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BACKGROUND: External ventricular drain (EVD) is used for monitoring intracranial pressure or diverting cerebrospinal fluid. However, confirmation of an infection is not immediate and requires obtaining culture results, often leading to the excessive use of antibiotics. This study aimed to compare noninfectious ventriculitis and EVD infection in terms of the risk factors, predictors, prognosis, and effectiveness of care bundle interventions. METHODS: This retrospective study was conducted at a medical center with 1,006 beds in northern Taiwan between January 2018 and July 2022. Standard EVD insertion protocols and care bundles have been implemented since 2018, along with the initiation of chlorhexidine. RESULTS: In total, 742 EVD cases were identified. Noninfectious ventriculitis typically presents with fever approximately 8 days following EVD placement, whereas EVD infection typically manifests as fever after 20 days. Aneurysmal subarachnoid hemorrhage was strongly associated with the development of noninfectious ventriculitis (adjusted odds ratio [OR] 2.6, 95% confidence interval [CI] 1.5-4.4). Alcoholism (adjusted OR 3.5, 95% CI 1.1-12.3) and arteriovenous malformation (adjusted OR 13.1, 95% CI 2.9-58.2) significantly increased the risk of EVD infection. The EVD infection rate significantly decreased from 3.6% (14 of 446) to 1.0% (3 of 219) (p = 0.03) after the implementation of chlorhexidine gluconate bathing. CONCLUSIONS: Aneurysmal subarachnoid hemorrhage or fever with neuroinflammation within 2 weeks of EVD placement is indicative of a higher likelihood of noninfectious ventriculitis. Conversely, patients with arteriovenous malformation, alcoholism, or fever with neuroinflammation occurring after more than 3 weeks of EVD placement are more likely to necessitate antibiotic treatment for EVD infection. Chlorhexidine gluconate bathing decreases EVD infection.
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Ventriculitis Cerebral , Clorhexidina , Drenaje , Humanos , Ventriculitis Cerebral/etiología , Ventriculitis Cerebral/prevención & control , Masculino , Estudios Retrospectivos , Femenino , Persona de Mediana Edad , Factores de Riesgo , Anciano , Adulto , Taiwán , Clorhexidina/análogos & derivados , Clorhexidina/uso terapéutico , Hemorragia Subaracnoidea , Paquetes de Atención al Paciente , Alcoholismo/complicacionesRESUMEN
BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) accounts for up to 20% of all strokes and results in 40% mortality at 30 days. Although conservative medical management is still the standard treatment for ICH patients with small hematoma, patients with residual hematoma ≤15 mL after surgery are associated with better functional outcomes and survival rates. This study reported our clinical experience with using Robotic Stereotactic Assistance (ROSA) as a safe and effective approach for stereotactic ICH aspiration and intra-clot catheter placement. METHODS: A retrospective analysis was conducted of patients with spontaneous ICH who underwent ROSA-guided ICH aspiration surgery. ROSA-guided ICH surgical techniques, an aspiration and intra-clot catheter placement protocol, and a specific operative workflow (pre-operative protocol, intraoperative procedure and postoperative management) were employed to aspirate ICH using the ROSA One Brain, and appropriate follow-up care was provided. RESULTS: From September 14, 2021 to May 4, 2022, a total of 7 patients were included in the study. Based on our workflow design, ROSA-guided stereotactic ICH aspiration effectively aspirated more than 50% of hematoma volume (or more than 30 mL for massive hematomas), thereby reducing the residual hematoma to less than 15 mL. The mean operative time of entire surgical procedure was 1.3 ± 0.3 h, with very little perioperative blood loss and no perioperative complications. No patients required catheter replacement and all patients' functional status improved. CONCLUSIONS: Within our clinical practice ROSA-guided ICH aspiration, using our established protocol and workflow, was safe and effective for reducing hematoma volume, with positive functional outcomes.
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Glioblastoma multiforme (GBM) is a highly heterogeneous disease with a mesenchymal subtype tending to exhibit more aggressive and multitherapy-resistant features. Glioblastoma stem-cells derived from mesenchymal cells are reliant on iron supply, accumulated with high reactive oxygen species (ROS), and susceptible to ferroptosis. Temozolomide (TMZ) treatment is the mainstay drug for GBM despite the rapid development of resistance in mesenchymal GBM. The main interconnection between mesenchymal features, TMZ resistance, and ferroptosis are poorly understood. Herein, we demonstrated that a subunit of NADPH oxidase, CYBB, orchestrated mesenchymal shift and promoted TMZ resistance by modulating the anti-ferroptosis circuitry Nrf2/SOD2 axis. Public transcriptomic data re-analysis found that CYBB and SOD2 were highly upregulated in the mesenchymal subtype of GBM. Accordingly, our GBM cohort confirmed a high expression of CYBB in the GBM tumor and was associated with mesenchymal features and poor clinical outcome. An in vitro study demonstrated that TMZ-resistant GBM cells displayed mesenchymal and stemness features while remaining resilient to erastin-mediated ferroptosis by activating the CYBB/Nrf2/SOD2 axis. The CYBB maintained a high ROS state to sustain the mesenchymal phenotype, TMZ resistance, and reduced erastin sensitivity. Mechanistically, CYBB interacted with Nrf2 and consequently regulated SOD2 transcription. Compensatory antioxidant SOD2 essentially protected against the deleterious effect of high ROS while attenuating ferroptosis in TMZ-resistant cells. An animal study highlighted the protective role of SOD2 to mitigate erastin-triggered ferroptosis and tolerate oxidative stress burden in mice harboring TMZ-resistant GBM cell xenografts. Therefore, CYBB captured ferroptosis resilience in mesenchymal GBM. The downstream compensatory activity of CYBB via the Nrf2/SOD2 axis is exploitable through erastin-induced ferroptosis to overcome TMZ resistance.
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Neoplasias Encefálicas , Glioblastoma , Animales , Humanos , Ratones , Antineoplásicos Alquilantes/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , NADPH Oxidasa 2 , Factor 2 Relacionado con NF-E2/genética , Especies Reactivas de Oxígeno/metabolismo , Temozolomida/farmacología , Temozolomida/uso terapéuticoRESUMEN
PURPOSE: This study investigated the protective effect of probucol on Müller cells exposed to high glucose conditions and examined potential mechanisms of action. METHODS: Primary human retinal Müller cells were incubated with high glucose (HG, 35 mM) in the present or absence of different concentrations of probucol for 24 h. Cell viability was determined using the CCK-8 method. Mitochondrial membrane potential (MMP) was measured using JC-1 staining and cell cycle by flow cytometry. The expression of nuclear factor E2-related factor 2 (Nrf2), glutamate-cysteine ligase catalytic subunit, and p62 was quantified using quantitative polymerase chain reaction and western blot. RESULTS: We found that HG inhibited cell proliferation, arrested cell cycle, and increased MMP in human Müller cells. Probucol activated the Nrf2/p62 pathway and upregulated the anti-apoptotic protein, Bcl2, and attenuated HG-mediated damage in Müller cells. CONCLUSIONS: Our results suggest that probucol may protect Müller cells from HG-induced damage through enhancing the Nrf2/p62 signaling pathway.
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Células Ependimogliales , Probucol , Transducción de Señal , Humanos , Células Ependimogliales/efectos de los fármacos , Células Ependimogliales/metabolismo , Glucosa/metabolismo , Glucosa/farmacología , Factor 2 Relacionado con NF-E2 , Probucol/farmacologíaRESUMEN
OBJECTIVE: The use of robotics in spinal surgery has gained popularity because of its promising accuracy and safety. ROSA is a commonly used surgical robot system for spinal surgery. The aim of this study was to compare outcomes between robot-guided and freehand fluoroscopy-guided instrumentation in minimally invasive surgery (MIS)-transforaminal lumbar interbody fusion (TLIF). METHODS: This retrospective consecutive series reviewed 224 patients who underwent MIS-TLIF from March 2019 to April 2020 at a single institution. All patients were diagnosed with degenerative pathologies. Of those, 75 patients underwent robot-guided MIS-TLIF, and 149 patients underwent freehand fluoroscopy-guided MIS-TLIF. The incidences of pedicle breach, intraoperative outcomes, postoperative outcomes, and short-term pain control were compared. RESULTS: The patients who underwent robot-guided surgery had a lower incidence of pedicle breach (0.27% vs 1.75%, p = 0.04) and less operative blood loss (313.7 ± 214.1 mL vs 431.6 ± 529.8 mL, p = 0.019). Nonsignificant differences were observed in operative duration (280.7 ± 98.1 minutes vs 251.4 ± 112.0 minutes, p = 0.056), hospital stay (6.6 ± 3.4 days vs 7.3 ± 4.4 days, p = 0.19), complications (intraoperative, 1.3% vs 1.3%, p = 0.45; postoperative surgery-related, 4.0% vs 4.0%, p = 0.99), and short-term pain control (postoperative day 1, 2.1 ± 1.2 vs 1.8 ± 1.2, p = 0.144; postoperative day 30, 1.2 ± 0.5 vs 1.3 ± 0.7, p = 0.610). A shorter operative duration for 4-level spinal surgery was found in the robot-guided surgery group (388.7 ± 107.3 minutes vs 544.0 ± 128.5 minutes, p = 0.047). CONCLUSIONS: This retrospective review revealed that patients who underwent robot-guided MIS-TLIF experienced less operative blood loss. They also benefited from a shorter operative duration with higher-level (> 3 levels) spinal surgery. The postoperative outcomes were similar for both robot-guided and freehand fluoroscopy-guided procedures.
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Robótica , Fusión Vertebral , Estudios de Casos y Controles , Fluoroscopía , Humanos , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/cirugía , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Estudios Retrospectivos , Fusión Vertebral/métodos , Resultado del TratamientoRESUMEN
Azo dyes constitute a significant environmental burden due to its toxicity, carcinogenicity, and hard biodegradation. The report here is focused on the decolorization and degradation treatment of azo dye methyl red (MR). Decolorization of MR using Aspergillus versicolor LH1 isolated from activated sludge was investigated. The maximum decolorization rate of 92.3% was obtained under the optimized conditions of sucrose as carbon source, 5d incubation age, pH 6.0, 140 mg/L initial concentration of MR and 2.5 g/L initial concentration of NaNO3. Biodegradation products of MR were investigated using HPLC-MS, FTIR, and GC-MS assays. It was revealed the three bonds of -C-N = in MR aromatic nucleus were disrupted, and benzoic acid was detected. Micronucleus test with Glycine max L. and Vicia faba L. demonstrated that MCN (micronucleus permillage) of MR metabolites was less than MR solution. These findings provided evidence that A. versicolor LH1 is a candidate for MR degradation in industrial wastewater treatment.
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Aspergillus/metabolismo , Compuestos Azo/metabolismo , Aguas Residuales/microbiología , Contaminantes Químicos del Agua/metabolismo , Purificación del Agua , Biodegradación AmbientalRESUMEN
In recent years, there have been a number of reports on the phenomenon in which ferric iron (Fe(III)) is reduced to ferrous iron [Fe(II)] in anaerobic environments, accompanied by simultaneous oxidation of ammonia to NO2-, NO3-, or N2. However, studies on the relevant reaction characteristics and mechanisms are rare. Recently, in research on the effect of Fe(III) on the activity of Anammox sludge, excess ammonia oxidization has also been found. Hence, in the present study, Fe(III) was used to serve as the electron acceptor instead of NO2-, and the feasibility and characteristics of Anammox coupled to Fe(III) reduction (termed Feammox) were investigated. After 160days of cultivation, the conversion rate of ammonia in the reactor was above 80%, accompanied by the production of a large amount of NO3- and a small amount of NO2-. The total nitrogen removal rate was up to 71.8%. Furthermore, quantities of Fe(II) were detected in the sludge fluorescence in situ hybridization (FISH) and denaturated gradient gel electrophoresis (DGGE) analyses further revealed that in the sludge, some Anammox bacteria were retained, and some microbes were enriched during the acclimatization process. We thus deduced that in Anammox sludge, Fe(III) reduction takes place together with ammonia oxidation to NO2- and NO3- along with the Anammox process.
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Amoníaco/química , Hierro/química , Aguas del Alcantarillado/microbiología , Aclimatación , Amoníaco/metabolismo , Respiración de la Célula , Crecimiento Quimioautotrófico , Electroforesis en Gel de Gradiente Desnaturalizante , Ambiente , Compuestos Férricos , Hibridación Fluorescente in Situ , Hierro/metabolismo , Nitrógeno , Oxidantes , Oxidación-ReducciónRESUMEN
Citrobacter koseri is a gram-negative bacillus that causes mostly meningitis and brain abscesses in neonates and infants. However, brain abscess caused by Citrobacter koseri infection in an adult is extremely rare, and only 2 cases have been described. Here, we reported a 73-year-old male presenting with a 3-week headache. A history of diabetes mellitus was noted. The images revealed a brain abscess in the left frontal lobe and pus culture confirmed the growth of Citrobacter koseri. The clinical symptoms improved completely postoperatively.
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Absceso Encefálico/etiología , Absceso Encefálico/microbiología , Citrobacter koseri , Infecciones por Enterobacteriaceae/complicaciones , Infecciones por Enterobacteriaceae/microbiología , Anciano , Absceso Encefálico/cirugía , Humanos , Imagen por Resonancia Magnética , Masculino , Procedimientos Neuroquirúrgicos , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Immunotherapy can potentially suppress the highly aggressive glioblastoma (GBM) by promoting T lymphocyte infiltration. Nevertheless, the immune privilege phenomenon, coupled with the generally low immunogenicity of vaccines, frequently hampers the presence of lymphocytes within brain tumors, particularly in brain tumors. In this study, the membrane-disrupted polymer-wrapped CuS nanoflakes that can penetrate delivery to deep brain tumors via releasing the cell-cell interactions, facilitating the near-infrared II (NIR II) photothermal therapy, and detaining dendritic cells for a self-cascading immunotherapy are developed. By convection-enhanced delivery, membrane-disrupted amphiphilic polymer micelles (poly(methoxypoly(ethylene glycol)-benzoic imine-octadecane, mPEG-b-C18) with CuS nanoflakes enhances tumor permeability and resides in deep brain tumors. Under low-power NIR II irradiation (0.8 W/cm2), the intense heat generated by well-distributed CuS nanoflakes actuates the thermolytic efficacy, facilitating cell apoptosis and the subsequent antigen release. Then, the positively charged polymer after hydrolysis of the benzoic-imine bond serves as an antigen depot, detaining autologous tumor-associated antigens and presenting them to dendritic cells, ensuring sustained immune stimulation. This self-cascading penetrative immunotherapy amplifies the immune response to postoperative brain tumors but also enhances survival outcomes through effective brain immunotherapy.
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Neoplasias Encefálicas , Membrana Celular , Células Dendríticas , Inmunoterapia , Rayos Infrarrojos , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Animales , Ratones , Humanos , Membrana Celular/química , Línea Celular Tumoral , Micelas , Nanopartículas/química , Terapia Fototérmica , Polietilenglicoles/química , Glioblastoma/terapia , Glioblastoma/inmunología , Glioblastoma/patología , Apoptosis/efectos de los fármacosRESUMEN
BACKGROUND: Percutaneous vertebroplasty (PVP) is a common procedure, but cement leaks are not uncommon. Leakages do not always have consequences, but rarely complications do occur. Spinal subdural hematomas (sSDHs) are rare and even rarer presented as a complication after PVP. The best management for sSDH is, therefore, difficult to decide. OBSERVATIONS: The patient first received PVP for acute low back pain after falling. Cement leakages were noted after the procedure, but a sudden new-onset leg weakness only developed later. An emergency lumbar computed tomography scan showed cement leakages anterior to the dural sac; lumbar magnetic resonance imaging revealed a subdural spinal hematoma, and a decompressive laminectomy was performed. During the operation, a small cement mass in the shape of a horn was seen and was believed to have caused the sSDH. Postoperatively, the patient recovered to leg strength 5/5. LESSONS: PVP is considered a low-risk procedure, and cement leaks rarely give rise to complications. However, when leakages present anterior to the dural sac, they may cause dural tear and possible sSDH, regardless of size. This possibility draws attention to keeping awareness of such rare but possible complications after routine PVP procedures. Timely intervention for sSDH is necessary to ensure meaningful recovery.
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OBJECTIVE: To investigate the regulatory effect of miRNA-29a-3p (miR-29a-3p ) on hepatoma-derived growth factor (HDGF), and its influences on the proliferation and apoptosis of acute lymphoblastic leukemia (ALL) cell line E6-1. METHODS: Thirty-five patients with ALL treated in our hospital from January 2017 to January 2019 were selected as research objects, and 35 adults who underwent physical examination in the same period were selected as healthy control group. The miR-29a-3p overexpression vector, miR-29a-3p inhibitory expression vector, and miR-29a-3p and HDGF co-overexpression vector were transfected into E6-1 cells. The expression levels of miR-29a-3p and HDGF mRNA were detected by RT-qPCR. The expression of protein was detected by Western blot. The targeting relationship between miR-29a-3p and HDGF was detected by dual luciferase reporter assay. The cell proliferation was detected by CCK-8 method, while apoptosis detected by flow cytometry. RESULTS: Compared with healthy control group, HDGF was highly expressed in serum of patients with ALL and leukemia cells HuT 78, E6-1, CCRF-CEM, while miR-29a-3p was low expressed (P<0.05). After overexpression of miR-29a-3p , the expression levels of CyclinD1 and Bcl-2 in leukemia cells E6-1 were significantly reduced, while the expression levels of p21 and Bax were significantly increased (P<0.05). The activity of E6-1 cells was also significantly reduced, while the apoptosis rate of E6-1 cells was significantly increased (P<0.05). miR-29a-3p could target and regulate the expression of HDGF, while overexpression of HDGF reversed the inhibitory effect of miR-29a-3p overexpression on the proliferation and promotion effect on the apoptosis of leukemia cells E6-1. CONCLUSION: Overexpression of miR-29a-3p can inhibit the proliferation and promote the apoptosis of ALL cells E6-1, and its mechanism may be related to the regulation of HDGF expression.
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Leucemia , MicroARNs , Humanos , Apoptosis , Proliferación Celular , MicroARNs/genéticaRESUMEN
OBJECTIVE: The study investigated our institutional learning curve for the ROSA ONE spine system (ROSA) based on ROSA usage time. METHODS: ROSA was designed to provide high accuracy for spinal pedicle screw placement through a built-in tracking technique. This study was conducted from November 2018 to January 2021. The time taken to complete each step of the robotic workflow was recorded. Patient demographics, comorbidities, surgical indications, and number of screw placements were examined in subgroup analysis. The Curve Fitting-General package (a part of NCSS 2021 software) was used to fit a mathematical model to the learning curve. Patient demographics, imaging data, and surgical time were reviewed retrospectively. RESULTS: A total of 167 patients who had undergone surgery were included. The mean total ROSA usage time was 107.1 ± 27.3 minutes. The estimated learning rate was 90.4%, and the largest slope change occurred close to the time of the 20th surgery. The observed overall learning trend in the 4-screw group could be attributed to screw planning. The presence of scoliosis (p = 0.73) or spondylolisthesis (p = 0.70) did not significantly influence the mean total time (TT) for all patients; however, the mean TT differed significantly (p < 0.01) among subgroups stratified by body mass index, screw number placement, and thoracic spine involvement. CONCLUSION: To the best of our knowledge, this is the first study to examine the learning curve for the various crucial steps of ROSA-guided pedicle screw placement. The indicative learning curve involved 20 patients who had undergone surgery.
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Diabetic retinopathy (DR) is a sight-threatening complication of diabetes. This study investigated the therapeutic effect of probucol in a mouse model of diabetic retinopathy. C57BL/6 mice were rendered diabetic through Streptozotocin (STZ) intraperitoneal injection. Mice were treated with probucol (150 mg/kg, gavage administration) or vehicle (DMSO) for 12 weeks. Optical coherence tomography (OCT), fundus photography (FP), and fundus fluorescein angiography (FFA) were conducted to evaluate retinal structure and damage. Eyes were collected for histology, reactive oxygen species (ROS) assay, apoptotic cells count, and western blot. After STZ injection, all mice developed hyperglycemia. Compared with the retina of the control group, the retina of diabetic mice showed enhanced arterial reflex and beaded vein dilatation. Besides, reduced inner and middle retinal thickness and significantly fewer nuclei were found in diabetic retina. Moreover, the diabetic retina also presented increased ROS generation and more TUNEL-positive cells. Probucol treatment prevented diabetes-induced lesions. In addition, the treatment also upregulated Nrf2 expression in diabetic retina. It was suggested that probucol attenuated diabetes-induced retinal neuronal degeneration via upregulating the Nrf2 signaling pathway possibly. Probucol may be repurposed for DR management.
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Antioxidantes/farmacología , Factor 2 Relacionado con NF-E2 , Probucol/farmacología , Retina/efectos de los fármacos , Degeneración Retiniana/inducido químicamente , Animales , Retinopatía Diabética/inducido químicamente , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/análisis , Factor 2 Relacionado con NF-E2/metabolismo , Neuronas/efectos de los fármacos , Retina/química , Retina/metabolismo , Degeneración Retiniana/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The authors wish to make the following corrections to this paper [...].
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OBJECTIVE: To measure the expression of hOCT1 gene in patients with Chronic Myelogeneous Leukemia (CML) and to explore its role in the progress of the disease and responding to Imatinib Mesylate (IM) treatment. METHODS: Sixty three peripheral blood or bone marrow samples were taken from 30 patients with CML (20 in chronic phase, 10 in advanced phase). The samples were divided into two groups: responding (optimal and suboptimal) and non-responding according to effectiveness of the IM treatment. The mRNA levels of hOCT1 gene were detected with RT-PCR (SQ-PCR), 3, 6, 9, 12 and 15 months after the IM therapy. The associations between hOCT1 gene levels and clinical presentations, laboratory indicators and cytogenetic findings were analysed. RESULTS: No significant difference in the expression levels of hOCT1 gene was found before and after the IM treatment (0.5110+/-0.1629 vs 0.5207+/-0.1909, P=0.5840). No significant difference in the expression levels of hOCT1 genes was found between the patients in chronic phase and the patients in advanced phase before the IM treatment (0.5525+/-0.1985 vs 0.4490+/-0.1717, P=0.1090). The levels of hOCT1 did not have significant changes 3, 6, 9, 12 and 15 months after the IM treatment (P=0.3412). No significant difference in the expression levels of hOCT1 genes was found between the 15 patients with optimal and suboptimal responding to IM and the 5 patients with no responding to IM (0.5820+/-0.1460 vs 0.4640+/-0.1781, P=0.127). Although the hOCT1 levels of the 16 chronic patients increased after IM treatment compared to the baseline (0.5207+/-0.1909 vs 0.5110+/-0.1629, P=0.001), there was no significant correlation between the increase of hOCT1 and the decrease of BCR-ABL (P=0.821). CONCLUSION: hOCT1 has no association with the stage and course of CML, nor with the effectiveness of IM therapy.
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Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Factor 1 de Transcripción de Unión a Octámeros/metabolismo , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Adolescente , Adulto , Anciano , Benzamidas , Niño , Preescolar , Femenino , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Persona de Mediana Edad , Factor 1 de Transcripción de Unión a Octámeros/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Glioblastoma (GBM), a malignant grade IV tumor, is the most malignant brain tumor due to its hyper-proliferative and apoptosis-evading characteristics. The signal transducer and activators of transcription (STAT) family genes, including STAT3 and STAT5A, have been indicated to play important roles in GBM progression. Increasing number of reports suggest that garcinol, a polyisoprenylated benzophenone and major bioactive component of Garcinia indica contains potent anti-cancer activities. MATERIAL AND METHODS: The present study investigated the anti-GBM effects of garcinol, focusing on the STAT3/STAT5A activation, using a combination of bioinformatics, in vitro, and ex vivo assays. RESULTS: Our bioinformatics analysis of The Cancer Genome Atlas (TCGA)-GBM cohort (n = 173) showed that STAT3 and STAT5A are preferentially elevated in primary and recurrent GBM, compared to non-tumor brain tissues, and is significantly correlated with reduced overall survival. In support, our immunohistochemical staining of a GBM cohort (n = 45) showed an estimated 5.3-fold (p < 0.001) elevation in STAT3 and STAT5A protein expression in primary and recurrent GBM versus the non-tumor group. In vitro, garcinol treatment significantly suppressed the proliferative, invasive, and migratory potential of U87MG or GBM8401 cells, dose-dependently. In addition, garcinol anticancer effect significantly attenuated the GBM stem cell-like phenotypes, as reflected by diminished ability of U87MG or GBM8401 to form colonies and tumorspheres and suppressed expression of OCT4 and SOX2. Furthermore, analysis on GBM transcriptome revealed an inverse correlation between the level of STAT3/5A and hsa-miR-181d. Garcinol-mediated anti-GBM effects were associated with an increased hsa-miR-181d/STAT3 and hsa-miR-181d/5A ratio. The results were further verified in vivo using U87MG mouse xenograft model where administration of garcinol significantly inhibited tumor growth. CONCLUSIONS: We present evidence of anti-GBM efficacy of garcinol mediated by enhancing the hsa-miR-181d/STAT3 and hsa-miR-181d/5A ratios in GBM cells. Our findings suggest a potential new therapeutic agent for combating aggressive GBM.
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BACKGROUND: The tumor microenvironment (TME) plays a crucial role in virtually every aspect of tumorigenesis of glioblastoma multiforme (GBM). A dysfunctional TME promotes drug resistance, disease recurrence, and distant metastasis. Recent evidence indicates that exosomes released by stromal cells within the TME may promote oncogenic phenotypes via transferring signaling molecules such as cytokines, proteins, and microRNAs. RESULTS: In this study, clinical GBM samples were collected and analyzed. We found that GBM-associated macrophages (GAMs) secreted exosomes which were enriched with oncomiR-21. Coculture of GAMs (and GAM-derived exosomes) and GBM cell lines increased GBM cells' resistance against temozolomide (TMZ) by upregulating the prosurvival gene programmed cell death protein 4 (PDCD4) and stemness markers SRY (sex determining region y)-box 2 (Sox2), signal transducer and activator of transcription 3 (STAT3), Nestin, and miR-21-5p and increasing the M2 cytokines interleukin 6 (IL-6) and transforming growth factor beta 1(TGF-ß1) secreted by GBM cells, promoting the M2 polarization of GAMs. Subsequently, pacritinib treatment suppressed GBM tumorigenesis and stemness; more importantly, pacritinib-treated GBM cells showed a markedly reduced ability to secret M2 cytokines and reduced miR-21-enriched exosomes secreted by GAMs. Pacritinib-mediated effects were accompanied by a reduction of oncomiR miR-21-5p, by which the tumor suppressor PDCD4 was targeted. We subsequently established patient-derived xenograft (PDX) models where mice bore patient GBM and GAMs. Treatment with pacritinib and the combination of pacritinib and TMZ appeared to significantly reduce the tumorigenesis of GBM/GAM PDX mice as well as overcome TMZ resistance and M2 polarization of GAMs. CONCLUSION: In summation, we showed the potential of pacritinib alone or in combination with TMZ to suppress GBM tumorigenesis via modulating STAT3/miR-21/PDCD4 signaling. Further investigations are warranted for adopting pacritinib for the treatment of TMZ-resistant GBM in clinical settings.
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The feasibility of using Feammox coupled with nitrate-dependent Fe(II) oxidizing (NAFO) to cause the simultaneous conversion of NH4+ and NO3- was explored by inoculation with Feammox sludge and the use Fe cycling as catalyst. After 61days operation, the simultaneous conversion of NO3- and NH4+ occurred with the presence of interconversion between Fe(III) and Fe(II). The conversion ratio of NH4+ to NO3- stabilized at 0.9-1. The results of isotopic tracing and microbial diversity analysis indicated that NH4+ was first oxidized to NO2- by Fe(III), then NO3- was reduced to NO2- and N2 by the Fe(II) produced in Feammox process, and finally, the NO2- produced in NAFO process underwent an Anammox process with the remaining NH4+ to yield N2. The results showed the simultaneous continuous conversion process of NO3- and NH4+ with limited Fe as a catalyst was a coupled process of Feammox, Anammox, and NAFO under the anaerobic conditions.
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BACKGROUND: Glioblastoma (GBM), a malignant form of glioma, is characterized by resistance to therapy and poor prognosis. Accumulating evidence shows that the initiation, propagation, and recurrence of GBM is attributable to the presence of GBM stem cells (GBM-CSCs). EXPERIMENTAL APPROACH: Herein, we investigated the effect of 4-Acetylantroquinonol B (4-AAQB), a bioactive isolate of Antrodia cinnamomea, on GBM cell viability, oncogenic, and CSCs-like activities. RESULTS: We observed that aberrant expression of catenin is characteristic of GBM, compared to other glioma types (p = 0.0001, log-rank test = 475.2), and correlates with poor prognosis of GBM patients. Lower grade glioma and glioblastoma patients (n = 1152) with low catenin expression had 25% and 21.5% better overall survival than those with high catenin expression at the 5 and 10-year time-points, respectively (p = 3.57e-11, log-rank test = 43.8). Immunohistochemistry demonstrated that compared with adjacent non-tumor brain tissue, primary and recurrent GBM exhibited enhanced catenin expression (~10-fold, p < 0.001). Western blot analysis showed that 4-AAQB significantly downregulated ß-catenin and dysregulated the catenin/LEF1/Stat3 signaling axis in U87MG and DBTRG-05MG cells, dose-dependently. 4-AAQBâ»induced downregulation of catenin positively correlated with reduced Sox2 and Oct4 nuclear expression in the cells. Furthermore, 4-AAQB markedly reduced the viability of U87MG and DBTRG-05MG cells with 48 h IC50 of 9.2 M and 12.5 M, respectively, effectively inhibited the nuclear catenin, limited the migration and invasion of GBM cells, with concurrent downregulation of catenin, vimentin, and slug; similarly, colony and tumorsphere formation was significantly attenuated with reduced expression of c-Myc and KLF4 proteins. CONCLUSIONS: Summarily, we show for the first time that 4-AAQB suppresses the tumor-promoting catenin/LEF1/Stat3 signaling, and inhibited CSCs-induced oncogenic activities in GBM in vitro, with in vivo validation; thus projecting 4-AAQB as a potent therapeutic agent for anti-GBM target therapy.