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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Motivated by the promising benefits of dynamic time division duplex (TDD), in this paper, we use a unified framework to investigate both the technical issues of applying dynamic TDD in homogeneous small-cell networks (HomSCNs) and the feasibility of introducing dynamic TDD into heterogeneous networks (HetNets). First, HomSCNs are analyzed, and a small-cell base-station (BS) scheduler that dynamically and independently schedules downlink (DL) and uplink (UL) subframes is presented, such that load balancing between the DL and UL traffic can be achieved. Moreover, the effectiveness of various interlink interference mitigation (ILIM) schemes and their combinations is systematically investigated and compared. Moreover, the interesting possibility of partial interference cancelation (IC) is also explored. Second, based on the proposed schemes, the joint operation of dynamic TDD together with cell range expansion (CRE) and almost blank subframe (ABS) in HetNets is studied. In this regard, scheduling polices in small cells and an algorithm to derive the appropriate macrocell traffic offload and ABS duty cycle under dynamic TDD operation are proposed. Moreover, the full IC and the partial IC schemes are investigated for dynamic TDD in HetNets. The user-equipment (UE) packet throughput performance of the proposed/discussed schemes is benchmarked using system-level simulations. [ABSTRACT FROM AUTHOR]

Bitterness is a basic flavor in alcoholic beverages (beer, wine, liquor, and rice wine) and has physiological significance, although excessive and disharmonious bitterness is unpleasant. Current research on flavor in alcoholic beverages is primarily focused on volatile constituents and distinctive flavor compounds. However, studies on the recognition, identification, and metabolic mechanism of bitter substances are still in the preliminary phase. This review provides an integrated account of the signal transduction and recognition, composition and sensory properties of bitterness in alcoholic beverages. Abiotic and biotic factors within fermentation systems that may influence the bitterness of the fermented beverages are summarized. Future research on the molecular characteristics, taste attributes, and metabolic pathways of bitterness are discussed herein. Polyphenol and iso- α -acid extracted from grapes and hops are the typical bitter substances in wine and beer. Microbial metabolites, including bitter peptides and higher alcohols, are the primary contributors to bitterness in liquor and rice wine. These compounds can activate one or more specific bitter taste receptors. Manufacturing processes and sensory interactions also influence the perception of bitterness. Establishing normative bitterness scoring methods and distinguishing acceptable and unacceptable bitterness based on sensory physiology will continue to be the goals of bitterness research. Further elucidation of the metabolic mechanism underlying bitterness through a combination of omics and synthetic microbiology will allow for taste characteristics of alcoholic beverages to be manipulated. Image 1 • The bitterness profile in alcoholic beverages was described. • Polyphenols, iso-α-acids, higher alcohols, and bitter peptides are the major bitter compounds. • Raw materials and microbial metabolism were the major contributor to bitterness. • Improvement on bio-electronic sensor to identify bitter components was suggested. • The bitterness metabolic mechanism is needed further microbial exploration. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

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., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

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.