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Objective: To investigate the anatomical structure changes of the anterior segment and dynamic pupil changes in eyes with suspected primary angle-closure (PACS) under light and dark conditions, and their correlation with the occurrence of acute primary angle-closure (APAC). Methods: This cross-sectional study collected data from 37 PACS patients (66 eyes) who visited the ophthalmology clinic of the Second Affiliated Hospital of Harbin Medical University between September 2019 and March 2021. The patients included 12 males and 25 females, with an average age of (61.27±7.35) years. Of the 66 eyes, 58 had no history of APAC in the contralateral eye, while 8 had a history of APAC in the contralateral eye. Patients without a history of APAC in both eyes underwent the dark room prone provocative test (DRPPT), and the eyes were divided into three groups: DRPPT- (44 eyes), DRPPT+ (14 eyes), and APAC (8 eyes). The DRPPT+ and APAC groups were combined into the APAC+ group. All patients underwent ultrasound biomicroscopy (UBM) to measure the changes in various parameters under light and dark conditions, including anterior chamber angle 500 (ACA 500Δ ) and 1000 (ACA 1000Δ ), angle opening distance 500 (AOD 500Δ ) and 1000 (AOD 1000Δ ), and iris thickness 500 (IT 500Δ ) and 1000 (IT 1000Δ ). Anterior segment analysis was performed to capture the pupil changes under light and dark conditions, recording pupil diameter, maximum dilation speed (V max ), maximum constriction speed (V min ), and average speed (V m ). Results: There was no significant difference in the parameters between DRPPT+ group and APAC group ( P> 0.05). In the difference analysis, it was found that the V m value of DRPPT- group [(0.17±0.07) mm/s] was higher than that of APAC+ group [(0.13±0.06)mm/s], and the difference was statistically significant ( P <0.05). There was no significant difference in other parameters ( P >0.05). V max was positively correlated with temporal ACA 1000Δ and temporal AOD 1000Δ in all patients with PACS ( r =0.302, 0.260; P <0.05), V min was negatively correlated with temporal ACA 1000Δ and temporal AOD 1000Δ ( r =-0.338, -0.330; P <0.05). Conclusions: The dynamic changes in the anterior segment and pupil under different lighting conditions provide insights into the risk factors and potential predictive indicators for the occurrence of APAC in PACS patients.

Background: Inflammatory bowel disease (IBD) is a chronic and relapsing disease marked by chronic tissue inflammation that alters the integrity and function of the gut, seriously impacting patient health and quality of life. Aucklandiae Radix (AR), known as Mu Xiang in Chinese, is a traditional Chinese medicine documented in Chinese Pharmacopoeia with effects of strengthening the intestine and stopping diarrhea. However, the potential of AR in treating intestinal inflammation and its underlying mechanism have yet to be further elucidated., Purpose: The objective of this study was to explore the protective effect and the potential mechanism attributable to AR for treating ulcerative colitis (UC)., Study Design and Methods: A murine model of UC was constructed using dextran sulfate sodium (DSS) to examine the therapeutic potential of AR in alleviating inflammation and modulating the immune response. Advanced techniques such as photocrosslinking target fishing technique, click chemistry, Western blot analysis, real-time quantitative PCR, flow cytometry, immunofluorescence, and immunohistochemistry were employed to unveil the therapeutic mechanism of AR for treating IBD., Results: AR decreased disease activity index (DAI) score to alleviate the course of IBD through ameliorating intestinal barrier function in DSS-induced mice. Furthermore, AR suppressed NF-κB and NLRP3 pathways to reduce the release of pro-inflammatory factors interleukin-6 and 1β (IL-6 and IL-1β) and tumor necrosis factor α (TNF-α), allowing to alleviate the inflammatory response. Flow cytometry revealed that AR could reduce the accumulation of intestinal macrophages and neutrophils, maintaining intestinal immune balance by regulating the ratio of Treg to Th17 cells. It was worth noting that pyruvate kinase isozyme type M2 (PKM2) served as a potential target of AR using the photocrosslinking target fishing technology, which was further supported by cellular thermal shift assay (CETSA), drug affinity target stability (DARTS), and PKM2 knockdown experiments., Conclusion: AR targeted PKM2 to inhibit NF-κB and NLRP3 pathways, thereby modulating the inflammatory response and immunity to alleviate DSS-induced UC. These findings suggested the potential of AR in the treatment of UC and AR as a candidate for developing PKM2 regulators., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Transcranial magnetic stimulation (TMS) is pivotal in the field of major depressive disorder treatment. Due to its unsatisfied response rate, an increasing number of researchers have turned their attention towards optimizing TMS site localization. Since the influence of TMS in reducing heart rate (HR) offers insights into its regulatory impact on the autonomic nervous system, a novel approach, called neurocardiac-guided TMS (NCG-TMS), has been proposed to pinpoint the brain region eliciting the maximal individual reduction in HR as a personalized optimal stimulation target. The present study intends to systematically explore the effects of stimulation frequency, left and right hemispheres, stimulation positions, and individual differences on HR modulation using the NCG-TMS method. In experiment 1, low-frequency TMS was administered to 30 subjects, and it was found that low-frequency NCG-TMS significantly downregulated HR, with more significant effects in the right hemisphere than in the left hemisphere and the prefrontal cortex than in other brain areas. In experiment 2, high-frequency NCG-TMS stimulation was administered to 30 subjects, showing that high-frequency NCG-TMS also downregulated HR and had the greatest modulatory effect in the right prefrontal region. Simultaneously, both experiments revealed sizeable individual variability in the optimal stimulation site, which in turn validated the feasibility of the NCG-TMS method. In conclusion, the present experiments independently replicated the effect of NCG-TMS, provided an effect of high-/low-frequency TMS stimulation to downregulate HR, and identified a right lateralization of the HR modulation effect., (© 2024 Society for Psychophysiological Research.)

Grafting onto pumpkin rootstock is widely applied in cucumber production to improve growth and yield, as well as to overcome soil-borne diseases and enhance resistance to abiotic stresses. In this study, we constructed the cucumber-pumpkin heterografts with the one-cotyledon grafting method, and examined the effects of heterografting on biomass allocation and sugar partitioning, with cucumber and pumpkin self-grafts used as control. Compared with cucumber self-grafts, heterografting onto pumpkin rootstock promoted photosynthesis in cucumber scion, and led to higher sucrose contents in the 1st true leaf (source) and newly emerged leaf (sink). Thereby, the scion part of heterografts accumulated more biomass than cucumber self-grafts. In contrast, when compared to pumpkin self-grafts, grafting with cucumber scion reduced root vigor and biomass but promoted cotyledon growth in pumpkin rootstock. The roots (sink) of heterografts contained less sucrose and hexoses, and showed reduced sucrose synthase (SuSy) and hexokinase (HXK) activities. However, the rootstock cotyledon (source) contained more sucrose and starch, and showed higher activities of HXK, cell-wall invertase (CWIN), and enzymes for starch synthesis and degradation. Furthermore, removal or shade of rootstock cotyledon led to reduced growth of root and scion. Silencing of CmoMEX1a gene in rootstock cotyledon inhibited maltose export and reduced root growth of heterografts. These results indicated that rootstock cotyledon, especially its starch content, played a buffering role in the growth regulation of cucumber-pumpkin heterografts. Taken together, our results provided a major contribution to our understanding of source-sink sugar partitioning and scion-rootstock growth balancing in cucumber-pumpkin heterografts., (© 2024 Scandinavian Plant Physiology Society.)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has attracted lots of attention in preventing the clearance of plasma low-density lipoprotein cholesterol (LDL-C). PCSK9 inhibitors are developed to primarily reduce the cardiovascular risk by lowering LDL-C level. Recently, a number of pleiotropic extrahepatic functions of PCSK9 beyond the regulation of cholesterol metabolism, particularly its effects on central nervous system (CNS) diseases have been increasingly identified. Emerging clinical evidence have revealed that PCSK9 may play a significant role in neurocognition, depression, Alzheimer's disease, and stroke. The focus of this review is to elucidate the functions of PCSK9 and highlight the effects of PCSK9 in CNS diseases, with the aim of identifying the potential risks that may arise from low PCSK9 level (variant or inhibitor) in the clinical practice., (© 2023 Wiley Periodicals LLC.)

This study aims to develop fatty acid metabolism-related molecular subtypes and construct a fatty acid metabolism-related novel model for bladder cancer (BCa) by bioinformatic profiling. Genome RNA-seq expression data of BCa samples from the TCGA database and GEO database were downloaded. We then conducted consensus clustering analysis to identify fatty acid metabolism-related molecular subtypes for BCa. Univariate and multivariate Cox regression analysis were performed to identify a novel prognostic fatty acid metabolism-related prognostic model for BCa. Finally, we identified a total of three fatty acid metabolismrelated molecular subtypes for BCa. These three molecular subtypes have significantly different clinical characteristics, PD-L1 expression levels, and tumor microenvironments. Also, we developed a novel fatty acid metabolism-related prognostic model. Patients with low-risk score have significantly preferable overall survival compared with those with high-risk score in the training, testing, and validating cohorts. The area under the ROC curve (AUC) for overall survival prediction was 0.746, 0.681, and 0.680 in the training, testing and validating cohorts, respectively. This model was mainly suitable for male, older, high-grade, cluster 2-3, any TCGA stage, any N-stage, and any T-stage patients. Besides, we selected FASN as a hub gene for BCa and further qRT-PCR validation was successfully conducted. In conclusion, we developed and successfully validated a novel fatty acid metabolism-related prognostic model for predicting outcome for BCa patients.

Fertilizer-based biofortification is a strategy for combating worldwide malnutrition of zinc (Zn), iron (Fe) and selenium (Se). Field experiments were conducted to investigate the effects of foliar treatments on concentrations of Zn, Fe, Se, N and bioavailability of Zn and Fe in grains of three maize cultivars grown at three locations. We compared the efficacy of ZnO nanoparticles (ZnO-NPs), Zn complexed chitosan nanoparticles (Zn-CNPs), conventional ZnSO 4 and a cocktail solution (containing Zn, Fe and Se). All treatments were foliar-applied at rate of 452 mg Zn L -1 , plus urea. Applying ten-fold less Zn (at rate of 45.2 mg Zn L -1 ) plus urea in the form of ZnO-NPs, Zn-CNPs, or ZnSO 4 resulted in no increase, or a negligible increase, in grain Zn concentration compared with deionized water. By contrast, among the different Zn sources plus urea applied by foliar sprays, conventional ZnSO 4 was the most efficient in improving grain Zn concentration. Furthermore, foliar application of a cocktail solution effectively improved grain concentrations of Zn, Fe, Se and N simultaneously, without a grain yield trade-off. For example, the average grain concentrations were simultaneously increased from 13.8 to 22.1 mg kg -1 for Zn, from 17.2 to 22.1 mg kg -1 for Fe, from 21.4 to 413.5 ug kg -1 for Se and from 13.8 to 14.7 g kg -1 for N by foliar application of a cocktail solution. Because grain yield was significantly negatively correlated with grain nutrient concentrations, the magnitude of increase in grain concentrations of Zn and Fe was most pronounced in the maize cultivar with the lowest grain yield (Zhengdan958 grown in Linyi). Foliar application of a cocktail solution also significantly decreased the phytic acid (PA) concentration, ratios of PA/Fe and PA/Zn in grains, indicating an increased bioavailability of Fe and Zn for human health. In conclusion, we found that a foliar application of a cocktail solution including Zn, Fe, Se and N was most effective for biofortification, but that the grains with the lowest yield contained the greatest concentration of these elements. This finding highlights the need to breed maize varieties that are capable of achieving both high grain yield and high grain nutritional quality to address food security and human health challenges., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xue, Li, Yan, Miao, Zhang, Huang, Sun, Qi, Ding and Cui.)

Metal-assisted plasma etching (MAPE) of silicon (Si) is an etching technique driven by the catalytic activity of metals such as gold in fluorine-based plasma environments. In this work, the role of the Si substrate was investigated by examining the effects of the dopant concentration in both n- and p-type Si and the dopant atom type in n-type Si in SF 6 /O 2 mixed gas plasma. At the highest dopant concentrations, both n- and p-type Si initially exhibit inhibition of the MAPE-enhanced etching. As the etch progresses, MAPE initiates, resulting in catalytic etching of the underlying Si at the metal-Si interface. Interestingly, MAPE-enhanced etching increases with decreasing doping concentrations for both n- and p-type Si substrates, distinct from results for the similar but divergent, metal-assisted chemical etching of silicon in liquid. Our findings show that the metal-Si interface remains essential to MAPE, and surface enrichment of the dopant atoms or other surface chemistries and the size of metal nanoparticles play roles in modulating catalytic activity.

Background: The purpose of this study was to observe the safety and efficacy of CalliSpheres microspheres drug-eluting beads (DEB) transhepatic arterial chemoembolization (CSM-TACE) for liver metastasis of gastric cancer (GCLM) combined with trans-arterial infusion therapy (TAIT) as the primary focus of gastric cancer., Research Design and Methods: Unresectable advanced GCLM patients were collected for retrospective analysis. Patients who progressed after chemotherapy or could not receive systematic chemotherapy were selected. CSM-TACE was used for GCLM treatment and oxaliplatin for TAIT of primary focus of gastric cancer. Adverse reactions, tumor reactions, survival rate, and survival time during treatment were recorded, and prognostic factors were analyzed., Results: Forty-three patients from four oncology centers met inclusion criteria and were enrolled. CSM-TACE averaged (1.51 ± 0.51) times and TAIT averaged (4.58 ± 1.65) times. The follow-up time was 2.5-49 months, and the 6-month, 1-year, and 2-year survival rates were 86.0%, 72.1%, and 41.9%, respectively, with a median overall survival of 11.5 months. The adverse reactions during treatment were grade 1-3. The hazard ratio (HR) of combination therapy was 0.51 ( P  = 0.040), and the HR of TAIT frequency was 0.34 ( P  = 0.002), which were independent protective factors affecting prognosis., Conclusions: CSM-TAC for GCLM combined with TAIT for primary focus of gastric cancer is safe and efficacious, which is worthy of clinical promotion and application.

Objective: To explore whether 68 Ga-PSMA-11 PET/CT-derived parameters could predict biochemical response to abiraterone acetate (AA) treatment and prognosis in metastatic prostate cancer patients developing castration resistance after chemohormonal therapy at hormone-sensitive stage., Methods: The clinicopathologic data of 106 mCRPC cases receiving AA treatment were retrospectively analyzed. Logistic regression analysis was used to determine the independent predictors of biochemical response to AA treatment. Cox analyses were applied to investigate the independent prognostic factors for time to biochemical progression (TTBP) and radiological progression-free survival (rPFS). Survival analysis and ROC curve were also used., Results: Multivariable Logistic analysis demonstrated that prior ADT duration ≥ 12 months, low prostate specific membrane antigen receptor-expressing tumor volume (PSMA-TV), low tumor to liver ratio (TLR) were independent predictors of biochemical response to AA treatment. Multivariate Cox analysis demonstrated that low PSMA-TV and low TLR were independent prognostic factors of longer TTBP and rPFS. The TTBP and rPFS of patients with higher PSMA-TV or TLR were significantly decreased compared with that of patients with lower PSMA-TV and TLR. The area under ROC curve (AUC) of combining ADT duration, PSMA-TV and TLR was 0.82 for predicting biochemical response to AA, which was significantly increased compared with that of other 68 Ga-PSMA-11 PET/CT-derived parameters alone., Conclusions: Low PSMA-TV, low TLR were vital independent predictors of biochemical response to AA treatment and were associated with preferable prognosis in mCRPC patients. Combining ADT duration, PSMA-TV and TLR performed well in distinguishing AA responders from non-responders in mCRPC patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To explore the diagnosis, surgical management and outcome of jugular foramen chondrosarcoma (CSA). Methods: Fifteen patients with jugular foramen CSA hospitalized in the Department of Otorhinolaryngology Head and Neck Surgery of Chinese PLA General Hospital from December 2002 to February 2020 were retrospectively collected,of whom 2 were male and 13 were female, aging from 22 to 61 years old. The clinical symptoms and signs, imaging features, differential diagnosis, surgical approaches, function of facial nerve and cranial nerves IX to XII, and surgical outcomes were analyzed. Results: Patients with jugular foramen CSA mainly presented with facial paralysis, hearing loss, hoarseness, cough, tinnitus and local mass. Computed tomography (CT) and magnetic resonance (MR) could provide important information for diagnosis. CT showed irregular destruction on bone margin of the jugular foramen. MR demonstrated iso or hypointense on T1WI, hyperintense on T2WI and heterogeneous contrast-enhancement. Surgical approaches were chosen upon the sizes and scopes of the tumors. Inferior temporal fossa A approach was adopted in 12 cases, inferior temporal fossa B approach in 2 cases and mastoid combined parotid approach in 1 case. Five patients with facial nerve involved received great auricular nerve graft. The House Brackmann (H-B) grading scale was used to evaluate the facial nerve function. Preoperative facial nerve function ranked grade Ⅴ in 4 cases and grade Ⅵ in 1 case. Postoperative facial nerve function improved to grade Ⅲ in 2 cases and grade Ⅵ in 3 cases. Five patients presented with cranial nerves Ⅸ and Ⅹ palsies. Hoarseness and cough of 2 cases improved after operation, while the other 3 cases did not. All the patients were diagnosed CSA by histopathology and immunohistochemistry, with immunohistochemical staining showing vimentin and S-100 positive, but cytokeratin negative in tumor cells. All patients survived during 28 to 234 months' follow-up. Two patients suffered from tumor recurrence 7 years after surgery and received revision surgery. No complications such as cerebrospinal fluid leakage and intracranial infection occurred after operation. Conclusions: Jugular foramen CSA lacks characteristic symptoms or signs. Imaging is helpful to differential diagnosis. Surgery is the primary treatment of jugular foramen CSA. Patients with facial paralysis should receive surgery in time as to restore the facial nerve. Long-term follow-up is necessary after surgery in case of recurrence.

Background: Immunogenic cell death (ICD) plays a vital role in tumor progression and immune response. However, the integrative role of ICD-related genes and subtypes in the tumor microenvironment (TME) in prostate cancer (PCa) remains unknown., Materials and Methods: The sample data were obtained from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Memorial Sloan Kettering Cancer Center (MSKCC) prostate cancer-related databases. We first divided the subtypes based on ICD genes from 901 PCa patients and then identified the prognosis- related genes (PRGs) between different ICD subtypes. Subsequently, all the patients were randomly split into the training and test groups. We developed a risk signature in the training set by least absolute shrinkage and selection operator (LASSO)-Cox regression. Following this, we verified this prognostic signature in both the training test and external test sets. The relationships between the different subgroups and clinical pathological characteristics, immune infiltration characteristics, and mutation status of the TME were examined. Finally, the artificial neural network (ANN) and fundamental experiment study were constructed to verify the accuracy of the prognostic signature., Results: We identified two ICD clusters with immunological features and three gene clusters composed of PRGs. Additionally, we demonstrated that the risk signature can be used to evaluate tumor immune cell infiltration, prognostic status, and an immune checkpoint inhibitor. The low-risk group, which has a high overlap with group C of the gene cluster, is characterized by high ICD levels, immunocompetence, and favorable survival probability. Furthermore, the tumor progression genes selected by the ANN also exhibit potential associations with risk signature genes., Conclusion: This study identified individuals with high ICD levels in prostate cancer who may have more abundant immune infiltration and revealed the potential effects of risk signature on the TME, immune checkpoint inhibitor, and prognosis of PCa., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kang, Sun, Lin, Huang, Huang, Chen, Zheng, Xue, Xu and Wei.)

Phytosterols (PS) have been shown to regulate cholesterol metabolism and alleviate hyperlipidemia (HLP), but the mechanism is still unclear. In this study, we investigated the mechanism by which PS regulates cholesterol metabolism in high-fat diet (HFD) mice. The results showed that PS treatment reduced the accumulation of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) in the serum of HFD mice, while increasing the serum levels of high-density lipoprotein cholesterol (HDL-C). Compared with HFD mice, PS not only increased the antioxidant activity of the liver but also regulated the mRNA expression levels of enzymes and receptors related to cholesterol metabolism. The hypolipidemic effect of PS was abolished by antibiotic (Abx) intervention and reproduced by fecal transplantation (FMT) intervention. The results of 16S rRNA sequencing analysis showed that PS modulated the gut microbiota of mice. PS reduced the relative abundance of Lactobacillus and other bile salt hydrolase- (BSH-) producing gut microbiota in HFD mice, which are potentially related to cholesterol metabolism. These findings partially explain the mechanisms by which PS regulates cholesterol metabolism. This implies that regulation of the gut microbiota would be a potential target for the treatment of HLP., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wei-Jie Lv et al.)

Objective: This study aimed to prospectively observe the efficacy and safety of CalliSpheres drug-eluting beads bronchial arterial chemoembolization (DEB-BACE) for refractory non-small-cell lung cancer (NSCLC)., Methods: The interventional therapy plan was as follows: 300-500 μm CalliSpheres drug-loaded microspheres were loaded with epirubicin, and then slow embolization of tumor supplying artery was performed after microcatheter superselection. Chest enhanced computed tomography and related hematological examination were reviewed after 2 months of DEB-BACE, and the tumor response after the first interventional therapy was evaluated using modified response evaluation criteria in solid tumors. The overall survival (OS) of patients was determined, and the quality of life and the incidence rate of adverse reactions were observed., Results: From January 2019 to January 2021, 43 patients with refractory NSCLC were enrolled. The patients were followed up until June 2022. All 43 patients underwent DEB-BACE 1.79 ± 0.69 times on average. The 3-, 6-, 12-, and 24-month survival rates were 100%, 86.0%, 41.9%, and 11.8%, respectively. The median OS was 11.5 months. After the first interventional treatment, cough and wheezing significantly improved in 31 patients, hemoptysis was effectively controlled in 12 patients, and superior vena cava compression disappeared in 2 patients after 2 times of treatment. The general health status of the patients after treatment significantly improved compared with that before treatment, including the improvement in physical and emotional functions. Fatigue, nausea and vomiting, dyspnea, and insomnia improved significantly after treatment. No serious adverse events, such as spinal cord injury and cerebral embolism, were observed during the perioperative period. The main adverse reaction after DEB-BACE was chest pain (13/43, grade 1) followed by fever (10/43, grade 1-2), which was significantly relieved within 3-5 days after symptomatic treatment. Other adverse reactions included irritating cough, nausea and vomiting, and bone marrow suppression, and the incidence was less than 20%., Conclusions: DEB-BACE was effective and safe in treating refractory NSCLC, which could significantly improve patients' quality of life and was worthy of clinical promotion and application., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhao, Liu, Qin, Sun, Su, Yu, Zhou, Gao, Wang, Zhao and Zhao.)

Objective: To investigate the predictive value of body composition parameters for biochemical response to abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC) patients with prior chemohormonal therapy., Methods: We retrospectively evaluated the clinicopathologic information of 132 mCRPC cases receiving AA treatment after chemohormonal therapy at hormone-sensitive stage from July 2018 to June 2021. All patients were divided into AA responders and non-responders according to the biochemical response to AA (prostate-specific antigen (PSA) reduction ≥50% than pretreatment). Multivariate Logistic analysis was used to determine the independent predictors and develop predictive model of biochemical response to AA. Cox regression analysis was utilized to investigate the prognostic factors for time to biochemical progression (TTBP), radiological progression-free survival (rPFS), failure-free survival (FFS), and overall survival (OS) after AA treatment., Results: There were 57 AA responders and 75 AA non-responders. Periprostatic fat area/prostate area (PPFA/PA) was decreased and skeletal muscle index (SMI) was increased in AA responders compared with AA non-responders. Multivariable logistic analysis demonstrated that ADT duration ≥12 months, bone metastasis only, high SMI and low PPFA/PA were independent predictors of biochemical response to AA treatment. The FFS, TTBP, rPFS, and OS of patients with lower SMI or higher PPFA/PA was decreased compared with that of patients with higher SMI or lower PPFA/PA, respectively. Combining SMI, PPFA/PA, ADT duration and metastatic sites performed well in differentiating AA responders from non-responders., Conclusions: High SMI and low PPFA/PA could predict biochemical response to AA treatment and preferable prognosis in mCRPC patients with prior chemohormonal therapy at hormone-sensitive stage., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To investigate the clinical efficacy and advantages of Tianji orthopedic robot assisted cannulated screw internal fixation for femoral neck fracture., Methods: The clinical data of 41 patients with femoral neck fracture who underwent internal fixation with cannulated screws from January 2019 to January 2022 were retrospectively analyzed. According to different surgical methods, they were divided into Tianji robot group and traditional cannulated screw fixation group (traditional operation group). Among them, there were 18 patients in Tianji robot group including 8 males and 10 females with age of (56.00±4.22) years old, Garden typeⅠ (4 cases), type Ⅱ (11 cases), type Ⅲ (2 cases), and type Ⅳ (1 case). There were 23 patients in the traditional operation group, including 10 males and 13 females, aged (54.87±4.81) years old;there were 5 cases of Garden typeⅠ, 14 cases of type Ⅱ, 3 cases of type Ⅲ and 1 case of type Ⅳ. The operation time, intraoperative blood loss, fluoroscopy times, guide needle placement times, operation costs and other indicators were observed and compared between two groups. Harris score was used to evaluate hip joint function 12 months after operation., Results: The wounds of all patients healed in Grade A without complications. There were significant differences between two groups in terms of operation time, times of intraoperative fluoroscopy, times of guide needle placement, amount of intraoperative bleeding, and operation cost ( P <0.05). All 41 patients were followed up for at least 12 months. The fractures of both groups were healed. There was no infection, screw loosening, fracture displacement and femoral head necrosis in Tianji robot group during follow-up;Screw loosening occurred in 2 patients in the traditional operation group during follow-up. At 12 months after operation, Harris hip joint function score of Tianji robot group was higher than that of traditional operation group in daily activity, lameness, joint activity score and total score ( P <0.05)., Conclusion: Tianji robot assisted nail placement is a better method for the treatment of femoral neck fracture, which improves the surgical efficiency, is more accurate, has higher success rate of one-time nail placement, shorter operation time, less radiation, and has better hip joint function recovery after surgery.

Objective: Myocardial infarction (MI) has gained widespread interest due to its high death and disability rate worldwide. Some miRNAs are markers of heart disease. Therefore, it is necessary to understand the mechanism for repairing MI injury., Methods: Here, we evaluated the relative expression levels of miR-199a-3p in mouse and human myocardial cell models of injury, and its effect on myocardial cells viability using Cell Counting Kit-8 (CCK-8) assay, 5-ethynyl-2'-deoxyuridline (EdU) assay, and flow cytometry assay as well as western blot in vitro. Furthermore, we performed bioinformatic online analysis to investigate the role that miR-199a-3p plays in cardiomyocyte injury, measured by dual-luciferase reporter assay., Results: The results showed that miR-199a-3p significantly increased the growth rate of cardiomyocytes after treating them with hydrogen peroxide (H 2 O 2 ). miR-199a-3p also acted as an inhibitor that directly targeted NACC2, resulting in a higher NACC2 expression level in the injury model of cardiomyocytes than normal myocardial cells and thus preventing miR-199a-3p-induced proliferation promotion in model cardiomyocytes., Conclusion: Our results demonstrate that miR-199a-3p may be a prognostic biomarker in myocardial injury., Competing Interests: None., (IJCEP Copyright © 2023.)

To identify liquid-liquid phase separation (LLPS)-related molecular clusters, and to develop and validate a novel index based on LLPS for predicting the prognosis of prostate cancer (PCa) patients. We download the clinical and transcriptome data of PCa from TCGA and GEO database. The LLPS-related genes (LRGs) were extracted from PhaSepDB. Consensus clustering analysis was used to develop LLPS-related molecular subtypes for PCa. The LASSO cox regression analysis was performed to establish a novel LLPS-related index for predicting biochemical recurrence (BCR)-free survival (BCRFS). Preliminary experimental verification was performed. We initially identified a total of 102 differentially expressed LRGs for PCa. Three LLPS related molecular subtypes were identified. Moreover, we established a novel LLPS related signature for predicting BCRFS of PCa patients. Compared to low-risk patients in the training cohort, testing cohort and validating cohort, high-risk populations meant a higher risk of BCR and significantly poorer BCRFS. The area under receiver operating characteristic curve were 0.728, 0.762, and 0.741 at 1 year in the training cohort, testing cohort and validating cohort. Additionally, the subgroup analysis indicated that this index was especially suitable for PCa patients with age ≤ 65, T stage III-IV, N0 stage or in cluster 1. The FUS , which was the potential biomarker related to PCa liquid-liquid phase separation, was preliminarily identified and verified. This study successfully developed three LLPS-related molecular subtypes and identified a novel LLPS related molecular signature, which performed well in predicting BCRFS of PCa.

Background: Previous research has found that transcutaneous auricular vagus nerve stimulation (taVNS) can improve working memory (WM) performance. It has also been shown that 0.1 Hz slow-paced breathing (SPB, i.e., breathing at a rate of approximately 6 breaths/min) can significantly influence physical state and cognitive function via changes in autonomic afferent activity. In the present study, we investigated the synergistic effects of taVNS and SPB on WM performance., Methods: A total of 96 healthy people participated in this within-subjects experiment involving four conditions, namely taVNS, SPB, combined taVNS with SPB (taVNS + SPB), and sham. Each participant underwent each intervention for 30 min and WM was compared pre- and post-intervention using the spatial and digit n-back tasks in a random order four times. Permutation-based analysis of variance was used to assess the interaction between time and intervention., Results: For the spatial 3-back task, a significant interaction between time and intervention was found for the accuracy rate of matching trials (mACC, p = 0.03). Post hoc analysis suggested that both taVNS and taVNS + SPB improved WM performance, however, no significant difference was found in the SPB or sham groups., Conclusion: This study has replicated the effects of taVNS on WM performance reported in previous studies. However, the synergistic effects of combined taVNS and SPB warrant further research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tian, Cheng, Liu, Yin, Zhang, Cui, Zhao, Deng, Lu, Tang, Xu, Yang, Sun and Qin.)

Background: Previous sleep electroencephalography studies have detected abnormalities in sleep architecture and sleep spindle deficits in schizophrenia (SCZ), but the consistency of these results was not robust, which might be due to the small sample size and the influence of clinical factors such as the various medication therapies and symptom heterogeneity. This study aimed to regard auditory verbal hallucinations (AVHs) as a pointcut to downscale the heterogeneity of SCZ and explore whether some sleep architecture and spindle parameters were more severely impaired in SCZ patients with AVHs compared with those without AVHs., Methods: A total of 90 SCZ patients with AVHs, 92 SCZ patients without AVHs, and 91 healthy control subjects were recruited, and parameters of sleep architecture and spindle activities were compared between groups. The correlation between significant sleep parameters and clinical indicators was analyzed., Results: Deficits of sleep spindle activities at prefrontal electrodes and intrahemispheric spindle coherence were observed in both AVH and non-AVH groups, several of which were more serious in the AVH group. In addition, deficits of spindle activities at central and occipital electrodes and interhemispheric spindle coherence mainly manifested accompanying AVH symptoms, most of which were retained in the medication-naive first-episode patients, and were associated with Auditory Hallucination Rating Scale scores., Conclusions: Our results suggest that the underlying mechanism of spindle deficits might be different between SCZ patients with and without AVHs. In the future, the sleep feature of SCZ patients with different symptoms and the influence of clinical factors, such as medication therapy, should be further illustrated., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: The optimal tool to evaluate the tumour therapeutic responses to neoadjuvant chemohormonal therapy (NCHT) in patients with high-risk non-metastatic prostate cancer (PCa) remains uncertain. We compared the role of [ 68 Ga]-labeled prostate-specific membrane antigen (PSMA)-11 positron emission tomography/computerized tomography ([ 68 Ga]Ga-PSMA-11 PET/CT), multiparametric MRI (mpMRI), and prostate-specific antigen (PSA) and assessed the practical value of the recent European Association of Urology and European Association of Nuclear Medicine (EAU/EANM) recommended criteria of PSMA PET/CT to evaluate the therapeutic responses to NCHT in patients with high-risk non-metastatic PCa., Methods: This prospective study included 72 high-risk non-metastatic PCa patients receiving NCHT followed by radical prostatectomy from June 2021 to March 2022. PSA testing, [ 68 Ga]Ga-PSMA-11 PET/CT, and mpMRI scanning were conducted in all patients before and after NCHT. Therapeutic responses to NCHT were evaluated with PSA, RECIST 1.1, PERCIST 1.0, and EAU/EANM recommended criteria. Postoperative pathological results were considered the reference standard. A favourable pathological response was defined as pathologic complete remission (pCR) or minimal residual disease (MRD). Diagnostic accuracy was assessed by sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), positive predictive value (PPV), negative predictive value (NPV), and Cohen's kappa index. Logistic regression analysis was used to determine the independent predictive value of [ 68 Ga]Ga-PSMA-11 PET/CT-derived parameters., Results: All cases experienced a marked decrease in PSA levels after NCHT. Twenty-four (33.33%) cases experienced a favourable pathological response, including five (6.94%) cases of pCR and 19 (26.39%) cases of MRD. According to the results of [ 68 Ga]Ga-PSMA-11 PET/CT, EAU/EANM recommended criteria indicated that 20 (27.78%) cases had a CR, whereas PERCIST 1.0 criteria indicated that 23 (31.94%) cases had a CR. There was a strong association between EAU/EANM recommended criteria and PERCIST 1.0 criteria (Pearson's R=0.857). The sensitivity (75.00%, 79.17% vs. 58.33%, 58.33%), specificity (95.83%, 91.67% vs. 83.33%, 68.75%), PLR (18.00, 9.50 vs. 3.50, 1.87), NLR (0.26, 0.23 vs. 0.50, 0.61), PPV (90.0%, 82.6% vs. 63.6%, 48.3%), and NPV (88.5%, 89.8% vs. 80.0%, 76.7%) of [ 68 Ga]Ga-PSMA-11 PET/CT (including EAU/EANM recommended criteria and PERCIST 1.0 criteria) to predict favourable pathological responses were all superior to those of mpMRI and nadir PSA. The kappa index to predict a favourable pathological response was 0.257 for PSA, 0.426 for RECIST 1.1, 0.716 for PERCIST 1.0, and 0.739 for EAU/EANM recommended criteria. Multivariate logistic analysis revealed that the post-NCHT maximum standardized uptake value (SUVmax) before radical prostatectomy was an independent predictor of a favourable pathological response to NCHT., Conclusions: [ 68 Ga]Ga-PSMA-11 PET/CT had a better concordance with a favourable pathological response to NCHT compared with nadir PSA and mpMRI. EAU/EANM recommended criteria and PERCIST 1.0 criteria performed equally to identify pathological responders when [ 68 Ga]Ga-PSMA-11 PET/CT was used as a therapeutic response assessment tool., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Many human activities require high cognitive performance over long periods, while impairments induced by sleep deprivation influence various aspects of cognitive abilities, including working memory (WM), attention, and processing speed. Based on previous research, vagal nerve stimulation can modulate cognitive abilities, attention, and arousal. Two experiments were conducted to assess the efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) to relieve the deleterious effects of sleep deprivation. In the first experiment, 35 participants completed N-back tasks at 8:00 a.m. for two consecutive days in a within-subject study. Then, the participants received either taVNS or earlobe stimulation (active control) intervention in two sessions at random orders after 24 h of sustained wakefulness. Then, they completed the N-back tasks again. In the second experiment, 30 participants completed the psychomotor vigilance task (PVT), and 32 completed the N-back tasks at 8:00 a.m. on the first and second days. Then, they received either taVNS or earlobe stimulation at random orders and finished the N-back and PVT tasks immediately after one hour. In Experiment 1, taVNS could significantly improve the accuracy rate of participants in spatial 3-back tasks compared to active control, which was consistent with experiment 2. However, taVNS did not specifically enhance PVT performance. Therefore, taVNS could be a powerful intervention for acute sleep deprivation as it can improve performance on high cognitive load tasks and is easy to administer., Competing Interests: Declarations of interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: To investigate the clinical characteristics and treatment of pancreatic pseudocyst after pegaspargase treatment in children. Methods: The clinical data of 6 children with pancreatic pseudocyst after pegaspargase treatment in the Department of Pediatrics in Peking University Third Hospital from July 2018 to February 2021 were analyzed retrospectively. Results: There were 4 males and 2 females, and their age of onset was 9.5 (5.8, 13.0) years. The total number of pegaspargase applications was 2.5 (2.0, 3.5) times. The course from the last dose of pegaspargase to the onset of pancreatitis was 11.0 (9.0, 17.2) days, and 42.5 (35.0, 129.5) days from the onset of pancreatitis to the diagnosis of pancreatic pseudocyst. Abdominal pain was the most prominent manifestation of pancreatitis (6/6). All of the 6 children were asymptomatic when pancreatic pseudocyst was noted, and were treated conservatively at first, but one case later developed intermittent abdominal distension or nausea after eating. All the cases had pancreatic pseudocyst enlargement during the conservative treatment. Three children were treated with endoscopic ultrasound-guided transgastric drainage, and the cyst disappeared from 10 days to 4 months after the operation. The other 3 children received endoscopic retrograde cholangiopancreatography (ERCP)-guided transpapillary drainage, but one of them turned to surgery due to pancreatic duct stricture, and in the rest 2 children the cyst disappeared at 1 and 3 months after operation respectively. Regarding safety issues, 1 child who received ERCP-guided transpapillary drainage had acute postoperative pancreatitis, which were improved after treatment, and the other 5 had no complications. Conclusions: Pancreatic pseudocyst after pegaspargase chemotherapy can be asymptomatic in the early stage, and should be diagnosed with a history of pegaspargase treatment and timely imaging examination. Conservative treatment is the first choice for asymptomatic pseudocyst. When the pseudocyst enlarges, different endoscopic drainage treatments are required according to whether the pseudocyst is connected with the main pancreatic duct.

Background: Circadian rhythm was involved in the pathogenesis of depression. The detection of circadian genes and white matter (WM) integrity achieved increasing focus for early prediction and diagnosis of major depressive disorder (MDD). This study aimed to explore the effects of PER1 gene polymorphisms (rs7221412), one of the key circadian genes, on the association between depressive level and WM microstructural integrity., Materials and Methods: Diffusion tensor imaging scanning and depression assessment (Beck Depression Inventory, BDI) were performed in 77 healthy college students. Participants also underwent PER1 polymorphism detection and were divided into the AG group and AA group. The effects of PER1 genotypes on the association between the WM characteristics and BDI were analyzed using tract-based spatial statistics method., Results: Compared with homozygous form of PER1 gene (AA), more individuals with risk allele G of PER1 gene (AG) were in depression state with BDI cutoff of 14 ( χ 2 = 7.37, uncorrected p = 0.007). At the level of brain imaging, the WM integrity in corpus callosum, internal capsule, corona radiata and fornix was poorer in AG group compared with AA group. Furthermore, significant interaction effects of genotype × BDI on WM characteristics were observed in several emotion-related WM tracts. To be specific, the significant relationships between BDI and WM characteristics in corpus callosum, internal capsule, corona radiata, fornix, external capsule and sagittal stratum were only found in AG group, but not in AA group., Conclusion: Our findings suggested that the PER1 genotypes and emotion-related WM microstructure may provide more effective measures of depression risk at an early phase., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Sun, Deng, Cheng, Li, Wang, He, Chang, Lu, Tang, Xu, Yang and Qin.)

Atopic dermatitis (AD) is a common chronic allergic skin disease characterized clinically by severe skin lesions and pruritus. Portulaca oleracea L. (PO) is a resourceful plant with homologous properties in medicine and food. In this study, we used two different methods to extract PO, and compared the therapeutic effects of PO aqueous extract (POAE) and PO ultrasound-assisted ethanol extract (POEE) on 2,4-dinitrochlorobenzene (DNCB)-induced AD mice. The results showed that in POAE and POEE, the extraction rates of polysaccharides were 16.95% and 9.85%, while the extraction rates of total flavonoids were 3.15% and 3.25%, respectively. Compared with AD mice, clinical symptoms such as erythema, edema, dryness and ulceration in the back and left ear were alleviated, and pruritus behavior was reduced after POAE and POEE treatments. The thickness of the skin epidermis was thinned, the density of skin nerve fibers labeled with protein gene product 9.5 (PGP9.5) was decreased, and mast cell infiltration was reduced. There was a decrease in blood lymphocytes, eosinophils and basophils, a significant decrease in spleen index and a noticeable decrease in serum immunoglobulin E (Ig E). POEE significantly reduced the concentration of the skin pruritic factor interleukin (Il)-31. POAE and POEE reduced the concentration of skin histamine (His), down-regulated mRNA expression levels of interferon-γ (Ifnγ), tumor necrosis factor-α (Tnf-α), thymic stromal lymphopoietin (Tslp) and Il-4, with an increase of Filaggrin (Flg) and Loricrin (Lor) in skin lesions. These results suggested that POAE and POEE may inhibit atopic response and alleviate the clinical symptoms of AD by inhibiting the expression of immune cells, inflammatory mediators and cytokines. PO may be a potential effective drug for AD-like diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lv, Huang, Li, Gong, Sun, Mao and Guo.)

A simple and efficient sample extraction and preconcentration method based on reversed-phase ionic liquid dispersive liquid-liquid microextraction (RP-IL-DLLME) had been developed and used to quantify the domoic acid in human urine samples. The analysis was performed by ultra-performance liquid chromatography and photodiode array detection. During the procedure, hydrophilic ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate [C 4 mim] BF 4 as dispersive solvent and NaOH solution was chosen as extraction solvent. Some important parameters in the method were investigated to get high enrichment factors. Under optimal conditions, the linearity of the method was in the range of 0.1-10 ng mL -1 and the correlation coefficient was above 0.9996. The relative standard deviations (RSDs) of the developed methods for intra-day ( n = 5 ) and inter-day ( n = 5 ) precision ranged from 1.9 to 3.9%. Meanwhile, limit of detection (LOD) was 0.03 ng mL -1 ( S/N = 3) and that of quantification (LOQ) was 0.1 ng mL -1 ( S/N = 10) with the enrichment factors ( EF ) being 230. Eventually, the proposed method was successfully applied to the determination of Dominic acid in human urine samples., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

A previous study found that combining transcranial direct current stimulation (tDCS) and transcutaneous auricular vagus nerve stimulation (taVNS) could evoke significantly larger activation on a range of cortical and subcortical brain regions than the numerical summation of tDCS and taVNS effects. In this study, two within-subject experiments were employed to investigate its effects on working memory (WM). In experiment 1, the WM modulatory effects of tDCS over the left dorsolateral prefrontal cortex (DLPFC), taVNS, and simultaneous joint simulation of tDCS over the left DLPFC and taVNS (SJS-L) were compared among 60 healthy subjects. They received these three interventions between the baseline test and post-test in a random manner three times. In spatial 3-back task, there was a significant interaction between time and stimulations in the accuracy rate of matching trials (mACC, p = 0.018 ). MACCs were significantly improved by SJS ( p = 0.001 ) and taVNS ( p = 0.045 ), but not by tDCS ( p = 0.495 ). Moreover, 41 subjects in the SJS group showed improvement, which was significantly larger than that in the taVNS group (29 subjects) and tDCS group (26 subjects). To further investigate the generalization effects of SJS, 72 students were recruited in experiment 2. They received tDCS over the right DLPFC, taVNS, simultaneous joint simulation of tDCS over the right DLPFC and taVNS (SJS-R), and sham stimulation in a random manner four times. No significant results were found, but there was a tendency similar to experiment 1 in the spatial 3-back task. In conclusion, combining tDCS and taVNS might be a potential non-invasive neuromodulation technique which is worthy of study in future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, He, Cheng, Tian, Cui, Chang, Wang, Kong, Deng, Yang and Sun.)

Background: Central vein occlusion (CVO) is a serious problem in hemodialysis patients. There is an unsatisfactory result for refractory CVO by sharp recanalization alone. This study evaluated the efficacy and safety of blunt impingement followed by sharp recanalization for the treatment of CVO in hemodialysis patients., Methods: This study retrospectively examined hemodialysis patients with CVO who failed to recanalize using standard guidewire and catheter techniques in our department. In the first instance, all CVOs were recanalized using blunt impingement techniques, including a 6-Fr long sheath (Cook Incorporated, Bloomington, IN USA) and an 8-Fr sheath of Rosch-Uchida Transjugular Liver Access Set (RUPS-100; Cook Incorporated, Bloomington, IN, USA). If this was not successful, sharp recanalization devices were applied, including the stiff tip of a guidewire (Terumo, Tokyo, Japan), the RUPS-100, and the percutaneous transhepatic cholangial drainage (PTCD) needle (Cook Incorporated, USA). All patients were followed up at least 4 months postoperatively. The technical success rate, arteriovenous access patency rates, and operation-related complications were analyzed., Results: The procedural success rate was 100.0% (30 of 30). Thirty patients with CVO underwent blunt impingement with a technique success rate of 70.0% (21 of 30), and 9 patients received sharp recanalization after failed blunt impingement, with a technique success rate of 100.0% (9 of 9). The primary patency rates at 6 and 12 months postoperatively were 86.7% and 53.3%, respectively. The primary assisted patency rates were 93.3% and 63.3%, and the secondary patency rates were 93.3% and 70.0% at 6 and 12 months, respectively. One major procedure-related complication was detected, namely, a small injury of the superior vena cava (SVC) wall in a patient receiving recanalization via the stiff end of a guidewire, but this did not require further treatment., Conclusions: It is potentially effective and safe for interventionalists to use blunt impingement followed by sharp recanalization techniques to treat chronic CVO that is refractory to traversal using traditional catheter and guidewire techniques., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-3131/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Purpose: To establish and verify a novel radiation resistance related index for predicting biochemical recurrence and tumor immune environment in prostate cancer (PCa) patients., Materials and Methods: The transcriptome information of PCa were obtained from GEO and TCGA portal. We identified radiation resistance related genes (RRGs) between radioresistant and radiosensitive PCa cells. We conducted multivariate Cox analysis to construct a novel radiation resistance related index for predicting biochemical recurrence (BCR)-free survival (BCRFS). Internal and external validations were conducted. Preliminary experimental verifications were performed., Results: We identified 194 differentially expressed RRGs and three radiation resistance related molecular clusters for PCa. Moreover, we established a novel radiation resistance related index and succeeded in conducting internal and external validations. High-risk populations meant significantly worse BCRFS in training, testing and validating cohort. The area under receiver operating characteristic curve were 0.809, 0.698, and 0.712 in training, testing, and validating cohort. The immune microenvironment was significantly different between high and low-risk score patients. Preliminary experiment identified and validated three potential biomarkers related to radiation resistance (ZNF695, TM4SF19, CCDC3) of PCa., Conclusions: This study successfully established and verified a novel radiation resistance related index, which had an excellent performance in predicting BCR and tumor immune microenvironment in patients with PCa., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Gastric cancer (GC) is a common malignant disease worldwide, and finding novel agents and strategies for the treatment of GC are of urgent need. Celastrol (CEL) is a well-known natural product with antineoplastic activity. In this study, pyrazole analogues were introduced at the C-29 position of CEL. A total of 24 new derivatives were designed, synthesized, and evaluated for their mechanism and antitumor activity in vitro and in vivo. Among them, compound 21 exhibited the best activity against BGC-823 cells (IC 50 = 0.21 ± 0.01 μM). Further biological studies showed that 21 significantly raised the reactive oxygen species (ROS) levels to activate the apoptotic pathway, causing mitochondrial dysfunction in BGC-823 cells. In addition, 21 also arrested cells in the G2/M phase to induce tumor cell apoptosis. In a nude mouse tumor xenograft model, 21 exhibited a better tumor inhibition rate (89.85%) than CEL (inhibition rate 76.52%). Taken together, the present study has provided an anticancer lead compound candidate, 21 , and has revealed that increased ROS generation may be an effective strategy in the treatment of GC.

The lack of clinically applicable mucosal adjuvants is a major hurdle in designing effective mucosal vaccines. We hereby report that the calcium-binding protein S100A4, which regulates a wide range of biological functions, is a potent mucosal adjuvant in mice for co-administered antigens, including the SARS-CoV-2 spike protein, with comparable or even superior efficacy as cholera toxin but without causing any adverse reactions. Intranasal immunization with recombinant S100A4 elicited antigen-specific antibody and pulmonary cytotoxic T cell responses, and these responses were remarkably sustained for longer than 6 months. As a self-protein, S100A4 did not stimulate antibody responses against itself, a quality desired of adjuvants. S100A4 prolonged nasal residence of intranasally delivered antigens and promoted migration of antigen-presenting cells. S100A4-pulsed dendritic cells potently activated cognate T cells. Furthermore, S100A4 induced strong germinal center responses revealed by both microscopy and mass spectrometry, a novel label-free technique for measuring germinal center activity. Importantly, S100A4 did not induce olfactory bulb inflammation after nasal delivery, which is often a safety concern for nasal vaccination. In conclusion, S100A4 may be a promising adjuvant in formulating mucosal vaccines, including vaccines against pathogens that infect via the respiratory tract, such as SARS-CoV-2., (© 2022. The Author(s).)

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) may modulate cardiac autonomic function. However, the response rate of the traditional tonic paradigm is low, and the results remain inconsistent. A recent pilot study presented a novel burst paradigm to activate the cardiac parasympathetic system, which might offer a new approach to treat cardiac autonomic function. The present study reassessed the effect of burst taVNS on modulating heart rate variability and explored the difference between burst and traditional tonic paradigms., Materials and Methods: Forty-two young adults were recruited for this study. Each participant underwent three types of taVNS with sham (30 sec of stimulation), tonic (25 Hz, 500 μsec), and burst (five pulses at 500 Hz every 200 msec) paradigms, respectively, with simultaneous electrocardiogram recording. One-way analysis of variance, multivariate analysis of variance, and linear regression were used for analysis. Multiple testing was performed using Bonferroni correction., Results: Both burst and tonic paradigms induced a significant decrease in heart rate, which continued until poststimulation, and increased cardiac parasympathetic activity. Moreover, two parasympathetic system indicators showed significant increase only in burst taVNS. The response rates during burst (35.7%) and tonic (38.1%) stimulations were both higher than that during sham stimulation (11.9%). The response to taVNS showed parameter specificity with few nonresponders to the tonic paradigm responding to the burst paradigm. The overall response rate increased from 38.1% in tonic taVNS to 54.8% in taVNS using both burst and tonic paradigms. For both burst and tonic responders, baseline cardiac parasympathetic activity was found to be significantly negatively correlated with changes during stimulation., Conclusion: The burst parameter could be used as an alternative strategy for regulating cardiac parasympathetic function by taVNS, which has the potential to be used as a complementary paradigm to traditional tonic taVNS for promoting clinical treatment efficacy., (Copyright © 2022. Published by Elsevier Inc.)

Attempts to determine why some patients respond to electroconvulsive therapy (ECT) are valuable in schizophrenia. Schizophrenia is associated with aberrant dynamic functional architecture, which might impact the efficacy of ECT. We aimed to explore the relationship between pre-treatment temporal variability and ECT acute efficacy. Forty-eight patients with schizophrenia and 30 healthy controls underwent functional magnetic resonance imaging to examine whether patterns of temporary variability of functional architecture differ between high responders (HR) and low responders (LR) at baseline. Compared with LR, HR exhibited significantly abnormal temporal variability in right inferior front gyrus (IFGtriang.R), left temporal pole (TPOsup.L) and right middle temporal gyrus (MTG.R). In the pooled patient group, ∆PANSS was correlated with the temporal variability of these regions. Patients with schizophrenia with a distinct dynamic functional architecture appear to reveal differential response to ECT. Our findings provide not only an understanding of the neural functional architecture patterns that are found in schizophrenia but also the possibility of using these measures as moderators for ECT selection., (© 2022 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Objective: To identify ferroptosis-related molecular clusters, and to develop and validate a ferroptosis-based molecular signature for predicting biochemical recurrence-free survival (BCRFS) and tumor immune microenvironment of prostate cancer (PCa). Materials and Methods: The clinical data and transcriptome data of PCa were downloaded from TCGA and GEO database. Ferroptosis-related genes (FRGs) were obtained from FerrDb database. We performed consensus clustering analysis to identify ferroptosis-related molecular subtypes for PCa. Univariate and multivariate Cox regression analysis were used to establish a ferroptosis-based signature for predicting BCRFS. Internal verification, external verification and subgroup survival analysis were then successfully performed. Results: There was a total of 40 differentially expressed FRGs in PCa. We then identified three ferroptosis-related molecular clusters of PCa, which have significantly different immune infiltrating cells, tumor immune microenvironment and PD-L1 expression level. More importantly, a novel ferroptosis-based signature for predicting BCRFS of PCa based on four FRGs (including ASNS, GPT2, NFE2L2, RRM2) was developed. Internal and external verifications were then successfully performed. Patients with high-risk score were associated with significant poor BCRFS compared with those with low-risk score in training cohort, testing cohort and validating cohort, respectively. The area under time-dependent Receiver Operating Characteristic (ROC) curve were 0.755, 0.705 and 0.726 in training cohort, testing cohort and validating cohort, respectively, indicating the great performance of this signature. Independent prognostic analysis indicated that this signature was an independent predictor for BCRFS of PCa. Subgroup analysis revealed that this signature was particularly suitable for younger or stage T III-IV or stage N0 or cluster 1-2 PCa patients. Patients with high-risk score have significantly different tumor immune microenvironment in comparison with those with low-risk score. The results of qRT-PCR successfully verified the mRNA expression levels of ASNS, GPT2, RRM2 and NFE2L2 in DU-145 and RWPE-1 cells while the results of IHC staining exactly verified the relative protein expression levels of ASNS, GPT2, RRM2 and NFE2L2 between PCa and BPH tissues. Conclusions: This study successfully identified three ferroptosis-related molecular clusters. Besides, we developed and validated a novel ferroptosis-based molecular signature, which performed well in predicting BCRFS and tumor immune microenvironment of PCa., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ke, You, Sun, Zhu, Li, Chen, Su, Zheng, Wei, Xue and Xu.)

Working memory (WM) is one of the core components of higher cognitive functions. There exists debate regarding the extent to which current techniques can enhance human WM capacity. Here, we examined the WM modulation effects of a previously less studied technique, transcutaneous auricular vagus nerve stimulation (taVNS). In experiment 1, a within-subject study, we aimed to investigate whether and which stimulation protocols of taVNS can modulate spatial WM performance in healthy adults. Forty-eight participants performed baseline spatial n-back tasks (1, 3-back) and then received online taVNS, offline taVNS, or sham stimulation before or during (online group) the posttest of spatial n-back tasks in random order. Results showed that offline taVNS could significantly increase hits in spatial 3-back task, whereas no effect was found in online taVNS or sham group. No significant taVNS effects were found on correct rejections or reaction time of accurate trials (aRT) in both online and offline protocols. To replicate the results found in experiment 1 and further investigate the generalization effect of offline taVNS, we carried out experiment 2. Sixty participants were recruited and received offline taVNS or offline earlobe stimulation in random order between baseline and posttests of behavioral tests (spatial/digit 3-back tasks). Results replicated the findings; offline taVNS could improve hits but not correct rejections or aRT in spatial WM performance, which were found in experiment 1. However, there were no significant stimulation effects on digit 3-back task. Overall, the findings suggest that offline taVNS has potential on modulating WM performance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sun, Cheng, Tian, Yuan, Yang, Deng, Guo, Cui, Zhang, Yin, Wang and Qin.)

Since the first case of the hemolytic disease of the fetus and newborn (HDFN) caused by anti-K was reported in 1946, the fetal diagnosis of K-HDFN has made rapid progress from invasive immunological and biochemical tests to noninvasive Doppler ultrasound and molecular biology techniques. However, its treatment, especially prenatal intervention, has developed slowly compared with RhD-HDFN. This review attempts to clarify the current key points and explore the direction of the next phase by systematically reviewing the development of diagnosis and treatment of this disease, which involving multidisciplinary participation.

Dysiscalarones A-E (1-5), five new scalarane-type bishomoscalarane sesterterpenoids, were isolated from marine sponge Dysidea granulosa collected from the South China Sea, together with two known ones, honulactone A (6) and phyllofolactone I (7). The new structures were determined by extensive spectroscopic analysis including HR-ESI-MS and 1D and 2D NMR data, and their absolute configurations were assigned by single crystal X-ray diffraction analyses. The inhibitory activity of all the seven isolates on the production of nitric oxide (NO) stimulated by lipopolysaccharide (LPS) in mouse RAW 264.7 macrophages was evaluated. Of these metabolites, dysiscalarones A-B (1-2), honulactone A (6), and phyllofolactone I (7) showed inhibitory activities with respective IC 50 values of 16.4, 18.5, 2.6, and 3.7 μM, which suggested that the γ-methylated α,β-unsaturated γ-lactone might be the functional group. In addition, all the seven metabolites showed no significant cytotoxicity against lung cancer PC9 cell line at the concentration of 20 μM., (Copyright © 2021. Published by Elsevier Inc.)

To study the spatiotemporal variations in fine particulate matter (PM 2.5 ) and the impact of air quality management in autumn and winter in Zhengzhou, five sites were selected to collect PM 2.5 samples from the autumn of 2017 to the winter of 2018, and the characteristics of the chemical components were analyzed. The positive matrix factorization (PMF) model was also applied to identify the sources of PM 2.5 , and the effect of air quality control was evaluated to provide support for air quality control in autumn and winter in the next stage. The PM 2.5 concentrations in the four seasons in Zhengzhou were ranked as winter > autumn > spring > summer. The PM 2.5 concentration at Zhengzhou University (ZZU) was the highest (8.7% higher than the average concentration), and the PM 2.5 concentrations at the other sites were slightly lower than the average concentration. The concentration of water-soluble ions (WSIs) was low in spring and summer and high in autumn and winter. The average proportions of SO 4 2- , NO 3 - , and NH 4 + in the nine WSIs were as high as 22.5%, 43.6%, and 23.4%, respectively. The proportion of Cl - in winter was higher than that in the other seasons owing to coal combustion (6.7% and 6.6% in 2017 and 2018, respectively). Owing to wind and sand, the proportions of Ca 2+ and Mg 2+ in spring were the highest (4.4% and 0.4%, respectively), and those at the Jiancezhan (JCZ) and ZZU sites were higher than those at the other sites. K + , as a marker of biomass burning, had a higher proportion in spring, autumn, and winter. The proportion of K + in the spring of 2018 was 1.9%, those in the autumn and winter of 2017 were 1.6% and 2.1%, respectively, and those in the autumn and winter of 2018 were 1.3% and 1.8%, respectively. JCZ, Hangkonggang (HKG), and Xinmi (XM) had higher proportions of NO 3 - , and the proportions of SO 4 2- were lower. Secondary organic carbon (SOC) pollution was serious in autumn and winter, and the concentration accounted for more than half of the organic carbon (OC). In 2018, the SOC/OC at the JCZ and ZZU sites decreased compared with that in 2017, but that at the other three sites increased significantly, thereby indicating that different air pollutant emissions in these regions had different performances in response to control policies. The chemical composition reconstruction results showed that the proportion of sulfate was highest in summer (25.0%), the contribution of nitrate was higher in autumn (23.1% and 25.1% for 2017 and 2018, respectively) and winter (20.6% and 23.0% for 2017 and 2018, respectively), the proportion of crustal material was higher in spring (18.2%), and the contribution of secondary organic aerosol (SOA) was the highest in winter (14.1% and 20.5% for 2017 and 2018, respectively). SOA had higher contributions at the JCZ and HKG sites (16.9% and 16.4%, respectively), and ZZU was affected more by primary organic aerosol (14.3%) and crustal materials (12.1%). The PMF results showed that secondary inorganic salts (37.5%), SOA (15.4%), traffic (14.9%), industry (4.8%), coal combustion (16.0%), fugitive dust (6.5%), and biomass burning (2.8%) were the main pollution sources of PM 2.5 in Zhengzhou. SOA and coal combustion contributed more in winter and fugitive dust contributed more in spring, followed by autumn. Biomass burning contributed more in spring and autumn. The urban sites JCZ and ZZU and the characteristic site HKG near the airport were more affected by traffic sources (16.9%, 16.2%, and 16.0%, respectively) than the other sites. The impact of biomass burning on the non-urban sites XM and HKG was slightly larger (both 2.7%), and the contribution of coal combustion to the suburban site XM was higher (16.8%). Owing to the construction around ZZU, the loading of fugitive dust at ZZU was higher than that at other sites. Comparing the results of the two-year autumn and winter, the contribution of SOA, traffic, and industry increased in the autumn and winter of 2018, whereas the contribution of secondary inorganic salts, coal combustion, and biomass burning decreased and the contribution of fugitive dust in winter also decreased. The results showed that the control strategies in autumn and winter had significant effects on the primary sources, including fugitive dust, coal combustion, and industry, and SOA precursor volatile organic compounds should be targeted for further pollution control.

Myocardial infarction (MI) leads to the loss of cardiomyocytes, left ventricle dilation and cardiac dysfunction, eventually developing into heart failure. Mzb1 (Marginal zone B and B1 cell specific protein 1) is a B-cell-specific and endoplasmic reticulum-localized protein. Mzb1 is an inflammation-associated factor that participates a series of inflammatory processes, including chronic periodontitis and several cancers. In this study we investigated the role of Mzb1 in experimental models of MI. MI was induced in mice by ligation of the left descending anterior coronary artery, and in neonatal mouse ventricular cardiomyocytes (NMVCs) by H 2 O 2 treatment in vitro. We showed that Mzb1 expression was markedly reduced in the border zone of the infarct myocardium of MI mice and in H 2 O 2 -treated NMVCs. In H 2 O 2 -treated cardiomyocytes, knockdown of Mzb1 decreased mitochondrial membrane potential, impaired mitochondrial function and promoted apoptosis. On contrary, overexpression of Mzb1 improved mitochondrial membrane potential, ATP levels and mitochondrial oxygen consumption rate (OCR), and inhibited apoptosis. Direct injection of lentiviral vector carrying Len-Mzb1 into the myocardial tissue significantly improved cardiac function and alleviated apoptosis in MI mice. We showed that Mzb1 overexpression significantly decreased the levels of Bax/Bcl-2 and cytochrome c and improved mitochondrial function in MI mice via activating the AMPK-PGC1α pathway. In addition, we demonstrated that Mzb1 recruited the macrophages and alleviated inflammation in MI mice. We conclude that Mzb1 is a crucial regulator of cardiomyocytes after MI by improving mitochondrial function and reducing inflammatory signaling pathways, implying a promising therapeutic target in ischemic cardiomyopathy.

Objective: The aim of the present study was to evaluate the potential protective mechanism of icariin against oxidative damage caused by hydrogen peroxide in MC3T3-E1 cells., Methods: MC3T3-E1 cells were treated with different concentrations of icariin to explore the optimal dose of icariin. MC3T3-E1 cells were divided into groups treated with various concentrations of hydrogen peroxide (H 2 O 2 ; 0, 0.1, 0.2, 0.5, 1, and 2 mM) for 24 h to induce oxidative damage and cell viability was assessed by Cell Counting Kit-8 (CCK-8) assay. Then, cells were divided into five groups: control, H 2 O 2 (0.2 mM), icariin (0.1 μM) and H 2 O 2 (0.2 mM), + icariin (0.1 μM). Cell viability was detected by CCK-8 assay. In addition, the content of glutathione and superoxide dismutase and the activity level of malondialdehyde in these treatment groups were determined. Alkaline phosphatase (ALP) and alizarin red S (ARS) staining were also performed to measure the early and late osteogenesis, respectively. Protein expression of β-catenin and cyclin D1 was measured by western blot assay. Then, we used an antagonist of Wnt/β-catenin signaling pathway (DKK-1) and western blot analysis to further explore potential mechanism., Results: After 24 h of exposure to 0.2 mM H 2 O 2 , the viability of MC3T3-E1 cells was significantly decreased compared to that of the control cells. We first found that icariin can promote cell proliferation of MC3T3-E1 cells in a dose-dependent manner, with the dosage 0.1 μM showing the best pro-proliferative effect. Furthermore, icariin could promote the protein expression of OSX and RUNX2. The results showed that icariin can reverse the inhibitory osteogenic effects of MC3T3-E1 caused by H 2 O 2 . In addition, icariin could increase the Wnt-signaling related proteins. The results showed that MC3T3-E1 cells in the H 2 O 2 (0.2 mM) + icariin (0.1 μM) + Wnt-signaling antagonist (DKK-1) group had weaker ALP and ARS staining compared with that observed in the control and H 2 O 2 (0.2 mM) + icariin (0.1 μM) groups. The ALP activity and calcium content were decreased in the 0.2 mM H 2 O 2 + 0.1 μM icariin + DKK-1 group compared to that observed in the 0.2 mM H 2 O 2 + 0.1 μM icariin group., Conclusion: The results showed that icariin can increase the viability of MC3T3-E1 cells, reverse the oxidative stress induced by H 2 O 2 and protect MC3T3-E1 cells against H 2 O 2 -induced inhibition of osteogenic differentiation, which may occur through the Wnt/β-catenin signaling pathway., (© 2021 The Authors. Orthopaedic Surgery published by Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)

Background: The purpose of this study is to explore the association between extravascular lung water (EVLW) and prognosis of sepsis (PS)., Methods: We will carry out comprehensive literature search in electronic databases (PUBMED/MEDLINE, EMBASE, CENTRAL, WorldSciNet, PsycINFO, Allied and Complementary Medicine Database, CBM, and CNKI) and additional sources. All electronic databases will be searched from their initial to the present without language restrictions. Case-controlled studies reporting the association between EVLW and PS will be evaluated for inclusion. Outcomes of interest will include mortality rate, extravascular lung water index, pulmonary vascular permeability index, blood lactate clearance, oxygenation index, blood gas analysis, PaO2/FiO2, cardiac output index, global end diastolic volume index, intrathoracic blood volume index, systemic resistance index, acute physiology and chronic health scoring system II, and infection-related organ failure scoring system. Study quality will be evaluated using Newcastle-Ottawa Tool, and statistical analysis will be performed utilizing RevMan 5.4 software., Results: This study will summarize the most recent evidence to investigate the association between EVLW and PS., Conclusions: The results of this study will provide an exhaustive view of the association between EVLW and PS., Study Registration Osf: osf.io/vhnxw., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To investigate the effect of oral administration of branched-chain amino acids (BCAA) supplementation on the mortality of patients with hepatocellular carcinoma (HCC) after treatment. Methods: Computer searching of PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and Chinese Biomedical Literature Database was conducted to search for clinical controlled trials and randomized controlled trials (RCTs) on the effect of oral administration of BCAA on the mortality of patients with HCC. The retrieval time limit was from the time of the establishment of each database to December 30, 2019. Two researchers independently screened the literature and extracted the data. Another researcher assessed the risk of bias in the included studies and then used RevMan 5.3 software for meta-analysis. Results: A total of 14 studies were included with 1 179 patients. The overall results showed that oral administration of BCAA had no significant effect on the mortality of HCC patients at 1 year after treatment ( RR= 0.85, 95% CI: 0.68-1.06, P= 0.16), while the mortalities of patients at 3 years ( RR= 0.73, 95% CI: 0.61-0.88, P= 0.000 7) and 5 years ( RR= 0.57, 95% CI: 0.34-0.96, P= 0.03) after treatment were significantly lower than those of the control group. The subgroup analysis showed that for radiofrequency ablation (RFA) patients, there was no significant difference in 1-year mortality between the BCAA group and the control group ( RR= 0.96, 95 %CI :0.14-6.5, P= 0.97), while 3-year mortality was significantly reduced ( RR= 0.59, 95% CI: 0.43-0.81, P= 0.001); for hepatectomy patients, there was no significant differences in 1 -and 3-year mortality between the two groups ( RR= 0.90, 95% CI: 0.44-1.88, P= 0.79; RR= 0.97, 95 %CI :0.71-1.33, P= 0.85, respectively). In addition, as for albumin levels, BCAA supplementation significantly increased albumin levels without considering the treatment of HCC ( SD =0.45, 95 %CI : 0.29-0.90; P= 0.000 1), but had no significant effect on hepatectomy patients ( SD =0, 95 %CI : -0.41-0.41, P= 0.99). Conclusion: BCAA supplementation might improve liver reserve function and long-term prognosis of HCC patients, which was related to the surgical method. Supplementing BCAA reduced the long-term mortality of RFA patients, but had no significant effect on hepatectomy patients.

The immense patient number caused by coronavirus disease 2019 (COVID-19) global pandemic brings the urge for more knowledge about its immunological features, including the profile of basic immune parameters. In this study, eighty-eight reported COVID-19 patients in Wuhan were recruited from January to February, 2020, including 32 severe/critical cases and 56 mild/moderate cases. Their mean age was 56.43 years (range 17-83) and gender ratio (male/female) was 43:45. We tested SARS-CoV-2 RNA with commercial kits, investigated the level of serologic IgM and IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using magnetic particle chemiluminescence immunoassays, and compared the results of serologic tests and nucleic acid test (NAT). Among 88 patients, 95.45% were confirmed as positive by the combination of NAT and antibody test, which was significantly higher (P < 0.001) than by single nucleic acid test (73.86%) or serologic test (65.91%). Then the correlation between temporal profile and the level of antibody response was analyzed. It showed that seroconversion started on day 5 after disease onset and IgG level was rose earlier than IgM. Comparison between patients with different disease severity suggested early seroconversion and high antibody titer were linked with less severe clinical symptoms. These results supported the combination of serologic testing and NAT in routine COVID-19 diagnosis and provided evidence on the temporal profile of antibody response in patients with different disease severity.