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Abstract The characteristic neuropathology of Parkinson’s disease (PD) involves the abnormal accumulation of phosphorylated α-synuclein (αSyn), as well as a significant decrease in neuromelanin (NM) levels within dopamine neurons (DaNs). Unlike αSyn aggregates, the relationship between NM levels and PD pathogenesis is not well understood. In this study, we engineered an E. coli MG1655 strain to produce exosomes containing melanin (E.melanin), and investigated its potential neuroprotective effects on DaNs in the context of PD. By employing a combination of cell cultures, biochemical studies, single nuclear RNA sequencing (snRNA seq), and various in vivo validations, we found that administration of E.melanin effectively alleviated DaNs loss and improved motor behavior impairments observed in both pharmacological and transgenic PD mouse models. Mechanistically, snRNA seq data suggested that E.melanin activated the PSAP-GPR37L1 signaling pathway specifically within astrocytes, leading to a reduction in astrocytic engulfment of synapses. Notably, activation of the GPR37L1 receptor using Tx14(A) peptide successfully rescued motor defects as well as protected against DaNs degeneration in mice with PD. Overall, our findings provide novel insights into understanding the molecular mechanisms underlying melanin’s protective effects on DaNs in PD while offering potential strategies for manipulating and treating its pathophysiological progression.

BackgroundThere is a lack of individualized evidence on surgical choices for glioblastoma (GBM) patients.AimThis study aimed to make individualized treatment recommendations for patients with GBM and to determine the importance of demographic and tumor characteristic variables in the selection of extent of resection.MethodsWe proposed Balanced Decision Ensembles (BDE) to make survival predictions and individualized treatment recommendations. We developed several DL models to counterfactually predict the individual treatment effect (ITE) of patients with GBM. We divided the patients into the recommended (Rec.) and anti-recommended groups based on whether their actual treatment was consistent with the model recommendation.ResultsThe BDE achieved the best recommendation effects (difference in restricted mean survival time (dRMST): 5.90; 95% confidence interval (CI), 4.40–7.39; hazard ratio (HR): 0.71; 95% CI, 0.65–0.77), followed by BITES and DeepSurv. Inverse probability treatment weighting (IPTW)-adjusted HR, IPTW-adjusted OR, natural direct effect, and control direct effect demonstrated better survival outcomes of the Rec. group.ConclusionThe ITE calculation method is crucial, as it may result in better or worse recommendations. Furthermore, the significant protective effects of machine recommendations on survival time and mortality indicate the superiority of the model for application in patients with GBM. Overall, the model identifies patients with tumors located in the right and left frontal and middle temporal lobes, as well as those with larger tumor sizes, as optimal candidates for SpTR.

Abstract Background Due to the heterogeneity of low‐grade gliomas (LGGs), the lack of randomized control trials, and strong clinical evidence, the effect of the extent of resection (EOR) is currently controversial. Aim To determine the best choice between subtotal resection (STR) and gross‐total resection (GTR) for individual patients and to identify features that are potentially relevant to treatment heterogeneity. Methods Patients were enrolled from the SEER database. We used a novel DL approach to make treatment recommendations for patients with LGG. We also made causal inference of the average treatment effect (ATE) of GTR compared with STR. Results The patients were divided into the Consis. and In‐consis. groups based on whether their actual treatment and model recommendations were consistent. Better brain cancer‐specific survival (BCSS) outcomes in the Consis. group was observed. Overall, we also identified two subgroups that showed strong heterogeneity in response to GTR. By interpreting the models, we identified numerous variables that may be related to treatment heterogeneity. Conclusions This is the first study to infer the individual treatment effect, make treatment recommendation, and guide surgical options through deep learning approach in LGG research. Through causal inference, we found that heterogeneous responses to STR and GTR exist in patients with LGG. Visualization of the model yielded several factors that contribute to treatment heterogeneity, which are worthy of further discussion.

Abstract The scale-free ferroelectric polarization of fluorite MO2 (M = Hf, Zr) due to flat polar phonon bands are promising for nonvolatile memories. Defects are also widely introduced to improve the emergent ferroelectricity. However, their roles are still not fully understood at the atomic-level. Here, we report a significant effect of point-defect-driven flattening of polar phonon bands with more polar modes and polarization contribution in doped MO2. The polar phonon bands in La-doped MO2 (M = Hf, Zr) can be significantly flattened, compared with pure ones. However, the lower energy barrier with larger polarization of V O -only doped MO2 compared with La-doped cases suggest that V O and local lattice distortion should be balanced for high-performance fluorite ferroelectricity. The work is believed to bridge the relation between point defects and the generally enhanced induced ferroelectricity in fluorite ferroelectrics at the atomic-level and inspire their further property optimization via defect-engineering.

BackgroundThis study focused on minimizing the costs and toxic effects associated with unnecessary chemotherapy. We sought to optimize the adjuvant therapy strategy, choosing between radiotherapy (RT) and chemoradiotherapy (CRT), for patients based on their specific characteristics. This selection process utilized an innovative deep learning method.MethodsWe trained six machine learning (ML) models to advise on the most suitable treatment for glioblastoma (GBM) patients. To assess the protective efficacy of these ML models, we employed various metrics: hazards ratio (HR), inverse probability treatment weighting (IPTW)-adjusted HR (HRa), the difference in restricted mean survival time (dRMST), and the number needed to treat (NNT).ResultsThe Balanced Individual Treatment Effect for Survival data (BITES) model emerged as the most effective, demonstrating significant protective benefits (HR: 0.53, 95% CI, 0.48–0.60; IPTW-adjusted HR: 0.65, 95% CI, 0.55–0.78; dRMST: 7.92, 95% CI, 7.81–8.15; NNT: 1.67, 95% CI, 1.24–2.41). Patients whose treatment aligned with BITES recommendations exhibited notably better survival rates compared to those who received different treatments, both before and after IPTW adjustment. In the CRT-recommended group, a significant survival advantage was observed when choosing CRT over RT (p

Abstract Traumatic brain injury (TBI) is a cause of disability and death worldwide, but there are currently no specific treatments for this condition. Release of excess reactive oxygen species (ROS) in the injured brain leads to a series of pathological changes; thus, eliminating ROS could be a potential therapeutic strategy. Herein, we synthesized insulin-incubated ultrasmall palladium (Pd@insulin) clusters via green biomimetic chemistry. The Pd@insulin clusters, which were 3.2 nm in diameter, exhibited marked multiple ROS-scavenging ability testified by the theoretical calculation. Pd@insulin could be rapidly excreted via kidney-urine metabolism and induce negligible adverse effects after a long-time treatment in vivo. In a TBI mouse model, intravenously injected Pd@insulin clusters aggregated in the injured cortex, effectively suppressed excessive ROS production, and significantly rescued motor function, cognition and spatial memory. We found that the positive therapeutic effects of the Pd@insulin clusters were mainly attributed to their ROS-scavenging ability, as they inhibited excessive neuroinflammation, reduced cell apoptosis, and prevented neuronal loss. Therefore, the ability of Pd@insulin clusters to effectively eliminate ROS, as well as their simple structure, easy synthesis, low toxicity, and rapid metabolism may facilitate their clinical translation for TBI treatment.

Abstract Dysfunction of ionotropic glutamate receptors (iGluRs) is a key molecular mechanism of excitotoxic neuronal injury following traumatic brain injury (TBI). Edonerpic maleate is a low molecular-weight compound that was screened as a candidate neuroprotective agent. In this study, we investigated its effects on TBI and GluRs signaling. Traumatic neuronal injury (TNI) induced by scratch followed by glutamate treatment was performed to mimic TBI in vitro. Edonerpic maleate at 1 and 10 μM exerted protective activity when it was added within 2 h following injury. The protective activities were also confirmed by the reduction of lipid peroxidation and oxidative stress. In addition, edonerpic maleate inhibited the expression of surface NR2B, total GluR1, and surface GluR1, and mitigated the intracellular Ca2+ responses following injury in vitro. Western blot analysis showed that edonerpic maleate reduced the cleavage of collapsing response mediator protein 2 (CRMP2), but increased the expression of postsynaptic protein Arc. By using gene overexpression and silencing technologies, CRMP2 was overexpressed and Arc was knockdown in cortical neurons. The results showed that the effect of edonerpic maleate on NMDA receptor expression was mediated by CRMP2, whereas the edonerpic maleate-induced AMPA receptor regulation was dependent on Arc activation. In in vivo TBI model, 30 mg/kg edonerpic maleate alleviated the TBI-induced brain edema, neuronal loss, and microglial activation, with no effect on locomotor function at 24 h. However, edonerpic maleate improves long-term neurological function after TBI. Furthermore, edonerpic maleate inhibited CRMP2 cleavage but increased Arc activation in vivo. In summary, our results identify edonerpic maleate as a clinically potent small compound with which to attenuate TBI-related brain damage through regulating GluRs signaling.

BackgroundStroke is an acute disorder and dysfunction of the focal neurological system that has long been recognized as one of the leading causes of death and severe disability in most regions globally. This study aimed to supplement and exploit multiple comorbidities, laboratory tests and demographic factors to more accurately predict death related to stroke, and furthermore, to make inferences about the heterogeneity of treatment in stroke patients to guide better treatment planning.MethodsWe extracted data from the Medical Information Mart from the Intensive Care (MIMIC)-IV database. We compared the distribution of the demographic factors between the control and death groups. Subsequently, we also developed machine learning (ML) models to predict mortality among stroke patients. Furthermore, we used meta-learner to recognize the heterogeneity effects of warfarin and human albumin. We comprehensively evaluated and interpreted these models using Shapley Additive Explanation (SHAP) analysis.ResultsWe included 7,483 patients with MIMIC-IV in this study. Of these, 1,414 (18.9%) patients died during hospitalization or 30 days after discharge. We found that the distributions of age, marital status, insurance type, and BMI differed between the two groups. Our machine learning model achieved the highest level of accuracy to date in predicting mortality in stroke patients. We also observed that patients who were consistent with the model determination had significantly better survival outcomes than the inconsistent population and were better than the overall treatment group.ConclusionWe used several highly interpretive machine learning models to predict stroke prognosis with the highest accuracy to date and to identify heterogeneous treatment effects of warfarin and human albumin in stroke patients. Our interpretation of the model yielded a number of findings that are consistent with clinical knowledge and warrant further study and verification.

BackgroundConsidering the huge population in China, the available mental health resources are inadequate. Thus, our study aimed to evaluate whether mental questionnaires, serving as auxiliary diagnostic tools, have efficient diagnostic ability in outpatient psychiatric services.MethodsWe conducted a retrospective study of Chinese psychiatric outpatients. Altogether 1,182, 5,069, and 4,958 records of Symptom Checklist-90 (SCL-90), Hamilton Anxiety Rating Scale (HAM-A), and Hamilton Depression Rating Scale (HAM-D), respectively, were collected from March 2021 to July 2022. The Mann–Whitney U test was applied to subscale scores and total scores of SCL-90, HAM-A, and HAM-D between the two sexes (male and female groups), different age groups, and four diagnostic groups (anxiety disorder, depressive disorder, bipolar disorder, and schizophrenia). Kendall's tau coefficient analysis and machine learning were also conducted in the diagnostic groups.ResultsWe found significant differences in most subscale scores for both age and gender groups. Using the Mann–Whitney U test and Kendall's tau coefficient analysis, we found that there were no statistically significant differences in diseases in total scale scores and nearly all subscale scores. The results of machine learning (ML) showed that for HAM-A, anxiety had a small degree of differentiation with an AUC of 0.56, while other diseases had an AUC close to 0.50. As for HAM-D, bipolar disorder was slightly distinguishable with an AUC of 0.60, while the AUC of other diseases was lower than 0.50. In SCL-90, all diseases had a similar AUC; among them, bipolar disorder had the lowest score, schizophrenia had the highest score, while anxiety and depression both had an AUC of approximately 0.56.ConclusionThis study is the first to conduct wide and comprehensive analyses on the use of these three scales in Chinese outpatient clinics with both traditional statistical approaches and novel machine learning methods. Our results indicated that the univariate subscale scores did not have statistical significance among our four diagnostic groups, which highlights the limit of their practical use by doctors in identifying different mental diseases in Chinese outpatient psychiatric services.

Subarachnoid hemorrhage (SAH) is a severe type of stroke featuring exceptionally high rate of morbidity and mortality due to the lack of effective management. Ferroptosis can be defined as a novel iron-dependent programmed cell death in contrast to classical apoptosis and necrosis. Astragaloside IV (AS-IV) is an active ingredient extracted from Astragalus membranaceus with established therapeutic effect on CNS diseases. However, the exact role of ferroptosis in Astragaloside IV-mediated neuroprotection after SAH is yet to be demonstrated. In the present study, the SAH model of SD male rats with endovascular perforation was used to gauge the neuroprotective effect of AS-IV on SAH-induced early brain injury (EBI) and to clarify the potential molecular mechanism. We found that the induction of SAH reduced the levels of SLC7A11 and glutathione peroxidase 4 (GPX4) in the brain, exacerbated iron accumulation, enhanced lipid reactive oxygen species (ROS) level, and stimulated neuronal ferroptosis. However, the administration of AS-IV and the ferroptosis inhibitor Ferrostatin-1 (Fer-1) enhanced the antioxidant capacity after SAH and suppressed the accumulation of lipid peroxides. Meanwhile, AS-IV triggered Nrf2/HO-1 signaling pathway and alleviated ferroptosis due to the induction of SAH. The Nrf2 inhibitor ML385 blocked the beneficial effects of neuroprotection. These results consistently suggest that ferroptosis is profoundly implicated in facilitating EBI in SAH, and that AS-IV thwarts the process of ferroptosis in SAH by activating Nrf2/HO-1 pathway.

Propofol is an established intravenous anesthetic agent with potential neuroprotective effects. In this study, we investigated the roles and the underlying mechanisms of propofol in inhibiting the pro-inflammatory responses of microglia. Propofol significantly reduced the messenger RNA (mRNA) levels of Tnf, Nos2, and NF-κB pathway related genes Ticam1, Myd88, Irf3, and Nfkb1 in lipopolysaccharide (LPS)-treated primary microglia. After screening the miRNA profiles in microglia under LPS and propofol treatment conditions, we found propofol abrogated the LPS-induced misexpression of miRNAs including miR-106b, miR-124, miR-185, and miR-9. Perturbation of function approaches suggested miR-106b as the core miRNA that mediated the anti-inflammatory effects of propofol on microglial activation. RNA sequencing (RNA-seq) analysis further identified Pi3k/Akt signaling as one of the most affected pathways after miR-106b perturbation of function. The treatment of Pi3k/Akt signaling agonist 740Y-P elevated miR-106b-reduced Akt phosphorylation and abolished the inhibitory effects of miR-106b on the pro-inflammatory responses of microglia. Our results suggest propofol inhibits microglial activation via miR-106b/Pi3k/Akt axis, shedding light on a novel molecular mechanism of propofol-mediated immunomodulatory effects and implying propofol as potential therapeutics for treating neuroinflammation-related neurodegenerative diseases.

In this research paper, we explored the predictive capabilities of three different models of Polynomial Regression (PR), Extreme Gradient Boosting (XGB), and LASSO to estimate the density of supercritical carbon dioxide (SC-CO 2 ) and the solubility of niflumic acid as functions of the input variables of temperature and pressure. The optimization of hyperparameters for these models is achieved using the innovative Barnacles Mating Optimizer (BMO) algorithm. For SC-CO 2 density estimation, PR exhibits remarkable accuracy, showing an R-squared value of 0.99207 for data fitting. XGB performs admirably with an R 2 of 0.92673, while LASSO model demonstrates good predictive ability, showing an R 2 of 0.81917. Furthermore, we assess the models' performance in predicting the solubility of niflumic acid. PR exhibits excellent predictive capabilities with an R 2 of 0.96949. XGB also delivers strong performance, yielding an R-squared score of 0.92961. LASSO performs well, achieving an R-squared score of 0.82094. The results indicated promising performance of machine learning models and optimizer in estimating drug solubility in supercritical CO 2 as the solvent applicable for pharmaceutical industry., (© 2024. The Author(s).)

Inflammation is a potential risk factor of voriconazole (VCZ) overdose, procalcitonin (PCT) is reported to act as a diagnostic marker for bacterial infections. However, the association of PCT with VCZ trough serum concentrations (VCZ-C min ) is not fully clear. Our study aims to investigate the associations between PCT and VCZ-C min . In this retrospective cohort study, we collected the clinical data of 147 patients who received VCZ and monitored the VCZ concentration of them in our hospital from August 2017 to August 2021. All patients underwent routine clinical examinations on the day or the day before VCZ administration. General information and clinical symptoms of these patients were recorded. Multivariate liner analysis showed that PCT was significantly associated with VCZ-C min (p < 0.001). Overall, it was shown that VCZ-C min was significantly increased by 0.32 µg/mL for each fold increment in PCT in crude model. In the minor adjusted model (Model 1, adjustment for sex, age, albumin, direct bi1irubin, WBC) and fully adjusted model (Model 2, adjustment for sex, age, albumin, direct bilirubin, WBC, AST and ALT), VCZ-C min was significantly increased by 0.23 µg/mL and 0.21 µg/mL, respectively, for each fold increment in PCT. In conclusion, this research reveals the correlation between PCT and VCZ-C min , indicating that PCT has the potential to serve as a valuable biomarker for drug monitoring in the treatment of VCZ., (© 2024. The Author(s).)

Esketamine, the right-handed optical isomer of racemic ketamine, is a rapidly acting antidepressant approved by the FDA for treatment-resistant depression in 2019. However, few studies have investigated esketamine's role in learning and memory, particularly in the context of memory reconsolidation. Herein, we evaluated esketamine's role in memory reconsolidation in 7-week-old male Institute of Cancer Research mice subjected to the novel object recognition (NOR) memory task. The NOR reconsolidation procedure comprised three phases: sampling, reactivation, and testing. Esketamine-enhanced NOR memory performance when injected into mice 0 h after reactivation rather than following a 6 h delay. Conversely, administering esketamine 24 h after sampling without reactivation did not enhance NOR memory performance. Notably, esketamine exhibited no discernible effects on nonspecific responses, such as locomotor activity and exploratory behavior. Furthermore, the α-amino-3‑hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type receptor antagonist NBQX effectively blocked the esketamine-induced enhancement of memory reconsolidation. In conclusion, esketamine treatment markedly improves memory reconsolidation in NOR tasks, and this effect is linked to AMPA receptor activity., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

There is a body of evidence to suggest that chronic stress modulates neurochemical homeostasis, alters neuronal structure, inhibits neurogenesis and contributes to development of mental disorders. Chronic stress-associated mental disorders present common symptoms of cognitive impairment and depression with complex disease mechanisms. P-coumaric acid (p-CA), a natural phenolic compound, is widely distributed in vegetables, cereals and fruits. p-CA exhibits a wide range of health-related effects, including anti-oxidative-stress, anti-mutagenesis, anti-inflammation and anti-cancer activities. The current study aims to evaluate the therapeutic potential of p-CA against stress-associated mental disorders. We assessed the effect of p-CA on cognitive deficits and depression-like behavior in mice exposed to chronic restraint stress (CRS); we used network pharmacology, biochemical and molecular biological approaches to elucidate the underlying molecular mechanisms. CRS exposure caused memory impairments and depression-like behavior in mice; p-CA administration attenuated these CRS-induced memory deficits and depression-like behavior. Network pharmacology analysis demonstrated that p-CA was possibly involved in multiple targets and a variety of signaling pathways. Among them, the protein kinase A (PKA) - cAMP-response element binding protein (CREB) - brain derived neurotrophic factor (BDNF) signaling pathway was predominant and further characterized. The levels of PKA, phosphorylated CREB (pCREB) and BDNF were significantly lowered in the hippocampus of CRS mice, suggesting disruption of the PKA-CREB-BDNF signaling pathway; p-CA treatment restored the signaling pathway. Furthermore, CRS upregulated expression of proinflammatory cytokines in hippocampus, while p-CA reversed the CRS-induced effects. Our findings suggest that p-CA will offer therapeutic benefit to patients with stress-associated mental disorders., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Traditional Chinese Medicines have been used for thousands of years but without any sound empirical basis. One such preparation is the Qijudihuang pill (QP), a mixture of eight herbs, that has been used in China for the treatment of various conditions including age-related macular degeneration (AMD), the most common cause of blindness in the aged population. In order to explain the mechanism behind the effect of QP, we used an AMD model of high-fat diet (HFD) fed mice to investigate cholesterol homeostasis, oxidative stress, inflammation and gut microbiota., Methods: Mice were randomly divided into three groups, one group was fed with control diet (CD), the other two groups were fed with high-fat-diet (HFD). One HFD group was treated with QP, both CD and the other HFD groups were treated with vehicles. Tissue samples were collected after the treatment. Cholesterol levels in retina, retinal pigment epithelium (RPE), liver and serum were determined using a commercial kit. The expression of enzymes involved in cholesterol metabolism, inflammation and oxidative stress was measured with qRT-PCR. Gut microbiota was analyzed using 16S rRNA sequencing., Results: In the majority of the lipid determinations, analytes were elevated by HFD but this was reversed by QP. Cholesterol metabolism including the enzymes of bile acid (BA) formation was suppressed by HFD but again this was reversed by QP. BAs play a major role in signaling between host and microbiome and this is disrupted by HFD resulting in major changes in the composition of colonic bacterial communities. Associated with these changes are predictions of the metabolic pathway complexity and abundance of individual pathways. These concerned substrate breakdowns, energy production and the biosynthesis of pro-inflammatory factors but were changed back to control characteristics by QP., Conclusion: We propose that the ability of QP to reverse these HFD-induced effects is related to mechanisms acting to lower cholesterol level, oxidative stress and inflammation, and to modulate gut microbiota., Competing Interests: The author(s) 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 Cao, Ibrahim, Li, Wong, Wu, Yu, Zhou, Tan, He, Craft and Shu.)

Trans-urocanic acid (UCA), an isomer of cis-UCA that is mainly located in the skin, has recently been reported to have a role in short-term working memory and in the consolidation, reconsolidation and retrieval of long-term memory. However, its effect on memory acquisition remains unclear. In the present study, the effect of UCA on short-term and long-term memory acquisition in mice was investigated using novel object recognition (NOR) and object location recognition (OLR) protocols that each involved three stages: habituation, sampling and testing. UCA was intraperitoneally injected 0.5 h pre-sampling, and the discrimination index during subsequent testing was determined in NOR and OLR tasks. The results showed that 10 mg/kg UCA significantly facilitated short-term and long-term memory acquisition in both types of tasks. Furthermore, 30 mg/kg UCA significantly facilitated long-term memory acquisition in the NOR task and tended to facilitate long-term memory acquisition in the OLR tasks but did not facilitate short-term memory acquisition in either task. Additionally, the enhancing role of UCA on memory acquisition was not dependent on changes of nonspecific responses, e.g. exploratory behavior and locomotor activity. The current study suggests that UCA facilitates short-term and long-term recognition memory acquisition, which further extends the functional role of UCA in the brain function., Competing Interests: Declaration of Competing Interest None, (Copyright © 2023. Published by Elsevier Inc.)

Background: Cellular senescence is a stable state of cell cycle arrest that plays a crucial role in the tumor microenvironment (TME) and cancer progression. Nevertheless, the accurate prognosis of gastric cancer (GC) is complicated to predict due to tumor heterogeneity. The work aimed to build a novel prognostic model in GC., Methods: LASSO and Cox regression analysis were constructed to develop a prognostic senescence-related signature. The Gene Expression Omnibus dataset was used for external validation of signature. Afterward, we performed correlation analysis for the risk score and the infiltrating abundance of immune cells, TME scores, drug response, tumor mutational burden (TMB), and immunotherapy efficacy., Results: Five senescence-related genes (AKR1B1, CTNNAL1, DUSP16, PLA2R1, and ZFP36) were screened to build a signature. The high-risk group had a shorter overall survival, cancer-specific survival, and progression-free survival when compared to the low-risk group. We further constructed a nomogram based on risk score and clinical traits, which can predict the prognosis of GC patients more accurately. Moreover, the risk score was evidently correlated with infiltration of immune cells, TME score, TMB, TIDE score, and chemotherapy sensitivity. Meanwhile, the Kyoto Encyclopedia of Genes and Genomes pathway showed that the PI3K-Akt and Wnt signaling pathway were differentially enriched in the high-risk group., Conclusions: The senescence-related signature was an accurate tool to guide the prognosis and might promote the progress of personalized treatment., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Necroptosis plays a crucial role in the progression of multiple types of cancer. However, the role of necroptosis in gastric cancer (GC) remains unclear. The aim of this study is to establish a necroptosis-related prediction model, which could provide information for treatment monitoring. Methods: The TCGA-STAD cohort was employed to establish a prognostic prediction signature and the GEO dataset was employed for external validation. The correlation between the risk score and the immune landscape, tumor mutational burden (TMB), microsatellite instability (MSI), as well as therapeutic responses of different therapies were analyzed. Results: We constructed a prognostic model based on necroptosis-associated genes (NAGs), and its favorable predictive ability was confirmed in an external cohort. The risk score was confirmed as an independent determinant, and a nomogram was further established for prognosis. A high score implies higher tumor immune microenvironment (TIME) scores and more significant TIME cell infiltration. High-risk patients presented with lower TMB, and low-TMB patients had worse overall survival (OS). Meanwhile, Low-risk scores are characterized by MSI-high (MSI-H), lower Tumor Immune Dysfunction and Exclusion (TIDE) score, and higher immunogenicity in immunophenoscore (IPS) analysis. Conclusion: The developed NAG score provides a novel and effective method for predicting the outcome of GC as well as potential targets for 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 © 2022 Zhu, Zhang and Liu.)

Background: Senescence, as an effective barrier against tumorigenesis, plays a critical role in cancer therapy. However, the role of senescence in colorectal cancer (CRC) has not yet been reported. This study aimed to build a prognostic signature for the prognosis of patients with CRC based on senescence-related genes. Methods: A prognostic signature was built from TCGA based on differentially expressed senescence-related genes by the least absolute shrinkage and selection operator (LASSO) and Cox regression analyses, which were further validated using two Gene Expression Omnibus (GEO) cohorts. The CIBERSORT and ssGSEA algorithms were utilized to analyze the infiltrating abundance of immune cells. The relationship of signature with the immune therapy and the sensitivity of different therapies was explored. Results: We found 93 genes associated with senescence that were differentially expressed. Based on expression and clinical parameters, we developed a senescence-related prognostic signature and its effectiveness was verified using two external validation cohorts. Overall survival was predicted using a prognostic nomogram that incorporated the predictive values of the risk score and clinical traits. Additionally, the risk score was significantly correlated with immune cells infiltration, tumor immune microenvironment (TME) score, immune checkpoints, immunotherapeutic efficacy, and chemotherapy sensitivity. Conclusion: The senescence-related prognostic model can well predict the prognosis, immunotherapeutic response, and identify potential drug targets, which can help guide individualized treatment., 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 Dong, Liu, Zhou and Zhang.)

Necroptosis is a mode of programmed cell death that overcomes apoptotic resistance. The accurate prognosis of cutaneous melanoma is complicated to predict due to tumor heterogeneity. Necroptosis contributes to the regulation of oncogenesis and cancer immunity. We comprehensively investigated different necroptosis patterns by the non-negative matrix factorization (NMF) clustering analysis and explored the relationships among necroptosis patterns, infiltered immune cells, and tumor microenvironment (TME) scores. Two different necroptosis patterns were identified, and the two clusters could predict prognosis and immune landscape. A four-gene signature was successfully constructed and validated its predictive capability of overall survival (OS) in cutaneous melanoma patients. The prognostic value of the signature was further enhanced by incorporating other independent prognostic factors such as age and clinicopathological stages in a nomogram-based prediction model. Patients with lower risk scores tended to have better OS, higher TME score, immune checkpoints, immunophenoscore (IPS), and lower Tumor Immune Dysfunction and Exclusion (TIDE), which indicated better responses to immunotherapy. In addition, the pigmentation score of the high-risk group was visibly higher than those of the low-risk group. In conclusion, the necroptosis-related signature indicated favorable predictive performance in cutaneous melanoma patients, which provides guidance for immunotherapy and provide novel insights into precision medicine., (© 2022. The Author(s).)

Background: Accumulating evidence have revealed that pretreatment albumin to globulin ratio (AGR) may be a predictor of prognosis among patients with colorectal cancer (CRC). However, these findings are inconsistent. The aim of the present study was to investigate the prognostic value of pretreatment AGR in CRC., Methods: A systematic meta-analysis was conducted by searching MEDLINE, EMBASE, and Cochrane Library databases., Results: A total of 9 studies with 7939 patients were finally included. Low pretreatment AGR was associated with worse overall survival (pooled hazard ratio [HR]: 2.07, 95% CI: 1.60-2.67, P < .001) and disease-free survival/progress-free survival (pooled hazard ratio [HR]: 2.10, 95% confidence interval [CI]: 1.34-3.31, P = .001). Subgroup analyses revealed that the pooled correlation did not alter these results. Moreover, low pretreatment AGR were associated with elderly patients, tumor diameter (≥50 mm), tumor node metastasis stage (III-IV), depth of tumor (T3-4), and CA19-9 (>37 U/mL)., Conclusion: The present meta-analysis suggests that low pretreatment AGR was associated with advanced clinicopathological features and worse prognosis, suggesting AGR is a useful prognostic biomarker for CRC patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Context: Neuregulin 4 (Nrg4) and neuregulin 1 (Nrg1) have been shown to play vital roles in several disorders of glucose metabolism. The pathophysiological role of Nrg4 and Nrg1 in gestational diabetes mellitus (GDM), however, remains poorly understood. We assessed the clinical relevance of the two cytokines in patients with GDM., Methods: The study recruited 36 GDM patients and 38 age-matched, gestational age (24-28 weeks of gestation)-matched, and BMI (during pregnancy)-matched controls in this study. Serum Nrg4 and Nrg1 were measured using ELISA. Inflammatory factors such as IL-6, IL-1β, leptin, TNF-α, and monocyte chemotactic protein 1 (MCP-1) were determined via Luminex technique., Results: Serum Nrg4 in GDM patients was significantly lower than that in the controls, while Nrg1 was significantly higher in the GDM group ( p  < 0.01). Inflammatory factors such as IL-6, leptin, and TNF-α were significantly increased in GDM patients, while MCP-1 and IL-1β were not significantly different between the two groups. In addition, serum Nrg4 was negatively correlated with fasting glucose ( r  = -0.438, p  = 0.008), HOMA-IR ( r  = -0.364, p  = 0.029), IL-6 ( r  = -0.384, p  = 0.021), leptin ( r  = -0.393, p  = 0.018), TNF-α ( r  = -0.346, p  = 0.039), and MCP-1 ( r  = -0.342, p  = 0.041), and positively correlated with high-density lipoprotein cholesterol (HDL-C) ( r  = -0.357, p  = 0.033) in GDM group. Serum Nrg1 was positively correlated with BMI ( r  = 0.452, p  = 0.006), fasting glucose ( r  = 0.424, p  = 0.010), HOMA-IR ( r  = 0.369, p  = 0.027), and triglyceride ( r  = 0.439, p  = 0.007). The decrease of Nrg4 and the increase of Nrg1 were significantly related to the increased prevalence of GDM. Finally, ROC curve results indicated that Nrg1 combined with IL-6 and TNF-α might be an effective means for GDM screening., Conclusions: Lower circulating Nrg4 and higher circulating Nrg1 serve risk factors of GDM. Nrg1 combined with IL-6 and TNF-α might be a potential tool for GDM screening., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2021.)

Background: Endometriosis is a debilitating gynecological condition that manifests many common malignant features, including migration and invasion. Hypoxia is a hallmark of endometriosis, characterized by endometrial cell metastasis via epithelial-mesenchymal transition (EMT). The long noncoding RNA (lncRNA) UBOX antisense RNA 1 (UBOX5-AS1) has been shown to be upregulated in ovarian endometriosis. However, the molecular mechanisms and biological functions of lncRNA UBOX5-AS1 in hypoxia-induced endometriosis EMT remain to be explored., Methods: Normal, eutopic, and ectopic endometrium from ovarian endometriosis tissues were collected, and the expressions of hypoxia inducible factor (HIF)-1α, lncRNA UBOX5-AS1, E-cadherin, and vimentin were analyzed by quantitative real time polymerase chain reaction (qRT-PCR) and western blotting analysis. Primary human endometrial epithelial cells and human endometrial epithelial adenocarcinoma Ishikawa cell lines were cultured under hypoxic conditions, and western blotting analysis and immunocytochemistry were performed to investigate hypoxia-induced EMT. Moreover, HIF-1α and lncRNA UBOX5-AS1 were overexpressed and knocked down in endometrial epithelial cells to explore the role and mechanisms of lncRNA UBOX5-AS1 in hypoxia-triggered EMT. The migration and invasion potential of human endometrial epithelial cells was detected by Transwell migration/invasion assays., Results: In ovarian endometriosis, the expression of hypoxia-inducible factor-1α ( HIF-1α ) and lncRNA UBOX5-AS1 were significantly increased, and this was accompanied by EMT. Furthermore, endometrial epithelial cells cultured under hypoxic conditions exhibited elevated lncRNA UBOX5-AS1 expression, as well as migration, invasion, and an EMT-like phenotype. This data indicated that HIF-1α signaling was crucial for hypoxia-induced lncRNA UBOX5-AS1 upregulation and the EMT process. Moreover, downregulation of lncRNA UBOX5-AS1 inhibited the hypoxia-induced EMT and attenuated cell migration and invasion., Conclusions: The present research demonstrated that hypoxia upregulated the expression of lncRNA UBOX5-AS1 via HIF-1α -dependent signaling. The increased expression of lncRNA UBOX5-AS1 plays a vital role in mediating the hypoxia-regulated EMT and invasiveness of endometriosis, suggesting that lncRNA UBOX5-AS1 may be an important potential therapeutic target for endometriosis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/ atm-20-4546). HL served as an unpaid Section Editor for the Annals of Translational Medicine from January 2020 to December 2020. The other authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

4-Hexylresorcinol (4HR) is a small organic compound that is widely used as an antiseptic and antioxidant. In the present study, its role in osteoclastogenesis was investigated. Bone marrow-derived macrophages from mice were used to examine the role of 4HR in osteogenesis. An ovariectomy (OVX) mouse model was constructed to examine the effect of 4HR in vivo , followed by hematoxylin and eosin and tartrate resistant acid phosphatase staining. In the present study, 4HR effectively suppressed receptor activator of NF-κB ligand-induced osteoclastogenesis in a dose-dependent manner. 4HR was also found to significantly suppress the expression of osteoclast (OC)-specific markers, including tartrate-resistant acid phosphatase, cathepsin K, nuclear factor of activated T-cell cytoplasmic 1 and c-Fos in the presence of RANKL in BMMs. Furthermore, 4HR inhibited osteoclastogenesis by inhibiting the activation of the NF-κB signaling pathway in BMMs. Consistent with the in vitro results, 4HR effectively ameliorated OVX-induced bone loss and markedly reduced OC number in the proximal tibia in vivo . In conclusion, the present results suggested that 4HR inhibited osteoclastogenesis in vitro and rescued bone loss in vivo , suggesting that 4HR may serve as a novel therapeutic agent for osteoporosis treatment., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Yi et al.)

Listeriosis, caused by Listeria monocytogenes , is a severe food-borne infection. The nationwide surveillance in China concerning listeriosis is urgently needed. In the present study, 144 L. monocytogenes isolates were collected from the samples of blood, cerebrospinal fluid (CSF), and fetal membrane/placenta in China for 12 years from 2008 to 2019. We summarized these listeriosis patients' demographical and clinical features and outcomes. The susceptibility profile for 12 antibiotics was also determined by the broth microdilution method. Multilocus sequence typing (MLST) and serogroups of these listeria isolates were analyzed to designate epidemiological types. We enrolled 144 cases from 29 healthcare centers, including 96 maternal-neonatal infections, 33 cases of bacteremia, 13 cases of neurolisteriosis, and two cutaneous listeriosis. There were 31 (59.6%) fetal loss in 52 pregnant women and four (9.8%) neonatal death in 41 newborns. Among the 48 nonmaternal-neonatal cases, 12.5% (6/48) died, 41.7% (20/48) were female, and 64.6% (31/48) occurred in those with significant comorbidities. By MLST, the strains were distinguished into 23 individual sequence types (STs). The most prevalent ST was ST87 (49 isolates, 34.0%), followed by ST1 (18, 12.5%), ST8 (10, 6.9%), ST619 (9, 6.3%), ST7 (7, 4.9%) and ST3 (7, 4.9%). Furthermore, all L. monocytogenes isolates were uniformly susceptible to penicillin, ampicillin, and meropenem. In summary, our study highlights a high genotypic diversity of L. monocytogenes strains causing clinical listeriosis in China. Furthermore, a high prevalence of ST87 and ST1 in the listeriosis should be noted., 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 Lu, Yang, Gao, Li, Cui, Huang, Chen, Wang, Wang, Liu, Li, Zhang, Jiao, Xu, Song, Fu, Xu, Yang, Ning, Wang, Bao, Luo, Wu, Yang, Li, Tang, Wang, Guo, Zeng and Zhong.)

Purpose: Pseudomonas aeruginosa bacteremia presents a severe challenge to hospitalized patients. However, to date, the risk factors for mortality among inpatients with P. aeruginosa bacteremia in China remain unclear., Patients and Methods: This retrospective multicenter study was performed to analyze 215 patients with culture-confirmed P. aeruginosa bacteremia in five healthcare centers in China during the years 2012-2019., Results: Of 215 patients with P. aeruginosa bacteremia, 61 (28.4%) died during the study period. Logistic multivariable analysis revealed that cardiovascular disease (OR=3.978, P =0.001), blood transfusion (OR=5.855, P <0.001) and carbapenem-resistant P. aeruginosa (CRPA) phenotype (OR=4.485, P =0.038) constituted the independent risk factors of mortality. Furthermore, both CRPA and multidrug-resistant P. aeruginosa (MDRPA) phenotypes were found to be significantly associated with 5-day mortality (Log-rank, P <0.05)., Conclusion: This study revealed a high mortality rate amongst hospitalized patients with P. aeruginosa bacteremia, and those with cardiovascular diseases, CRPA and MDRPA phenotypes, should be highlighted and given appropriate management in China., Competing Interests: The authors declare that they have no conflicts of interest., (© 2020 Zhang et al.)

Circular RNAs (circRNAs) have displayed dysregulated expression in several types of cancer. Nevertheless, their function and underlying mechanisms in papillary thyroid cancer (PTC) remains largely unknown. This study aimed to describe the regulatory mechanisms in PTC. The expression profile of circRNA was download from the Gene Expression Omnibus (GEO) database. The mRNA and miRNA data of PTC was downloaded from The Cancer Genome Atlas (TCGA) database. The circRNA-miRNA-mRNA network by Cytoscape. The interactions between proteins were analyzed using the STRING database and hubgenes were identified using MCODE plugin. Then, we conducted a circRNA-miRNA-hubgenes regulatory module. Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genomes (KEGG) pathway analysis were conducted using R packages "Clusterprofile". We identified 14 differential expression circRNAs (DEcircRNA), 3106 differential expression mRNAs (DEmRNA), 142 differential expression miRNAs (DEmiRNA) and in PTC. Twelve circRNAs, 33 miRNAs, and 356 mRNAs were identified to construct the ceRNA network of PTC. PPI network and module analysis identified 5 hubgenes. Then, a circRNA-miRNA-hubgene subnetwork was constructed based on the 2 DEcircRNAs, 3 DEmiRNAs, and 4 DEmRNAs. GO and KEGG pathway analysis indicated DEmRNAs might be associated with PTC onset and progression. These ceRNAs are critical in the pathogenesis of PTC and may serve as future therapeutic biomarkers.