Improved neurological function in a patient with complete spinal cord injury through bone marrow mesenchymal stem cells implantation: a case report.

Aim: Spinal cord injury (SCI) can cause severe disability. Several clinical trials of stem-cell based therapies are ongoing. We describe our experience of bone marrow mesenchymal stem cell (BMSC) therapy in a patient with complete SCI in the chronic stage. Case report: A 25-year-old man with complete SCI at T6 level presented with paraplegia for 5 years. We transplanted autologous BMSCs intramedullary. After 12 months follow-up, his Barthel index score was noticeably improved from severe to moderate dependency, and the sensation level improved from T7 to S5, but no improvement of motor function. Conclusion: Autologous BMSCs are potentially safe for patients with complete SCI in the chronic stage and may improve neurological function and quality of life.

Enhanced IRE1α Phosphorylation/Oligomerization-Triggered XBP1 Splicing Contributes to Parkin-Mediated Prevention of SH-SY5Y Cell Death under Nitrosative Stress.

Mutations in parkin, a neuroprotective protein, are the predominant cause of autosomal recessive juvenile Parkinson's disease. Neuroinflammation-derived nitrosative stress has been implicated in the etiology of the chronic neurodegeneration. However, the interactions between genetic predisposition and nitrosative stress contributing to the degeneration of dopaminergic (DA) neurons remain incompletely understood. Here, we used the SH-SY5Y neuroblastoma cells to investigate the function of parkin and its pathogenic mutants in relation to cell survival under nitric oxide (NO) exposure. The results showed that overexpression of wild-type parkin protected SH-SY5Y cells from NO-induced apoptosis in a reactive oxygen species-dependent manner. Under nitrosative stress conditions, parkin selectively upregulated the inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) signaling axis, an unfolded protein response signal through the sensor IRE1α, which controls the splicing of XBP1 mRNA. Inhibition of XBP1 mRNA splicing either by pharmacologically inhibiting IRE1α endoribonuclease activity or by genetically knocking down XBP1 interfered with the protective activity of parkin. Furthermore, pathogenic parkin mutants with a defective protective capacity showed a lower ability to activate the IRE1α/XBP1 signaling. Finally, we demonstrated that IRE1α activity augmented by parkin was possibly mediated through interacting with IRE1α to regulate its phosphorylation/oligomerization processes, whereas mutant parkin diminished its binding to and activation of IRE1α. Thus, these results support a direct link between the protective activity of parkin and the IRE1α/XBP1 pathway in response to nitrosative stress, and mutant parkin disrupts this function.

Lumbar-peritoneal shunt for idiopathic normal pressure hydrocephalus and secondary normal pressure hydrocephalus.

Objectives: Normal-pressure hydrocephalus is a clinical syndrome consisting of dilated cerebral ventricles with the clinical triad of gait disturbance, cognitive impairment and/or urinary dysfunction. Lumbar-peritoneal (LP) shunt could improve idiopathic normal pressure hydrocephalus (iNPH) while its effectiveness on secondary NPH (sNPH) is elusive. We compared the clinical results of the patients who received LP shunt surgery between iNPH and sNPH. Materials and Methods: We retrospectively analyzed the patients who received LP shunt surgery in a single center from January 1, 2017, to June 30, 2017. Patients selected for LP shunt placement had at least two of three cardinal symptoms of iNPH. The symptoms should persist for more than 3 months with compatible brain magnetic resonance imaging findings. All patients were followed up with iNPH grading scale (iNPHGS) and Modified Rankin Scale (MRS) for evaluation. Results: Thirty-three patients (23 male and 10 female patients) with mean age 76-year-old completed follow-up in this study, and 17 patients received lumbar drainage tests and intracranial pressure measurements. Both iNPH (n = 22) and sNPH (n = 11) groups did not have major complications such as infection, nerve root injury, or shunt failure. Both groups have significant improvement in iNPHGS and MRS. Interestingly, we found the correlation between both opening intracranial pressure and pressure gradient difference to the improvement percentage from LP shunt. Conclusion: The safety and effectiveness for sNPH patients who received LP shunt placement are equivalent to the iNPH patients. Lumbar drainage test provides prerequisite outcome prediction and should be considered to identify NPH patients planned to receive LP shunt.

Pilot study of a new type of machine vision-assisted stereotactic neurosurgery for EVD placement.

BACKGROUND: The usage of machine vision technologies for image-based analysis and inspection is increasing. With the advent of the ability to process high-dimension data instantly, the possibilities of machine vision multiply exponentially. Robots now use this technology to assist in surgery. OBJECTIVE: The aim of this study is to explore the efficacy of Surgical Navigation Robot NaoTrac (Brain Navi Biotechnology Co., Ltd.), which utilizes machine vision-inspired technology for patient registration and stereotactic external ventricular drainage (EVD) by the robotic arm. METHODS: Preoperative and postoperative computed tomography (CT) scans were acquired for each case. The surgeons planned the targets and trajectories with the preoperative CT images. The postoperative CT images were utilized in the accuracy measurements. RESULTS: All 14 cases had cerebrospinal fluid drained through the catheter. The NaoTrac placed the catheter into the frontal horn in one attempt in 13 cases and was able to drain CSF in 12 cases. Not a single case had any bleeding or intraoperative complications. The average time spent on the patient registration was 142.8 s. The mean target deviation was 1.68 mm, and the mean angular deviation was 1.99°, all within the accepted tolerance for minimal tissue damage. CONCLUSION: The results of this report demonstrate that machine vision-inspired patient registration is feasible and fast. NaoTrac has demonstrated its accuracy and safety in performing frameless catheter placement in 13 clinical cases. Other stereotactic neurosurgical operations such as stereotactic biopsy, depth electrode placement, deep brain stimulation electrode positioning, and neuroendoscopy may also be benefited from the assistance of NaoTrac.

Targeting the Axl and mTOR Pathway Synergizes Immunotherapy and Chemotherapy to Butylidenephthalide in a Recurrent GBM.

Background: The role of inherent tumor heterogeneity and an immunosuppressive microenvironment in therapeutic resistance has been determined to be of importance for the better management of glioblastoma multiforme (GBM). Some studies have suggested that combined drugs with divergent mechanisms may be promising in treating recurrent GBM. Methods: Intracranial sustained (Z)-n-butylidenephthalide [(Z)-BP] delivery through Cerebraca Wafers (CWs) to eliminate unresectable brain tumors was combined with the administration of temozolomide (TMZ), pembrolizumab, and cytokine-induced killer (CIK) cells for treating a patient with recurrent glioblastoma. Neurological adverse events and wound healing delay were monitored for estimating tolerance and efficacy. Response Assessment in Neuro-Oncology criteria were applied to evaluate progression-free survival (PFS); further, the molecular characteristics of GBM tissues were analyzed, and the underlying mechanism was investigated using primary culture. Results: Intracerebral (Z)-BP in residual tumors could not only inhibit cancer stem cells but also increase interferon gamma levels in serum, which then led to the regression of GBM and an immune-responsive microenvironment. Targeting receptor tyrosine kinases, including Axl and epidermal growth factor receptor (EGFR), and inhibiting the mechanistic target of rapamycin (mTOR) through (Z)-BP were determined to synergize CIK cells in the presence of pembrolizumab and TMZ in recurrent GBM. Therefore, this well-tolerated regimen could simultaneously block multiple cancer pathways, which allowed extended PFS and improved quality of life for 22 months. Conclusion: Given the several unique functions of (Z)-BP, greater sensitivity of chemotherapy and the synergism of pembrolizumab and CIK cells could have affected the excellent prognosis seen in this patient with recurrent GBM.

Biodegradable controlled-release polymer containing butylidenephthalide to treat a recurrent cervical spine glioblastoma with promising result: a compassionate trial report.

Intramedullary spinal glioblastoma multiforme (GBM) tends to recur within 11 months of surgical resection, even after adjuvant chemoradiation therapy. Treatment options for recurrent spinal GBM are often limited. (Z)-n-butylidenephthalide [(Z)-BP] is a natural compound that induces apoptosis, antiproliferation, anti-invasion and antistemness effects in GBM cells. The Cerebraca wafer consists of (Z)-BP within a biodegradable wafer that can be implanted in the parenchyma of the central nervous system to treat high-grade glioma. We present a 44-year-old woman with a recurrent spinal GBM who underwent microscopic surgical tumor excision under fluorescein sodium guidance and intraoperative neurophysiologic monitoring. Four Cerebraca wafers were implanted into the cord and intradural space during the operation. MRI revealed that both tumor volume and spinal cord edema had decreased 4 days after surgery; both had substantially decreased 16 months after surgery. Neurologic functions and quality of life were improved after salvage therapy. No adverse events were reported. Cerebraca wafer implantation during surgical re-excision of spinal GBM may be a novel therapeutic approach for reduction of the tumor size and subsequent spinal cord edema with no toxicity to the spinal cord.

Interstitial Control-Released Polymer Carrying a Targeting Small-Molecule Drug Reduces PD-L1 and MGMT Expression in Recurrent High-Grade Gliomas with TMZ Resistance.

In recurrent glioblastoma, Gliadel wafer implantation after surgery has been shown to result in incomplete chemical removal of residual tumor and development of brain edema. Furthermore, temozolomide (TMZ) resistance caused by O6-methylguanine-DNA-methyltransferase (MGMT) activation and programmed cell death-ligand 1 (PD-L1) expression leads to immune-cold lesions that result in poorer prognosis. Cerebraca wafer, a biodegradable polymer containing (Z)-n-butylidenephthalide (BP), is designed to eliminate residual tumor after glioma resection. An open-label, one-arm study with four dose cohorts, involving a traditional 3 + 3 dose escalation clinical trial, of the Cerebraca wafer combined with TMZ on patients with recurrent high-grade glioma, was conducted. Of the 12 patients who receive implantation of Cerebraca wafer, there were no drug-related adverse events (AEs) or serious AEs (SAEs). The median overall survival (OS) of patients receiving low-dose Cerebraca wafer was 12 months in the group with >25% wafer coverage of the resected tumor, which is longer than OS duration in previously published studies (Gliadel wafer, 6.4 months). Patients who received high-dose Cerebraca wafer treatment had not yet died at the data cut-off date; a 100% progression-free survival (PFS) rate at six month was achieved, indicating the median OS of cohort IV was more than 17.4 months. In vitro study of the primary cells collected from the patients revealed that the IC50 of BP against tumor stem cells was four times lower than that of bis-chloroethylnitrosourea (BCNU). A synergistic effect between BP and TMZ was demonstrated by a reduction in MGMT expression. Furthermore, BP inhibited PD-L1 expression, thereby activating T-cell cytotoxicity and increasing interferon-gamma (IFN-γ) secretion. The better therapeutic effect of Cerebraca wafer on recurrent high-grade glioma could occur through re-sensitization of TMZ and reduction of PD-L1.

Intracerebral transplantation of autologous adipose-derived stem cells for chronic ischemic stroke: A phase I study.

Current therapy does not provide significant benefits for patients with chronic stroke. Pre-clinical studies suggested that autologous adipose-derived stem cells have benefits for the treatment of chronic stroke. This Phase I open-label study was conducted to demonstrate the safety and efficacy of autologous adipose-derived stem cells (GXNPC1) in chronic stroke. Three patients with chronic stroke were treated with stereotactic implantation of autologous adipose-derived stem cells (1 × 108 cells). The primary endpoints of safety evaluation included adverse events, over a 6 months post-implantation period. The secondary endpoints included improvements in neurological functions. Evolutional change of brain parenchyma was also followed with magnetic resonance imaging (MRI). All three participants improved significantly at 6 months follow-up. The extent of improvement from pre-treatment was: National Institutes of Health Stroke Scale improved 5-15 points, Barthel Index: 25-50 points, Berg balance scale 0-21 points and Fugl-Meyer modified sensation 3-28 points. All three patients had signal change along the implantation tract on MRI one month after surgery. There is no related safety issue through 6 months observation. Clinical measures of neurological symptoms of these patients with chronic stroke improved at 6 months without adverse effects after implantation of autologous adipose-derived stem cells (GXNPC1), which might be correlated with post-implantation changes on brain MRI. Clinical Trial Registration-URL: https://clinicaltrials.gov/ct2/show/NCT02813512?term=ADSC&cond=Stroke&cntry=TW&draw=2&rank=1 Unique identifier: NCT02813512.

Complete Restoration of Motor Function in Acute Cerebral Stroke Treated with Allogeneic Human Umbilical Cord Blood Monocytes: Preliminary Results of a phase I Clinical Trial.

Stem cell therapy has been explored for the treatment of cerebral stroke. Several types of stem cells have been investigated to ensure the safety and efficacy in clinical trials.Cryopreserved umbilical cord blood (UCB) mononuclear cells (MNCs) obtained from healthy donors have a more stabilized quality, thereby ensuring a successful therapy. A phase I study was conducted on patients aged 45-80 years who sustained acute ischemic stroke. An UCB unit was obtained from a public cord blood bank based on ABO/Rh blood type, HLA matching score (6/6), and cell dose (total MNC count of 0.5-5 × 107 cells/kg). In addition, to facilitate blood brain barrier penetration of UCB, 4 doses of 100 mL mannitol was administered intravenously after 30 min after UCB transplantation and every 4 h thereafter. The primary outcomes were the number of disease (GVHD) within 100 days after transfusion. The secondary outcomes were changes in the National Institutes of Health Stroke Scale (NIHSS), Barthel index, and Berg Balance Scale scores. A 46-year-old male patient with identical ABO/Rh blood type, HLA matching score of 6/6, and MNC count of 2.63 × 108 cells/kg was enrolled. The patient did not present with serious AEs or GVHD during the 12-month study period. The patient's NIHSS score decreased from 9 to 1. Moreover, the Berg Balance Scale score increased from 0 to 48 and the Barthel index score from 0 to 90. This preliminary study showed that an adult patient with hemiplegia due to ischemic stroke completely recovered within 12 months after receiving allogeneic UCB therapy.

Granulocyte Colony-Stimulating Factor for Treatment of Patients with Chronic Traumatic Brain Injury: A Preliminary Pre-Post Study.

Chronic traumatic brain injury (TBI) can cause permanent disability and thereby negatively affect patients, families, and society. Currently, there is no effective treatment for patients with chronic TBI. One possible option is granulocyte colony-stimulating factor (G-CSF), which has potential neuroregenerative and neuroprotective effects through its ability to mobilize hematopoietic stem cells and increase neurogenic growth factor levels. Previous studies have shown that G-CSF administration is safe for patients with neurological diseases such as stroke and dementia. The present study aimed to explore the safety and efficacy of G-CSF use in patients with chronic TBI. METHODS: 38 patients with chronic TBI were administered 3-day rounds of G-CSF (10 µg/kg per day) once a month for 6 months. These patients were clinically evaluated using the modified Rankin scale (mRS) and Karnofsky Performance Score (KPS). Laboratory measures of the leucocyte counts and differential count percentage were also assessed. RESULTS: At the 6-month follow-up, further assessment showed that patients tolerated the treatment well with only mild and transient side effects being observed. Further clinical evaluation showed significant improvements in mRS and KPS after G-CSF treatment. Laboratory results also confirmed the action of the medication, with increased leukocytosis and band forms. CONCLUSIONS: The results suggest that 6-month chronic G-CSF treatment is safe for patients with chronic TBI and may provide clinical benefits and neurological improvements. The adverse effects of the treatment, however, are transient and usually tolerable. Thus, these preliminary findings suggest that future clinical trials of G-CSF use in patients with chronic TBI are warranted.

Hispolon Induces Apoptosis, Suppresses Migration and Invasion of Glioblastoma Cells and Inhibits GBM Xenograft Tumor Growth In Vivo.

Hispolon, a polyphenol compound isolated from Phellinus linteus, has been reported to exhibit antioxidant, antiproliferative, and antitumor activities. This study aimed to explore the antitumor effects of hispolon on glioblastoma multiforme (GBM) cells in vitro and in vivo. The results revealed that hispolon significantly inhibited GBM cell proliferation and induced apoptosis through caspase-9 and caspase-3 activation and PARP cleavage. Hispolon also induced cell cycle G2/M phase arrest in GBM cells, as supported by flow cytometry analysis and confirmed by a decrease in cyclin B1, cdc2, and cdc25c protein expressions in a dose- and time-dependent manner. Furthermore, hispolon suppressed the migration and invasion of GBM cells by modulating epithelial-mesenchymal transition (EMT) markers via wound healing, transwell assays, and real-time PCR. Moreover, hispolon significantly reduced tumor growth in DBTRG xenograft mice and activated caspase-3 in hispolon-treated tumors. Thus, our findings revealed that hispolon is a potential candidate for the treatment of GBM.

Dopaminergic Degeneration and Small Vessel Disease in Patients with Normal Pressure Hydrocephalus Who Underwent Shunt Surgery.

The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) and the outcome of lumboperitoneal shunt treatment remains to be systematically explored. Here, we aim to evaluate whether the severity of dopaminergic degeneration and white matter small vessel disease could be predictors of outcome for iNPH patients subjected to lumboperitoneal shunt treatment. This is a single center retrospective study with 39 patients with probable iNPH undergoing programmable surgical lumboperitoneal shunt from June 2016 to March 2018 at Hualien Tzu Chi Hospital. In all patients, dopaminergic degeneration was determined with 99mTc- TRODAT-1 SPECT scan, while white matter small vessel disease (Fazekas scale) was assessed with Brain MRI. The iNPH grading scale (iNPHGS) score and Karnofsky Performance Score (KPS) pre- and post-operation (6-month follow-up) were available for all patients. Linear regression was used to correlate the severities of dopaminergic degeneration and small vessel disease with lumboperitoneal shunt treatment outcomes. Their iNPHGS score improved significantly after surgery (pre-operatively, 7.8 ± 2.6; post-operatively, 5.7 ± 2.6 (26.9% improvement) (p < 0.05)). Moreover, the KPS was also improved significantly after surgery, by a mean of 24.6% from the baseline score (p < 0.05). A significant correlation was observed between the severity of dopaminergic degeneration and a poorer improvement of iNPHGS score (p = 0.03). However, improvement of the iNPHGS score was not correlated with white matter small vessel disease. Dopaminergic degeneration comorbidity neutralized the degree of improvement after surgery. Although white matter small vessel disease was correlated with iNPH incidence, it may not be a prognostic factor for shunt operation. These findings have implications for the use of dopaminergic imaging, as they might help predict the surgical outcome of patients with iNPH, while vascular mechanisms seem to be involved in iNPH pathophysiology.

Peroxiredoxin 5 Silencing Sensitizes Dopaminergic Neuronal Cells to Rotenone via DNA Damage-Triggered ATM/p53/PUMA Signaling-Mediated Apoptosis.

Peroxiredoxins (Prxs) are a family of thioredoxin peroxidases. Accumulating evidence suggests that changes in the expression of Prxs may be involved in neurodegenerative diseases pathology. However, the expression and function of Prxs in Parkinson's disease (PD) remains unclear. Here, we showed that Prx5 was the most downregulated of the six Prx subtypes in dopaminergic (DA) neurons in rotenone-induced cellular and rat models of PD, suggesting possible roles in regulating their survival. Depletion of Prx5 sensitized SH-SY5Y DA neuronal cells to rotenone-induced apoptosis. The extent of mitochondrial membrane potential collapse, cytochrome c release, and caspase activation was increased by Prx5 loss. Furthermore, Prx5 knockdown enhanced the induction of PUMA by rotenone through a p53-dependent mechanism. Using RNA interference approaches, we demonstrated that the p53/PUMA signaling was essential for Prx5 silencing-exacerbated mitochondria-driven apoptosis. Additionally, downregulation of Prx5 augmented rotenone-induced DNA damage manifested as induction of phosphorylated histone H2AX (γ-H2AX) and activation of ataxia telangiectasia mutated (ATM) kinase. The pharmacological inactivation of ATM revealed that ATM was integral to p53 activation by DNA damage. These findings provided a novel link between Prx5 and DNA damage-triggered ATM/p53/PUMA signaling in a rotenone-induced PD model. Thus, Prx5 might play an important role in protection against rotenone-induced DA neurodegeneration.

Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer: Implications for REDD1 Activation and mTOR Inhibition.

BACKGROUND/AIMS: Radix Angelica Sinensis (danggui in Chinese) is widely used in traditional chinese medicine (TCM). N-butylidenephthalide (BP), a bioactive compound in danggui, is a potential antitumor agent for various cancer types. However, its clinical effect and mechanism in the treatment of gastric cancer remain undetermined. METHODS: The in vivo protective effect of danggui in patients with gastric cancer were validated using data from Taiwan's National Health Insurance Research Database (NHIRD). The genes induced by BP-treatment were analyzed by whole transcriptome RNA sequencing (RNA-seq) and validated by real-time PCR, western blot and siRNA transfection. The effect of BP on AGS cell migration and invasion was evaluated in transwell assays. The antitumor effects of BP were evaluated in vivo in an AGS xenograft animal model. RESULTS: Danggui users were found to have an increased survival rate when compared with danggui nonusers (log-rank test p = 0.002) . The use of danggui highly associated with decreased mortality (the adjusted hazard ratio (HR) of danggui user was 0.72 [95 % CI, 0.57-0.92] (p = 0.009). The in vitro results showed that BP inhibited gastric cancer cell proliferation, and triggered cellular apoptosis depending on the activation of mitochondrial apoptotic pathway. Using RNA-seq analysis we found that REDD1 was the highest transcript induced by BP in gastric cancer cells. BP induce an increase of REDD1 expression that inhibits mTOR signaling, thus inhibiting gastric cancer growth. We used RNA interference to demonstrate that the knock-down of REDD1 attenuated the BP-induced mTORC1 activation and growth inhibition. BP suppressed the growth of AGS xenografts tumor in vivo. CONCLUSION: Danggui can prolong the survival rate of gastric cancer patients in Taiwan. BP caused gastric cancer cell death through the activation of mitochondria-intrinsic pathway and induced the REDD1 expression leading to mTOR signal pathway inhibition in gastric cancer cells. BP inhibited the in vivo growth of AGS xenograft tumors. These results may provide the basis for a new therapeutic approach toward the treatment of gastric cancer progression.

Superficial temporal artery-middle cerebral artery bypass for the treatment of complex middle cerebral artery aneurysms.

OBJECTIVES: Direct microsurgical clipping for complex middle cerebral artery (MCA) aneurysms may require a long ischemic time. Sacrifice of the parent artery with trapping or endovascular coiling also may lead to ischemic stroke. We described our institutional experience with the treatment of complex MCA aneurysms using extracranial-intracranial (EC-IC) (superficial temporal artery [STA]-MCA) bypass. MATERIALS AND METHODS: We retrospectively reviewed patients who had treatment of IC aneurysms with the assistance of STA-MCA bypass from July 2002 to December 2016. Six patients with complex MCA aneurysms were identified, and we reviewed their clinical characteristics. RESULTS: There were three men and three women with age ranging from 27 to 59 (mean 49) years old. Image studies showed subarachnoid hemorrhage in three cases. All patients underwent STA-MCA anastomosis, and the follow-up period ranged from 2 to 116 months (mean 51.5 months). Two of the six MCA aneurysms were fusiform, two aneurysms had bizarre configurations, one was a dissecting saccular aneurysm, and one had a blister configuration. Three patients received direct vessel trapping, two patients received aneurysm clipping, and one received aneurysm coiling. The postoperative bypass patency rate was 100%. The modified Rankin scale showed good outcomes in the six patients. CONCLUSIONS: EC-IC bypass plays an important role as a salvage procedure in the treatment of complex MCA aneurysms which have a fusiform, bizarre, or blister configuration.

Potential therapeutic effects of N-butylidenephthalide from Radix Angelica Sinensis (Danggui) in human bladder cancer cells.

BACKGROUND: N-butylidenephthalide (BP) isolated from Radix Angelica Sinensis (Danggui) exhibits anti-tumorigenic effect in various cancer cells both in vivo and in vitro. The effect of BP in bladder cancer treatment is still unclear and worth for further investigate. METHODS: Changes of patients with bladder cancer after Angelica Sinensis exposure were evaluated by analysis of Taiwan's National Health Insurance Research Database (NHIRD) database. The anti-proliferative effect of BP on human bladder cancer cells was investigated and their cell cycle profiles after BP treatment were determined by flow cytometry. BP-induced apoptosis was demonstrated by Annexin V-FITC staining and TUNEL assay, while the expressions of apoptosis-related proteins were determined by western blot. The migration inhibitory effect of BP on human bladder cancer cells were shown by trans-well and wound healing assays. Tumor model in NOD-SCID mice were induced by injection of BFTC human bladder cancer cells. RESULTS: The correlation of taking Angelica sinensis and the incidence of bladder cancer in NHIRD imply that this herbal product is worth for further investigation. BP caused bladder cancer cell death in a time- and dose- dependent manner and induced apoptosis via the activation of caspase-9 and caspase-3. BP also suppressed the migration of bladder cancer cells as revealed by the trans-well and wound healing assays. Up-regulation of E-cadherin and down-regulation of N-cadherin were evidenced by real-time RT-PCR analysis after BP treatment in vitro. Besides, in combination with BP, the sensitivity of these bladder cancer cells to cisplatin increased significantly. BP also suppressed BFTC xenograft tumor growth, and caused 44.2% reduction of tumor volume after treatment for 26 days. CONCLUSIONS: BP caused bladder cancer cell death through activation of mitochondria-intrinsic pathway. BP also suppressed the migration and invasion of these cells, probably by modulating EMT-related genes. Furthermore, combination therapy of BP with a lower dose of cisplatin significantly inhibited the growth of these bladder cancer cell lines. The incidence of bladder cancer decreased in patients who were exposed to Angelica sinensis, suggesting that BP could serve as a potential adjuvant in bladder cancer therapy regimen.

Treating intracranial dural arteriovenous fistulas with gamma knife radiosurgery: A single-center experience.

OBJECTIVE: We evaluated the effectiveness and safety of gamma knife radiosurgery (GKRS) for the treatment of intracranial dural arteriovenous fistulas (dural AVFs) over the past 10 years. MATERIALS AND METHODS: The records of 21 patients diagnosed with dural AVFs between 2004 and 2014 and treated with GKRS were reviewed retrospectively. Complete obliteration (CO) was defined as total symptom relief plus confirmation through magnetic resonance imaging or conventional angiography. RESULTS: The median follow-up was 70.5 months (range 3-136 months). Five patients underwent embolization (2 after GKRS). One patient underwent GKRS twice. The CO rate was 47%, and partial to CO rate was 88%. The complete symptom resolution rate was 77%, and all patients achieved partial to complete symptom resolution. The CO rates for Borden Type I and Type II/III dural AVFs were 66.7% and 25% (P = 0.153), respectively, and complete symptom-free rates were 76.9% and 75.0% (P = 1.000%), respectively. The median duration between initial GKRS and complete symptom resolution was 14.3 months. The median treatment to image-free durations for Borden Type I and Type II/III dural AVFs were 25.9 and 60.4 months (P = 0.028), respectively, and treatment to symptom-free durations were 10.6 and 36.7 months (P = 0.103), respectively. One patient had a recurrent hemorrhage. Two patients experienced brain edema after stereotactic radiosurgery and one patient experienced cystic formation after GKRS. The morbidity rate was 19% (four patients) and there was no mortality. CONCLUSION: Treatment with GKRS for dural AVFs offers a favorable rate of obliteration. Patients with dural AVFs that are refractory or not amenable to endovascular or surgical therapy may be safely and effectively treated using GKRS.

Volume-staged gamma knife surgery for the treatment of large skull base meningioma surrounding the optical apparatus: A snowman-shape design.

BACKGROUND: In cases of meningioma surrounding the optical apparatus, this study sought to reduce the incidence of radiation-induced optical neuropathy resulting from gamma knife surgery (GKS) by dividing the treatment volume into 2 or 3 fractions. METHODS: Four patients with a large skull base meningioma (1 male and 3 females; median age: 42 years; range: 33-43 yrs) were treated using volume-staged GKS. In stage I, the large basal part of the tumor (13.2 mL; range: 3.9-54.7 mL) was treated with a marginal dose of 13.5 Gy (range: 12-15 Gy). In stage II, treatment focused on the smaller upper portion of the tumor located close to the optical apparatus (4.3 mL; range: 1.5-16.2 mL), and the marginal dose was 9 Gy (range: 8-10 Gy). RESULTS: All patients tolerated the treatments well, and tumors regressed over a median follow-up period of 100.5 months (range: 42-122 mos). Specifically, a 34-46% reduction in tumor volume was observed. All four patients presented improvements in the neurological deficits observed prior to GKS treatment, albeit to varying degrees. No adverse effects of radiation or new visual deterioration were observed during the follow-up period. Furthermore, no evidence of new endocrine dysfunction or new cranial nerve neuropathy was observed within a follow-up period of 100.5 months. CONCLUSION: The application of volume-staged GKS using snowman-shape design appears to be an effective approach to control tumor growth when treating benign meningiomas surrounding the optical apparatus. This approach enables the application of higher radiation dosages to facilitate tumor control while still preserving optic nerve function.

Tanshinone IIA increases protein expression levels of PERK, ATF6, IRE1α, CHOP, caspase­3 and caspase­12 in pancreatic cancer BxPC­3 cell­derived xenograft tumors.

Tanshinone (Tan)-IIA is a derivative of phenanthrenequinone and the main active ingredient isolated from Salviae miltiorrhizae radix (Danshen). Previous studies have demonstrated that Tan­IIA increased the protein expressions levels of protein kinase RNA­like endoplasmic reticulum kinase (PERK), activating transcription factor (ATF) 6, caspase­12 and CCAAT­enhancer­binding protein homologous protein (CHOP), to induce endoplasmic reticulum (ER) stress and apoptosis in human pancreatic cancer BxPC­3 cells. However, to the best of our knowledge, the effects of Tan­IIA on pancreatic cancer cells have not been investigated in vivo. Further studies are required to elucidate the therapeutic potential of Tan­IIA in inducing ER stress in cancer cells in vivo. The present study aimed to investigate the effects of Tan­IIA on the expression of ER stress­related proteins in BxPC­3­derived xenograft tumors. A total of 30 male severe combined immunodeficiency mice (age, 4 weeks) were implanted with BxPC­3 cells (2x106/0.2 ml) and subsequently treated with various doses of Tan­IIA (0, 30 and 90 mg/kg) for 4 weeks. After mice were sacrificed on day 33, the xenograft tumors were dissected and total protein was extracted for western blot analysis. The results of the present study demonstrated that Tan­IIA inhibited the growth of BxPC­3­derived xenograft tumors. In addition, Tan­IIA increased the protein expression levels of PERK, ATF6, caspase­12, inositol­requiring enzyme (IRE) 1α, eukaryotic initiation factor (eIF) 2α, phosphorylated (p)­c­Jun N­terminal kinase (JNK), CHOP and caspase­3 in a dose­dependent manner. These results indicated that Tan­IIA induced ER stress via increasing the protein expression levels of PERK, ATF6, caspase­12, IRE1α, eIF2α, p­JNK, CHOP and caspase­3 in BxPC­3 cells in vivo. Therefore, it may be hypothesized that Tan­IIA has potential for the development of novel therapeutic strategies for the treatment of patients with pancreatic cancer.