A Receptor on Acid.

Wacker et al. report the crystal structure of LSD in complex with one of its major targets in the brain, the 5-HT2B receptor, the first such structure for any psychedelic drug. The results shed light on the molecular mechanisms underlying its ability to induce hallucinations with greater duration and potency than closely related compounds.

Structures of rhodopsin in complex with G-protein-coupled receptor kinase 1.

G-protein-coupled receptor (GPCR) kinases (GRKs) selectively phosphorylate activated GPCRs, thereby priming them for desensitization1. Although it is unclear how GRKs recognize these receptors2-4, a conserved region at the GRK N terminus is essential for this process5-8. Here we report a series of cryo-electron microscopy single-particle reconstructions of light-activated rhodopsin (Rho*) bound to rhodopsin kinase (GRK1), wherein the N terminus of GRK1 forms a helix that docks into the open cytoplasmic cleft of Rho*. The helix also packs against the GRK1 kinase domain and stabilizes it in an active configuration. The complex is further stabilized by electrostatic interactions between basic residues that are conserved in most GPCRs and acidic residues that are conserved in GRKs. We did not observe any density for the regulator of G-protein signalling homology domain of GRK1 or the C terminus of rhodopsin. Crosslinking with mass spectrometry analysis confirmed these results and revealed dynamic behaviour in receptor-bound GRK1 that would allow the phosphorylation of multiple sites in the receptor tail. We have identified GRK1 residues whose mutation augments kinase activity and crosslinking with Rho*, as well as residues that are involved in activation by acidic phospholipids. From these data, we present a general model for how a small family of protein kinases can recognize and be activated by hundreds of different GPCRs.

Enhanced Photocatalytic Hydrogen Evolution of In2S3 by Decorating In2O3 with Rich Oxygen Vacancies.

The hydrogen (H2) evolution rates of photocatalysts suffer from weak oxidation and reduction ability and low photogenerated charge carrier separation efficiency. Herein, by combining band-gap structure optimization and vacancy modulation through a one-step hydrothermal method, In2O3 containing oxygen vacancy (Ov/In2O3) is simply introduced into In2S3 to promote photocatalytic hydrogen evolution. Specifically, the change in the sulfur source ratio can induce the coexistence of Ov/In2O3 and In2S3 in a high-temperature hydrothermal process. Under light irradiation, In2S3@Ov/In2O3-0.1 nanosheets hold a remarkable average H2 evolution rate up to 4.04 mmol g-1 h-1, which is 32.14, 11.91, and 2.25-fold better than those of pristine In2S3, In2S3@Ov/In2O3-0.02, and In2S3@Ov/In2O3-0.25 nanosheets, respectively. The ultraviolet-visible (UV-vis) diffuse reflectance and photoluminescence (PL) spectra reveal that the formation of Ov/In2O3 in In2S3 optimizes the band-gap structure and accelerates the migration of the photogenerated charge carrier of In2S3@Ov/In2O3-x nanosheets, respectively. Both the enhancement of oxidation and reduction ability and photogenerated charge carrier separation ability are responsible for the remarkable improvement in photocatalytic H2 evolution performance. This work provides a new strategy to prepare a composite of metal sulfide and metal oxide through a one-step hydrothermal method.

Insomnia in epilepsy is associated with nocturnal seizures and anxiety.

PURPOSE: The purpose of this study was to identify the factors associated with insomnia in patients with epilepsy (PWE) and provide evidence for clinical prevention and treatment. METHODS: PWE who visited our epilepsy clinic from December 2021 to December 2022 were enrolled in our study. All participants completed the Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), Self-rating Anxiety Scale (SAS), and Self-rating Depression Scale (SDS). Based on their ISI scores, they were categorized into two groups: PWE with insomnia (ISI score ≥ 10) and PWE without insomnia (ISI score < 10). Univariate analysis and stepwise logistic regression analysis were conducted to identify the factors associated with insomnia in PWE. RESULTS: A total of 196 Chinese PWE were recruited in this study(men, 39.8 %). Of these, 39 PWE(19.9 %) had insomnia.The incidence of nocturnal seizures (43.6 %vs19.7 %), depression (46.2 %vs9.6 %), anxiety (59.0 %vs11.5 %), and excessive daytime sleepiness(EDS,28.2 %vs5.7 %) in PWE with insomnia were significantly higher than in those without insomnia(all p＜0.01). Univariate regression analysis showed that seizures greater than or equal to once per month, nocturnal seizures, anxiety, depression, and EDS may associate with insomnia in PWE(all p＜0.05). Stepwise logistic regression analysis demonstrated that nocturnal seizures (OR = 2.611,95 % CI 1.040-6.478, P = 0.038) and anxiety (mild OR = 4.830,95 %CI 1.741-13.186, P = 0.002;moderate OR = 24.239,95 %CI 4.719-183.935, P＜0.001; severe OR = 37.653,95 %CI 4.931-782.741, P = 0.002) were independently associated with insomnia in PWE. CONCLUSION: PWE with insomnia are more likely to experience depression and EDS. Nocturnal seizures and anxiety are identified as independent factors associated with insomnia in PWE. Furthermore, Anxiety has a greater impact on insomnia in PWE and the likelihood of insomnia has increased significantly with the aggravation of anxiety levels.

Insomnia in patients with MRI-negative epilepsy: The associated factors and 3D-pCASL cerebral blood flow perfusion changes.

OBJECTIVE: This study aimed to identify the factors associated with insomnia in MRI-negative epilepsy and uncover the underlying pathological mechanism driving insomnia within the context of epilepsy. METHODS: We conducted a retrospective study of patients with MRI-negative epilepsy recruited consecutively from December 2021 to December 2022. All subjects completed the Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), Self-rating Anxiety Scale (SAS), and Self-rating Depression Scale (SDS). Additionally, some subjects underwent the three-dimensional pseudo continuous arterial spin labeling(3D-pCASL) imaging examination. Bilateral frontal lobe, temporal lobe, hippocampus, thalamus, amygdala, caudate nucleus and lenticular nucleus were selected as regions of interest(ROI) and cerebral blood flow(CBF) values were measured in these regions. Subjects were classified into insomnia (ISI ≥ 10) or non-insomnia (ISI < 10) groups, and univariate and stepwise logistic regression analyses were employed to identify the factors associated with insomnia. Furthermore, CBF values in each ROI were compared between the two groups to identify the brain regions potentially related to the underlying pathological mechanism of insomnia in epilepsy. RESULTS: A total of 73 patients with MRI-negative epilepsy were recruited in this study(men, 49.3 %). Among them, 14 patients(19.2 %) had insomnia. Univariate regression revealed that nocturnal seizures, number of anti-seizure medication(ASM), anxiety, use of valproic acid(VPA), depression, and excessive daytime sleepiness(EDS) may be associated with insomnia in MRI-negative epilepsy (all p＜0.05). Stepwise regression demonstrated that nocturnal seizures, anxiety, and EDS were independently associated with insomnia in MRI-negative epilepsy (OR[95 %CI]P: 14.64[2.02-106.27]0.008,49.35[3.06-796.61]0.006, 13.28[1.25-140.66]0.032, respectively). Furthermore, CBF values in the left amygdala were significantly lower in patients with MRI- negative epilepsy who had insomnia. CONCLUSION: The prevalence of insomnia in MRI-negative epilepsy is 19.2%. Nocturnal seizures, anxiety, and EDS were independently associated with insomnia in MRI-negative epilepsy. The noteworthy decrease in CBF values in the left amygdala might be connected to the underlying pathological mechanism of insomnia in epilepsy.

Concurrent chemoradiotherapy followed by adjuvant cisplatin-gemcitabine versus cisplatin-fluorouracil chemotherapy for N2-3 nasopharyngeal carcinoma: a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Patients with N2-3 nasopharyngeal carcinoma have a high risk of treatment being unsuccessful despite the current practice of using a concurrent adjuvant cisplatin-fluorouracil regimen. We aimed to compare the efficacy and safety of concurrent adjuvant cisplatin-gemcitabine with cisplatin-fluorouracil in N2-3 nasopharyngeal carcinoma. METHODS: We conducted an open-label, randomised, controlled, phase 3 trial at four cancer centres in China. Eligible patients were aged 18-65 years with untreated, non-keratinising, stage T1-4 N2-3 M0 nasopharyngeal carcinoma, an Eastern Cooperative Oncology Group performance status score of 0-1, and adequate bone marrow, liver, and renal function. Eligible patients were randomly assigned (1:1) to receive concurrent cisplatin (100 mg/m2 intravenously) on days 1, 22, and 43 of intensity-modulated radiotherapy followed by either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 3 weeks or fluorouracil (4 g/m2 in continuous intravenous infusion for 96 h) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 4 weeks, for three cycles. Randomisation was done using a computer-generated random number code with a block size of six, stratified by treatment centre and nodal category. The primary endpoint was 3-year progression-free survival in the intention-to-treat population (ie, all patients randomly assigned to treatment). Safety was assessed in all participants who received at least one dose of chemoradiotherapy. This study was registered at ClinicalTrials.gov, NCT03321539, and patients are currently under follow-up. FINDINGS: From Oct 30, 2017, to July 9, 2020, 240 patients (median age 44 years [IQR 36-52]; 175 [73%] male and 65 [27%] female) were randomly assigned to the cisplatin-fluorouracil group (n=120) or cisplatin-gemcitabine group (n=120). As of data cutoff (Dec 25, 2022), median follow-up was 40 months (IQR 32-48). 3-year progression-free survival was 83·9% (95% CI 75·9-89·4; 19 disease progressions and 11 deaths) in the cisplatin-gemcitabine group and 71·5% (62·5-78·7; 34 disease progressions and seven deaths) in the cisplatin-fluorouracil group (stratified hazard ratio 0·54 [95% CI 0·32-0·93]; log rank p=0·023). The most common grade 3 or worse adverse events that occurred during treatment were leukopenia (61 [52%] of 117 in the cisplatin-gemcitabine group vs 34 [29%] of 116 in the cisplatin-fluorouracil group; p=0·00039), neutropenia (37 [32%] vs 19 [16%]; p=0·010), and mucositis (27 [23%] vs 32 [28%]; p=0·43). The most common grade 3 or worse late adverse event (occurring from 3 months after completion of radiotherapy) was auditory or hearing loss (six [5%] vs ten [9%]). One (1%) patient in the cisplatin-gemcitabine group died due to treatment-related complications (septic shock caused by neutropenic infection). No patients in the cisplatin-fluorouracil group had treatment-related deaths. INTERPRETATION: Our findings suggest that concurrent adjuvant cisplatin-gemcitabine could be used as an adjuvant therapy in the treatment of patients with N2-3 nasopharyngeal carcinoma, although long-term follow-up is required to confirm the optimal therapeutic ratio. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Major Project of Basic and Applied Basic Research, Sci-Tech Project Foundation of Guangzhou City, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Natural Science Foundation of Guangdong Province for Distinguished Young Scholar, Natural Science Foundation of Guangdong Province, Postdoctoral Innovative Talent Support Program, Pearl River S&T Nova Program of Guangzhou, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, the Rural Science and Technology Commissioner Program of Guangdong Province, and Fundamental Research Funds for the Central Universities.

Atypical Chemokine Receptor 3 "Senses" CXC Chemokine Receptor 4 Activation Through GPCR Kinase Phosphorylation.

Atypical chemokine receptor 3 (ACKR3) is an arrestin-biased receptor that regulates extracellular chemokine levels through scavenging. The scavenging process restricts the availability of the chemokine agonist CXCL12 for the G protein-coupled receptor (GPCR) CXCR4 and requires phosphorylation of the ACKR3 C-terminus by GPCR kinases (GRKs). ACKR3 is phosphorylated by GRK2 and GRK5, but the mechanisms by which these kinases regulate the receptor are unresolved. Here we determined that GRK5 phosphorylation of ACKR3 results in more efficient chemokine scavenging and ß-arrestin recruitment than phosphorylation by GRK2 in HEK293 cells. However, co-activation of CXCR4-enhanced ACKR3 phosphorylation by GRK2 through the liberation of Gßγ, an accessory protein required for efficient GRK2 activity. The results suggest that ACKR3 "senses" CXCR4 activation through a GRK2-dependent crosstalk mechanism, which enables CXCR4 to influence the efficiency of CXCL12 scavenging and ß-arrestin recruitment to ACKR3. Surprisingly, we also found that despite the requirement for phosphorylation and the fact that most ligands promote ß-arrestin recruitment, ß-arrestins are dispensable for ACKR3 internalization and scavenging, suggesting a yet-to-be-determined function for these adapter proteins. Since ACKR3 is also a receptor for CXCL11 and opioid peptides, these data suggest that such crosstalk may also be operative in cells with CXCR3 and opioid receptor co-expression. Additionally, kinase-mediated receptor cross-regulation may be relevant to other atypical and G protein-coupled receptors that share common ligands. SIGNIFICANCE STATEMENT: The atypical receptor ACKR3 indirectly regulates CXCR4-mediated cell migration by scavenging their shared agonist CXCL12. Here, we show that scavenging and ß-arrestin recruitment by ACKR3 are primarily dependent on phosphorylation by GRK5. However, we also show that CXCR4 co-activation enhances the contribution of GRK2 by liberating Gßγ. This phosphorylation crosstalk may represent a common feedback mechanism between atypical and G protein-coupled receptors with shared ligands for regulating the efficiency of scavenging or other atypical receptor functions.

G protein-coupled receptor interactions with arrestins and GPCR kinases: The unresolved issue of signal bias.

G protein-coupled receptor (GPCR) kinases (GRKs) and arrestins interact with agonist-bound GPCRs to promote receptor desensitization and downregulation. They also trigger signaling cascades distinct from those of heterotrimeric G proteins. Biased agonists for GPCRs that favor either heterotrimeric G protein or GRK/arrestin signaling are of profound pharmacological interest because they could usher in a new generation of drugs with greatly reduced side effects. One mechanism by which biased agonism might occur is by stabilizing receptor conformations that preferentially bind to GRKs and/or arrestins. In this review, we explore this idea by comparing structures of GPCRs bound to heterotrimeric G proteins with those of the same GPCRs in complex with arrestins and GRKs. The arrestin and GRK complexes all exhibit high conformational heterogeneity, which is likely a consequence of their unusual ability to adapt and bind to hundreds of different GPCRs. This dynamic behavior, along with the experimental tactics required to stabilize GPCR complexes for biophysical analysis, confounds these comparisons, but some possible molecular mechanisms of bias are beginning to emerge. We also examine if and how the recent structures advance our understanding of how arrestins parse the "phosphorylation barcodes" installed in the intracellular loops and tails of GPCRs by GRKs. In the future, structural analyses of arrestins in complex with intact receptors that have well-defined native phosphorylation barcodes, such as those installed by the two nonvisual subfamilies of GRKs, will be particularly illuminating.

Analysis of Angiogenesis-Related Signatures in the Tumor Immune Microenvironment and Identification of Clinical Prognostic Regulators in Lung Adenocarcinoma.

Tumor angiogenesis is considered to be an important part of the mechanism of tumor progression and metastasis, and its specific function in lung adenocarcinoma has not been fully studied. In this study, we used the transcriptome and genome data of lung adenocarcinoma patients to analyze the expression of 36 angiogenesis regulators in lung adenocarcinoma. Consensus clustering analysis divided lung adenocarcinoma samples into 4 subtypes, A, B, C, and D, and the expression of most angiogenesis regulators in subtype B was higher than that in other subtypes. Immunological analysis indicated that subtype B is likely to display the characteristics of a hot tumor with a more active TME. With the help of Lasso-Cox regression analysis, we successfully constructed a risk model involving five Angiogenesis Regulators genes (CCND2, JAG1, MSX1, STC1, TIMP1), which will be helpful for clinical personalized treatment and prognosis prediction. In addition, JAG1 has the highest mutation rate in tumors, and its cancer-promoting function is reflected in a variety of tumors, which provides important clues for the development of new broad-spectrum anti-cancer targets in the future. We successfully constructed a risk model involving five angiogenesis regulators genes (CCND2, JAG1, MSX1, STC1, TIMP1), which may be helpful for clinical personalized treatment and prognosis prediction. In addition, JAG1 has the highest mutation rate in tumors and plays a leading role in the protein interaction network. Its tumor-promoting function is reflected in a variety of tumors and may become a broad-spectrum anti-cancer target in the future.

The efficacy and safety of apatinib plus capecitabine in platinum-refractory metastatic and/or recurrent nasopharyngeal carcinoma: a prospective, phase II trial.

BACKGROUND: Previous studies have shown that monotherapy with apatinib, an oral tyrosine kinase inhibitor, has promising efficacy for treating recurrent or metastatic (RM) nasopharyngeal carcinoma (NPC) patients. In this study, we aimed to assess the efficacy and safety of apatinib combined with capecitabine as a second-line therapy or beyond for treating RM-NPC patients who failed the first-line platinum-based chemotherapy. METHODS: In this single-arm, phase II study, we enrolled RM-NPC patients who had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). The sample size was determined using Simon's two-stage design. All patients were administered with apatinib 500 mg once daily and capecitabine 1000 mg/m2 twice per day on days 1-14 of each 21-day cycle. The primary endpoint was the objective response rate (ORR), and the secondary endpoints comprised disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: We enrolled 64 patients from September 2018 to August 2020. The ORR and DCR were 39.1% (95% CI, 27.1-52.1) and 85.9% (95% CI, 75.0-93.4), respectively. The median DoR was 14.4 months (95% CI, 7.8-21.0). As of April 20, 2021, the median follow-up duration was 12.0 months. The median PFS was 7.5 months (95% CI, 5.0-10.0) and the median OS was 15.7 months (95% CI, 11.3-20.1). The most common toxicities of any grade were anemia (75.0%), hand-foot syndrome (65.6%), and proteinuria (64.0%). Grade 3-4 toxicities were observed in 36 (56.3%) patients, with hypertension (14.1%), mucositis (12.4%), and fatigue (10.9%) most commonly observed. CONCLUSIONS: Apatinib plus capecitabine shows promising efficacy as a second-line treatment option in pretreated platinum-refractory RM-NPC patients. Dose selection of this combination needs further investigation considering the toxicity. TRIAL REGISTRATION: Chi-CTR1800017229.

Radiomic signatures reveal multiscale intratumor heterogeneity associated with tissue tolerance and survival in re-irradiated nasopharyngeal carcinoma: a multicenter study.

BACKGROUND: Post-radiation nasopharyngeal necrosis (PRNN) is a severe adverse event following re-radiotherapy for patients with locally recurrent nasopharyngeal carcinoma (LRNPC) and associated with decreased survival. Biological heterogeneity in recurrent tumors contributes to the different risks of PRNN. Radiomics can be used to mine high-throughput non-invasive image features to predict clinical outcomes and capture underlying biological functions. We aimed to develop a radiogenomic signature for the pre-treatment prediction of PRNN to guide re-radiotherapy in patients with LRNPC. METHODS: This multicenter study included 761 re-irradiated patients with LRNPC at four centers in NPC endemic area and divided them into training, internal validation, and external validation cohorts. We built a machine learning (random forest) radiomic signature based on the pre-treatment multiparametric magnetic resonance images for predicting PRNN following re-radiotherapy. We comprehensively assessed the performance of the radiomic signature. Transcriptomic sequencing and gene set enrichment analyses were conducted to identify the associated biological processes. RESULTS: The radiomic signature showed discrimination of 1-year PRNN in the training, internal validation, and external validation cohorts (area under the curve (AUC) 0.713-0.756). Stratified by a cutoff score of 0.735, patients with high-risk signature had higher incidences of PRNN than patients with low-risk signature (1-year PRNN rates 42.2-62.5% vs. 16.3-18.8%, P < 0.001). The signature significantly outperformed the clinical model (P < 0.05) and was generalizable across different centers, imaging parameters, and patient subgroups. The radiomic signature had prognostic value concerning its correlation with PRNN-related deaths (hazard ratio (HR) 3.07-6.75, P < 0.001) and all causes of deaths (HR 1.53-2.30, P < 0.01). Radiogenomics analyses revealed associations between the radiomic signature and signaling pathways involved in tissue fibrosis and vascularity. CONCLUSIONS: We present a radiomic signature for the individualized risk assessment of PRNN following re-radiotherapy, which may serve as a noninvasive radio-biomarker of radiation injury-associated processes and a useful clinical tool to personalize treatment recommendations for patients with LANPC.

Clinical characteristics and prognostic factors affecting survival after radical radiotherapy for early and late post-treatment metastatic nasopharyngeal carcinoma.

OBJECTIVE: We compared the clinical characteristics and survival outcomes after radical radiotherapy between nasopharyngeal carcinoma (NPC) with early and late metastases based on a relatively large cohort, which provides valuable data for the planning of clinical surveillance strategies. METHODS: This was a single-center retrospective analysis of 10,566 patients who received radical radiotherapy in China from January 2000 to December 2016. Overall survival was the primary endpoint. Kaplan-Meier survival analysis and log-rank tests were applied to investigate the association between early or late metastasis and the endpoints. The prognostic value of clinicopathological features was identified using univariate and multivariate Cox proportional hazards models. RESULTS: The cutoff value for time to metastasis was based on ROC analysis. A total of 559 (5.3%) patients developed distant metastases, 297 (53.1%) of which developed early metastatic disease, with the rest (46.9%) developing late metastatic disease. The K-M analysis showed that the patients with late metastatic foci had significantly better post-metastatic OS (P = 0.0056). Multivariate analysis indicated that age, liver metastasis, the number of metastatic foci and time to metastasis (P = 0.013) are independent prognostic factors for OS. After analyzing the impact of different treatment methods, we found that local treatment was an independent protective factor for LM, while local treatment was not associated with a survival benefit for EM disease. CONCLUSIONS: The time to metastasis after radical radiotherapy affected the prognosis of NPC patients and local treatment was an independent protective factor that could improve the survival of late metastatic NPC patients.

Insight into extracellular vesicles in vascular diseases: intercellular communication role and clinical application potential.

BACKGROUND: Cells have been increasingly known to release extracellular vesicles (EVs) to the extracellular environment under physiological and pathological conditions. A plethora of studies have revealed that EVs contain cell-derived biomolecules and are found in circulation, thereby implicating them in molecular trafficking between cells. Furthermore, EVs have an effect on physiological function and disease development and serve as disease biomarkers. MAIN BODY: Given the close association  between EV circulation and vascular disease, this review aims to provide a brief introduction to EVs, with a specific focus on the EV cargoes participating in pathological mechanisms, diagnosis, engineering, and clinical potential, to highlight the emerging evidence suggesting promising targets in vascular diseases. Despite the expansion of research in this field, some noticeable limitations remain for clinical translational research. CONCLUSION: This review makes a novel contribution to a summary of recent advances and a perspective on the future of EVs in vascular diseases. Video Abstract.

Factors Influencing Quality of Life and Functional Outcomes in Patients With Bladder Cancer.

Here, we review the quality of life and functional outcomes of patients with bladder cancer after treatment and assess potential contributing factors. For current scoring systems, we highlighted the most commonly used specificity scores. In addition, we discuss the impact and bias on the quality of life of patients undergoing urinary diversion modalities, robotic surgery, perioperative rehabilitation, and bladder-preserving radiochemotherapy. Through this review, clinicians will gain better insights regarding the importance of improving patients' quality of life with the goal of restoring their patients' normal function and participating in social activities.

Nasopharyngeal necrosis contributes to overall survival in nasopharyngeal carcinoma without distant metastasis: a comprehensive nomogram model.

OBJECTIVES: This study focused on developing and validating a nomogram to predict the overall survival (OS) of patients with nasopharyngeal carcinoma (NPC) without distant metastasis based on their clinical characteristics, serum biomarkers, and presence of nasopharyngeal (NP) necrosis. METHODS: This study included 9298 patients with NPC. Patients from January 2009 to December 2014 were randomly categorized into the training cohort and validation cohort A. Validation cohort B, whose data were collected from January 2015 to December 2017, was also included. OS was the primary endpoint of this study. Cox regression analysis was used to detect independent risk variables. Decision curve analysis, calibration curve, time-dependent receiver operating characteristic (ROC) curve, and concordance index (C-index) were used to evaluate the performance of the nomogram model. RESULTS: A total of 267 patients developed NP necrosis after the first routine radiotherapy. After radiotherapy, patients with NP necrosis had significantly lower OS than other patients in all three cohorts (p < 0.001). Eleven factors, including NP necrosis, were involved in the nomogram, which had favorable discrimination and calibration with a C-index of 0.768 in the training cohort, 0.749 in validation cohort A, and 0.739 in validation cohort B. The nomogram exhibited a significantly larger area under the ROC curve for predicting OS than the TNM stage and Epstein-Barr virus (EBV) DNA (p < 0.001). CONCLUSION: Compared with the TNM system and EBV DNA, we established a nomogram model with an accurate prognostic prediction for patients with NPC, which might help with patient management in NPC. KEY POINTS: • This study included 9298 patients with NPC, and 11 factors were involved in the final model. • The nomogram had a significantly higher C-index and area under the ROC curve than the TNM stage and EBV DNA. • We established the first nomogram model for NPC involving the occurrence of NP necrosis, which was valuable for providing individual counseling and clinical assessments.

Head and neck MRI-based T stage and [18F]FDG PET/CT-based N/M stage improved prognostic stratification in primary nasopharyngeal carcinoma.

OBJECTIVES: To evaluate whether MRI-based T stage (TMRI), [18F]FDG PET/CT-based N (NPET/CT), and M stage (MPET/CT) are superior in NPC patients' prognostic stratification based on long-term survival evidences, and whether TNM staging method involving TMRI + NPET/CT + MPET/CT could improve NPC patients' prognostic stratification. METHODS: From April 2007 to December 2013, 1013 consecutive untreated NPC patients with complete imaging data were enrolled. All patients' initial stages were repeated based on (1) the NCCN guideline recommended "TMRI + NMRI + MPET/CT" ("MMP") staging method; (2) the traditional "TMRI + NMRI + Mconventional work-up (CWU)" ("MMC") staging method; (3) the single-step "TPET/CT + NPET/CT + MPET/CT" ("PPP") staging method; or (4) the "TMRI + NPET/CT + MPET/CT" ("MPP") staging method recommended in present research. Survival curve, ROC curve, and net reclassification improvement (NRI) analysis were used to evaluate the prognosis predicting ability of different staging methods. RESULTS: [18F]FDG PET/CT performed worse on T stage (NRI = - 0.174, p < 0.001) but better on N (NRI = 0.135, p = 0.004) and M stage (NRI = 0.126, p = 0.001). The patients whose N stage upgraded by [18F]FDG PET/CT had worse survival (p = 0.011). The "TMRI + NPET/CT + MPET/CT" ("MPP") method performed better on survival prediction when compared with "MMP" (NRI = 0.079, p = 0.007), "MMC" (NRI = 0.190, p < 0.001), or "PPP" method (NRI = 0.107, p < 0.001). The "TMRI + NPET/CT + MPET/CT" ("MPP") method could reclassify patients' TNM stage to a more appropriate stage. The improvement is significant in patients with more than 2.5-years follow-up according to the time-dependent NRI values. CONCLUSIONS: The MRI is superior to [18F]FDG PET/CT in T stage, and [18F]FDG PET/CT is superior to CWU in N/M stage. The "TMRI + NPET/CT + MPET/CT" ("MPP") staging method could significantly improve NPC patients' long-term prognostic stratification. CLINICAL RELEVANCE STATEMENT: The present research provided long-term follow-up evidence for benefits of MRI and [18F]FDG PET/CT in TNM staging for nasopharyngeal carcinoma, and proposes a new imaging procedure for TNM staging incorporating MRI-based T stage and [18F]FDG PET/CT-based N and M stage, which significantly improves long-term prognostic stratification for patients with NPC. KEY POINTS: • The long-term follow-up evidence of a large-scale cohort was provided to evaluate the advantages of MRI, [18F]FDG PET/CT, and CWU in the TNM staging of nasopharyngeal carcinoma. • A new imaging procedure for TNM stage of nasopharyngeal carcinoma was proposed.

Intrusive rumination and academic burnout among adolescents in ethnic minority areas of China during the COVID-19 pandemic: PTSS as mediator and cognitive reappraisal as moderator.

BACKGROUND: The COVID-19 pandemic has had a significant negative impact on public health, prompting scholarly research in related fields. In this context, the present study reveals the psychological characteristics of adolescents in ethnic minority areas of China approximately five months after the 2020 outbreak of the COVID-19 pandemic, explores the relationship between intrusive rumination and academic burnout, and examines the role of post-traumatic stress symptoms (PTSS) and cognitive reappraisal in the relationship to provide an empirical foundation for developing effective psychological interventions for adolescents in the wake of the pandemic. METHODS: Based on cluster sampling, 941 middle school students (65.36% female, 74.71% senior high, Mage=15.95) in ethnic minority areas of China were surveyed using the Event Related Rumination Scale, Adolescent Academic Burnout Scale, Post-traumatic Stress Checklist Scale, Emotion Regulation Strategy Scale, and a self-designed demographic questionnaire. RESULTS: During the COVID-19 pandemic, 7.44% of Chinese ethnic minority adolescents in our study sample were classified as PTSD positive, and 10.95% exhibited partial PTSD. Intrusive rumination significantly predicted academic burnout, and PTSS played a key mediating role between the two, accounting for 58.51% of the total effect. After controlling for PTSS, cognitive reappraisal moderated the effects of intrusive rumination on academic burnout. Specifically, the effect of intrusive rumination on academic burnout decreased with improvement in cognitive reappraisal. CONCLUSIONS: Intrusive rumination indirectly affected academic burnout in adolescents through PTSS as a crucial mediator, and the remnant direct effect was alleviated by cognitive reappraisal. This finding emphasises the importance of adopting a comprehensive approach that encompasses cognitive, emotional, and physiological symptoms to understand and address academic burnout among adolescents during the COVID-19 pandemic.

Independent and combined associations of dietary antioxidant intake with bone mineral density and risk of osteoporosis among elderly population in United States.

BACKGROUND: The influence of dietary antioxidant intake on the occurrence and progression of osteoporosis may be significant. However, to date, evidence on the link between combined effect of dietary antioxidants on bone mineral density (BMD) level and risk of osteoporosis is limited. We aimed to assess the independent and combined association of dietary antioxidant intake with BMD level and risk of osteoporosis among elderly population in United States through analysis of data in the National Health and Nutrition Examination Survey. METHODS: The dietary antioxidant intake was assessed based on six antioxidants, including vitamin A, vitamin C, vitamin E, zinc, selenium, and total carotenoid. A composite dietary antioxidant index (CDAI) was used to evaluate the combined exposure of dietary antioxidant intake. RESULTS: A total of 5618 participants were included. Higher dietary vitamin A, vitamin C, vitamin E, zinc, selenium, and total carotenoid, were positively associated with BMD level. Compared with participants in the first quartile, those in the higher quartile of vitamin E (Q4: OR 0.652; 95% CI 0.463-0.918), zinc (Q4: OR 0.581; 95% CI 0.408-0.826), and selenium (Q3: OR 0.673; 95% CI 0.503-0.899) were associated with decreased risk of overall osteoporosis. Furthermore, compared to those in the first quartile, participants in the highest quartile of CDAI were associated with increased total femur (ß 0.019; 95% CI 0.007-0.032), femur neck (ß 0.020; 95% CI 0.009-0.032), trochanter (ß 0.012; 95% CI 0.001-0.023), and intertrochanter BMD level (ß 0.022; 95% CI 0.007-0.037); participants in the highest quartile of CDAI were associated with decreased risk of overall osteoporosis (OR 0.536; 95% CI 0.376-0.763). Furthermore, the associations of CDAI with the BMD level and osteoporosis risk were more significant among female participants. CONCLUSION: Our study provides evidence that a combination of dietary antioxidants intake was associated increased BMD level and decreased osteoporosis risk.

Toripalimab Plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: The JUPITER-02 Randomized Clinical Trial.

Importance: There are currently no therapies approved by the US Food and Drug Administration for nasopharyngeal carcinoma (NPC). Gemcitabine-cisplatin is the current standard of care for the first-line treatment of recurrent or metastatic NPC (RM-NPC). Objective: To determine whether toripalimab in combination with gemcitabine-cisplatin will significantly improve progression-free survival and overall survival as first-line treatment for RM-NPC, compared with gemcitabine-cisplatin alone. Design, Setting, and Participants: JUPITER-02 is an international, multicenter, randomized, double-blind phase 3 study conducted in NPC-endemic regions, including mainland China, Taiwan, and Singapore. From November 10, 2018, to October 20, 2019, 289 patients with RM-NPC with no prior systemic chemotherapy in the RM setting were enrolled from 35 participating centers. Interventions: Patients were randomized (1:1) to receive toripalimab (240 mg [n = 146]) or placebo (n = 143) in combination with gemcitabine-cisplatin for up to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxicity, or completion of 2 years of treatment. Main Outcome: Progression-free survival as assessed by a blinded independent central review. Secondary end points included objective response rate, overall survival, progression-free survival assessed by investigator, duration of response, and safety. Results: Among the 289 patients enrolled (median age, 46 [IQR, 38-53 years; 17% female), at the final progression-free survival analysis, toripalimab treatment had a significantly longer progression-free survival than placebo (median, 21.4 vs 8.2 months; HR, 0.52 [95% CI, 0.37-0.73]). With a median survival follow-up of 36.0 months, a significant improvement in overall survival was identified with toripalimab over placebo (hazard ratio [HR], 0.63 [95% CI, 0.45-0.89]; 2-sided P = .008). The median overall survival was not reached in the toripalimab group, while it was 33.7 months in the placebo group. A consistent effect on overall survival, favoring toripalimab, was found in subgroups with high and low PD-L1 (programmed death-ligand 1) expression. The incidence of all adverse events, grade 3 or greater adverse events, and fatal adverse events were similar between the 2 groups. However, adverse events leading to discontinuation of toripalimab or placebo (11.6% vs 4.9%), immune-related adverse events (54.1% vs 21.7%), and grade 3 or greater immune-related adverse events (9.6% vs 1.4%) were more frequent in the toripalimab group. Conclusions and Relevance: The addition of toripalimab to chemotherapy as first-line treatment for RM-NPC provided statistically significant and clinically meaningful progression-free survival and overall survival benefits compared with chemotherapy alone, with a manageable safety profile. These findings support the use of toripalimab plus gemcitabine-cisplatin as the new standard of care for this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT03581786.

Anti-Aging Effects of Anthocyanin Extracts of Sambucus canadensis Caused by Targeting Mitochondrial-Induced Oxidative Stress.

Anthocyanin is a natural antioxidant agent extracted from the fruits of Sambucus canadensis, which has been considered to have potential anti-aging effects. Cell senescence is the primary cause of aging and related diseases. Recently, research on the development of compounds for eliminating senescent cells or damaged organs have shown prospects. The compounds which promote the clearing of senescent cells are called "senolytics". Though anthocyanin is considered to have potential anti-aging effects owing to its anti-inflammatory and antioxidant activities, the mechanism of the elimination of senescent cells remains unclear. In this study, we prepared anthocyanins extracted from the fruits of Sambucus canadensis and evaluated their anti-aging effects in vivo and in vitro. We found that anthocyanin could significantly reduce cell senescence and aging of the lens by inhibiting the activity of the PI3K/AKT/mTOR signaling pathway, consequently promoting the apoptosis of senescent cells, increasing the autophagic and mitophagic flux, and enhancing the renewal of mitochondria and the cell to maintain cellular homeostasis, leading to attenuating aging. Therefore, our study provided a basis for anthocyanin to be used as new "senolytics" in anti-aging.