Iron gallic acid biomimetic nanoparticles for targeted magnetic resonance imaging.

Developing T1-weighted magnetic resonance imaging (MRI) contrast agents with enhanced biocompatibility and targeting capabilities is crucial owing to concerns over current agents' potential toxicity and suboptimal performance. Drawing inspiration from "biomimetic camouflage," we isolated cell membranes (CMs) from human glioblastoma (T98G) cell lines via the extrusion method to facilitate homotypic glioma targeting. At an 8:1 mass ratio of ferric chloride hexahydrate to gallic acid (GA), the resulting iron (Fe)-GA nanoparticles (NPs) proved effective as a T1-weighted MRI contrast agent. T98G CM-coated Fe-GA NPs demonstrated improved homotypic glioma targeting, validated through Prussian blue staining and in vitro MRI. This biomimetic camouflage strategy holds promise for the development of targeted theranostic agents in a safe and effective manner.

The efficacy of adjuvant chemotherapy in patients with different midpoint-radiotherapy Epstein-Barr virus DNA plasma loads.

OBJECTIVES: This study aimed to evaluate the efficacy of adjuvant chemotherapy (AC) in patients with different midpoint-radiotherapy (mid-RT) Epstein-Barr virus (EBV) DNA plasma loads for locoregionally advanced nasopharyngeal carcinoma (NPC), and to provide decision-making regarding the use of AC. MATERIALS AND METHODS: A total of 675 consecutive patients diagnosed with stage III-IVa NPC were enrolled in this study. All patients underwent concurrent chemoradiotherapy (CCRT), either with or without induction chemotherapy or AC, or a combination of both. The primary endpoint of this study was progression-free survival (PFS). RESULTS: Among the 675 enrolled patients, 248 (36.7 %) received AC and 427 (63.3 %) were only observed after CCRT. In total, 149 (22.1 %) patients had detectable mid-RT EBV DNA levels, whereas 526 (77.9 %) had undetectable mid-RT EBV DNA levels. Patients with detectable mid-RT EBV DNA had worse 5-year PFS than those with undetectable mid-RT EBV DNA (74.8 % vs. 81.9 %, P = 0.045). AC group showed significantly better 5-year PFS than observation in patients with detectable mid-RT EBV DNA (82.8 % vs. 66.8 %; HR, 0.480; 95 % CI 0.250-0.919, P = 0.027). Multivariate analyses demonstrated that the treatment methods (AC vs. observation) were independent prognostic factors for PFS (HR, 0.37; 95 % CI 0.19-0.74, P = 0.005). However, in patients with undetectable mid-RT EBV DNA (5-year PFS: HR 0.873, 95 % CI 0.565-1.349, P = 0.52), AC group showed no survival benefit for observation. CONCLUSION: AC could reduce the risk of disease progression compared to observation in patients with detectable mid-RT EBV DNA. Our findings suggest that AC is effective in patients at a high risk of treatment failure.

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.

A novel high sensitive, specificity duplex enzyme-activated differentiating probes PCR method for the SNP detection and differentiation of MS-H vaccine strains from wild-type Mycoplasma synoviae strains.

Mycoplasma synoviae (MS) is a contagious pathogen that poses a significant threat to the poultry industry. Detection plays an important role in the prevention and control of MS, particularly in differentiating between wild-type MS and live attenuated vaccine strains for vaccination selection and culling of animals with wild-type only. The live attenuated ts+ vaccine strain MS-H is recognized as the most effective and widely used vaccine. In this study, we have developed a method called double enzyme-activated differentiation probes PCR (DEA-probes PCR) for the differentiation of MS-H vaccine strain from wild-type strain by targeting the single nucleotide polymorphism (SNP) of the 367th nucleotide in the Obg gene sequence. We developed 2 modified probes with the ribonucleotide insert. When the probe perfectly complements with the target, the ribonuclease H2 (RNase H2) will cleave the ribonucleotide, resulting in the generation of fluorescent signal. With a detection limit of 5.8 copies/µL, the DEA-probes PCR method demonstrates 100% specificity in distinguishing wild-type MS from MS-H strains in 1 h. The method demonstrated great performance in real application of 100 superior palate cleft swab samples from chickens in poultry farms. Twenty-eight samples were detected as MS positive, consistent with the results of the Chinese industry standard method. Additionally, our method was able to distinguish 19 wild-type MS strains from 9 MS-H vaccine strains. The DEA-probes PCR method is rapid, specific and sensitive for SNP detection, overcoming the misidentification in MS detection and differentiation. It can be also applied to the differentiation of infected from vaccinated animals (DIVA) for other pathogens.

Application of emerging technologies in ischemic stroke: from clinical study to basic research.

Stroke is a primary cause of noncommunicable disease-related death and disability worldwide. The most common form, ischemic stroke, is increasing in incidence resulting in a significant burden on patients and society. Urgent action is thus needed to address preventable risk factors and improve treatment methods. This review examines emerging technologies used in the management of ischemic stroke, including neuroimaging, regenerative medicine, biology, and nanomedicine, highlighting their benefits, clinical applications, and limitations. Additionally, we suggest strategies for technological development for the prevention, diagnosis, and treatment of ischemic stroke.

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.

Composite dietary antioxidant index is associated with reduced prevalence of metabolic syndrome but not mortality in metabolic syndrome: Results from NHANES 2001-2018.

The relationship between the composite dietary antioxidant index (CDAI), a comprehensive measure of individual dietary antioxidants, and the prevalence and mortality of metabolic syndrome (MetS) remains unknown. We aimed to explore these relationships in the National Health and Nutrition Examination Survey (NHANES). We explored these relationships using two independent cohorts. First, we addressed CDAI and the prevalence of MetS in the general population; second, we explored the association between CDAI and mortality in patients with MetS by following NHANES 2001-2018 participants through December 31, 2019. In addition, restricted cubic spline (RCS), stratified analysis, and sensitivity analysis were used for further interpretation. We included 24,514 participants aged 20-85 years, in which the prevalence of MetS was 27.61 %. CDAI was negatively and dose-responsively associated with the prevalence of MetS, however it was not associated with mortality in patients with MetS. In addition, CDAI was associated with a reduced prevalence of certain components of MetS, including dyslipidemia and central obesity. RCS showed a linear correlation between CDAI and MetS and the above components. Stratified analyses indicated that alcohol consumption was a significant influence of CDAI-MetS and that socioeconomic status and lifestyle specificity existed. Sensitivity analysis confirmed the stability of the results. CDAI was protective against the development of MetS in the general population, but not against mortality in patients with MetS. Clinicians need to develop individualized prevention strategies to reduce the development of MetS by modifying CDAI.

Radiomic signatures associated with tumor immune heterogeneity predict survival in locally recurrent nasopharyngeal carcinoma.

BACKGROUND: The prognostic value of traditional clinical indicators for locally recurrent nasopharyngeal carcinoma (lrNPC) is limited due to their inability to reflect intratumor heterogeneity. We aimed to develop a radiomic signature to reveal tumor immune heterogeneity and predict survival in lrNPC. METHODS: This multicenter, retrospective study included 921 patients with lrNPC. A machine learning signature and nomogram based on pretreatment MRI features were developed for predicting overall survival (OS) in a training cohort and validated in two independent cohorts. A clinical nomogram and an integrated nomogram were constructed for comparison. Nomogram performance was evaluated by concordance index (C-index) and receiver operating characteristic curve analysis. Accordingly, patients were classified into risk groups. The biological characteristics and immune infiltration of the signature were explored by RNA sequencing (RNA-seq) analysis. RESULTS: The machine learning signature and nomogram demonstrated comparable prognostic ability to a clinical nomogram, achieving C-indexes of 0.729, 0.718, and 0.731 in the training, internal, and external validation cohorts, respectively. Integration of the signature and clinical variables significantly improved the predictive performance. The proposed signature effectively distinguished patients between risk groups with significantly distinct OS rates. Subgroup analysis indicated the recommendation of local salvage treatments for low-risk patients. Exploratory RNA-seq analysis revealed differences in interferon response and lymphocyte infiltration between risk groups. CONCLUSIONS: An MRI-based radiomic signature predicted OS more accurately. The proposed signature associated with tumor immune heterogeneity may serve as a valuable tool to facilitate prognostic stratification and guide individualized management for lrNPC patients.

Notoginsenoside R1 alleviates cerebral ischemia/reperfusion injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway through microbiota-gut-brain axis.

BACKGROUND: Ischemic stroke (IS) ranks as the second common cause of death worldwide. However, a narrow thrombolysis timeframe and ischemia-reperfusion (I/R) injury limits patient recovery. Moreover, anticoagulation and antithrombotic drugs do not meet the clinical requirements. Studies have demonstrated close communication between the brain and gut microbiota in IS. Notoginsenoside R1 (NG-R1), a significant component of the total saponins from Panax notoginseng, has been demonstrated to be effective against cerebral I/R injury. Total saponins have been used to treat IS in Chinese pharmacopoeia. Furthermore, previous research has indicated that the absorption of NG-R1 was controlled by gut microbiota. STUDY DESIGN: This study aimed to access the impact of NG-R1 treatment on neuroinflammation and investigate the microbiota-related mechanisms. RESULTS: NG-R1 significantly reduced neuronal death and neuroinflammation in middle cerebral artery occlusion/reperfusion (MCAO/R) models. 16S rRNA sequencing revealed that NG-R1 treatment displayed the reversal of microbiota related with MCAO/R models. Additionally, NG-R1 administration attenuated intestinal inflammation, gut barrier destruction, and systemic inflammation. Furthermore, microbiota transplantation from NG-R1 exhibited a similar effect in the MCAO/R models. CONCLUSION: In summary, NG-R1 treatment resulted in the restoration of the structure of the blood-brain barrier (BBB) and reduction in neuroinflammation via suppressing the stimulation of astrocytes and microglia in the cerebral ischemic area. Mechanistic research demonstrated that NG-R1 treatment suppressed the toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor kappa B (TLR4/MyD88/NF-κB) signaling pathway in both the ischemic brain and colon. NG-R1 treatment enhanced microbiota dysbiosis by inhibiting the TLR4 signaling pathway to protect MCAO/R models. These findings elucidate the mechanisms by which NG-R1 improve stroke outcomes and provide some basis for Panax notoginseng saponins in clinical treatment.

Efficacy and safety of cadonilimab in previously treated recurrent or metastatic nasopharyngeal carcinoma(COMPASSION-06): A phase II multicenter study.

OBJECTIVE: This study was designed to assess the efficacy and safety of cadonilimab monotherapy, a first-in-class, bi-specific PD-1/CTLA-4 antibody, in patients with previously treated recurrent or metastatic nasopharyngeal carcinoma (R/M-NPC). PATIENTS AND METHODS: This multicenter, open-label, single-arm, phase II clinical trial enrolled patients with R/M-NPC who had failed first-line platinum-based chemotherapy and second-line single agent or combined chemotherapy, and immunotherapy-naive. Patients received cadonilimab for 6 mg/kg once every 2 weeks (Q2W). The primary endpoint was objective response rate (ORR) in full analysis set (FAS) assessed by investigators according to RECIST v.1.1. The secondary endpoint included progression-free survival (PFS), overall survival (OS), duration of response (DoR), time to response (TTR) and safety. RESULTS: A total of 23 patients were assessed. The median time from first dose to data cutoff was 16.56 (range, 0.8-25.2) months. ORR was 26.1 % (95 %CI:10.2-48.4). The ORR were 44.4 % (95 %CI: 13.7-78.8) and 14.3 % (95 %CI:1.8-42.8) in patients with tumor PD-L1 expression ≥50 % and <50 %, respectively. ORR was achieved in 40.0 % (95 %CI:12.2-73.8) of patients with EBV-DNA level <4000 IU/ml (n = 10) and 15.4 % (95 %CI:1.9-45.4) of those with ≥4000 IU/ml. The median PFS was 3.71 months (95 %CI: 1.84-9.30). respectively. Median OS was not reached, and the 12-month OS rate was 79.7 % (95 % CI:54.5-91.9). Only two patients (8.3 %) experienced Grade ≥3 treatment-related adverse events (TRAEs) with hypothyroidism (30.4 %), rash (21.7 %) and pruritus (21.7 %) being the most prevalent TRAEs. CONCLUSION: Cadonilimab monotherapy demonstrated a promising efficacy and manageable toxicity in patients with previously treated R-M/NPC and provide an efficacious salvage treatment option.

Puerarin alleviates diabetic nephropathy by inhibiting Caspase-1-mediated pyroptosis.

BACKGROUND AND PURPOSE: Diabetic nephropathy (DN) is an important cause of end-stage renal disease, with podocyte injury as the main feature. Pyroptosis plays a non-negligible role in the process of diabetic nephropathy. Puerarin (PR) treatment of diabetic nephropathy has great potential, but the mechanism is not very clear. This article aims to study the protective effect and mechanism of puerarin on DN. METHODS: Streptozotocin (STZ)-induced C57 BL/6J mouse model of DN was given PR, Necrosulfomide (NSA), Nigericin for 12 weeks; A 60 mM high glucose(HG) induced MPC5 cell injury model was administered to PR, NSA, and Nigericin interventions for 24 h. RESULTS: After 12 weeks of administration, PR reduced fasting blood glucose levels in DN mice, alleviated glomerular lesions, reduced podocyte damage, and protected renal function. Meanwhile, PR also inhibits the expression of pyroptosis-related proteins. In addition, PR alleviated the release of Interleukin 18 (IL-18), Interleukin 1beta (IL-1ß), and lactate dehydrogenase (LDH) in MPC5 cells under HG conditions, downregulated the expression of pyrozozois-related proteins, and improved Caspase-1-mediated pyroptosis in MPC5 cells. CONCLUSION: Our study suggests that the beneficial effects of PR in diabetic nephropathy may be associated with inhibition of Caspase-1-mediated pyroptosis.

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.

Phase I dose-escalation study of nab-paclitaxel combined with cisplatin and capecitabin as induction chemotherapy followed by concurrent chemoradiotherapy in patients with nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: Nab-paclitaxel is a promising albumin-bound paclitaxel with a therapeutic index superior to that of docetaxel, but the optimal dose of nab-paclitaxel combined with cisplatin and capecitabine as induction chemotherapy followed by concurrent chemoradiotherapy for patients with locally advanced nasopharyngeal carcinoma remains unknown. MATERIALS AND METHODS: This was an open-label, single-arm study investigating the safety and efficacy of nab-paclitaxel + cisplatin + capecitabin as IC for three cycles, followed by cisplatin CCRT, conducted by using the standard "3 + 3" design in LA-NPC. If more than one-third of the patients in a cohort experienced dose-limiting toxicity (DLT), the dose used in the previous cohort was designated the maximum tolerated dose (MTD). The recommended phase 2 dose (RP2D) was defined as one level below the MTD. RESULTS: From 29 May 2021 to 17 March 2022, 19 patients with LA-NPC were enrolled, one patient withdrew informed consent. Two DLTs occurred in cohort 4 (grade 4 febrile neutropenia and grade 3 peripheral neuropathy), and an MTD was established as 225 mg/m2. The most frequent grade 3 or 4 adverse events were neutropenia (16.7 %), hypertriglyceridemia (16.7 %), leukopenia (5.6 %) and peripheral neuropathy (5.6 %) during IC. CONCLUSION: The RP2D is nab-paclitaxel 200 mg/m2 on day 1, combined with cisplatin 75 mg/mg2 on day 1 and capecitabin1000 mg/m2 on days 1-14, twice a day, every 3 weeks, for three cycles as an IC regimen prior to CCRT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04850235.

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.

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.

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.

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.

PLEKHA4 is a novel prognostic biomarker that reshapes the tumor microenvironment in lower-grade glioma.

Background: Lower-grade glioma (LGG) is a primary intracranial tumor that carry a high risk of malignant transformation and limited therapeutic options. Emerging evidence indicates that the tumor microenvironment (TME) is a superior predictor for tumor progression and therapy response. PLEKHA4 has been demonstrated to be a biomarker for LGG that correlate with immune infiltration. However, the fundamental mechanism by which PLEKHA4 contributes to LGG is still poorly understood. Methods: Multiple bioinformatic tools, including Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA2), Shiny Methylation Analysis Resource Tool (SMART), etc., were incorporated to analyze the PLEKHA4. ESTIMATE, ssGSEA, CIBERSORT, TIDE and CellMiner algorithms were employed to determine the association of PLEKHA4 with TME, immunotherapy response and drug sensitivities. Immunohistochemistry (IHC)-based tissue microarrays and M2 macrophage infiltration assay were conducted to verify their associations. Results: PLEKHA4 expression was found to be dramatically upregulated and strongly associated with unfavorable overall survival (OS) and disease-specific survival (DSS) in LGG patients, as well as their poor clinicopathological characteristics. Cox regression analysis identified that PLEKHA4 was an independent prognostic factor. Methylation analysis revealed that DNA methylation correlates with PLEKHA4 expression and indicates a better outcome in LGG. Moreover, PLEKHA4 was remarkably correlated with immune responses and TME remodeling, as evidenced by its positive correlation with particular immune marker subsets and the putative infiltration of immune cells. Surprisingly, the proportion of M2 macrophages in TME was strikingly higher than others, inferring that PLEKHA4 may regulate the infiltration and polarization of M2 macrophages. Evidence provided by IHC-based tissue microarrays and M2 macrophage infiltration assay further validated our findings. Moreover, PLEKHA4 expression was found to be significantly correlated with chemokines, interleukins, and their receptors, further supporting the critical role of PLEKHA4 in reshaping the TME. Additionally, we found that PLEKHA4 expression was closely associated with drug sensitivities and immunotherapy responses, indicating that PLEKHA4 expression also had potential clinical significance in guiding immunotherapy and chemotherapy in LGG. Conclusion: PLEKHA4 plays a pivotal role in reshaping the TME of LGG patients, and may serve as a potential predictor for LGG prognosis and therapy.

Reduced-dose radiotherapy for Epstein-Barr virus DNA selected staged III nasopharyngeal carcinoma: A single-arm, phase 2 trial.

BACKGROUND: Radiotherapy-related toxicities of nasopharyngeal carcinoma (NPC) caused by a standard dose of 70 Gy remain a critical issue. Therefore, we assessed whether a radiotherapy dose of 60 Gy was non-inferior to the standard dose in patients with low-risk stage III NPC with a favourable response to induction chemotherapy (IC). PATIENTS AND METHODS: We did a single-arm, single-centre, phase II clinical trial in China. Patients with low-risk (Epstein-Barr virus [EBV] DNA level <4000 copies/ml) stage III NPC were treated with two cycles IC. Patients with complete/partial response and undetectable EBV DNA level were assigned 60 Gy intensity-modulated radiotherapy concurrently with three cycles of cisplatin. The primary end-point was 2-year progression-free survival (PFS). This trial is registered with ClinicalTrials.gov, number NCT03668730. RESULTS: One patient quit because of withdrawal of informed consent after IC. In total, 215 patients completed two cycles of IC, after which 116 (54.0%) and 99 (46.0%) patients were assigned 60 and 70 Gy radiotherapy, respectively. For 215 patients, the 2-year PFS was 90.7% (95% CI, 86.8%-94.6%) with a median follow-up of 43.9 months (interquartile range [IQR], 39.8-46.2). For patients treated with 60 Gy radiotherapy, the 2-year PFS rate was 94.8% (95%CI 90.7%-98.9%) with a median follow-up of 43.9 months (IQR 40.2-46.2). The most common late toxicity was grade 1-2 dry mouth (incidence rate: 54.3%). No grade 3+ long-term adverse event was observed, and most quality-of-life items, domains, and symptom scores returned to baseline by 6 months. CONCLUSION: Reduced-dose radiation (60 Gy) is associated with favourable survival outcomes and limited treatment-related toxicities in patients with low-risk stage III NPC sensitive to IC.