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Abstract Background The zero-profile implant system (Zero-P) and conventional plates have been widely used in anterior cervical discectomy and fusion (ACDF) to treat cervical spondylosis. The purpose of this study was to compare the effects of the application of Zero-P and new conventional plates (ZEVO, Skyline) in ACDF on the sagittal imaging parameters of cervical spondylosis patients and to analyze their clinical efficacy. Methods We conducted a retrospective study on 119 cervical spondylosis patients from January 2018 to December 2021, comparing outcomes between those receiving the Zero-P device (n = 63) and those receiving a novel conventional plate (n = 56, including 46 ZEVO and 10 Skyline plates) through ACDF. Cervical sagittal alignment was assessed pre- and postoperatively via lateral radiographs. The Japanese Orthopedic Association (JOA), Neck Disability Index (NDI), and visual analog scale (VAS) scores were recorded at baseline, after surgery, and at the 2-year follow-up to evaluate patient recovery and intervention success. Results There were significant differences in the postoperative C0-C2 Cobb angle and postoperative sagittal segmental angle (SSA) between patients in the novel conventional plate group and those in the Zero-P group (P

Abstract Osteoporosis (OP) is a bone metabolism disease that is associated with inflammatory pathological mechanism. Nonetheless, rare studies have investigated the diagnostic effectiveness of immune-inflammation index in the male population. Therefore, it is interesting to achieve early diagnosis of OP in male population based on the inflammatory makers from blood routine examination. We developed a prediction model based on a training dataset of 826 Chinese male patients through a retrospective study, and the data was collected from January 2022 to May 2023. All participants underwent the dual-energy X-ray absorptiometry (DXEA) and blood routine examination. Inflammatory markers such as systemic immune-inflammation index (SII) and platelet-to-lymphocyte ratio (PLR) was calculated and recorded. We utilized the least absolute shrinkage and selection operator (LASSO) regression model to optimize feature selection. Multivariable logistic regression analysis was applied to construct a predicting model incorporating the feature selected in the LASSO model. This predictive model was displayed as a nomogram. Receiver operating characteristic (ROC) curve, C-index, calibration curve, and clinical decision curve analysis (DCA) to evaluate model performance. Internal validation was test by the bootstrapping method. This study was approved by the Ethic Committee of the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine (Ethic No. JY2023012) and conducted in accordance with the relevant guidelines and regulations. The predictive factors included in the prediction model were age, BMI, cardiovascular diseases, cerebrovascular diseases, neuropathy, thyroid diseases, fracture history, SII, PLR, C-reactive protein (CRP). The model displayed well discrimination with a C-index of 0.822 (95% confidence interval: 0.798–0.846) and good calibration. Internal validation showed a high C-index value of 0.805. Decision curve analysis (DCA) showed that when the threshold probability was between 3 and 76%, the nomogram had a good clinical value. This nomogram can effectively predict the incidence of OP in male population based on SII and PLR, which would help clinicians rapidly and conveniently diagnose OP with men in the future.

Abstract Background Craniopharyngiomas (CPs) are generally derived from the craniopharyngeal duct epithelium, accounting for 38% and 24.5% of mortality in pediatric and adult patients, respectively. At present, the widespread application of the endoscopic endonasal transsphenoidal approach (EEA) has led to controversy between the traditional microscopic transcranial approach (TCA) and EEA in relation to the surgical management of CPs. Object and method We performed a systematic review and meta-analysis comparing the complications, surgical outcomes, and endocrine functions of patients with CPs to provide evidence-based decision-making in their surgical management. Result Overall, 11 observational studies with 12,212 participants were included in the meta-analysis, in which five of them only included an adult population, three of them only included a child population, and the other three studies included a mixed population (adult and child). In pediatric patients, the EEA achieved a higher gross total resection (GTR) rate (odds ratio (OR) = 5.25, 95%CI: 1.21–22.74), lower recurrence rate (OR = 0.54, 95%CI: 0.31–0.94, p = 0.030), and less hypopituitarism (OR = 0.34, 95%CI: 0.12–0.97, p = 0.043). In adult patients, EEA significantly improved mortality (OR = 0.09, 95%CI: 0.06–0.15, p

Abstract Background Headache is a common occurrence after endoscopic endonasal surgery (EES) for pituitary adenomas and significantly impacts the quality of life of patients. This study aims to investigate the effectiveness of nasal irrigation in relieving postoperative headache after EES. Methods A retrospective analysis was conducted on a cohort of 101 patients (Cohort I) who underwent EES for pituitary adenomas to explore the risk factors associated with postoperative headache. Another cohort of 72 patients (Cohort II) who received adjuvant nasal irrigation following surgery was enrolled for further analysis. The Headache Impact Test (HIT-6) was used to score the severity of headache, and patients with a HIT score > 55 were classified as having headache. Results In Cohort I, 21.78% of patients experienced headache one month after EES, which decreased to 5.94% at the three-month follow-up. Multivariate analysis revealed that postoperative nasal sinusitis (OR = 3.88, 95%CI 1.16–13.03, p = 0.028) and Hardy’s grade C-D (OR = 10.53, 95%CI 1.02-109.19, p = 0.049) independently predicted the presence of postoperative headache at one month. At the three-month follow-up, patients with sinusitis had higher HIT-6 scores compared to those without sinusitis (44.43 ± 9.78 vs. 39.72 ± 5.25, p = 0.017). In Cohort II, the incidence of sinusitis at three months was significantly lower than that in Cohort I (p = 0.028). Importantly, both the incidence of headache and HIT-6 scores in Cohort II were significantly lower than those in Cohort I at the one- and three-month follow-ups. Conclusions Postoperative sinusitis is an independent risk factor for the development of headache following EES for pituitary adenomas. Prophylactic nasal irrigation helps relieve postoperative headache, possibly by preventing the occurrence of sinusitis.

ABSTRACT: Egg production is an important economic trait in layer ducks and understanding the genetics basis is important for their breeding. In this study, a genome-wide association study (GWAS) for egg production traits in 303 female Longyan Shan-ma ducks was performed based on a genotyping-by-sequencing strategy. Sixty-two single nucleotide polymorphisms (SNPs) associated with egg weight traits were identified (P < 9.48 × 10-5), including 8 SNPs at 5% linkage disequilibrium (LD)-based Bonferroni-corrected genome-wide significance level (P < 4.74 × 10-6). One hundred and nineteen SNPs were associated with egg number traits (P < 9.48 × 10-5), including 13 SNPs with 5% LD-based Bonferroni-corrected genome-wide significance (P < 4.74 × 10-6). These SNPs annotated 146 target genes which contained known candidate genes for egg production traits, such as prolactin and prolactin releasing hormone receptor. This study identified that these associated genes were significantly enriched in egg production-related pathways (P < 0.05), such as the oxytocin signaling, MAPK signaling, and calcium signaling pathways. It was notable that 18 genes were differentially expressed in ovarian tissues between higher and lower egg production in Shan-ma ducks. The identified potential candidate genes and pathways provide insight into the genetic basis underlying the egg production trait of layer ducks.

Objective Foraminoplasty is an important step in transforaminal endoscopic lumbar discectomy (TELD). A trephine is widely used in foraminoplasty. However, foraminoplasty using a trephine alone sometimes fails to remove the resected bone, resulting in the bone remaining in the foramen or spinal canal, which can potentially cause neurological irritation or injury. The objective of this study is to introduce a self‐designed tool, referred to as an anchoring drill, for use with a trephine in foraminoplasty in TELD and to evaluate its advantages. Methods A retrospective review was performed to identify patients who underwent L4–5 TELD between January 2019 to January 2022. Foraminoplasty was performed in all patients. Depending on whether the anchoring drill was used or not, patients were divided into two groups. Surgery‐related parameters and complications were reviewed. Visual analog scale (VAS) and Japanese Orthopaedic Association (JOA) scores were also assessed for all patients. SPSS statistical software was used for statistical calculation. Results A total of 100 patients were included (55 in the anchoring drill group and 45 in the trephine group). The incidence of residual bone fragments after foraminoplasty of the anchoring drill group was 9.09%, which was lower than that of the trephine group, at 33.33% (p

Abstract Background There are no reports discussing anatomic distribution of basivertebral foramen (BVF) in the osteoporotic vertebral body, which is critical in the analysis of the risk of epidural cement leakage (ECL) after cement-augmented pedicle screw fixation (CAPSF). Methods 371 osteoporotic patients using 1898 cement-augmented screws were included. Preoperative computed tomography (CT) was used to determine the frequency, width, height, and depth of magistral BVF in T10~L5. Additionally, we measured the distance between BVF and the left/right borders of vertebral body as well as the distance between BVF and upper/lower endplates. Following CAPSF, the severity of ECL and the position of pedicle screws were determined by postoperative CT. Finally, significant risk factors for extensive ECL were identified through binary logistic regression analysis. Results Of 2968 vertebral bodies ranging from T10 to L5, 801 (42.2%) had a magistral BVF. From T10 to L5, the frequency of magistral BVF appeared to gradually increase. The magistral BVF was much closer to the upper endplate and the depth accounted for about a quarter of anteroposterior diameter of vertebral body. Overall, there were 19 patients (5.1%) and 32 screws (1.7%) with extensive ECL, nine of whom had neurological symptoms. The independent risk factors for extensive ECL were the magistral BVF (OR = 8.62, P

Diabetes can lead to a disorder of bone-fat balance, a significant cause of osteoporosis due to changes in environmental factors. Baicalin (Bai), an active ingredient of Scutellaria baicalensis, has been confirmed to possess antioxidant, hypoglycemic, and anti-osteoporotic effects. However, a comprehensive understanding of Bai's influence on diabetic osteoporosis (DOP), including its effects and underlying mechanisms, remains elusive. This study investigated Bai's impact on the bone-fat equilibrium in rats with DOP. The results indicated that Bai alleviated bone damage in DOP by promoting osteogenesis and inhibiting adipogenesis. Concurrently, through bioinformatics analysis, it was suggested that Bai's mechanism of action might involve the P38-MAPK pathway. In vitro, Bai was found to enhance the development of bone marrow mesenchymal stem cells (BMSCs) towards osteogenic lineages while suppressing their differentiation towards adipogenic lineages. It was discovered that Bai's promotion of BMSC osteogenic differentiation depends on the P38-MAPK pathway. Additionally, the synergistic effect mediated by Bai and P38-MAPK inhibitor suppressed BMSC adipogenic differentiation. Our research indicates that the P38-MAPK pathway play a role in Bai's effects on the osteogenic-adipogenic differentiation of BMSCs, showcasing the potential for DOP treatment. This study highlights Bai's ability to regulate the equilibrium between bone and fat, presenting a novel approach to adressing DOP.

Abstract Background T cell engagers (TCEs) have been established as an emerging modality for hematologic malignancies, but solid tumors remain refractory. However, the upregulation of programmed cell death 1 (PD-1) is correlated with T cell dysfunction that confer tumor-mediated immunosuppression. Developing a novel nanobody-based trispecific T cell engager (Nb-TriTE) would be a potential strategy to improve therapeutic efficacy. Methods Given the therapeutic potential of nanobodies (Nbs), we first screened Nb targeting fibroblast activation protein (FAP) and successfully generated a Nb-based bispecific T cell engager (Nb-BiTE) targeting FAP. Then, we developed a Nb-TriTE by fusing an anti-PD-1 Nb to the Nb-BiTE. The biological activity and antitumor efficacy of the Nb-TriTE were evaluated in vitro and in both cell line-derived and patient-derived xenograft mouse models. Results We had for the first time successfully selected a FAP Nb for the generation of novel Nb-BiTE and Nb-TriTE, which showed good binding ability to their targets. Nb-TriTE not only induced robust tumor antigen-specific killing, potent T cell activation and enhanced T cell function in vitro, but also suppressed tumor growth, improved survival and mediated more T cell infiltration than Nb-BiTE in mouse models of different solid tumors without toxicity. Conclusions This novel Nb-TriTE provides a promising and universal platform to overcome tumor-mediated immunosuppression and improve patient outcomes in the future.

Abstract Ferroptosis is an iron‐dependent cell death process mainly triggered by reactive oxygen species (ROS) and lipid peroxidation. Thioredoxin domain protein 12 (TXNDC12) promotes the development of some tumors; however, its function in tumor ferroptosis remains unclear. In this study, we found that knockdown of TXNDC12 promoted erastin‐induced increase in ROS, lipid peroxidation, and Fe2+ levels, and decreased glutathione content. TXNDC12 is involved in ferroptosis by regulating SLC7A11. Further studies showed that TXNDC12 knockdown promoted an erastin‐induced decrease in glioma cell viability. Overall, TXNDC12 played a significant role in ferroptosis by modulating SLC7A11 expression. Thus, TXNDC12 and ferroptosis may provide new targets for the treatment of gliomas.

Abstract Background Through bioinformatics analysis to identify the hub genes of Intervertebral disc degeneration (IVDD) associated with basement membranes (BMs) and find out the potential molecular targets and drugs for BMs-related annulus fibrosus (AF) degeneration based on bioinformatic analysis and molecular approach. Methods Intervertebral disc degeneration (IVDD) related targets were obtained from GeneCards, DisGenet and OMIM databases. BMs related genes were obtained from Basement membraneBASE database. The intersection targets were identified and subjected to protein-to-protein interaction (PPI) construction via STRING. Hub genes were identified and conducted Gene ontology (GO) and pathway enrichment analysis through MCODE and Clue GO in Cytospace respectively. DSigDB database was retrieved to predict therapeutic drugs and molecular docking was performed through PyMOL, AutoDock 1.5.6 to verify the binding energy between the drug and the different expressed hub genes. Finally, GSE70362 from GEO database was obtained to verify the different expression and correlation of each hub gene for AF degeneration. Results We identified 41 intersection genes between 3 disease targets databases and Basement membraneBASE database. PPI network revealed 25 hub genes and they were mainly enriched in GO terms relating to glycosaminoglycan catabolic process, the TGF-β signaling pathway. 4 core targets were found to be significant via comparison of microarray samples and they showed strong correlation. The molecular docking results showed that the core targets have strong binding energy with predicting drugs including chitosamine and retinoic acid. Conclusions In this study, we identified hub genes, pathways, potential targets, and drugs for treatment in BMs-related AF degeneration and IVDD.

Background Lateral displacement of cage is a rarely seen complication of oblique lumbar interbody fusion (OLIF). To the best of our knowledge, this complication has always been revised with posterior open surgery. However, open surgery often associates with large trauma and long period of recovery. Case Presentation In the case presented, a 64‐year‐old male patient with lateral displacement of cage which consequently caused neurological symptoms after OLIF, was reported and surgically revised with an endoscopic resection and decompression technique. The surgery was performed through a posterolateral approach which was similar to transforaminal approach, with estimated blood loss of 45mL and whole operation time of 70 min. Neurological symptoms were disappeared after operation immediately and the patient was discharged 2 days later. He reported no symptoms other than mild weakness of the lower back at the last follow‐up of 12 months. Conclusion Endoscopic decompression technique may be an effective alternative to surgically treat lateral displacement of cage after OLIF with advantages of minimal invasion and quick recovery.

Infection with severe acute respiratory syndrome coronavirus 2 Omicron variants still causes neurological complications in elderly individuals. However, whether and how aging brains are affected by Omicron variants in terms of neuroinvasiveness and neurovirulence are unknown. Here, we utilize resected paracarcinoma brain tissue from elderly individuals to generate primary brain spheroids (BSs) for investigating the replication capability of live wild-type (WT) strain and Omicron (BA.1/BA.2), as well as the mechanisms underlying their neurobiological effects. We find that both WT and Omicron BA.1/BA.2 are able to enter BSs but weakly replicate. There is no difference between Omicron BA.1/BA.2 and WT strains in neurotropism in aging BSs. However, Omicron BA.1/BA.2 exhibits ameliorating neurological damage. Transcriptional profiling indicates that Omicron BA.1/BA.2 induces a lower neuroinflammatory response than WT strain in elderly BSs, suggesting a mechanistic explanation for their attenuated neuropathogenicity. Moreover, we find that both Omicron BA.1/BA.2 and WT strain infections disrupt neural network activity associated with neurodegenerative disorders by causing neuron degeneration and amyloid-β deposition in elderly BSs. These results uncover Omicron-specific mechanisms and cellular immune responses associated with severe acute respiratory syndrome coronavirus 2-induced neurological complications.

PurposeThis study aims to depict the scientific advancements in immunotherapy for glioma by analyzing the top 100 most frequently cited articles over the past 20 years.MethodsThe top 100 most influential papers in immunotherapy for glioma were identified from the Web of Science Core Collection. Citations, countries/regions, institutions, journals, authorships, keywords, and references were extracted and analyzed by CiteSpace, VOSviewer, R software, and an online bibliometric platform.ResultsThe United States possessed a robust global presence, leading in terms of publications and maintaining strong collaborative ties with numerous countries. The institution that made the greatest contributions was Duke University, with 16 papers. Heimberger AB, Sampson JH, and Reardon DA secured the top three positions with 15, 12, and 11 papers, respectively. “Macrophage ontogeny,” “microglia,” “polarization,” “mass cytometry,” “tumor mutation burden,” “sensitivity,” “msh6,” “pd-1 blockade,” and “dna repair” were the recent hot keywords. “Microglia” and “polarization” as the emerging research directions should be given more consideration.ConclusionsThis is the first bibliometric analysis to identify the top 100 papers on immunotherapy for glioma. “Microglia” and “polarization” will be hot spots for future research. The clinical efficacy of glioma immunotherapy is not yet satisfactory, and there is an urgent need to search for more tumor specific antigens and targets that can assist in early diagnosis, precise treatment, prognosis, and recurrence prediction of glioma.

To investigate the effect of phenyllactic acid (PLA) on Listeria monocytogenes biofilms, crystal violet method was used to measure the biomass of L. monocytogenes biofilms, and inverted microscope and scanning electron microscope were used to observe the structure of L. monocytogenes biofilms, the content of extracellular polysaccharide, extracellular protein and extracellular DNA in biofilm was measured by phenol-sulfuric acid method, Folin-phenol method and diphenylamine method, respectively. The effect of PLA on the transcription of genes associated with biofilm formation of L. monocytogenes was detected by real-time quantitative PCR. The results showed that the minimum inhibitory concentration values of PLA against eight L. monocytogenes strains were 6 mg/mL. PLA inhibited L. monocytogenes biofilm formation by reducing the synthesis of extracellular polysaccharides and extracellular proteins. For mature biofilms of L. monocytogenes, PLA destroyed the biofilm structure and reduced the biofilm biomass by reducing the amount of extracellular polysaccharides and extracellular proteins. PLA also inhibited the swarming motility of L. monocytogenes. The transcription levels of quorum sensing system agr in L. monocytogenes were significantly (P

Objects Oblique lumbar interbody fusion (OLIF) has gained increasing popularity recently. However, complications resulting from intraoperative retraction of psoas major (PM) sometimes occur. The aim of this study is to evaluate the degree of PM swelling by developing a scoring system called the Psoas Major Swelling Grade (PMSG), and to investigate the correlation between the PMSG and clinical outcomes after OLIF. Methods Patients who underwent L4‐5 OLIF at our hospital from May 2019 to May 2021 were reviewed and all data were recorded. The extent of postoperative PM swelling was determined by calculating the percentage of change in the PM area before and after surgery on MRI and divided into three grades subsequently. Swelling within the range of 0% to 25% was defined as grade I, 25%–50% was grade II, and more than 50% was grade III. All patients were grouped into the new grade system and followed up for at least 1 year, during which the visual analog scale (VAS) and Oswestry disability index (ODI) scores were recorded. Categorical data were analyzed using chi‐square and Fisher's exact tests, while continuous variables were assessed with one‐way ANOVA and paired t‐tests. Results Eighty‐nine consecutive patients were enrolled in this study, with a mean follow‐up duration of 16.9 months. The proportion of female patients in the PMSG I, II, and III groups was 57.1%, 58.3%, and 84.1%, respectively (p = 0.024). Furthermore, the total complication rate was 43.2% in the PMSG III group, significantly higher than 9.5% and 20.8% in the PMSG I and II groups (p = 0.012). The incidence of thigh paraesthesia was also considerably higher in the PMSG III group at 34.1% (p = 0.015), compared to 9.5% and 8.3% in the PMSG I and II groups. Among the patients, 12.4% exhibited a teardrop‐shaped PM, with the majority (90.9%) belonging to the PMSG III group (p = 0.012). Additionally, the PMSG III group demonstrated a higher estimated blood loss (p = 0.007) and significantly worse clinical scores at the 1‐week follow‐up assessment (p

Abstract Background Intermediate vertebral collapse is a newly discovered complication of consecutive two-level anterior cervical discectomy and fusion (ACDF). There have been no analytical studies related to the effects of endplate defects on the biomechanics of the intermediate vertebral bone after ACDF. This study aimed to compare the effects of endplate defects on the intermediate vertebral bone biomechanics in the zero-profile (ZP) and cage-and-plate (CP) methods of consecutive 2-level ACDF and to determine whether collapse of the intermediate vertebra is more likely to occur using ZP. Methods A three-dimensional finite element (FE) model of the intact cervical spine (C2–T1) was constructed and validated. The intact FE model was then modified to build ACDF models and imitate the situation of endplate injury, establishing two groups of models (ZP, IM-ZP and CP, IM-ZP). We simulated cervical motion, such as flexion, extension, lateral bending and axial rotation, and compared the range of motion (ROM), upper and lower endplate stress, fusion fixation device stress, C5 vertebral body stress, intervertebral disc internal pressure (intradiscal pressure, or IDP) and the ROM of adjacent segments in the models. Results There was no significant difference between the IM-CP model and the CP model in the ROM of the surgical segment, upper and lower endplate stress, fusion fixation device stress, C5 vertebral body stress, IDP, or ROM of the adjacent segments. Compared with the CP model, the endplate stress of the ZP model is significantly higher in the flexion, extension, lateral bending and axial rotation conditions. Compared with the ZP model, endplate stress, screw stress, C5 vertebral stress and IDP in IM-ZP were significantly increased under flexion, extension, lateral bending and axial rotation conditions. Conclusions Compared to consecutive 2-level ACDF using CP, collapse of the intermediate vertebra is more likely to occur using ZP due to its mechanical characteristics. Intraoperative endplate defects of the anterior lower margin of the middle vertebra are a risk factor leading to collapse of the middle vertebra after consecutive 2-level ACDF using ZP.

Abstract Background Ferroptosis has been linked to tumor progression and resistance to antineoplastic therapy. Long noncoding RNA (lncRNA) exerts a regulatory role in various biological processes of tumor cells, while the function and molecular mechanism of lncRNA in ferroptosis are yet to be clarified in glioma. Methods Both gain-of-function and loss-of-function experiments were employed to investigate the effects of SNAI3-AS1 on the tumorigenesis and ferroptosis susceptibility of glioma in vitro and in vivo. Bioinformatics analysis, Bisulfite sequencing PCR, RNA pull-down, RIP, MeRIP and dual-luciferase reporter assay were performed to explore the low expression mechanism of SNAI3-AS1 and the downstream mechanism of SNAI3-AS1 in ferroptosis susceptibility of glioma. Results We found that ferroptosis inducer erastin downregulates SNAI3-AS1 expression in glioma by increasing the DNA methylation level of SNAI3-AS1 promoter. SNAI3-AS1 functions as a tumor suppressor in glioma. Importantly, SNAI3-AS1 enhances the anti-tumor activity of erastin by promoting ferroptosis both in vitro and in vivo. Mechanistically, SNAI3-AS1 competitively binds to SND1 and perturbs the m6A-dependent recognition of Nrf2 mRNA 3’UTR by SND1, thereby reducing the mRNA stability of Nrf2. Rescue experiments confirmed that SND1 overexpression and silence can rescue the gain- and loss-of-function ferroptotic phenotypes of SNAI3-AS1, respectively. Conclusions Our findings elucidate the effect and detailed mechanism of SNAI3-AS1/SND1/Nrf2 signalling axis in ferroptosis, and provide a theoretical support for inducing ferroptosis to improve glioma treatment.

Background Cage retropulsion after transforaminal lumbar interbody fusion (TLIF) is a common complication that is more frequently detected in the early postoperative period. Revision in the early stages is relatively less difficult in symptomatic cases. However, cage retropulsion is quite rare for patients with intervertebral osseous fusion in the long term after TLIF, and there are no relevant reports related to the revision plan. Case presentation Here, we report a case of a patient who underwent L4‐S1 TLIF at another hospital 4 years ago, accompanied by recurrent pain and discomfort of the left lower limb after the operation. Due to recent condition aggravation, it was considered to be caused by compression of the nerve root due to cage retropulsion. Nerve root sealing and endoscopy surgery were performed on the operative segment. It was found that cage retropulsion at the L4/5 level was a suspicious focus according to careful analysis of the clinical manifestations of the patient. Selective block of the nerve root on the level resulted in relief of the patient's original symptoms. After the posterior edge of the cage was exposed under the endoscope through an intervertebral foramen approach, the posterior edge of the cage protruding into the spinal canal was removed by high‐speed burr grinding, working casing reduction and other methods. Postoperative symptoms of pain in the low back and lower limb were relieved completely. Conclusions It is feasible to use the power system to remove the retrograde cage under the endoscope through the intervertebral foramen approach for the revision of symptomatic polyether ether ketone (PEEK) cage retropulsion in the long term after TLIF.

Starch is the main carbohydrate source in the food system, and its hydrothermal stability during food processing is closely related to its pasting properties and nutritional functionalities. By improving the hydrothermal stability of starch, the digestion rate and degree of starch in vivo can be significantly delayed, which is of great significance for the regulation of blood glucose in vivo. From the viewpoint of the intrinsic relationships between the multi-scale structures and functionalities of starch, this review summarizes the evaluation index and evaluation method of starch hydrothermal stability and systematically discusses the key structures and processing technologies affecting starch hydrothermal stability. The pathways to modulate starch hydrothermal stability are also discussed. Additionally, perspectives regarding the current of starch hydrothermal stability modulation are proposed, which may provide theoretical foundation for the development of starch-based functional foods.

Abstract Diffuse invasion is an important factor leading to treatment resistance and a poor prognosis in gliomas. Herein, we found that expression of the tripartite motif containing 56 (TRIM56), a RING-finger domain containing E3 ubiquitin ligase, was markedly higher in glioma than in normal brain tissue, and was significantly correlated with malignant phenotypes and a poor prognosis. In vitro and in vivo experimental studies revealed that TRIM56 promoted the migration and invasion of glioma cells. Mechanistically, TRIM56 was transcriptionally regulated by SP1 and promoted the K48-K63-linked poly-ubiquitination transition of IQGAP1 at Lys-1230 by interacting with it, which in turn promoted CDC42 activation. This mechanism was confirmed to mediate glioma migration and invasion. In conclusion, our study provides insights into the mechanisms through which TRIM56 promotes glioma motility, i.e., by regulating IQGAP1 ubiquitination to promote CDC42 activation, which might be clinically targeted for the treatment of glioma.

Background: Radiotherapy and surgery are the standard local treatments for lung cancer brain metastases (BMs). However, limited studies focused on the effects of radiotherapy and surgery in lung cancer BMs with poor prognosis factors. Methods: We retrospectively analyzed 714 patients with lung cancer BMs. Analyses of overall survival (OS) and risk factors for OS were assessed by the log-rank test and Cox proportional hazard model. Results: Age ≥ 65 years, a Karnofsky Performance Scale (KPS) score ≤ 70, anaplastic large-cell lymphoma kinase (ALK)/epidermal growth factor receptor (EGFR) wild type, and extracranial metastases were related to poor prognosis. Patients were stratified according to these poor prognosis factors. In patients with the ALK/EGFR wild type, whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and surgery improved the OS of patients. WBRT and SRS were the independent protective factors for OS. In patients with extracranial metastases, patients who received WBRT plus SRS or WBRT alone had longer OS than those who did not receive radiotherapy. WBRT plus SRS and WBRT were the independent protective factors for OS. Conclusions: Radiotherapy and surgery are associated with improved survival for lung cancer BMs with the ALK/EGFR wild type. Radiotherapy is associated with improved survival in lung cancer BMs with extracranial metastases.

The extracellular matrix (ECM) plays a vital role in the progression and metastasis of glioma and is an important part of the tumor microenvironment. The matrisome is composed of ECM components and related proteins. There have been several studies on the effects of matrisomes on the glioma immune microenvironment, but most of these studies were performed on individual glioma immune‐related matrisomes rather than integral analysis. Hence, an overall analysis of all potential immune‐related matrisomes in gliomas is needed. Here, we divided 667 glioma patients in The Cancer Genome Atlas (TCGA) database into low, moderate, and high immune infiltration groups. Immune‐related matrisomes differentially expressed among the three groups were analyzed, and a risk signature was established. Eight immune‐related matrisomes were screened, namely, LIF, LOX, MMP9, S100A4, SRPX2, SLIT1, SMOC1, and TIMP1. Kaplan–Meier analysis, operating characteristic curve analysis, and nomogram were constructed to analyze the relationships between risk signatures and the prognosis of glioma patients. The risk signature was significantly correlated with the overall survival of glioma patients. Both high‐ and low‐risk signatures were also associated with some immune checkpoints. In addition, analysis of somatic mutations and anti‐PD1/L1 immunotherapy responses in the high‐ and low‐risk groups showed that the high‐risk group had worse prognosis and a higher response to anti‐PD1/L1 immunotherapy. Our analysis of immune‐related matrisomes may improve understanding of the characteristics of the glioma immune microenvironment and provide direction for glioma immunotherapy development in the future.

Abstract Egg production traits are economically important in laying ducks. Genetic molecular mechanisms and candidate genes underlying these traits remain unclear. In this study, whole genome variants were identified through whole-genome resequencing using three high-egg producing (HEN) and three low-egg producing (LEN) laying ducks. The gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genome (KEGG) pathways for the genes of common differential variants between HEN and LEN ducks were determined. Frizzled class receptor 6 (FZD6) was further genotyped using the Sequenom MassARRAY iPLEX platform. The association of FZD6 gene polymorphisms with 73 egg production and weight traits in 329 female ducks were estimated. A total of 65,535 single nucleotide polymorphisms (SNPs) and 4,702 indels were identified across the genome. Fourteen GO terms and 14 KEGG pathways were determined for the genes of common differential variants, including MAPK signaling, Wnt signaling, melanogenesis and calcium signaling pathways, which are key functional pathways for poultry egg production reported in previous reports. Further analysis showed that 27 SNPs of FZD6 were associated with three early egg production of duck and egg weight traits, including egg production at 17 weeks (EP17), 18 weeks (EP18) and 19 weeks (EP19) and egg weight at 59 weeks (EW59). The FZD6 should be considered a novel candidate gene for egg production traits in laying ducks.

Endoscopic endonasal approach has been widely used for removing various sellae tumors including pituitary adenomas, meningiomas, etc. While, performing these surgeries in such a narrow space with different instruments remains a challenge for surgeons, due to the limited field of view, varying illumination, and occlusion of instruments during the operation. Thus, a proper surgical instrument detection method that can provide classification and location information of the operated surgical instrument is critical for surgeons to understand the surgical scenarios and enhance the safety of the clinical operation. To this end, we propose an anchor-free feature aggregation network (AFA-Net) to improve the detection precision of surgical instruments from the endoscopic operation view field. The proposed method utilizes the improved feature pyramid network (FPN) with the depthwise separable convolution and a weighted feature aggregation module to enhance the feature information of the operated surgical instruments. Based on the anchor-free method, a weighted heatmap aggregation module is used to detect surgical instruments. Experimental studies on a public dataset Cholec80 and an intraoperative dataset from a local hospital are conducted, and the detection performance is assessed by the mean precision (AP) and average recall (AR). From both datasets and comparisons, the proposed method achieves 74.1% AP, 67.0% AR and 73.6% AP, 66.7% AR, respectively, which show significant advantages over five mainstream methods in terms of detection performance.

Abstract Background Glioma is the most prevalent primary tumor of the central nervous system. Glioblastoma multiforme (GBM) is the most malignant form of glioma with an extremely poor prognosis. A novel, regulated cell death form of copper-induced cell death called “cuproptosis” provides a new prospect for cancer treatment by regulating cuproptosis. Methods Data from bulk RNA sequencing (RNA-seq) analysis (The Cancer Genome Atlas cohort and Chinese Glioma Genome Atlas cohort) and single cell RNA-seq (scRNA-seq) analysis were integrated to reveal their relationships. A scoring system was constructed according to the cuproptosis-related gene expression, and core genes were experimentally verified using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot (WB), immunohistochemistry (IHC), and immunofluorescence (IF). Moreover, cell counting kit-8 (CCK8), colony formation, 5-ethynyl-2’-deoxyuridine (EdU) incorporation, transwell, and flow cytometry cell cycle were performed to evaluate cell proliferation, invasion, and migration. Results The Cuproptosis Activation Scoring (CuAS) Model has stable and independent prognostic efficacy, as verified by two CGGA datasets. Epiregulin (EREG), the gene of the model has the most contributions in the principal component analysis (PCA), is an onco-immunological gene that can affect immunity by influencing the expression of programmed death-ligand 1 (PD-L1) and mediate the process of cuproptosis by influencing the expression of ferredoxin 1 (FDX1). Single cell transcriptome analysis revealed that high CuAS GBM cells are found in vascular endothelial growth factor A (VEGFA) + malignant cells. Oligodendrocyte transcription factor 1 (OLIG1) + malignant is the original clone, and VEGF and CD99 are the differential pathways of specific cell communication between the high and low CuAS groups. This was also demonstrated by immunofluorescence in the tissue sections. Furthermore, CuAS has therapeutic potential for immunotherapy, and we predict that many drugs (methotrexate, NU7441, KU -0063794, GDC-0941, cabozantinib, and NVP-BEZ235) may be used in patients with high CuAS. Conclusion EREG is the core onco-immunological biomarker of CuAS and modulates the cross-talk between VEGF and CD99 signaling in glioblastoma, and CuAS may provide support for immunotherapy and chemotherapy.

Benzalkonium chloride (BC) is widely used for disinfection in the food industry. However, Listeria monocytogenes strains with resistance to BC have been reported recently. In L. monocytogenes, the Agr communication system consists of a membrane-bound peptidase AgrB, a precursor peptide AgrD, a histidine kinase (HK) AgrC, and a response regulator (RR) AgrA. Our previous study showed that the agr genes are significantly upregulated by BC adaptation. This study aimed to investigate the role of the Agr system in BC resistance in L. monocytogenes. Our results showed that the Agr system was involved in BC resistance. However, a direct interaction between BC and AgrC was not observed, nor between BC and AgrA. These results indicated that BC could induce the Agr system via an indirect action. Both AgrBD and AgrC were required for growth under BC stress. Nevertheless, when exposed to BC, the gene deletion mutant ∆agrA strain exhibited better growth performance than its parental strain. The RR Lmo1172 played a role in BC resistance in the ∆agrA strain, suggesting that Lmo1172 may be an alternative to AgrA in the phosphotransfer pathway. Phosphorylation of Lmo1172 by AgrC was observed in vitro. The cognate HK Lmo1173 of Lmo1172 was not involved in BC stress, regardless of whether it was as the wild-type or the ∆agrA mutant strain. Our evidence suggests that the HK AgrC cross-phosphorylates its noncognate RR Lmo1172 to cope with BC stress when the cognate RR AgrA is absent. In vivo, further studies will be required to detect phosphotransfer of AgrC/AgrA and AgrC/Lmo1172.

Objective To investigate the effect of the in situ screw implantation region and angle on the stability of lateral lumbar interbody fusion (LLIF) from a biomechanical perspective. Methods A validated L2‐4 finite element (FE) model was modified for simulation. The L3‐4 fused segment undergoing LLIF surgery was modeled. The area between the superior and inferior edges and the anterior and posterior edges of the vertebral body (VB) is divided into four zones by three parallel lines in coronal and horizontal planes. In situ screw implantation methods with different angles based on the three parallel lines in coronal plane were applied in Models A, B, and C (A: parallel to inferior line; B: from inferior line to midline; C: from inferior line to superior line). In addition, four implantation methods with different regions based on the three parallel lines in horizontal plane were simulated as types 1–2, 1–3, 2–2, and 2–3 (1–2: from anterior line to midline; 1–3: from anterior line to posterior line; 2–2: parallel to midline; 2–3: from midline to posterior line). L3‐4 ROM, interbody cage stress, screw‐bone interface stress, and L4 superior endplate stress were tracked and calculated for comparisons among these models. Results The L3‐4 ROM of Models A, B, and C decreased with the extent ranging from 47.9% (flexion‐extension) to 62.4% (lateral bending) with no significant differences under any loading condition. Types 2–2 and 2–3 had 45% restriction, while types 1–2 and 1–3 had 51% restriction in ROM under flexion‐extension conditions. Under lateral bending, types 2–2 and 2–3 had 70.6% restriction, while types 1–2 and 1–3 had 61.2% restriction in ROM. Under axial rotation, types 2–2 and 2–3 had 65.2% restriction, while types 1–2 and 1–3 had 59.3% restriction in ROM. The stress of the cage in types 2–2 and 2–3 was approximately 20% lower than that in types 1–2 and 1–3 under all loading conditions in all models. The peak stresses at the screw‐bone interface in types 2–2 and 2–3 were much lower (approximately 35%) than those in types 1–2 and 1–3 under lateral bending, while no significant differences were observed under flexion‐extension and axial rotation. The peak stress on the L4 superior endplate was approximately 30 MPa and was not significantly different in all models under any loading condition. Conclusions Different regions of entry‐exit screws induced multiple screw trajectories and influenced the stability and mechanical responses. However, different implantation angles did not. Considering the difficulty of implantation, the ipsilateral‐contralateral trajectory in the lateral middle region of the VB can be optimal for in situ screw implantation in LLIF surgery.

Abstract Background Glioma is the most common cancer in the central nervous system, and low grade gliomas are notorious for many types of tumors and heterogeneity. PROS1 not only plays an important role in the blood coagulation system, and recent studies have found that it was correlated with the development of tumors, especially related to tumor immune infiltration. However, the study of underlying role and mechanism of PROS1 in gliomas, especially in low-grade gliomas, is almost absent. Methods We integrated the information of patients with LGG in The Cancer Genome Atlas (TCGA) cohort and Chinese Glioma Genome Atlas (CGGA) cohort. Then, we systematically demonstrated the differences and prognostic prognosis value of PROS1 based on multi-omics analyses. In addition, Cell counting kit-8 (CCK-8) assay, colony formation assay, 5-Ethynyl-2’-deoxyuridine (EdU) incorporation assay, and Transwell assays were performed to evaluate cell proliferation and invasion. qRT-PCR and immunohistochemistry were used to evaluate the expression of PROS1 in LGG. Results Various bioinformatics approaches revealed that PROS1 was a valuable prognostic marker and may influence tumour development via distinct mechanisms, including expression of DNA methyltransferase, RNA modification, and DNA mismatch repair system genes, copy number variation, single nucleotide variation frequency, genomic heterogeneity, cancer stemness, DNA methylation, and alternative PROS1 splicing. Our analyses indicated that the long non-coding RNA RP3-525N10.2 may “decoy” or “guide” the transcription factor NFKB1 and prevent its association with PROS1, thereby reducing PROS1 expression and improving poor LGG prognosis. PROS1 expression was also closely associated with tumour infiltration by immune cells, especially tumour-associated macrophages, as well as the expression of various immune checkpoint inhibitors, immunomodulators, and immune cell markers. Conclusion long non-coding RNA RP3-525N10.2-NFKB1-PROS1 triplet-mediated PROS1 expression could serve as a biomarker for cancer diagnosis, prognosis, therapy selection, and follow-up in LGG patients.

Abstract Due to the negligence of the complex tumor immune microenvironment, traditional treatment for glioblastoma has reached its limitation and cannot achieve a satisfying outcome in the past decade. The emergence of immunotherapy based on the theory of cancer-immunity cycle has brought a new dawn to glioblastoma patients. However, the results of most phase II and phase III clinical trials are not optimistic due to the simple focus on T cells activation rather than other immune cells involved in anti-tumor immunity. NK cells play a critical role in both innate and adaptive immunity, having the ability to coordinate immune response in inflammation, autoimmune disease and cancer. They are expected to cooperate with T cells to maximize the anti-tumor immune effect and have great potential in treating glioblastoma. Here, we describe the traditional treatment methods and current immunotherapy strategies for glioblastoma. Then, we list a microenvironment map and discuss the reasons for glioblastoma inhibitory immunity from multiple perspectives. More importantly, we focus on the advantages of NK cells as potential immune regulatory cells and the ways to maximize their anti-tumor immune effect. Finally, our outlook on the directions and potential applications of NK cell-based therapy combining with the advance technologies is presented. This review depicts NK cell awakening as the precondition to unleash the cancer-immunity cycle against glioblastoma and elaborate this idea from biology to clinical treatment.

ABSTRACT The Agr quorum sensing (QS) system is known to contribute to biofilm formation in Listeria monocytogenes. Cinnamaldehyde, a natural food preservative, is considered an inhibitor of Agr-mediated QS in L. monocytogenes. However, the exact mechanism by which cinnamaldehyde acts on Agr remains unclear. In this study, we assessed the effects of cinnamaldehyde on the histidine kinase AgrC and the response regulator AgrA in the Agr system. AgrC kinase activity was not influenced by cinnamaldehyde, and binding between AgrC and cinnamaldehyde was not observed when microscale thermophoresis (MST) was performed, indicating that AgrC was not the target of cinnamaldehyde. AgrA is specifically bound to the agr promoter (P2) to activate the transcription of the Agr system. However, AgrA-P2 binding was prevented by cinnamaldehyde. The interaction between cinnamaldehyde and AgrA was further confirmed with MST. Two conserved amino acids, Asn-178 and Arg-179, located in the LytTR DNA-binding domain of AgrA, were identified as the key sites for cinnamaldehyde-AgrA binding by alanine mutagenesis and MST. Coincidentally, Asn-178 was also involved in the AgrA-P2 interaction. Taken together, these results suggest that cinnamaldehyde acts as a competitive inhibitor of AgrA in AgrA-P2 binding, which leads to suppressed transcription of the Agr system and reduced biofilm formation in L. monocytogenes. IMPORTANCE Listeria monocytogenes can form biofilms on various food contact surfaces, posing a serious threat to food safety. Biofilm formation of L. monocytogenes is positively regulated by the Agr quorum sensing system. Thus, an alternative strategy for controlling L. monocytogenes biofilms is interfering with the Agr system. Cinnamaldehyde is considered an inhibitor of the L. monocytogenes Agr system; however, its exact mechanism of action is still unclear. Here, we found that AgrA (response regulator), rather than AgrC (histidine kinase), was the target of cinnamaldehyde. The conserved Asn-178 in the LytTR DNA-binding domain of AgrA was involved in cinnamaldehyde-AgrA and AgrA-P2 binding. Therefore, the occupation of Asn-178 by cinnamaldehyde suppressed transcription of the Agr system and reduced biofilm formation in L. monocytogenes. Our findings could provide a better understanding of the mechanism by which cinnamaldehyde inhibits L. monocytogenes biofilm formation.

Abstract Tumor‐associated macrophage (TAM) infiltration facilitates glioma malignancy, but the underlying mechanisms remain unclear. Herein, it is reported that TAMs secrete exosomal LINC01232 to induce tumor immune escape. Mechanistically, LINC01232 is found to directly bind E2F2 and promote E2F2 entry into the nucleus; the two synergistically promots the transcription of NBR1. The increase in binding between NBR1 binding and the ubiquitinating MHC‐I protein through the ubiquitin domain causes an increase in the degradation of MHC‐I in autophagolysosomes and a decrease in the expression of MHC‐I on the surface of tumor cells, which in turn led to tumor cell escape from CD8+ CTL immune attack. Disruption of E2F2/NBR1/MHC‐I signaling with shRNAs or blockade with the corresponding antibodies largely abolishes the tumor‐supportive effects of LINC01232 and inhibits tumor growth driven by M2‐type macrophages. Importantly, knockdown of LINC01232 enhances the expression of MHC‐I on the surface of tumor cells and improves the response to reinfusion with CD8+ T cells. This study reveals the existence of critical molecular crosstalk between TAMs and glioma mediates through the LINC01232/E2F2/NBR1/MHC‐I axis to support malignant tumor growth, indicating that targeting this axis may have therapeutic potential.

Background: Ossification of ligamentum flavum (OLF) is a hidden, indolent disease condition with variable unexplained etiology and pathology. Growing evidences show a correlation between senile osteoporosis (SOP) and OLF, but the fundamental relationship between SOP and OLF remains unclear. Therefore, the purpose of this work is to investigate unique SOP-related genes and their potential functions in OLF. Methods: Gene Expression Omnibus (GEO) database was utilized to gather the mRNA expression data (GSE106253) and then analyzed by R software. A variety of methods, including ssGSEA, machine learning (LASSO and SVM-RFE), GO and KEGG enrichment, PPI network, transcription factor enrichment analysis (TFEA), GSEA and xCells were employed to verified the critical genes and signaling pathways. Furthermore, ligamentum flavum cells were cultured and used in vitro to identify the expression of the core genes. Results: The preliminary identification of 236 SODEGs revealed their involvement in BP pathways associated with ossification, inflammation, and immune response, including the TNF signaling pathway, PI3K/AKT signaling pathway and osteoclast differentiation. Four down-regulated genes (SERPINE1, SOCS3, AKT1, CCL2) and one up-regulated gene (IFNB1) were among the five hub SODEGs that were validated. Additionally, they were performed by ssGSEA and xCell to show the relationship of immune cells infiltrating in OLF. The most fundamental gene, IFNB1, which was only found in the classical ossification- and inflammation-related pathways, suggested that it may affect OLF via regulating the inflammatory response. In vitro experiment, we found that IFNB1 expression was dramatically higher in cells cocultured with osteogenic induction than in controls. Conclusion: As far as we are concerned, this is the first observation using transcriptome data mining to reveal distinct SOP-related gene profiles between OLF and normal controls. Five hub SODEGs were ultimately found using bioinformatics algorithms and experimental verification. These genes may mediate intricate inflammatory/immune responses or signaling pathways in the pathogenesis of OLF, according to the thorough functional annotations. Since IFNB1 was discovered to be a key gene and was connected to numerous immune infiltrates in OLF, it is possible that IFNB1 expression has a substantial impact on the pathogenesis of OLF. Our research will give rise to new possibilities for potential therapeutics that target SOP reverent genes and immune-associated pathways in OLF.

Background Plastrum testudinis (PT), a widely used traditional Chinese medicine, exerts protective effects against bone diseases such as intervertebral disc degeneration (IDD). Despite its effectiveness, the molecular mechanisms underlying the effects of PT on IDD remain unclear. Methods In this study, we used a comprehensive strategy combining bioinformatic analysis with experimental verification to investigate the possible molecular mechanisms of PT against IDD. We retrieved targets for PT and IDD, and then used their overlapped targets for protein–protein interaction (PPI) analysis. In addition, we used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to investigate the anti-IDD mechanisms of PT. Moreover, in vivo and in vitro experiment validations including hematoxylin–eosin (HE) and safranine O-green staining, senescence-associated β-galactosidase (SA-β-gal) assay, cell immunofluorescence staining, intracellular ROS measurement and Western blot analysis were performed to verify bioinformatics findings. Results We identified 342 and 872 PT- and IDD-related targets (32 overlapping targets). GO enrichment analysis yielded 450 terms related to oxidative stress and inflammatory response regulation. KEGG analysis identified 48 signaling pathways, 10 of which were significant; the TNF-α signaling pathway had the highest p-value, and prostaglandin G/H synthase 2 (PTGS2), endothelin-1 (EDN1), TNF-α, JUN and FOS were enriched in this pathway. Histopathological results and safranin O/green staining demonstrated that PT attenuated IDD, and SA-β-gal assay showed that PT ameliorated nucleus pulposus cell (NPC) senescence. An ROS probe was adopted to confirm the protective effect of PT against oxidative stress. Western blot analyses confirmed that PT downregulated the protein expression of PTGS2, EDN1, TNF-α, JUN and FOS in the TNF-α signaling pathway as well as cellular senescence marker p16, proinflammatory cytokine interleukin-6 (IL6), while PT upregulated the expression of NPC-specific markers including COL2A1 and ACAN in a concentration-dependent manner. Conclusions To the best of our knowledge, this study is the first to report that PT alleviates IDD by downregulating the protein expression of PTGS2, EDN1, TNF-α, JUN and FOS in the TNF-α signaling pathway and upregulating that of COL2A1 and ACAN, thus suppressing inflammatory responses and oxidative stress in NPCs.

BackgroundPostmenopausal osteoporosis (PMOP) is a common bone disorder. Existing study has confirmed the role of exosome in regulating RNA N6-methyladenosine (m6A) methylation as therapies in osteoporosis. However, it still stays unclear on the roles of m6A modulators derived from serum exosome in PMOP. A comprehensive evaluation on the roles of m6A modulators in the diagnostic biomarkers and subtype identification of PMOP on the basis of GSE56815 and GSE2208 datasets was carried out to investigate the molecular mechanisms of m6A modulators in PMOP.MethodsWe carried out a series of bioinformatics analyses including difference analysis to identify significant m6A modulators, m6A model construction of random forest, support vector machine and nomogram, m6A subtype consensus clustering, GO and KEGG enrichment analysis of differentially expressed genes (DEGs) between different m6A patterns, principal component analysis, and single sample gene set enrichment analysis (ssGSEA) for evaluation of immune cell infiltration, experimental validation of significant m6A modulators by real-time quantitative polymerase chain reaction (RT-qPCR), etc.ResultsIn the current study, we authenticated 7 significant m6A modulators via difference analysis between normal and PMOP patients from GSE56815 and GSE2208 datasets. In order to predict the risk of PMOP, we adopted random forest model to identify 7 diagnostic m6A modulators, including FTO, FMR1, YTHDC2, HNRNPC, RBM15, RBM15B and WTAP. Then we selected the 7 diagnostic m6A modulators to construct a nomogram model, which could provide benefit with patients according to our subsequent decision curve analysis. We classified PMOP patients into 2 m6A subtypes (clusterA and clusterB) on the basis of the significant m6A modulators via a consensus clustering approach. In addition, principal component analysis was utilized to evaluate the m6A score of each sample for quantification of the m6A subgroups. The m6A scores of patients in clusterB were higher than those of patients in clusterA. Moreover, we observed that the patients in clusterA had close correlation with immature B cell and gamma delta T cell immunity while clusterB was linked to monocyte, neutrophil, CD56dim natural killer cell, and regulatory T cell immunity, which has close connection with osteoclast differentiation. Notably, m6A modulators detected by RT-qPCR showed generally consistent expression levels with the bioinformatics results.ConclusionIn general, m6A modulators exert integral function in the pathological process of PMOP. Our study of m6A patterns may provide diagnostic biomarkers and immunotherapeutic strategies for future PMOP treatment.

Background: To reveal candidate genes and the molecular genetic mechanism underlying primary feather color trait in ducks, a genome-wide association study (GWAS) for the primary feather color trait was performed based on the genotyping-by-sequencing (GBS) technology for a native Chinese female duck, Longyan Shan-ma ducks.Methods: Blood genomic DNA from 314 female Longyan Shan-ma duck were genotyped using GBS technology. A GWAS for the primary feather color trait with genome variations was performed using an univariate linear mixed model based on all SNPs in autosomes.Results: Seven genome-wide significant single nucleotide polymorphisms (SNPs, Bonferroni-adjusted p-value

ObjectiveMicroelectrode recording (MER) guided subthalamic nucleus deep brain stimulation (STN-DBS) under local anesthesia (LA) is widely applied in the management of advanced Parkinson's disease (PD). Whereas, awake DBS under LA is painful and burdensome for PD patients. We analyzed the influence of general anesthesia (GA) on intraoperative MER, to assess the feasibility and effectiveness of GA in MER guided STN-DBS.MethodsRetrospective analysis was performed on the PD patients, who underwent bilateral MER guided STN-DBS in Wuhan Union Hospital from July 2019 to December 2021. The patients were assigned to LA or GA group according to the anesthetic methods implemented. Multidimensional parameters, including MER signals, electrode implantation accuracy, clinical outcome and adverse events, were analyzed.ResultsA total of 40 PD patients were enrolled in this study, including 18 in LA group and 22 in GA group. There were no statistically significant differences in patient demographics and baseline characteristics between two groups. Although, the parameters of MER signal, including frequency, inter-spike interval (ISI) and amplitude, were obviously interfered under GA, the waveforms of MER signals were recognizable and shared similar characteristics with LA group. Both LA and GA could achieve effective electrode implantation accuracy and clinical outcome. They also shared similar adverse events postoperatively.ConclusionGA is viable and comparable to LA in MER guided STN-DBS for PD, regarding electrode implantation accuracy, clinical outcome and adverse events. Notably, GA is more friendly and acceptable to the patients who are incapable of enduring intraoperative MER under LA.

BackgroundNicotinamide adenine dinucleotide (NAD+) metabolism is involved in a series of cancer pathogenesis processes, and is considered a promising therapeutic target for cancer treatment. However, a comprehensive analysis of NAD+ metabolism events on immune regulation and cancer survival has not yet been conducted. Here, we constructed a prognostic NAD+ metabolism-related gene signature (NMRGS) associated with immune checkpoint inhibitor (ICI) efficacy in glioma.Methods40 NAD+ metabolism-related genes (NMRGs) were obtained from the Reactome database and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Glioma cases with transcriptome data and clinical information were obtained from Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA). NMRGS was constructed based on the calculated risk score using univariate analysis, Kaplan–Meier analysis, multivariate Cox regression, and nomogram. This NMRGS was verified in training (CGGA693) and validation (TCGA and CGGA325) cohorts. The immune characteristics, mutation profile, and response to ICI therapy were subsequently analyzed for different NMRGS subgroups.ResultsSix NAD+ metabolism-related genes, including CD38, nicotinamide adenine dinucleotide kinase (NADK), nicotinate phosphoribosyltransferase (NAPRT), nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3 (NMNAT3), poly(ADP-Ribose) polymerase family member 6 (PARP6), and poly(ADP-Ribose) polymerase family member 9 (PARP9), were ultimately used to construct a comprehensive risk model for glioma patients. Patients in the NMRGS-high group showed a poorer survival outcome than those in the NMRGS-low group. The area under curve (AUC) indicated that NMRGS has good potential in glioma prognostic prediction. A nomogram with improved accuracy was established based on independent prognostic factors (NMRGS score, 1p19q codeletion status, and WHO grade). Furthermore, patients in the NMRGS-high group showed a more immunosuppressive microenvironment, higher tumor mutation burden (TMB), higher human leucocyte antigen (HLA) expression and a more therapeutic response to ICI therapy.ConclusionsThis study constructed a prognostic NAD+ metabolism-related signature associated with the immune landscape in glioma, which can be used for guiding individualized ICI therapy.

ObjectiveLocal anesthesia (LA) is recommended for percutaneous transforaminal endoscopic discectomy(PTED), but satisfactory pain management is not mostly achieved. The goal of this study was to examine the clinical efficacy of PTED for lumbar disc herniation when performed under local anaesthetic vs. general anesthesia (GA).MethodsFrom August 2018 to August 2020, the clinical data of 108 patients treated with PTED were retrospectively evaluated and separated into two groups: LA and GA based on the anesthesia method. General information and clinical outcomes of patients were included. Visual analog scale (VAS) and Oswestry disability index (ODI) were recorded before operation, 1 week after operation, and 1 year after operation. In addition, VAS for back pain and leg pain on the second postoperative day were also recorded.ResultsWe divided the patients into two groups: 72 in LA and 36 in GA. There were no significant differences in gender, age, course of disease, body mass index, surgical segment, duration of operation, intraoperative bleeding, time of fluoroscopy, length of hospital stay, total hospitalization cost reoperation, surgical satisfaction, Macnab satisfaction, complications, preoperative and 1 year postoperatively VAS for back pain and leg pain and ODI, VAS for leg pain on the second day and 1 week postoperatively between the two groups (P > 0.05). VAS for back pain in GA group on the second day postoperatively, as well as the VAS for back pain and ODI at one week postoperatively, were better than those in LA group (P 0.05).ConclusionLong-term outcomes were similar for both PTED under LA and GA, while GA group had better short-term outcomes, especially in middle-aged and elderly patients.

Chronic inflammation develops when the immune system is unable to clear a persistent insult. Unresolved chronic inflammation leads to immunosuppression to maintain the internal homeostatic conditions, which is mediated primarily by myeloid-derived suppressor cells (MDSCs). Toll-like receptors 2 (TLR2) has an important role in chronic inflammation and can be activated by a vast number and diversity of TLR2 ligands, for example Pam 2 CSK4. However, the regulatory effect of TLR2 signaling on MDSCs in chronic inflammation remains controversial. This study demonstrated that heat-killed Mycobacterium bovis BCG-induced pathology-free chronic inflammation triggered suppressive monocytic MDSCs (M-MDSCs) that expressed TLR2. Activation of TLR2 signaling by Pam 2 CSK4 treatment enhanced immunosuppression of M-MDSCs by upregulating inducible nitric oxide synthase (iNOS) activity and nitric oxide (NO) production partly through signal transducer and activator of transcription 3 (STAT3) activation. Thus, TLR2 has a fundamental role in promoting the MDSC-mediated immunosuppressive environment during chronic inflammation and might represent a potentially therapeutic target in chronic inflammation disease.

Abstract Background Emerging evidences have indicated that the aberrant liquid–liquid phase separation (LLPS) leads to the dysfunction of biomolecular condensates, thereby contributing to the tumorigenesis and progression. Nevertheless, it remains unclear whether or how the LLPS of specific molecules affects the prognosis and tumor immune microenvironment (TIME) of patients with lower-grade glioma (LGG). Methods We integrated the transcriptome information of 3585 LLPS-related genes to comprehensively evaluate the LLPS patterns of 423 patients with LGG in The Cancer Genome Atlas (TCGA) cohort. Then, we systematically demonstrated the differences among four LLPS subtypes based on multi-omics analyses. In addition, we constructed the LLPS-related prognostic risk score (LPRS) for individualized integrative assessment. Results Based on the expression profiles of 85 scaffolds, 355 regulators, and 3145 clients in LGG, we identified four LLPS subtypes, namely LS1, LS2, LS3 and LS4. We confirmed that there were significant differences in prognosis, clinicopathological features, cancer hallmarks, genomic alterations, TIME patterns and immunotherapeutic responses among four LLPS subtypes. In addition, a prognostic signature called LPRS was constructed for individualized integrative assessment. LPRS exhibited a robust predictive capacity for prognosis of LGG patients in multiple cohorts. Moreover, LPRS was found to be correlated with clinicopathological features, cancer hallmarks, genomic alterations and TIME patterns of LGG patients. The predictive power of LPRS in response to immune checkpoint inhibitor (ICI) therapy was also prominent. Conclusions This study provided a novel classification of LGG patients based on LLPS. The constructed LPRS might facilitate individualized prognosis prediction and better immunotherapy options for LGG patients.

Background and Aim: High-grade glioma is the most common malignant primary brain tumor in the central nervous system. Multiple strategies such as surgery, radiotherapy, and chemotherapy have been used, but the prognosis of patients with high-grade glioma remains poor. No standard treatment exists for recurrent gliomas; however, combination therapies of programmed cell death protein 1 blockades with antiangiogenic agents have demonstrated promising effects in different solid tumors. Therefore, since the end of 2020, a clinical trial designed to evaluate the safety and efficiency of neoadjuvant therapy using camrelizumab and apatinib in patients with recurrent high-grade gliomas has been carried out in our institution. Methods/Design: In this prospective, Phase II, single-arm study, patients with recurrent high-grade gliomas will receive single-dose intravenous injection of camrelizumab (200 mg) and daily oral administration of apatinib (250 mg/day for 7 days) 14 days before reoperation for tumor resection. Sequential therapy will begin 2 weeks after surgery with the biweekly injection of camrelizumab and 4 weeks after surgery with the daily administration of apatinib. Treatment of camrelizumab and apatinib will be continued until disease progression or unacceptable toxicity or death. The primary outcome measure will be the median overall survival rate. Secondary outcome measures will include progression-free survival rate at 6 months and at 12 months and other measures. The trial is planned to enroll 30 patients. This study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center (Guangzhou, China; approval No. SL-B2020-149-01) on July 27, 2020. Results and Conclusions: Although an evaluation is still impossible to be conducted yet, 11 patients had been enrolled by the end of January 2022. Some patients have shown a promising outcome. These preliminary data suggest that this study would be worthwhile. We hope that this study will provide scientific evidence to better care of patients with recurrent high-grade glioma. Trial registration: This study was registered with ClinicalTrials.gov under identifier NCT04588987 on October 19, 2020.

POLD4 plays a crucial part in the complex machinery of DNA replication and repair as a vital component of the DNA polymerase delta complex. In this research, we obtained original information from various publicly available databases. Using a blend of R programming and internet resources, we initiated an extensive examination into the correlation between POLD4 expression and the various elements of cancers. In addition, we performed knockdown experiments in glioma cell lines to authenticate its significant impact. We discovered that POLD4 is upregulated in various malignant tumors, demonstrating a significant correlation with poor patient survival prognosis. Using function analysis, it was uncovered that POLD4 exhibited intricate associations with signaling pathways spanning multiple tumor types. Subsequent investigations unveiled the close association of POLD4 with the immune microenvironment and the effectiveness of immunotherapy. Drugs like trametinib, saracatinib, and dasatinib may be used in patients with high POLD4. Using experimental analysis, we further confirmed the overexpression of POLD4 in gliomas, as well as its correlation with glioma recurrence, proliferation, and the suppressive immune microenvironment. Our research findings indicate that the expression pattern of POLD4 not only serves as a robust indicator of prognosis in cancer patients but also holds promising potential as a new focus for treatment.

Abstract Background Prolactinoma is the major cause of hyperprolactinemia, and dopamine agonists (DAs) are generally the first-line treatment for them. Several studies have reviewed the recurrent rate of hyperprolactinemia after DAs withdrawal. However, few of them have concerned the recurrence risk of prolactinoma following the withdrawal of DAs. Methods Three medical databases, PubMed, EMBASE and Cochrane library, were retrieved up to February, 14, 2021 to identify studies related to recurrence of prolactinoma and withdrawal of DAs. Statistical analyses including meta-analysis, sensitivity analysis, meta-regression, funnel plot and Egger test were performed through software R. Results A total of 3225 studies were retrieved from the three data bases, and 13 studies consisted of 616 patients and 19 arms were finally included in this systematic analysis. There was no significant heterogeneity among the included studies, and fixed effect model was thus used. The pooled recurrence proportion of prolactinoma after withdrawal of DA was 2% with a 95% confidence interval (CI) of 1–3%. Conclusion Our study showed a very low recurrent rate of prolactinomas after DAs withdrawal. Much more prospective studies with larger cases and longer follow-up period are encouraged to confirm our finding. Trial registration Registration number CRD42021245888 (PROSPERO).

Abstract Objective Postoperative cerebrospinal fluid (CSF) leakage represents a challenge even for experienced pituitary surgeons. We aimed to quantitatively synthesize data from studies regarding the risk factors for postoperative CSF leakage after transsphenoidal surgery (TSS) for pituitary adenoma (PA). Methods PubMed, Web of Science, The Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Wanfang database, and VIP database were searched for case–control and cohort studies, focusing on the risk factors associated with postoperative CSF leakage after TSS for PA. Pooled odds ratios (ORs) and 95% confidence intervals were calculated to determine the risk factors. Results A total of 34 case–control and cohort studies involving a total of 9,144 patients with PA were included in this systematic review. The overall rate of postoperative CSF leakage after TSS for PA was 5.6%. Tumor size, adenoma consistency, revision surgery, and intraoperative CSF leakage were independent risk factors for postoperative CSF leakage (ORs, 3.18–6.33). By contrast, the endoscopic approach showed a slight protective benefit compared with the microscopic approach in TSS (OR, 0.69). Conclusions This review provides a comprehensive overview of the quality of the evidence base, informing clinical staff of the importance of screening risk factors for postoperative CSF leakage after TSS for PA. More attention should be paid to PA patients at high risk for CSF leakage after TSS to reduce complications and improve prognosis.

EGFRvⅢ is an established target for immunotherapy of glioblastoma (GBM). Current study aims to explore the efficacy of EGFRvⅢ-targeted immunotoxin combined with temozolomide (TMZ) or T cell-engaged bispecific antibody for the treatment of GBM. We generated three rabbit monoclonal antibodies (R1, R2, and R6) that specifically bound to EGFRvⅢ, but not EGFR, with high affinity. Immunotoxins were made by fusing the scFv of these antibodies with engineered Pseudomonas exotoxin PE24. The in vitro cytotoxicity and specificity of the immunotoxins was rigorously validated by EGFRvⅢ and EGFR-expressed cell lines. The in vivo efficacy of immunotoxin monotherapy and in combination with TMZ or EGFRvⅢ-targeted bispecific antibody was evaluated in orthotopic and subcutaneous xenograft mouse models. EGFRvⅢ immunotoxins potently killed U87, U251 and GL261 cells that were forcefully expressing EGFRvⅢ, with IC50 values bellow 1.2 ng/ml. In a subcutaneous model, multiple intratumoral injections of immunotoxin at a dose of 2 mg/kg resulted in complete tumor regression in 3/5 of mice. In a C57BL/6 orthotopic glioblastoma model transplanted with GL261 cells that expressed a mouse version of EGFRvⅢ, two injections of 10 micrograms of immunotoxin in the lateral ventricles significantly improved the survival, with 2/5 mice being completely cured. Furthermore, in a subcutaneous xenograft model transplanted with EGFRvⅢ-expressed U87 cells, a single intratumoral injection of immuntoxin followed by i.v. injections of TMZ or EGFRvⅢ-targeted bispecific antibody achieved complete regression in mice. Taken together, EGFRvⅢ immunotoxin combined with TMZ or T cell-engaged bispecific antibody offers promise for curative treatment of GBM.

A correct preoperative diagnosis is essential for the treatment and prognosis of necrotic glioblastoma and brain abscess, but the differentiation between them remains challenging. We constructed a diagnostic prediction model with good performance and enhanced clinical applicability based on data from 86 patients with necrotic glioblastoma and 32 patients with brain abscess that were diagnosed between January 2012 and January 2020. The diagnostic values of three regions of interest based on contrast-enhanced T1 weighted images (including whole tumor, brain-tumor interface, and an amalgamation of both regions) were compared using Logistics Regression and Random Forest. Feature reduction based on the optimal regions of interest was performed using principal component analysis with varimax rotation. The performance of the classifiers was assessed by receiver operator curves. Finally, clinical predictors were utilized to detect the diagnostic power. The mean area under curve (AUC) values of the whole tumor model was significantly higher than other two models obtained from Brain-Tumor Interface (BTI) and combine regions both in training (AUC mean = 0.850) and test/validation set (AUC mean = 0.896) calculated by Logistics Regression and in the testing set (AUC mean = 0.876) calculated by Random Forest. Among these three diagnostic prediction models, the combined model provided superior discrimination performance and yielded an AUC of 0.993, 0.907, and 0.974 in training, testing, and combined datasets, respectively. Compared with the brain-tumor interface and the combined regions, features obtained from the whole tumor showed the best differential value. The radiomic features combined with the peritumoral edema/tumor volume ratio provided the prediction model with the greatest diagnostic performance.

Previous studies have shown that myristic acid (MA), a saturated fatty acid, could promote the proliferation and differentiation of neural stem cells in vitro. However, the effect of MA on hippocampal neurons aging has not been reported in vivo. Here we employed 22-month-old naturally aged C57BL/6 mice to evaluate the effect and mechanism of MA on hippocampal aging. First, we examined a decreased exploration and spatial memory ability in aging mice using the open field test and Morris water maze. Consistently, aging mice showed degenerative hippocampal histomorphology by H&E and Nissl staining. In terms of mechanism, imbalance of GABRB2 and GABRA2 expression in aging mice might be involved in hippocampus aging by mRNA high throughput sequencing (mRNA-seq) and immunohistochemistry (IHC) validation. Then, we revealed that MA alleviated the damage of exploration and spatial memory ability and ameliorated degeneration and aging of hippocampal neurons. Meanwhile, MA downregulated GABRB2 and upregulated GABRA2 expression, indicating MA might alleviate hippocampal aging correlated with GABAergic signaling. In conclusion, our findings revealed MA alleviated hippocampal aging correlated with GABAergic signaling, which might provide insight into the treatment of aging-associated diseases.

BackgroundTuberculum sellae meningioma (TSM), a common benign tumor in the sellae region, usually causes neurological deficits, such as vision impairment, by squeezing the peripheral neurovascular structures. Surgical management is recommended as the optimal strategy for TSM treatment and vision restoration. However, it remains challenging to resect TSM in the traditional transcranial approach (TCA). Recently, the endoscopic endonasal approach (EEA) has emerged as an effective option in skull base surgeries. Besides the effectivity, the advantages and limitations of EEA in TSM surgery remain controversial.ObjectWe compared the surgical outcomes and complications between TCA and EEA surgeries to identify the principles in TSM surgical management.MethodsRetrospective analysis was performed on the patients, who underwent TSM surgery in Wuhan Union Hospital between January 2017 and December 2021. The patients were assigned to TCA or EEA group according to the surgery they experienced. All patients were analyzed with the extent of tumor resection, vision outcome, postoperative complications, and follow-up results.ResultsA total of 112 patients were enrolled in this study, including 78 in TCA group and 34 in EEA group. The mean follow-up was 20.5 months (range 3–36 months). There were no statistically significant differences in patient demographic data, preoperative symptoms, and tumor characteristics between TCA and EEA groups. Both TCA and EEA surgeries are effective in TSM resection with relatively high gross total resection rates (85.9% in TCA vs. 91.2% in EEA, p > .05). Meanwhile, EEA surgery has a better outcome in vision restoration or stabilization than TCA surgery (74.6% in TCA vs. 93.1% in EEA, p