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Migraine without aura is a multidimensional neurological disorder characterized by sensory, emotional, and cognitive symptoms linked to structural and functional abnormalities in the anterior cingulate cortex. Anterior cingulate cortex subregions play differential roles in the clinical symptoms of migraine without aura; however, the specific patterns and mechanisms remain unclear. In this study, voxel-based morphometry and seed-based functional connectivity were used to investigate structural and functional alterations in the anterior cingulate cortex subdivisions in 50 patients with migraine without aura and 50 matched healthy controls. Compared with healthy controls, patients exhibited (1) decreased gray matter volume in the subgenual anterior cingulate cortex, (2) increased functional connectivity between the bilateral subgenual anterior cingulate cortex and right middle frontal gyrus, and between the posterior part of anterior cingulate cortex and right middle frontal gyrus, orbital part, and (3) decreased functional connectivity between the anterior cingulate cortex and left anterior cingulate and paracingulate gyri. Notably, left subgenual anterior cingulate cortex was correlated with the duration of each attack, whereas the right subgenual anterior cingulate cortex was associated with migraine-specific quality-of-life questionnaire (emotion) and self-rating anxiety scale scores. Our findings provide new evidence supporting the hypothesis of abnormal anterior cingulate cortex subcircuitry, revealing structural and functional abnormalities in its subregions and emphasizing the potential involvement of the left subgenual anterior cingulate cortex-related pain sensation subcircuit and right subgenual anterior cingulate cortex -related pain emotion subcircuit in migraine.
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Giro do Cíngulo , Enxaqueca sem Aura , Humanos , Giro do Cíngulo/diagnóstico por imagem , Enxaqueca sem Aura/diagnóstico por imagem , Córtex Cerebral , Dor/diagnóstico por imagem , Emoções , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND: Adrenal corticomedullary mixed tumours are very rare. Its mechanism is rarely reported. Here we report the first case of a corticomedullary mixed tumour resembling a "small adrenal gland" with distinct arrangement of the cortical and medullary layers. We further hypothesize regarding the tumorigenic mechanism of this tumour. CASE PRESENTATION: A 58-year man had been diagnosed with diabetes and hypertension for 3 years. His 24-h urine vanillylmandelic acid (VMA) levels were slightly elevated. An abnormal circadian cortisol rhythm was noted, and his cortisol levels were not suppressed by dexamethasone. Abdominal computed tomography (CT) revealed a right adrenal gland lesion (diameter, 30 × 38 mm), while an enhanced CT showed enhancement and hypervascularization. The tumour was positive for adrenocorticotropic hormone, chromogranin A (CGA), and steroidogenic factor-1 (SF-1) on the tumour surface. Acetaldehyde dehydrogenase 1(ALDH1), CD44, CD133, Nestin, Nerve growth factor receptor (NGFR), and Sex determining region y-box 9(SOX9) staining were positive. Although administration of medications for diabetes and hypertension was stopped until surgery was performed, the blood sugar level and blood pressure were maintained after surgery. CONCLUSIONS: This is the first report about a possible mechanism by which cancer stem cells induce adrenal corticomedullary tumours.
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Neoplasias das Glândulas Suprarrenais/patologia , Células-Tronco Neoplásicas/patologia , Neoplasias das Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Cromogranina A/metabolismo , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/metabolismo , Fator Esteroidogênico 1/metabolismo , Tomografia Computadorizada por Raios X , Ácido Vanilmandélico/urinaRESUMO
Postoperative cognitive dysfunction (POCD) is a common postoperative complication in elderly patients, and neuroinflammation is a key hallmark. Recent studies suggest that the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-mediated astrocytes pyroptosis is involved in the regulation of neuroinflammation in many neurocognitive diseases, while its role in POCD remains obscure. Carnosine is a natural endogenous dipeptide with anti-inflammatory and neuroprotective effects. To explore the effect of carnosine on POCD and its mechanism, we established a POCD model by exploratory laparotomy in 24-month-old male Sprague-Dawley rats. We found that the administrated of carnosine notably attenuated surgery-induced NLRP3 inflammasome activation and pyroptosis in astrocytes, central inflammation, and neuronal damage in the hippocampus of aged rats. In addition, carnosine dramatically ameliorated the learning and memory deficits of surgery-induced aged rats. Then in the in vitro experiments, we stimulated primary astrocytes with lipopolysaccharide (LPS) after carnosine pretreatment. The results also showed that the application of carnosine alleviated the activation of the NLRP3 inflammasome, pyroptosis, and inflammatory response in astrocytes stimulated by LPS. Taken together, these findings suggest that carnosine improves POCD in aged rats via inhibiting NLRP3-mediated astrocytes pyroptosis and neuroinflammation.
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Postoperative depression (POD) and postoperative cognitive dysfunction (POCD) have placed heavy burden on patients' physical and mental health in recent years. Sleep disturbance before surgery is a common phenomenon that has been increasingly believed to affect patients' recovery, especially in aged patients, while little attention has been paid to sleep disruption before surgery and the potential mechanism remains ambiguous. Ketamine has been reported to attenuate POCD after cardiac surgery and elicit rapid-acting and sustained antidepressant actions. The present study aimed to clarify the effect of esketamine's (the S-enantiomer of ketamine) protective effects and possible mechanisms of action in POCD and POD. Our results showed that sleep disturbance before surgery exacerbated microglial M1 polarization and microglial BDNF-TrkB signalling dysfunction induced by surgery, resulting in postoperative emotional changes and cognitive impairments. Notably, treatment with esketamine reversed the behavioural abnormalities through inhibiting the M1 polarization of microglia and the inflammatory response thus improving BDNF-TrkB signalling in vivo and vitro. In addition, esketamine administration also reversed the impaired hippocampal synaptic plasticity which has been perturbed by sleep disturbance and surgery. These findings warrant further investigations into the interplay of esketamine and may provide novel ideas for the implication of preoperative preparations and the prevention of postoperative brain-related complications.
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Envelhecimento , Fator Neurotrófico Derivado do Encéfalo , Disfunção Cognitiva , Ketamina , Microglia , Receptor trkB , Transtornos do Sono-Vigília , Animais , Masculino , Ratos , Envelhecimento/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Polaridade Celular/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/prevenção & controle , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Emoções/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Ketamina/farmacologia , Ketamina/uso terapêutico , Microglia/metabolismo , Microglia/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Ratos Sprague-Dawley , Receptor trkB/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transtornos do Sono-Vigília/metabolismo , Transtornos do Sono-Vigília/tratamento farmacológicoRESUMO
Introduction: Glycopyrrolate is commonly researched as a preoperative medication or in conjunction with cholinesterase inhibitors to counteract the lingering muscarinic effects of non-depolarizing muscarinic agents. However, studies have yielded inconsistent results regarding the superiority of glycopyrrolate over other anti-cholinergic drugs, such as atropine, particularly its effect on heart rate, blood pressure (BP), and glandular secretions. This study aimed to evaluate the differences in perioperative oral secretions, hemodynamics, and recovery quality with glycopyrrolate versus those with atropine before anesthesia induction in children undergoing tonsillectomy and adenoidectomy. Methods: In this prospective, single-center, randomized, double-blind, controlled trial, a total of 103 children were randomly assigned to group A (n = 51, glycopyrrolate 0.005 mg/kg) or B (n = 52, atropine 0.01 mg/kg). The follow-up anesthetic induction and maintenance protocols were the same in both groups. Vital signs, duration of surgery, extubation time, degree of wetness around the vocal cords during tracheal intubation, weight of oral secretions, and perioperative complications were recorded. Results: No significant differences were observed in the degree of wetness around the vocal cords during tracheal intubation, as well as in the weight of oral secretions, duration of surgery, or extubation time, between the two groups. The intraoperative and postoperative heart rates were lower in group A than in group B (110.18 ± 10.58 vs. 114.94 ± 11.14, p = 0.028; 96.96 ± 10.81 vs. 103.38 ± 10.09, p = 0.002). The differences observed in the intraoperative and preoperative heart rates were lower in group A than in group B (23.84 ± 9.62 vs. 29.65 ± 8.75, p = 0.002). The differences observed in the postoperative and preoperative heart rates were lower in group A than in group B (10.63 ± 9.97 vs. 18.09 ± 9.39, p = 0.000). Conclusion: Glycopyrrolate showed a smoother change in heart rate than atropine during and after tonsillectomy and adenoidectomy, with no effect on BP or recovery quality, and did not increase oral secretions. The findings indicate that glycopyrrolate can serve as an alternative to atropine to prevent secretions in anesthesia induction for tonsillectomy and adenoidectomy in children. Trial registration: This study was registered with the Chinese Clinical Trial Registry (Registration Number: ChiCTR2200063578; Date of Registration: 12/09/2022).
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Background: Electroacupuncture (EA), with varying stimulation intensities, has demonstrated therapeutic potentials in both animal and clinical studies for the treatment of chronic obstructive pulmonary disease (COPD). However, a comprehensive investigation of the intensity-related effects, particularly 1mA and 3mA of EA, and the underlying mechanisms remains lacking. Methods: A COPD rat model was established by prolonged exposure to cigarette smoke and intermittent intratracheal instillation of lipopolysaccharide. EA treatment was administered at acupoints BL13 (Feishu) and ST36 (Zusanli), 20 minutes daily for 2 weeks, with intensities of 1mA and 3mA. EA effectiveness was evaluated by pulmonary function, histopathological change, serum level of inflammatory cytokines, and level of oxidative stress markers in serum and lung tissues. Transcriptome profiling and weighted gene co-expression network analysis (WGCNA) were performed to reveal gene expression patterns and identify hub genes. Real-time quantitative PCR (RT-qPCR) and Western blot (WB) were performed to detect the mRNA and protein expression levels, respectively. Results: EA at both 1mA and 3mA exerted differing therapeutic effects by improving lung function and reducing inflammation and oxidative stress in COPD rats. Transcriptome analysis revealed distinct expression patterns between the two groups, functionally corresponding to shared and intensity-specific (1mA and 3mA) enriched pathways. Eight candidate genes were identified, including Aqp9, Trem1, Mrc1, and Gpnmb that were downregulated by EA and upregulated in COPD. Notably, Msr1 and Slc26a4 exclusively downregulated in EA-1mA, while Pde3a and Bmp6 upregulated solely in EA-3mA. WGCNA constructed 5 key modules and elucidated the module-trait relationship, with the aforementioned 8 genes being highlighted. Additionally, their mRNA and protein levels were validated by RT-qPCR and WB. Conclusion: Our results demonstrated that 1mA and 3mA intensities induce distinct gene expression patterns at the transcriptional level, associated with shared and 1mA vs 3mA-specific enriched pathways. Genes Mrc1, Gpnmb, Trem1, and Aqp9 emerge as promising targets, and further studies are needed to elucidate their functional consequences in COPD.
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Objectives: Cancer-related insomnia (CRI) is one of the most common and serious symptoms in patients with cancer. Acupuncture and moxibustion have been widely applied in the treatment of CRI. Nevertheless, the comparative efficacy and safety of different acupuncture and moxibustion techniques remain unclear. This study aimed to evaluate and compare the efficacy and safety of different acupuncture and moxibustion techniques in the treatment of CRI. Methods: Eight medical databases were comprehensively searched for relevant randomized controlled trials (RCTs) as of June 2022. Two independent reviewers assessed the risk of bias and conducted the research selection, data extraction, and quality assessment of the included RCTs. A network meta-analysis (NMA) was performed using frequency models, combining all available direct and indirect evidence from RCTs. The Pittsburgh Sleep Quality Index (PSQI) was set as the primary outcome, and adverse events and effective rates were set as the secondary outcomes. The efficacy rate was calculated as the ratio of patients with insomnia symptom relief to the total number of patients. Results: Thirty-one RCTs with 3,046 participants were included, including 16 acupuncture- and moxibustion-related therapies. Transcutaneous electrical acupoint stimulation [surface under the cumulative ranking curve (SUCRA) 85.7%] and acupuncture and moxibustion (SUCRA 79.1%) were more effective than Western medicine, routine care, and placebo-sham acupuncture. Furthermore, Western medicine showed significantly better effects than placebo-sham acupuncture. In the NMA, the acupuncture and moxibustion treatments with the best therapeutic effects for CRI were transcutaneous electrical acupoint stimulation (SUCRA 85.7%), acupuncture and moxibustion (SUCRA 79.1%), auricular acupuncture (SUCRA 62.9%), routine care combined with intradermal needling (SUCRA 55.0%), and intradermal needling alone (SUCRA 53.3%). No serious acupuncture- or moxibustion-related adverse events were reported in the included studies. Conclusion: Acupuncture and moxibustion are effective and relatively safe in treating CRI. The relatively conservative recommended order of acupuncture- and moxibustion-related therapies for CRI is as follows: transcutaneous electrical acupoint stimulation, acupuncture and moxibustion, and auricular acupuncture. However, the methodological quality of the included studies was generally poor, and further high-quality RCTs are needed to strengthen the evidence base.
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PURPOSE: Infiltrative growth pattern is a hallmark of glioblastoma (GBM). Radiation therapy aims to eradicate microscopic residual GBM cells after surgical removal of the visible tumor bulk. However, in-field recurrences remain the major pattern of therapy failure. We hypothesized that the radiosensitivity of peripheral invasive tumor cells (peri) may differ from the predominantly investigated tumor bulk. METHODS AND MATERIALS: Invasive GBM populations were generated via debulking of the visible tumor core and serial orthotopic transplantation of peri cells, and sustained proinvasive phenotype of peri cells was confirmed in vitro by scratch assay and time lapse imaging. In parallel, invasive GBM cells were selected by transwell assay and from peri cells of patient-derived 3-dimensional spheroid cultures. Transcriptome analysis deciphered a GBM invasion-associated gene signature, and functional involvement of key pathways was validated by pharmacologic inhibition. RESULTS: Compared with the bulk cells, invasive GBM populations acquired a radioresistant phenotype characterized by increased cell survival, reduced cell apoptosis, and enhanced DNA double-strand break repair proficiency. Transcriptome analysis revealed a reprograming of invasive cells toward augmented activation of epidermal growth factor receptor- and nuclear factor-κB-related pathways, whereas metabolic processes were downregulated. An invasive GBM score derived from this transcriptional fingerprint correlated well with patient outcome. Inhibition of epidermal growth factor receptor and nuclear factor-κB signaling resensitized invasive cells to irradiation. Invasive cells were eradicated with similar efficacy by particle therapy with carbon ions. CONCLUSIONS: Our data indicate that invasive tumor cells constitute a phenotypically distinct and highly radioresistant GBM subpopulation with prognostic impact that may be vulnerable to targeted therapy and carbon ions.
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Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/radioterapia , Linhagem Celular Tumoral , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/radioterapia , Humanos , Tolerância a Radiação/genética , Transdução de SinaisRESUMO
PURPOSE: To investigate brain tissue response to ultra-high dose rate (uHDR, FLASH) and standard dose rate (SDR) proton irradiations in the Bragg peak region. METHODS AND MATERIALS: Active scanning uHDR delivery was established for proton beams for investigation of dose rate effects between clinical SDR and uHDR at â¼10 Gy in the Bragg peak region (dose-averaged linear energy transfer [LETD] ranging from 4.5 to 10.2 keV µm-1 ). Radiation- induced injury of neuronal tissue was assessed by studying the DNA double strand break repair kinetics surrogated by nuclear γH2AX staining (radiation induced foci [RIF]), microvascular density and structural integrity (MVD, CD31+ endothelium), and inflammatory microenvironmental response (CD68+ microglia/macrophages and high mobility group box protein 1[HMGB]) in healthy C57BL/6 mouse brains. RESULTS: Averaged dose rates achieved were 0.17 Gy/s (SDR) and 120 Gy/s (uHDR). The fraction of RIF-positive cells increased after SDR â¼10-fold, whereas a significantly lower fraction of RIF-positive cells was found after uHDR versus SDR (â¼2 fold, P < .0001). Moreover, uHDR substantially preserved the microvascular architecture and reduced microglia/macrophage regulated associated inflammation as compared with SDR. CONCLUSIONS: The feasibility of uHDR raster scanning proton irradiation is demonstrated to elicit FLASH sparing neuroprotective effects compared to SDR in a preclinical in vivo model.
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Fármacos Neuroprotetores , Terapia com Prótons , Lesões por Radiação , Animais , Transferência Linear de Energia , Camundongos , Camundongos Endogâmicos C57BL , Terapia com Prótons/métodos , PrótonsRESUMO
Localized radiotherapy (RT) induces an immunogenic antitumor response that is in part counterbalanced by activation of immune evasive and tissue remodeling processes, e.g., via upregulation of programmed cell death-ligand 1 (PD-L1) and transforming growth factor ß (TGF-ß). We report that a bifunctional fusion protein that simultaneously inhibits TGF-ß and PD-L1, bintrafusp alfa (BA), effectively synergizes with radiotherapy, leading to superior survival in multiple therapy-resistant murine tumor models with poor immune infiltration. The BA + RT (BART) combination increases tumor-infiltrating leukocytes, reprograms the tumor microenvironment, and attenuates RT-induced fibrosis, leading to reconstitution of tumor immunity and regression of spontaneous lung metastases. Consistently, the beneficial effects of BART are in part reversed by depletion of cytotoxic CD8+ T cells. Intriguingly, targeting of the TGF-ß trap to PD-L1+ endothelium and the M2/lipofibroblast-like cell compartment by BA attenuated late-stage RT-induced lung fibrosis. Together, the results suggest that the BART combination has the potential to eradicate therapy-resistant tumors while sparing normal tissue, further supporting its clinical translation.
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Inibidores de Checkpoint Imunológico/uso terapêutico , Evasão da Resposta Imune/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Fator de Crescimento Transformador beta/metabolismo , Animais , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Camundongos , Microambiente TumoralRESUMO
We report on a unique microfluidic device that can enrich nanoparticles in a continuous flow by railing them along activated tracks (electrodes). This was achieved based on dielectrophoretic force and electrohydrodynamic drag (electrothermal rolls and AC electroosmosis) in both low and high conductive media. The results have implication for the isolation of high quality and pure nanoparticles such as exosomes from biofluids for applications in cancer diagnosis and prognosis.
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Técnicas Analíticas Microfluídicas , Nanopartículas , Condutividade Elétrica , Eletro-Osmose , Dispositivos Lab-On-A-ChipRESUMO
Background: Glioma therapy is challenged by the diffuse and invasive growth of glioma. Lysosomal protein transmembrane 5 (LAPTM5) was identified as an invasion inhibitor by an in vivo screen for invasion-associated genes. The aim of this study was to decipher the function of LAPTM5 in glioblastoma and its interaction with the CD40 receptor which is intensively evaluated as a target in the therapy of diverse cancers including glioma. Methods: Knockdown of LAPTM5 was performed in different glioma cell lines to analyze the impact on clonogenicity, invasiveness, sensitivity to temozolomide chemotherapy, and tumorigenicity in vitro and in vivo. An expression array was used to elucidate the underlying pathways. CD40 knockdown and overexpression were induced to investigate a potential crosstalk of LAPTM5 and CD40. LAPTM5 and CD40 were correlated with the clinical outcome of glioma patients. Results: Knockdown of LAPTM5 unleashed CD40-mediated NFκB activation, resulting in enhanced invasiveness, clonogenicity, and temozolomide resistance that was overcome by NFκB inhibition. LAPTM5 expression correlated with better overall survival in glioblastoma patients depending on CD40 expression status. Conclusion: We conclude that LAPTM5 conveyed tumor suppression and temozolomide sensitation in CD40-positive glioblastoma through the inhibition of CD40-mediated NFκB activation. Hence, LAPTM5 may provide a potential biomarker for sensitivity to temozolomide in CD40-positive glioblastoma.
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In order to develop high-performance dielectric materials, poly(arylene ether nitrile)-based composites were fabricated by employing surface-hydroxylated calcium copper titanate (CCTO) particles. The results indicated that the surface hydroxylation of CCTO effectively improved the interfacial compatibility between inorganic fillers and the polymer matrix. The composites exhibit not only high glass transition temperatures and an excellent thermal stability, but also excellent flexibility and good mechanical properties, with a tensile strength over 60 MPa. Furthermore, the composites possess enhanced permittivity, relatively low loss tangent, good permittivity-frequency stability and dielectric-temperature stability under 160 °C. Therefore, it furnishes an effective path to acquire high-temperature-resistant dielectric materials for various engineering applications.
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Tumor radioresistance leading to local therapy failure remains a major obstacle for successful treatment of high-grade glioma. We hypothesized that distinct radiobiological features of particle therapy with carbon ions may circumvent glioma radioresistance. We demonstrate that carbon irradiation (CIR) efficiently eradicates radioresistant patient-derived glioma stem cells (GSCs), leading to growth inhibition and prolonged survival. The impact of CIR at the tumor-stroma interface was further investigated in 2 syngeneic mouse and 2 orthotopic GSC xenograft models. Intriguingly, tumor regressions and long-term local controls were observed at doses greater than or equal to 15-Gy CIR. Fractionated CIR further prolonged survival. The enhanced relative biological effectiveness of CIR in vivo was attributed to its potent antiangiogenic effects and eradication of radioresistant hypoxic tumor cells. Blockade of the HIF1-α/stromal cell-derived factor 1/CXCR4 axis by CIR reduced the recruitment of microglia and myeloid-derived suppressor cells (CD11b+Gr1+). Consequently, CIR abrogated M2-like immune polarization and enhanced the influx of CD8+ cells, generating an immunopermissive niche. We report that radiotherapy with carbon ions could surmount several central glioma resistance mechanisms by eradicating hypoxic and stem cell-like tumor cells, as well as modulating the glioma niche toward an antiangiogenic and less immunosuppressive state. Conclusively, potentially novel rationales for CIR in conquering glioma radioresistance are provided.
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Coal gangue is one of the largest industrial solid waste all over the world, and many methods have been proposed for the recycling of coal gangue. In the present study, the feasibility of using coal gangue as landfill liner material is studied through a series of laboratory tests in terms of hydraulic conductivity, sorption characteristics and leaching behavior. The results indicated that the hydraulic conductivity of coal gangue could be smaller than the regulatory requirement 1×10-7cm/s with a void ratio less than 0.60. The batch sorption experiments performed on Pb2+ and Zn2+ illustrated that the coal gangue showed remarkable sorption capacity for the two heavy metals, and the sorption capacity for Pb2+ was larger than that for Zn2+. Both the pseudo first-order and pseudo second-order models fitted well with the sorption kinetics data of the Pb2+ and Zn2+ on the coal gangue, and the Langmuir model was found to best-fit the sorption isotherms. The sorption capacity decreased in presence of multiple heavy metals, both for Pb2+ and Zn2+. Concentrations of heavy metals leached from the coal gangue were all below the regulatory limits from China MEP and U.S. EPA. These desirable characteristics indicated that the coal gangue has potential to be used as landfill liner materials.
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Carvão Mineral , Eliminação de Resíduos/métodos , Instalações de Eliminação de Resíduos , Adsorção , China , Estudos de Viabilidade , Cinética , Poluentes do SoloRESUMO
PURPOSE: To investigate the radiosensitivity of primary glioma stem cell (GSC) cultures with different CD133 status in a 3-dimensional (3D) model after photon versus proton versus carbon irradiation. METHODS AND MATERIALS: Human primary GSC spheroid cultures were established from tumor specimens of six consented glioblastoma patients. Human U87MG was used as a classical glioblastoma radioresistant cell line. Cell suspensions were generated by mechanical dissociation of GSC spheroids and embedded in a semi-solid 3D matrix before irradiation. Spheroid-like colonies were manually counted by microscopy. Cells were also recovered and quantified by fluorescence. CD133 expression and DNA damage were evaluated by flow cytometry. RESULTS: The fraction of CD133(+) cells varied between 0.014% and 96% in the six GSC cultures and showed a nonsignificant correlation with plating efficiency and survival fractions. The 4 most photon-radioresistant GSC cultures were NCH644, NCH421k, NCH441, and NCH636. Clonogenic survival for proton irradiation revealed relative biologic effectiveness (RBE) in the range of 0.7-1.20. However, carbon irradiation rendered the photon-resistant GSC cultures sensitive, with average RBE of 1.87-3.44. This effect was partly attributed to impaired capability of GSC to repair carbon ion-induced DNA double-strand breaks as determined by residual DNA repair foci. Interestingly, radiosensitivity of U87 cells was comparable to GSC cultures using clonogenic survival as the standard readout. CONCLUSIONS: Carbon irradiation is effective in GSC eradication with similar RBE ranges approximately 2-3 as compared with non-stem GSC cultures (U87). Our data strongly suggest further exploration of GSC using classic radiobiology endpoints such as the here-used 3D clonogenic survival assay and integration of additional GSC-specific markers.
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Glioblastoma/radioterapia , Glioma/radioterapia , Células-Tronco Neoplásicas/efeitos da radiação , Tolerância a Radiação/efeitos da radiação , Antígeno AC133 , Adulto , Idoso , Antígenos CD/análise , Antígenos de Neoplasias/análise , Carbono , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos da radiação , Reparo do DNA , Glioblastoma/imunologia , Glioblastoma/patologia , Glioma/imunologia , Glioma/patologia , Glicoproteínas/análise , Histonas/análise , Humanos , Células-Tronco Neoplásicas/imunologia , Peptídeos/análise , Fótons , Prótons , Eficiência Biológica Relativa , Esferoides Celulares/imunologia , Esferoides Celulares/patologia , Esferoides Celulares/efeitos da radiação , Células Tumorais Cultivadas , Ensaio Tumoral de Célula-Tronco/métodosRESUMO
Cancer is a common comorbidity of diabetic patients; however, little is known about the effects that antidiabetic drugs have on tumors. We discovered that common classes of drugs used in type 2 diabetes mellitus, the hypoglycemic dipeptidyl peptidase-4 inhibitors (DPP-4i) saxagliptin and sitagliptin, as well as the antineuropathic α-lipoic acid (ALA), do not increase tumor incidence but increase the risk of metastasis of existing tumors. Specifically, these drugs induce prolonged activation of the nuclear factor E2-related factor 2 (NRF2)-mediated antioxidant response through inhibition of KEAP1-C151-dependent ubiquitination and subsequent degradation of NRF2, resulting in up-regulated expression of metastasis-associated proteins, increased cancer cell migration, and promotion of metastasis in xenograft mouse models. Accordingly, knockdown of NRF2 attenuated naturally occurring and DPP-4i-induced tumor metastasis, whereas NRF2 activation accelerated metastasis. Furthermore, in human liver cancer tissue samples, increased NRF2 expression correlated with metastasis. Our findings suggest that antioxidants that activate NRF2 signaling may need to be administered with caution in cancer patients, such as diabetic patients with cancer. Moreover, NRF2 may be a potential biomarker and therapeutic target for tumor metastasis.
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Antioxidantes/farmacologia , Hipoglicemiantes/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Metástase Neoplásica/patologia , Adamantano/análogos & derivados , Adamantano/farmacologia , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Dipeptídeos/farmacologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Glutamato-Cisteína Ligase/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Fosfato de Sitagliptina/farmacologia , Ácido Tióctico/farmacologia , Ubiquitinação/efeitos dos fármacosRESUMO
BACKGROUND: Acupuncture has been commonly used for preventing migraine attacks and relieving pain during a migraine, although there is limited knowledge on the physiological mechanism behind this method. The objectives of this study were to compare the differences in brain activities evoked by active acupoints and inactive acupoints and to investigate the possible correlation between clinical variables and brain responses. METHODS AND RESULTS: A randomized controlled trial and resting-state functional magnetic resonance imaging (fMRI) were conducted. A total of eighty migraineurs without aura were enrolled to receive either active acupoint acupuncture or inactive acupoint acupuncture treatment for 8 weeks, and twenty patients in each group were randomly selected for the fMRI scan at the end of baseline and at the end of treatment. The neuroimaging data indicated that long-term active acupoint therapy elicited a more extensive and remarkable cerebral response compared with acupuncture at inactive acupoints. Most of the regions were involved in the pain matrix, lateral pain system, medial pain system, default mode network, and cognitive components of pain processing. Correlation analysis showed that the decrease in the visual analogue scale (VAS) was significantly related to the increased average Regional homogeneity (ReHo) values in the anterior cingulate cortex in the two groups. Moreover, the decrease in the VAS was associated with increased average ReHo values in the insula which could be detected in the active acupoint group. CONCLUSIONS: Long-term active acupoint therapy and inactive acupoint therapy have different brain activities. We postulate that acupuncture at the active acupoint might have the potential effect of regulating some disease-affected key regions and the pain circuitry for migraine, and promote establishing psychophysical pain homeostasis. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TRC-13003635.