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Porous carbon materials are highly desirable for removing benzene due to their low energy for capture and regeneration. Research has demonstrated that narrow microporous volume is crucial for effective adsorption of benzene at ultra-low concentration. Unfortunately, achieving directional increase in the narrow microporous volume in porous carbon remains a challenge. Here, nitrogen-doped hydrothermal carbon was prepared using urea-assisted hydrothermal method, and then porous carbon (PUC800) was prepared by KOH activation. The resulting material had 180 % higher pore volume and 179 % higher surface area compared to non-nitrogen activation methods. Then, using mechanochemical (mechanical compaction and KOH activation) approach to produce PUC800-3T, which had a 30 % increase in pore volume and a 33 % increase in surface area compared to PUC800. PUC800-3T showed benzene adsorption capacity of 4.2 mmol g-1 at 1 Pa and 5.8 mmol g-1 at 5 Pa. Experimental and molecular simulation indicate that the benzene adsorption at 1 and 5 Pa is determined by pore volume of less than 0.8 and 0.9 nm, respectively. Density functional theory calculations provided insight into the CHâ¯X (X = N/O) interactions drive benzene adsorption on the carbon framework. This work provides valuable theoretical and experimental support for designing, preparing, and applying adsorbents for trace removal of benzene vapor.
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BACKGROUND: Accumulating evidence supports the involvement of adaptive immunity in the development of radiation-induced brain injury (RIBI). Our previous work has emphasized the cytotoxic function of CD8+ T cells in RIBI. In this study, we aimed to investigate the presence and potential roles of cytotoxic CD4+ T cells (CD4+ CTLs) in RIBI to gain a more comprehensive understanding of adaptive immunity in this context. MAIN TEXT: Utilizing single-cell RNA sequencing (scRNA-seq), we analyzed 3934 CD4+ T cells from the brain lesions of four RIBI patients and identified six subclusters within this population. A notable subset, the cytotoxic CD4+ T cells (CD4+ CTLs), was marked with high expression of cytotoxicity-related genes (NKG7, GZMH, GNLY, FGFBP2, and GZMB) and several chemokine and chemokine receptors (CCL5, CX3CR1, and CCL4L2). Through in-depth pseudotime analysis, which simulates the development of CD4+ T cells, we observed that the CD4+ CTLs exhibited signatures of terminal differentiation. Their functions were enriched in protein serine/threonine kinase activity, GTPase regulator activity, phosphoprotein phosphatase activity, and cysteine-type endopeptidase activity involved in the apoptotic signaling pathway. Correspondingly, mice subjected to gamma knife irradiation on the brain showed a time-dependent infiltration of CD4+ T cells, an increase of MHCII+ cells, and the existence of CD4+ CTLs in lesions, along with an elevation of apoptotic-related proteins. Finally, and most crucially, single-cell T-cell receptor sequencing (scTCR-seq) analysis at the patient level determined a large clonal expansion of CD4+ CTLs in lesion tissues of RIBI. Transcriptional factor-encoding genes TBX21, RORB, and EOMES showed positive correlations with the cytotoxic functions of CD4+ T cells, suggesting their potential to distinguish RIBI-related CD4+ CTLs from other subsets. CONCLUSION: The present study enriches the understanding of the transcriptional landscape of adaptive immune cells in RIBI patients. It provides the first description of a clonally expanded CD4+ CTL subset in RIBI lesions, which may illuminate new mechanisms in the development of RIBI and offer potential biomarkers or therapeutic targets for the disease.
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Antineoplásicos , Lesões Encefálicas , Humanos , Camundongos , Animais , Linfócitos T CD8-Positivos , Linfócitos T CD4-Positivos , Linfócitos T Citotóxicos , Encéfalo , Lesões Encefálicas/metabolismoRESUMO
Radiotherapy for head and neck tumors can lead to a severe complication known as radiation-induced brain injury (RIBI). However, the underlying mechanism of RIBI development remains unclear, and limited prevention and treatment options are available. Neuroactive steroids have shown potential in treating neurological disorders. 5α-Androst-3ß, 5, 6ß-triol (TRIOL), a synthetic neuroprotective steroid, holds promise as a treatment candidate for RIBI patients. However, the neuroprotective effects and underlying mechanism of TRIOL on RIBI treatment are yet to be elucidated. In the present study, our findings demonstrate TRIOL's potential as a neuroprotective agent against RIBI. In gamma knife irradiation mouse model, TRIOL treatment significantly reduced brain necrosis volume, microglial activation, and neuronal loss. RNA-sequencing, immunofluorescence, real-time quantitative polymerase chain reaction, siRNA transfection, and western blotting techniques revealed that TRIOL effectively decreased microglial activation, proinflammatory cytokine release, neuron loss, and guanylate-binding protein 5 (GBP5) expression, along with its downstream signaling pathways NF-κB and NLRP3 activation in vitro. In summary, TRIOL effectively alleviate RIBI by inhibiting the GBP5/NF-κB/NLRP3 signal axis, reducing microglia activation and pro-inflammation cytokines release, rescuing neuron loss. This study highlights the potential of TRIOL as a novel and promising therapy drug for RIBI treatment.
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Introduction: Radiotherapy for patients with head and neck cancers raises their risk of aspiration pneumonia-related death. We aimed to develop and validate a model to predict radiation-associated aspiration pneumonia (RAP) among patients with dysphagia after radiotherapy for nasopharyngeal carcinoma (NPC). Materials and Methods: A total of 453 dysphagic patients with NPC were retrospectively recruited from Sun Yat-Sen Memorial Hospital from January 2012 to January 2018. Patients were randomly divided into training cohort (n = 302) and internal validation cohort (n = 151) at a ratio of 2 : 1. The concordance index (C-index) and calibration curve were used to evaluate the accuracy and discriminative ability of this model. Moreover, decision curve analysis was performed to evaluate the net clinical benefit. The results were externally validated in 203 dysphagic patients from the First People's Hospital of Foshan. Results: Derived from multivariable analysis of the training cohort, four independent factors were introduced to predict RAP, including Kubota water drinking test grades, the maximum radiation dose of lymph node gross tumor volume (Dmax of the GTVnd), neutrophil count, and erythrocyte sedimentation rate (ESR). The nomogram showed favorable calibration and discrimination regarding the training cohort, with a C-index of 0.749 (95% confidence interval (CI), 0.681 to 0.817), which was confirmed by the internal validation cohort (C-index 0.743; 95% CI, 0.669 to 0.818) and the external validation cohort (C-index 0.722; 95% CI, 0.606 to 0.838). Conclusions: Our study established and validated a simple nomogram for RAP among patients with dysphagia after radiotherapy for NPC.
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Transtornos de Deglutição , Neoplasias Nasofaríngeas , Pneumonia Aspirativa , Transtornos de Deglutição/etiologia , Humanos , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/complicações , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/radioterapia , Pneumonia Aspirativa/etiologia , Estudos RetrospectivosAssuntos
Bevacizumab/farmacologia , Encéfalo/efeitos da radiação , Linfócitos/classificação , Necrose/tratamento farmacológico , Neutrófilos/classificação , Adulto , Bevacizumab/uso terapêutico , Feminino , Humanos , Linfócitos/fisiologia , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/complicações , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/fisiopatologia , Necrose/etiologia , Necrose/fisiopatologia , Neutrófilos/fisiologia , Valor Preditivo dos Testes , Radioterapia/efeitos adversos , Radioterapia/métodos , Radioterapia/estatística & dados numéricosRESUMO
It is well known that non-small cell lung cancer (NSCLC) is a malignant tumor with high incidence in the world. We aimed to clarify a possible target and identify its precise molecular biological mechanism in NSCLC. NLR family CARD domain containing 5 (NLRC5) is widely expressed in tissues and exerts a vital role in anti-tumor immunity. We determined NLRC5 expression by RT-qPCR and western blot assay. The role of NLRC5 in the development of NSCLC was assessed by a loss-of-function assay. CCK-8, Annexin-V-FITC/PI Apoptosis Detection Kit, Transwell, and wound healing assays were used to determine the cell functions. Drug resistance-related proteins were analyzed by western blot assay. Furthermore, the modulation of NLRC5 on carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expression and subsequent PI3K/AKT signaling was assessed. In this study, a hyper-expression of NLRC5 was found in NSCLC tissues and cell lines. Knockdown of NLRC5 suppressed cell viability, invasion, and migration, and furthermore promoted cell apoptosis in NSCLC cells. Moreover, under normoxia or hypoxia treatment, the upregulation of NLRC5 was related to carboplatin resistance. NLRC5 silencing increased carboplatin-resistant cell chemosensitivity, as evidenced by the increase in the cell inhibition rate and decrease in drug resistance-related protein expression. Mechanistically, NLRC5 knockdown inhibited the expression of CEACAM1 and subsequently blocked the PI3K/AKT signaling pathway. In conclusion, NLRC5 promotes the malignant biological behaviors of NSCLC cells by activating the PI3K/AKT signaling pathway via the regulation of CEACAM1 expression under normoxia and hypoxia.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Carboplatina/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Pulmonares/patologia , Antígeno Carcinoembrionário , Molécula 1 de Adesão Celular , Domínio de Ativação e Recrutamento de Caspases , Fatores de Transcrição , Proliferação de Células/genética , Hipóxia , Linhagem Celular Tumoral , Movimento Celular/genéticaRESUMO
BACKGROUND: Blood-brain barrier (BBB) disruption after endothelial damage is a crucial part of radiation-induced brain necrosis (RN), but little is known of BBB disruption quantification and its role in the evaluation of therapeutic effect and prognosis for drug treatment. In this retrospective study, BBB repair by bevacizumab and corticosteroid and the correlation between BBB permeability and treatment response and relapse were evaluated by dynamic contrast-enhanced MRI (DCE-MRI). METHODS: Forty-one patients with RN after radiotherapy for nasopharyngeal carcinoma (NPC) (28 treated with bevacizumab and 13 with corticosteroid), 12 patients with no RN after NPC radiotherapy, and 12 patients with no radiotherapy history were included as RN, non-RN, and normal groups, respectively. DCE-MRI assessed BBB permeability in white matter of bilateral temporal lobe. DCE parameters were compared at baseline among the three groups. DCE parameters after treatment were compared and correlated with RN volume decrease, neurological improvement, and relapse. RESULTS: The extent of BBB leakage at baseline increased from the normal group and non-RN group and to RN necrosis lesions, especially K trans (Kruskal-Wallis test, P < 0.001). In the RN group, bevacizumab-induced K trans and v e decrease in radiation necrosis lesions (both P < 0.001), while corticosteroid showed no obvious effect on BBB. The treatment response rate of bevacizumab was significantly higher than that of corticosteroid [30/34 (88.2%) vs. 10/22 (45.4%), P < 0.001]. Spearman analysis showed baseline K trans, K ep, and v p positively correlated with RN volume decrease and improvement of cognition and quality of life in bevacizumab treatment. After a 6-month follow-up for treatment response cases, the relapse rate of bevacizumab and corticosteroid was 10/30 (33.3%) and 2/9 (22.2%), respectively, with no statistical difference. Post-bevacizumab K trans level predicted relapse in 6 months with AUC 0.745 (P < 0.05, 95% CI 0.546-0.943, sensitivity = 0.800, specificity = 0.631). CONCLUSIONS: Bevacizumab improved BBB leakage in RN necrosis. DCE parameters may be useful to predict therapeutic effect and relapse after bevacizumab.
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OBJECTIVE: Our aim was to compare the clinical outcomes of patients treated with bevacizumab combined with corticosteroids and those with bevacizumab monotherapy from a radiation-induced brain necrosis (RN) registry cohort (NCT03908502). METHODS: We utilized clinical data from a prospective RN registry cohort (NCT03908502) from July 2017 to June 2020. Patients were considered eligible if they had symptomatic RN after radiotherapy for nasopharyngeal carcinoma (NPC) and received bevacizumab (5 mg/kg, two to four cycles) with a minimum follow-up time of 3 months. The primary outcome was a 2-month response rate determined by MRI and clinical symptoms. Secondary outcomes included quality of life [evaluated by the abbreviated World Health Organization Quality of Life (WHOQOL-BREF) questionnaire] and cognitive function (evaluated by the Montreal Cognitive Assessment scale) at 2 months, RN recurrence during follow-up, and adverse events. RESULTS: A total of 123 patients (34 in the combined therapy group and 89 in the monotherapy group) were enrolled in our study with a median follow-up time of 0.97 year [interquartile range (IQR) = 0.35-2.60 years]. The clinical efficacy of RN did not differ significantly between patients in these two groups [odds ratio (OR) = 1.642, 95%CI = 0.584-4.614, p = 0.347]. Furthermore, bevacizumab combined with corticosteroids did not reduce recurrence compared with bevacizumab monotherapy [hazard ratio (HR) = 1.329, 95%CI = 0.849-2.079, p = 0.213]. The most common adverse events of bevacizumab were hypertension (17.89%), followed by nosebleed (8.13%) and fatigue (8.13%). There was no difference in grade 2 or more severe adverse events between the two groups (p = 0.811). INTERPRETATION: Our results showed that the treatment strategy of combining bevacizumab with corticosteroids did not lead to better clinical outcomes for RN patients with a background of radiotherapy for nasopharyngeal carcinoma.
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BACKGROUND: WBRT and systemic chemotherapy are the mainstay treatments for small-cell lung cancer (SCLC) brain metastases (BM). However, current recommendations are mainly based on evidence from retrospective analyses. A recent randomized trial found no benefits from WBRT compared with best supportive care (BSC) in patients with more than three BM from non-small-cell lung cancer (NSCLC). Herein, we aimed to evaluate the roles of WBRT and chemotherapy further in the management of BM from SCLC. MATERIALS AND METHODS: There were 698 patients with BM from SCLC included. Of these, 580 received anti cancer treatment (Group 1), including 178 who received WBRT only (Group 1a), 129 who received chemotherapy only (Group 1b), and 273 who received WBRT plus chemotherapy (Group 1c). The other 118 received BSC (Group 2). Propensity score matching (PSM) analysis was used to compare Group 2 with each of the other groups. RESULTS: After PSM, compared with Group 2 (n = 118), patients in Group 1 (n = 440) had a prolonged overall survival (OS) in both univariate and multivariate tests, with a median survival time of 10 months (95% CI = 9-11) in Group 1 and 3.5 months (95% CI = 2-7) in Group 2 (p < 0.001). In subgroup analyses, patients who received WBRT plus chemotherapy were more likely to benefit from treatment (p < 0.001). Chemotherapy alone or WBRT alone did not show survival benefits. CONCLUSION: WBRT plus chemotherapy improved OS in patients with BM from SCLC as compared to BSC. Chemotherapy alone and WBRT alone did not show survival benefits. This retrospective study suggests that SCLC patients with BM who receive WBRT combined with chemotherapy have a better outcome than those receiving BSC alone.
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PURPOSE: Several studies have explored the correlation between the neutrophil-to-lymphocyte ratio (NLR) and the prognosis of patients with lung cancer. However, little is known about the correlation between the pretreatment NLR and the prognosis of patients with brain metastases from non-small cell lung cancer (NSCLC)-harboring mutations in the epidermal growth factor receptor (EGFR) gene. We sought to evaluate the predictive values in brain metastasis from lung adenocarcinoma with EGFR mutations. METHODS: We retrospectively examined 133 patients with brain metastases (BMs) from lung adenocarcinoma with EGFR mutations. NLR was calculated using N/L, where N and L, respectively, refer to peripheral blood neutrophil (N) and lymphocyte (L) counts. The cut-off value of NLR was assessed by the area under the curve (AUC). The Log rank test and Cox proportional hazard model were used to confirm the impact of NLR and other variables on survival. RESULTS: An NLR value equal to or less than 2.99 was associated with prolonged survival in this cohort of patients in both variable and multivariable analysis. CONCLUSION: We concluded that NLR is an independent prognostic factor in BMs from lung adenocarcinoma with EGFR mutations. This could serve as a useful prognostic biomarker and could be incorporated in the clinical prognostic index specific to patients with BMs.
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The prognostic value of the systemic immune-inflammation index (SII) has been shown in various types of cancers. We aimed to evaluate the predictive values in brain metastases from lung adenocarcinoma with status of EGFR mutations. We, retrospectively, examined 310 patients with brain metastases from lung adenocarcinoma with status of EGFR mutations. SII was calculated using P * N/L, where P, N, and L, respectively refer to peripheral blood lymphocyte, neutrophil, and platelet counts. The cut-off value of SII was assessed by area under the curve (AUC). The log-rank test and Cox proportional hazard model were used to confirm the impact of SII and other variables on survival. The SII value ≤ 1218.81 was associated with prolonged survival in patients with brain metastases from lung adenocarcinoma in both variable and multivariable analysis In patients with EGFR mutations, the SII had statistical effect on OS only in invariable test. While, for patients with wild-type EGFR, SII achieved statistically significant differences both in variable and multivariable analyses. SII is an independent prognostic factor in brain metastases from lung adenocarcinoma. SII may have varying prognostic effects on patients with and without EGFR mutations and is a promising variable for the future prognostic systems.
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Adenocarcinoma de Pulmão/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Neoplasias Pulmonares/genética , Mutação , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/mortalidade , Receptores ErbB/genética , Feminino , Humanos , Inflamação/patologia , Neoplasias Pulmonares/patologia , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Contagem de Plaquetas , Prognóstico , Modelos de Riscos Proporcionais , Estudos RetrospectivosRESUMO
CF is caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) which is an anion selective transmembrane ion channel that mainly regulates chloride transport, expressed in the epithelia of various organs. Recently, we have demonstrated CFTR expression in the brain, the spinal cord and the sympathetic ganglia. This study aims to investigate the expression and distribution of CFTR in the ganglia of the human gastrointestinal tract. Fresh tissue and formalin-fixed paraffin-embedded normal gastrointestinal tract samples were collected from eleven surgical patients and five autopsy cases. Immunohistochemistry, in situ hybridization, laser-assisted microdissection and nested reverse transcriptase polymerase chain reaction were performed. Expression of CFTR protein and mRNA was detected in neurons of the ganglia of all segments of the human gastrointestinal tract examined, including the stomach, duodenum, jejunum, ileum, cecum, appendix, colon and rectum. The extensive expression of CFTR in the enteric ganglia suggests that CFTR may play a role in the physiology of the innervation of the gastro-intestinal tract. The presence of dysfunctional CFTRs in enteric ganglia could, to a certain extent, explain the gastrointestinal symptoms frequently experienced by CF patients.
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Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/tratamento farmacológico , Gânglios/patologia , Mucosa Intestinal/metabolismo , Neurônios/fisiologia , Adulto , Idoso , Biópsia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Intestinos/inervação , Masculino , Pessoa de Meia-IdadeRESUMO
Histone deacetylase inhibitors are promising chemotherapeutic agents and some are in clinical trials. Several molecular mechanisms have been invoked to describe their effects on cancer cells in vivo and in vitro. Autophagy has been observed in response to several anticancer reagents and has been demonstrated to be responsible for cell death. However, the exact mechanism of this phenomenon is still not clear. Here we demonstrated that suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, induces nonapoptotic cell death with several specific features characteristic of autophagy in Hela S3 cells. Suberoylanilide hydroxamic acid inhibits the activity of the mammalian target of rapamycin, a negative regulator of macroautophagy which induces the formation of autophagosomes in a Beclin 1- and autophagy-related 7-dependent manner. This process is mediated by Akt and tuberous sclerosis 2 as is demonstrated by inhibition by continuous active Akt plasmid transfection and RNA interference of tuberous sclerosis 2. Our data provide the first evidence that suberoylanilide hydroxamic acid induces autophagy in Hela S3 cells through interference with the mammalian target of rapamycin signaling pathway. These findings suggest that suberoylanilide hydroxamic acid may induce autophagic cancer cell death via its specific pathway, and invite further investigation into the detailed mechanism of this pathway to explore this compound's full potential as a chemotherapeutic agent.