological effects of the SDF-1α-conjugated nanoparticles (Au-Col-SDF1α) were assessed and the mechanisms were explored. Furthermore, we investigated the cell differentiation-inducing potential of these conjugated nanoparticles on MSCs toward endothelial cells, neurons, osteoblasts and adipocytes. We then ultimately explored the process of cell entry and transportation of the nanoparticles. Using a mouse animal model and retro-orbital sinus injection, we traced in vivo biodistribution to determine the biosafety of the Au-Col-SDF1α nanoparticles. In summary, our results indicate that Au-Col is a promising drug delivery system; it can be used to carry SDF1α to improve MSC therapeutic efficiency.

Involvement of Mitochondrial Damage and Oxidative Stress in Apoptosis Induced by Betulin Plus Arsenic Trioxide in Neuroblastoma Cells.

BACKGROUND/AIM: Arsenic trioxide (As2O3), a potent toxin in traditional Chinese medicine, has been utilized as an anticancer agent in Chinese culture for over a millennium. Betulin, commonly extracted from the bark of birch trees, has been identified for its pharmacological properties, including antibacterial, anti-inflammatory, antitumor, and antiviral activities. The aim of this study was to determine the efficacy and underlying anticancer signaling cascade induced by As2O3 and betulin in neuroblastoma cells. MATERIALS AND METHODS: SK-N-SH cells were treated with As2O3 with or without betulin. Cell viability and apoptotic signaling were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, measurement of mitochondrial membrane potential (MMP) loss and reactive oxygen species (ROS), and quantitative western blotting analysis. Student's t-test in addition to one- or two-way analysis of variance was used to examine significant differences between comparison groups. RESULTS: The combined treatment of As2O3 plus betulin was more effective than single treatments in suppressing cell viability and induction of apoptosis, which correlated well with elevated ROS levels. The apoptotic signaling cascade of As2O3 plus betulin was revealed as ROS elevation and relative loss of MMP, leading to the cleavage of caspase-3 and -9. As2O3 plus betulin treatment also reduced the expression of BCL2 apoptosis regulator, BH3-interacting domain death agonist, and BCL2-like-1. CONCLUSION: The novel combination of As2O3 plus betulin has the potential to serve as a practical anti-neuroblastoma drug.

Role of Matrix Metallopeptidase-2 Genotypes in Taiwanese Patients With Colorectal Cancer.

BACKGROUND/AIM: Matrix metalloproteinase-2 (MMP2) has been reported to plays a critical role in the metastatic behaviors of cancer via regulation of the extracellular matrix. However, its genotypes have seldom been examined in colorectal cancer (CRC). We examined the role of MMP2 promoter -1306 (rs243865) and -735 (rs2285053) genotypes in colorectal cancer (CRC). MATERIALS AND METHODS: Genotypes of MMP2 were determined by typical polymerase chain reaction-restriction fragment length polymorphism methodology in 362 CRC cases and 362 age-, sex- and behavior-matched controls. RESULTS: The genotypic analysis showed that MMP2 -1306 CT and TT genotypes were significantly associated with an increased CRC risk (odds ratios=1.41 and 3.55, 95% confidence intervals=1.02-1.96 and 1.75-7.19, and p=0.0482 and p=0.0004, respectively). The allelic frequency analysis showed that the T allele for MMP2 -1306 increased CRC risk (odds ratio=1.71, 95% confidence interval=1.32-2.23, p=4.89×105). Stratification analysis showed that MMP2 -1306 genotypes were specifically associated with alcohol drinking, and metastatic status among patients with CRC. There was no association with MMP2 -735. CONCLUSION: The MMP2 -1306 genotype serves as a novel predictive marker for CRC risk among Taiwanese, and patients who have a tendency to undergo metastasis.

Cordyceps militaris Reduces Oxidative Stress and Regulates Immune T Cells to Inhibit Metastatic Melanoma Invasion.

In this study, the water extract of Cordyceps militaris (Linn.) Link (CM) was used as a functional material to investigate the inhibitory mechanisms on B16F10 and lung metastatic melanoma (LMM) cells. Reducing power, chelating ability, and 2,2-diphenyl-2-picrylhydrazyl (DPPH) assays were applied for antioxidative capacities, and we obtained positive results from the proper concentrations of CM. To examine the ability of CM in melanoma proliferation inhibition and to substantiate the previous outcomes, three cellular experiments were performed via (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT, a tetrazole) assay, cell migration, and invasion evaluation. The addition of CM to the incubation medium increased the number of CD8+ T cells significantly, which improved the immunogenicity. This study showed that CM exhibits various biological capabilities, including antioxidation, anti-tumor, tumor invasion suppression, and T cytotoxic cell activity promotion.

The Contribution of Interleukin-8 Rs4073 Genotypes to Triple Negative Breast Cancer Risk in Taiwan.

BACKGROUND/AIM: Triple negative breast cancer (TNBC) is one of the most challenging breast cancer types. Interleukin-8 (IL-8) is a pro-tumorigenic cytokine, promoting tumor proliferation and migration. This study aimed to examine the contribution of IL-8 rs4073 genotypes to breast cancer risk and provide a summary of related literature. MATERIALS AND METHODS: IL-8 genotypic profiles were determined among 1,232 breast cancer cases and 1,232 controls via polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The IL-8 rs4073 AT and AA genotypes had significantly lower prevalence in the case group compared to control group. Allelic frequency analysis showed that individuals carrying the A allele have relatively decreased risk for breast cancer. The stratification analysis showed that IL-8 rs4073 genotypes were protective markers for those with younger (≤55) age. CONCLUSION: IL-8 rs4073 A allele is a novel predictor for breast cancer, especially TNBC.

Phenethyl Isothiocyanate Suppresses the Proinflammatory Cytokines in Human Glioblastoma Cells through the PI3K/Akt/NF-κB Signaling Pathway In Vitro.

Phenethyl isothiocyanate (PEITC), extracted from cruciferous vegetables, showed anticancer activity in many human cancer cells. Our previous studies disclosed the anticancer activity of PEITC in human glioblastoma multiforme (GBM) 8401 cells, including suppressing the cell proliferation, inducing apoptotic cell death, and suppressing cell migration and invasion. Furthermore, PEITC also inhibited the growth of xenograft tumors of human glioblastoma cells. We are the first to investigate PEITC effects on the receptor tyrosine kinase (RTK) signaling pathway and the effects of proinflammatory cytokines on glioblastoma. The cell viability was analyzed by flow cytometric assay. The protein levels and mRNA expressions of cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6), were determined by enzyme-linked immunosorbent assay (ELISA) reader and real-time polymerase chain reaction (PCR) analysis, respectively. Furthermore, nuclear factor-kappa B- (NF-κB-) associated proteins were evaluated by western blotting. NF-κB expression and nuclear translocation were confirmed by confocal laser microscopy. NF-κB binding to the DNA was examined by electrophoretic mobility shift assay (EMSA). Our results indicated that PEITC decreased the cell viability and inhibited the protein levels and expressions of IL-1ß, IL-6, and TNF-α genes at the transcriptional level in GBM 8401 cells. PEITC inhibited the binding of NF-κB on promoter site of DNA in GBM 8401 cells. PEITC also altered the protein expressions of protein kinase B (Akt), extracellular signal-regulated kinase (ERK), and NF-κB signaling pathways. The inflammatory responses in human glioblastoma cells may be suppressed by PEITC through the phosphoinositide 3-kinase (PI3K)/Akt/NF-κB signaling pathway. Thus, PEITC may have the potential to be an anti-inflammatory agent for human glioblastoma in the future.

Favorable Biological Performance Regarding the Interaction between Gold Nanoparticles and Mesenchymal Stem Cells.

Gold nanoparticles (AuNPs) are well known to interact with cells, leading to different cell behaviors such as cell proliferation and differentiation capacity. Biocompatibility and biological functions enhanced by nanomedicine are the most concerning factors in clinical approaches. In the present research, AuNP solutions were prepared at concentrations of 1.25, 2.5, 5 and 10 ppm for biocompatibility investigations. Ultraviolet-visible spectroscopy was applied to identify the presence of AuNPs under the various concentrations. Dynamic Light Scattering assay was used for the characterization of the size of the AuNPs. The shape of the AuNPs was observed through a Scanning Electron Microscope. Afterward, the mesenchymal stem cells (MSCs) were treated with a differentiation concentration of AuNP solutions in order to measure the biocompatibility of the nanoparticles. Our results demonstrate that AuNPs at 1.25 and 2.5 ppm could significantly enhance MSC proliferation, decrease reactive oxygen species (ROS) generation and attenuate platelet/monocyte activation. Furthermore, the MSC morphology was observed in the presence of filopodia and lamellipodia while being incubated with 1.25 and 2.5 ppm AuNPs, indicating that the adhesion ability was enhanced by the nanoparticles. The expression of matrix metalloproteinase (MMP-2/9) in MSCs was found to be more highly expressed under 1.25 and 2.5 ppm AuNP treatment, relating to better cell migrating ability. Additionally, the cell apoptosis of MSCs investigated with Annexin-V/PI double staining assay and the Fluorescence Activated Cell Sorting (FACS) method demonstrated the lower population of apoptotic cells in 1.25 and 2.5 ppm AuNP treatments, as compared to high concentrations of AuNPs. Additionally, results from a Western blotting assay explored the possibility that the anti-apoptotic proteins Cyclin-D1 and Bcl-2 were remarkably expressed. Meanwhile, real-time PCR analysis demonstrated that the 1.25 and 2.5 ppm AuNP solutions induced a lower expression of inflammatory cytokines (TNF-α, IL-1ß, IFN-γ, IL-6 and IL-8). According to the tests performed on an animal model, AuNP 1.25 and 2.5 ppm treatments exhibited the better biocompatibility performance, including anti-inflammation and endothelialization. In brief, 1.25 and 2.5 ppm of AuNP solution was verified to strengthen the biological functions of MSCs, and thus suggests that AuNPs become the biocompatibility nanomedicine for regeneration research.

Interaction of DNA Repair Gene XPC With Smoking and Betel Quid Chewing Behaviors of Oral Cancer.

BACKGROUND/AIM: Xeroderma pigmentosum complementation group C (XPC) is reported to play important roles in DNA integrity and genomic instability, however, the contribution of XPC to oral carcinogenesis is largely uncertain. Therefore, we aimed at examining the contribution of XPC genotypes to oral cancer. MATERIALS AND METHODS: The genotypes of XPC rs2228001 and rs2228000 were examined among 958 oral cancer patients and 958 control subjects by polymerase chain reaction-restriction fragment length polymorphism methodology and corresponding DNA repair capacity was checked. RESULTS: First, the percentages of XPC rs2228001 AC and CC were higher among oral cancer patients than controls. Second, no significant association was observed regarding XPC rs2228000. Third, there was a synergistic influence of smoking and betel quid chewing behaviors and XPC rs2228001 genotype on oral cancer risk. Last, functional experiments showed DNA repair capacity was lower for AC/CC carriers than AA carriers. CONCLUSION: XPC rs2228001 C allele, which was associated with decreased DNA repair capacity, may interact with smoking and betel quid chewing behaviors on oral cancer risk.

Interleukin-13 Promoter Genotypes and Taiwanese Breast Cancer Susceptibility.

BACKGROUND/AIM: The current study aimed at evaluating the contribution of IL-13 promoter rs1881457 and rs1800925 genotypes to the risk of breast cancer in Taiwan. MATERIALS AND METHODS: A total of 1,232 breast cancer cases and 1,232 age-matched controls were genotyped by typical polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. RESULTS: As for IL-13 rs1881457, the rates of AA, AC and CC genotypes were 54.8, 37.9 and 7.3% among the cases, and 53.8, 38.7 and 7.5% among the healthy controls, respectively; there were no statistically significant differences between the two groups (p for trend=0.8889). Also, regarding IL-13 rs1800925, there were no statistically significant differences between the two groups either (p for trend=0.6803). Furthermore, the allelic frequencies for IL-13 rs1881457 and rs1800925 were not differentially distributed between the case and control groups (p=0.6515 and 0.8753, respectively). CONCLUSION: The rs1881457 and rs1800925 IL-13 promoter polymorphisms may not serve as breast cancer susceptibility determinants for Taiwanese.

Interaction of Interleukin-16 Genotypes With Betel Quid Chewing Behavior on Oral Cancer in Taiwan.

BACKGROUND/AIM: Interleukin-16 (IL-16) is reported to play an important role in inflammation, carcinogenesis and tumoricidal processes, however, the contribution of IL-16 genotype to oral carcinogenesis is still largely unrevealed. Thus, the study aimed to investigate the contribution of IL-16 genotypes to Taiwan oral cancer risk. MATERIALS AND METHODS: The genotypes of IL-16 rs4778889, rs11556218, and rs4072111 were revealed among 958 oral cancer cases and 958 control subjects by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). RESULTS: First, the distributions of genotypic (p=0.0004) and allelic (p=0.0001) frequencies of IL-16 rs11556218 were significantly different between the case and control groups. In detail, the frequencies of IL-16 rs11556218 TG and GG were 28.1 and 5.8%, respectively, among oral cancer patients, significantly higher compared to those among controls (25.0% and 2.7%, respectively). Second, no difference was observed regarding IL-16 rs4778889 or IL-16 rs4072111. Last, there was a synergistic effect of betel quid chewing behavior and risky IL-16 rs11556218 genotype on oral cancer risk. CONCLUSION: The study indicates that the IL-16 rs11556218 G allele synergistically interacts with betel quid chewing behavior, contributing to increased risk of oral cancer in Taiwanese.

The Contribution of Interleukin-12A Genotypes to Oral Cancer Risk in Taiwanese.

BACKGROUND/AIM: Oral cancer incidence is highest worldwide in Taiwan, and practical markers for personalized therapeutic strategies such as immunotherapies, is lacking. Interleukin-12 (IL12) is a cytokine that is reported to exhibit potent tumoricidal effects, however, its genotypic contribution to oral cancer is still largely unknown. We aimed to examine whether IL12A rs568408 and rs2243115 genotypes are associated with oral cancer risk in Taiwan. MATERIALS AND METHODS: Genotypic characteristics of IL12A were determined among 958 oral cancer cases and age- and gender-matched individuals via typical polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The variant genotypes of IL12A rs568408 and rs2243115 were not found to be significantly associated with elevated oral cancer risk (all p>0.05). Moreover, there was no interaction between IL12A genotypes and personal smoking, alcohol drinking and betel quid chewing behaviors (all p>0.05). CONCLUSION: IL12A rs568408 and rs2243115 genotypes may not serve as good predictors for oral cancer risk.

The role of tailored intraoperative neurophysiological monitoring in glioma surgery: a single institute experience.

INTRODUCTION: Glioma surgery near the functional area is still a dilemma. Intraoperative neurophysiologic monitoring (IONM) and functional mapping can play a role to maximize the extent of resection (EOR), while minimizing the risk of sequelae. We herein review the utility of tailored intraoperative mapping and monitoring in patients undergoing glioma surgery in our institute. METHODS: Patients were divided into two groups on the basis of application tailored IONM (group A, 2013-2017, n = 53) or not (group B, 2008-2012, n = 49) between January 2008 and December 2017. The setup, tailored IONM protocols, surgery, and clinical results of all patients with eloquent glioma were analyzed with the EOR, functionality scores, overall survival (OS) and progression-free survival (PFS) retrospectively. RESULTS: The 102 patients were considered eligible for analysis. High grade and low grade gliomas accounted for 73 (72%) and 29 (28%) cases, respectively. There was a positive association between the application of neuromonitor and post-operative functional preservation, but no significant statistical differences over the EOR, OS and PFS between the two groups. CONCLUSIONS: In our experience, tailored intraoperative functional mapping provides an effective neurological function preservation. Routine implementation of neurophysiological monitoring with adequate pre-operative planning and intraoperative teamwork in eloquent glioma can get more satisfied functional preservation. Due to the maturation and experience of our IONM team may also be the variation factor, prospective studies with a more prominent sample and proper multivariate analysis will be expected to determine the real benefit.

Role of FOXC1 in regulating APSCs self-renewal via STI-1/PrPC signaling.

Forkhead box protein C1 (FOXC1) is known to regulate developmental processes in the skull and brain. Methods: The unique multipotent arachnoid-pia stem cells (APSCs) isolated from human and mouse arachnoid-pia membranes of meninges were grown as 3D spheres and displayed a capacity for self-renewal. Additionally, APSCs also expressed the surface antigens as mesenchymal stem cells. By applying the FOXC1 knockout mice and mouse brain explants, signaling cascade of FOXC1-STI-1-PrPC was investigated to demonstrate the molecular regulatory pathway for APSCs self-renewal. Moreover, APSCs implantation in stroke model was also verified whether neurogenic property of APSCs could repair the ischemic insult of the stroke brain. Results: Activated FOXC1 regulated the proliferation of APSCs in a cell cycle-dependent manner, whereas FOXC1-mediated APSCs self-renewal was abolished in FOXC1 knockout mice (FOXC1-/- mice). Moreover, upregulation of STI-1 regulated by FOXC1 enhanced cell survival and self-renewal of APSCs through autocrine signaling of cellular prion protein (PrPC). Mouse brain explants STI-1 rescues the cortical phenotype in vitro and induces neurogenesis in the FOXC1-/- mouse brain. Furthermore, administration of APSCs in ischemic brain restored the neuroglial microenvironment and improved neurological dysfunction. Conclusion: We identified a novel role for FOXC1 in the direct regulation of the STI-1-PrPC signaling pathway to promote cell proliferation and self-renewal of APSCs.

Novel Combination of Arsenic Trioxide (As2O3) Plus Resveratrol in Inducing Programmed Cell Death of Human Neuroblastoma SK-N-SH Cells.

AIM: Arsenic trioxide (As2O3), known as pi-shuang and the most toxic compound in traditional Chinese medicine, has been used as an antitumor agent for thousands of years. Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural phenol that has significant anti-bacterial, anti-fungaI and antiaging activities. Our study aimed to examine the combined anticancer effects of As2O3 and resveratrol against human neuroblastoma SK-N-SH cells, and elucidate the underlying intracellular signaling. MATERIALS AND METHODS: SK-N-SH cells were treated with an extremely low-dose (2-4 µM) of As2O3 alone or combined with 75 µg/ml resveratrol for further comparisons. Cell viability, apoptotic signaling as well as synergistic cytotoxic effects were estimated using the MTT assay, microscopy observation, flow cytometric analysis for loss of mitochondrial membrane potential (MMP) and reactive oxygen species (ROS), and typical quantitative western blotting analysis. Student's t-test, and one- and two-way analysis of variance (ANOVA) were used for examination of significant differences. RESULTS: The combined treatment was more effective than single treatment of As2O3 or resveratrol alone in suppressing cell viability, which correlated with the elevation of ROS levels. The intracellular mechanisms of cytotoxicity of As2O3 plus resveratrol were revealed as ROS accumulation and relative decrease of MMP, leading to activation of caspase-3 and -9, but not of caspase-1, -7 and-8. Combination treatment reduced the expression of B-cell lymphoma 2 (BCL2), BH3 interacting domain death agonist (BID), and BCL-x/L. CONCLUSION: Combined treatment at extremely low concentration of two agents from natural products, As2O3 and resveratrol, has high potential as a cocktail of anticancer drugs for neuroblastoma.

Phenethyl Isothiocyanate Inhibits In Vivo Growth of Xenograft Tumors of Human Glioblastoma Cells.

Phenethyl isothiocyanate (PEITC) from cruciferous vegetables can inhibit the growth of various human cancer cells. In previous studies, we determined that PEITC inhibited the in vitro growth of human glioblastoma GBM 8401 cells by inducing apoptosis, inhibiting migration and invasion, and altering gene expression. Nevertheless, there are no further in vivo reports disclosing whether PEITC can suppress the growth of glioblastoma. Therefore, in this study we investigate the anti-tumor effects of PEITC in a xenograft model of glioblastoma in nude mice. Thirty nude mice were inoculated subcutaneously with GBM 8401 cells. Mice with one palpable tumor were divided randomly into three groups: control, PEITC-10, and PEITC-20 groups treated with 0.1% dimethyl sulfoxide (DMSO), and 10 and 20 µmole PEITC/100 µL PBS daily by oral gavage, respectively. PEITC significantly decreased tumor weights and volumes of GBM 8401 cells in mice, but did not affect the total body weights of mice. PEITC diminished the levels of anti-apoptotic proteins MCL-1 (myeloid cell leukemia 1) and XIAP (X-linked inhibitor of apoptosis protein) in GBM 8401 cells. PEITC enhanced the levels of caspase-3 and Bax in GBM 8401 cells. The growth of glioblastoma can be suppressed by the biological properties of PEITC in vivo. These effects might support further investigations into the potential use of PEITC as an anticancer drug for glioblastoma.

Potential role of CBX7 in regulating pluripotency of adult human pluripotent-like olfactory stem cells in stroke model.

The adult olfactory mucosa, a highly regenerative tissue with unique life-long neurogenesis ability, is thought to harbor a naïve yet tightly controlled stem cell population. It will provide unique benefits in various stem cell-based therapies, such as stroke treatment. Here, we identified a subpopulation of adult pluripotent-like olfactory stem cells (APOSCs), which were modulated by an epigenetic repressor of CBX7. APOSCs form a floating sphere, express pluripotency markers Nanog, Oct-4, Sox-2, and SSEA-4 and show alkaline phosphatase activity. In addition, APOSCs display self-renewal and a pluripotent potential to differentiate into all three germ layers. Moreover, APOSCs coexpress pluripotency markers with CBX7. Within their natural niche, APOSCs from CBX7+/+ mice responded promptly to either spontaneous or injury-induced tissue regeneration. However, APOSCs from CBX7-/- mice manifested an impaired self-renewal and differentiation potential. Similarly, in vitro-cultivated CBX7-/- APOSCs underwent premature senescence, whereas CBX7+/+ APOSCs still actively divided, indicating that CBX7 is required for the self-renewal of APOSCs. Intracerebral implantation of APOSCs improved the stroke-mediated neurological dysfunction in rodents. These findings indicate that CBX7 plays a critical role in the regenerative properties of APOSCs and indicate the safety and feasibility of implantation of autologous APOSCs in stroke treatment.

Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression.

Forkhead box C1 (FOXC1) is a member of the forkhead family of transcription factors that are characterized by a DNA-binding forkhead domain. Increasing evidence indicates that FOXC1 is involved in tumor progression. However, the role of tumor hypoxia in FOXC1 regulation and its impact on lung cancer progression are unclear. Here, we report that FOXC1 was upregulated in hypoxic areas of lung cancer tissues from rodents or humans. Hypoxic stresses significantly induced FOXC1 expression. Moreover, hypoxia activated FOXC1 transcription via direct binding of hypoxia-inducible factor-1α (HIF-1α) to the hypoxia-responsive element (HRE) in the FOXC1 promoter. FOXC1 gain-of-function in lung cancer cells promoted cell proliferation, migration, invasion, angiogenesis, and epithelial-mesenchymal transition in vitro. However, a knockdown of FOXC1 in lung cancer cells inhibited these effects. Notably, knockdown of tumor hypoxia-induced FOXC1 expression via HIF-1-mediated FOXC1 shRNAs in lung cancer xenograft models suppressed tumor growth and angiogenesis. Finally, systemic delivery of FOXC1 siRNA encapsulated in lipid nanoparticles inhibited tumor growth and increased survival time in lung cancer-bearing mice. Taken together, these data indicate that FOXC1 is a novel hypoxia-induced transcription factor and plays a critical role in tumor microenvironment-promoted lung cancer progression. Systemic FOXC1 blockade therapy may be an effective therapeutic strategy for lung cancer.

Endoscope-assisted transsphenoidal puncture of the cavernous sinus for embolization of carotid-cavernous fistula in a neurosurgical hybrid operating suite.

Endovascular embolization is the treatment of choice for carotid-cavernous fistulas (CCFs), but failure to catheterize the cavernous sinus may occur as a result of vessel tortuosity, hypoplasia, or stenosis. In addition to conventional transvenous or transarterial routes, alternative approaches should be considered. The authors present a case in which a straightforward route to the CCF was accessed via transsphenoidal puncture of the cavernous sinus in a neurosurgical hybrid operating suite. This 82-year-old man presented with severe chemosis and proptosis of the right eye. Digital subtraction angiography revealed a Type B CCF with a feeding artery arising from the meningohypophyseal trunk of the right cavernous segment of the internal carotid artery. The CCF drained through a thrombosed right superior ophthalmic vein that ended deep in the orbit; there were no patent sinuses or venous plexuses connecting to the CCF. An endoscope-assisted transsphenoidal puncture created direct access to the nidus for embolization. Embolic agents were deployed through the puncture needle to achieve complete obliteration. Endoscope-assisted transsphenoidal puncture of the cavernous sinus is a feasible alternative to treat difficult-to-access CCFs in a neurosurgical hybrid operating suite.

Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells.

Glioblastoma is the most common and aggressive primary brain malignancy. Phenethyl isothiocyanate (PEITC), a member of the isothiocyanate family, can induce apoptosis in many human cancer cells. Our previous study disclosed that PEITC induces apoptosis through the extrinsic pathway, dysfunction of mitochondria, reactive oxygen species (ROS)-induced endoplasmic reticulum (ER) stress, and intrinsic (mitochondrial) pathway in human brain glioblastoma multiforme (GBM) 8401 cells. To the best of our knowledge, we first investigated the effects of PEITC on the genetic levels of GBM 8401 cells in vitro. PEITC may induce G0/G1 cell-cycle arrest through affecting the proteins such as cdk2, cyclin E, and p21 in GBM 8401 cells. Many genes associated with cell-cycle regulation of GBM 8401 cells were changed after PEITC treatment: 48 genes were upregulated and 118 were downregulated. The cell-division cycle protein 20 (CDC20), Budding uninhibited by benzimidazole 1 homolog beta (BUB1B), and cyclin B1 were downregulated, and clusterin was upregulated in GBM 8401 cells treated with PEITC. These changes of gene expression can provide the effects of PEITC on the genetic levels and potential biomarkers for glioblastoma. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 176-187, 2017.