The treatment of glioblastoma multiforme through activation of microglia and TRAIL induced by rAAV2-mediated IL-12 in a syngeneic rat model

<p>Abstract</p> <p>Background</p> <p>Microglial cells are the predominant immune cells in malignant brain tumors, but tumors may release some factors to reduce their defensive functions. Restoration of the anti-cancer function of microglia has been proposed as a treatment modality for glioblastoma. We examined the effect of intra-cranially administered recombinant adeno-associated virus encoding interleukin-12 (rAAV2/IL12) on transfection efficiency, local immune activity and survival in a rat model of glioblastoma multiforme.</p> <p>Methods</p> <p>F344 rats were injected with rAAV2/IL12 and implanted with syngeneic RG2 cells (glioblastoma cell line). Intracerebral interleukin-12 and interferon-γ concentrations were determined by ELISA. Activation of microglia was determined by expressions of ED1 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) which were evaluated by Western blotting and immunohistochemistry. The proliferation of cancer cells was evaluated with Ki67 immunohistochemistry and apoptosis of cancer cells with TUNEL.</p> <p>Results</p> <p>The brains treated with rAAV2/IL-12 maintained high expression of interleukin-12 and interferon-γ for at least two months. In syngeneic tumor model, brains treated with rAAV2/IL12 exhibited more infiltration of activated microglia cells as examined by ED1 and TRAIL stains in the tumor. In addition, the volume of tumor was markedly smaller in AAV2/IL12-treated group and the survival time was significantly longer in this group too.</p> <p>Conclusion</p> <p>The intra-cerebrally administered rAAV2/IL-12 efficiently induces long lasting expression of IL-12, the greater infiltration of activated microglia cells in the tumor associated improved immune reactions, resulting in the inhibited growth of implanted glioblastoma and the increased survival time of these rats.</p

Profit Maximization for Waste Furniture Recycled in Taiwan Using Cradle-to-Cradle Production Programming

This study proposes the use of cradle-to-cradle production programming for waste furniture and aims to achieve optimal efficiency by reusing waste furniture and maximizing the corresponding benefits so that the furniture industry is in line with cradle-to-cradle manufacturing. This study is increasingly important to manage products through a comprehensive green reverse logistics system that consists of three procedures, i.e., recycling, reuse, and remanufacturing of waste items. This study proposes a mathematical formula to establish a cradle-to-cradle production programming model for waste furniture. The fuzzy set theory is used to define the attributes that reflect production and market demands such as degree of damage, technical feasibility, market demands, environmental protection laws and regulations, and environmental performance. In addition, particle swarm optimization is adopted to ascertain the optimal profit from waste furniture sales. Through situational simulations and analyses, the fuzzy set information from Taiwan, Germany, and China is compared. The result reveals that the qualitative information proposed has a significant impact on the profit of waste furniture reuse. The production model can effectively assist in the production programming of waste furniture, thereby optimizing profit for cradle-to-cradle production planning

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

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

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

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

Neurosurgery for sinusitis-related and sinusitis-unrelated intracranial abscess

Background: Sinusitis-related intracranial abscess (ICA) is a rare but serious complication and is different from those of sinusitis-unrelated ICA. Purpose: This study aimed to analyze the differences in bacteriology, host factors, presentations, and prognoses between cases of sinusitis-related and sinusitis-unrelated ICA. Methods: This retrospective study was conducted at Buddhist Tzu Chi General Hospital (Hualien, Taiwan), during January 2010–August 2014, and enrolled patients with pathologically proven postsurgery ICA. P < 0.05 was considered statistically significant. Results: The number of patients with sinusitis-related and sinusitis-unrelated ICA was 10 and 17, respectively. Compared with sinusitis-unrelated ICA patients, significantly more patients with sinusitis-related ICA experienced cirrhosis, ophthalmic abnormalities, and frontal and cavernous sinus involvement. Among all ICA patients, diabetes mellitus (DM) was associated with an increased mortality risk. Patients with DM exhibited the highest positive culture rates for Klebsiella pneumoniae. Conclusion: Frontal sinusitis is associated with an increased risk of intracranial invasion. DM and liver cirrhosis patients exhibited the highest mortality rates among all ICA patients. Patient comorbidity should be considered when prescribing antibiotics for treatment

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