Decoding Macrophage Subtypes to Engineer Modulating Hydrogels for the Alleviation of Intervertebral Disk Degeneration.

A major pathological basis for low back pain is intervertebral disk degeneration, which is primarily caused by the degeneration of nucleus pulposus cells due to imbalances in extracellular matrix (ECM) anabolism and catabolism. The phenotype of macrophages in the local immune microenvironment greatly influences the balance of ECM metabolism. Therefore, the control over the macrophage phenotype of the ECM is promising to repair intervertebral disk degeneration. Herein, the preparation of an injectable nanocomposite hydrogel is reported by embedding epigallocatechin-3-gallate-coated hydroxyapatite nanorods in O-carboxymethyl chitosan cross-linked with aldehyde hyaluronic acid that is capable of modulating the phenotype of macrophages. The bioactive components play a primary role in repairing the nucleus pulposus, where the hydroxyapatite nanorods can promote anabolism in the ECM through the nucleopulpogenic differentiation of mesenchymal stem cells. In addition, epigallocatechin-3-gallate can decrease catabolism in the ECM in nucleus pulposus by inducing M2 macrophage polarization, which exists in normal intervertebral disks and can alleviate degeneration. The nanocomposite hydrogel system shows promise for the minimally invasive and effective treatment of intervertebral disk degeneration by controlling anabolism and catabolism in the ECM and inhibiting the IL17 signaling pathway (M1-related pathway) in vitro and in vivo.

Systematic characterization and identification of the chemical constituents of the Schisandra chinensis decoction based on a hybrid scanning technique of UHPLC/IM-QTOF-MS / 药学学报

italic>Schisandra chinensis is a traditional Chinese medicine with the functions of reinforcing deficiency, strengthening, and inducing astringency, appliable to treat the chronic cough and deficiency in breath, palpitation, and insomnia, etc. A hybrid mass spectrometry scanning strategy (high-definition data-independent/data-dependent acquisition, HDDIDDA), enabling the ion mobility separation and alternating data-independent acquisition/data-dependent acquisition, was established, which, in combination with in-house library-driven automatic peak annotation workflows facilitated by the UNIFI software, was utilized to systematically characterize the multi-classes of chemical components from S. chinensis. The use of an HSS T3 column (100 mm × 2.1 mm, 1.8 μm), 0.1% formic acid in H2O-acetonitrile as the mobile phase running at the flow rate of 0.3 mL·min-1, and column temperature at 35 ℃, could enable good separation of the S. chinensis components within 42 min. HDDIDDA scan in both the positive and negative ion modes was employed for data acquisition. Based on the automatic peak annotation, reference standards comparison, MS2 data interpretation, and literature analysis, we were able to identify or tentatively characterize 105 compounds in the S. chinensis decoction, involving 56 terpenoids, 42 lignans, five glycosides, one organic acid, and one flavonoid. HDDIDDA scanning can improve the coverage of data acquisition and improve the accuracy of identification, while CCS prediction analysis provides the possibility to distinguish isomers by the ion mobility technology. The results provide reference for the intelligent material basis research of TCM.

Improved bone and renal safety in younger tenofovir disoproxil fumarate experienced chronic hepatitis B patients after switching to tenofovir alafenamide or entecavir.

INTRODUCTION AND OBJECTIVES: Renal and bone impairment has been reported in chronic hepatitis B (CHB) patients receiving long-term tenofovir disoproxil fumarate (TDF) therapy. This study aimed to assess the incidence of renal and bone impairment in CHB patients with long-term TDF therapy and to identify the changes in bone mineral density (BMD) and renal function in these patients after switching to entecavir (ETV) or tenofovir alafenamide (TAF). MATERIALS AND METHODS: This retrospective study collected clinical data from CHB patients who received TDF monotherapy over 96 weeks. The changes in BMD and renal function were analyzed after 96 weeks of switching antiviral regimens (ETV or TAF) or maintenance TDF. RESULTS: At baseline, 154 patients receiving TDF monotherapy over 96 weeks were enrolled, with a younger median age of 36.75 years, 35.1% (54/154) of patients experienced elevated urinary ß2 microglobulin and 20.1% (31/154) of patients had reduced hip BMD (T<-1). At week 96, among the 123 patients with baseline normal BMD, patients who maintained TDF (n=85) had experienced a decrease in hip BMD, while patients who switched antiviral regimens (n=38) experienced an increase (-13.97% vs 2.34%, p<0.05). Among patients with a baseline reduced BMD (n=31), the alterations in BMD were similar in patients who maintained TDF (n=5) and those who switched antiviral regimens (n=26) (-15.81% vs 7.35%, p<0.05). Irrespective of baseline BMD status, renal function decreased significantly in patients who maintained TDF and improved in patients who switched antiviral regimens. CONCLUSIONS: Younger CHB patients on long-term TDF therapy are at high risk for bone and renal impairment, with the risk being reduced when switched to ETV or TAF.

Transanal endoscopic microsurgery versus radical resection for early-stage rectal cancer: a systematic review and meta- analysis.

PURPOSE: In the treatment of early-stage rectal cancer, a growing number of studies have shown that transanal endoscopic microsurgery is one of the alternatives to radical surgery adhering to total mesorectal excision that can reduce the incidence of adverse events without compromising treatment outcomes. The purpose of this meta-analysis is to compare the safety and treatment effect of transanal endoscopic microsurgery and radical surgery adhering to total mesorectal excision to provide a basis for clinical treatment selections. METHOD: We searched the literatures of four major databases, PubMed, Embase, Web of science, and Cochrane Library, without limitation of time. The literatures included randomized controlled studies and cohort studies comparing two surgical procedures of transanal endoscopic microsurgery and radical surgery adhering to total mesorectal excision. Treatment effectiveness and safety results of transanal endoscopic microsurgery and radical surgery were extracted from the included literatures and statistically analyzed using RevMan5.4 and stata17. RESULT: Ultimately, 13 papers were included in the study including 5 randomized controlled studies and 8 cohort studies. The results of the meta-analysis showed that the treatment effect and safety of both transanal endoscopic microsurgery and radical surgery in distant metastasis (RR, 0.59 (0.34, 1.02), P > 0.05), overall recurrence (RR, 1.49 (0.96, 2.31), P > 0.05), disease-specific-survival (RR, 0.74 (0.09, 1.57), P > 0.05), dehiscence of the sutureline or anastomosis leakage (RR, 0.57 (0.30, 1.06), P > 0.05), postoperative bleeding (RR, 0.47 (0.22, 0.99), P > 0.05), and pneumonia (RR, 0.37, (0.10, 1.40), P > 0.05) were not significantly different. However, they differ significantly in perioperative mortality (RR, 0.26 (0.07, 0.93, P < 0.05)), local recurrence (RR, 2.51 (1.53, 4.21), P < 0.05),_overall survival_ (RR, 0.88 (0.74, 1.00), P < 0.05), disease-free-survival (RR, 1.08 (0.97, 1.19), P < 0.05), temporary stoma (RR, 0.05 (0.01, 0.20), P < 0.05), permanent stoma (RR, 0.16 (0.08, 0.33), P < 0.05), postoperative complications (RR, 0.35 (0.21, 0.59), P < 0.05), rectal pain (RR, 1.47 (1.11, 1.95), P < 0.05), operation time (RR, -97.14 (-115.81, -78.47), P < 0.05), blood loss (RR, -315.52 (-472.47, -158.57), P < 0.05), and time of hospitalization (RR, -8.82 (-10.38, -7.26), P < 0.05). CONCLUSION: Transanal endoscopic microsurgery seems to be one of the alternatives to radical surgery for early-stage rectal cancer, but more high-quality clinical studies are needed to provide a reliable basis.

Calcium-Zinc Phosphate Chemical Conversion Coating Facilitates the Osteointegration of Biodegradable Zinc Alloy Implants by Orchestrating Macrophage Phenotype.

Zinc (Zn) alloys provide a new generation for orthopedic applications due to their essential physiological effects and promising degradation properties. However, excessive release of Zn ions (Zn2+ ) during degradation and the severe inflammatory microenvironment are not conducive to osseointegration, which is determined by the characteristics of the implant surface. Therefore, it is essential to modulate the release rate of Zn alloys by surface modification technology and endow them with anti-inflammatory and osteogenic effects. In this study, two kinds of phosphate chemical conversion (PCC) coatings with different compositions and morphological structures are prepared, namely Zn-P (with disk-like crystals) and Ca-Zn-P (with lamellar crystals). Although all the PCC-coated Zn implants have low cytotoxicity, Ca-Zn-P show better osteoimmunomodulation effects in several aspects: the induction of the M2-phenotype macrophage polarization and thus promotion of osteogenesis in vitro; the regulation of the bone immune microenvironment which is conducive to tissue regeneration and osseointegration in vivo; and the release of ions (through PI3K/AKT and Wnt signaling pathways) and the morphological structures (through RhoGTPase signaling pathways) act as possible mechanisms of M2 polarization. The Ca-Zn-P coating can be considered to provide new insights into bone immunomodulation and osseointegration.

Correlation between biomarker EHD3 and immune cell infiltration in gastric cancer / 西安交通大学学报(医学版)

【Objective】 To investigate the prognostic role of EHD3 and its association with immune cell infiltration in gastric cancer. 【Methods】 In this study, EHD3 expression was analyzed using RNA sequencing data from Cancer Genome Atlas (TCGA). Differential analysis, functional enrichment, immune infiltration, immune checkpoint exploration, and clinical baseline data analysis were performed. Independent prognostic factors were identified using univariate and multivariate Cox regression analysis; a column diagram model was developed and evaluated using C-index and calibration diagrams. 【Results】 EHD3 was significantly upregulated in STAD and functional enrichment analysis showed that EHD3 expression was associated with immune response, with most immune cells and immune checkpoints positively correlated with their expression. Cox regression showed that EHD3 was an independent prognostic factor in STAD patients (HR=2.112, 95% CI: 1.340-3.327, P=0.001). 【Conclusion】 EHD3 is considered to be a novel prognostic biomarker for STAD patients, and this study provides a potential therapeutic target for STAD treatment.

Composite Sophora Colon-Soluble Capsule Ameliorates DSS-Induced Ulcerative Colitis in Mice via Gut Microbiota-Derived Butyric Acid and NCR+ ILC3 / 中国结合医学杂志

OBJECTIVE@#To investigate the effects of composite Sophora colon-soluble Capsule (CSCC) on gut microbiota-mediated short-chain fatty acids (SCFAs) production and downstream group 3 innate lymphoid cells (ILC3s) of dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice model.@*METHODS@#The main components of CSCC were analyzed by hybrid ultra-high-performance liquid chromatography ion mobility spectromety quadrupole time-of-flight mass spectrometry (UHPLC-IM-QTOF/MS). Twenty-four male BALB/c mice were randomly divided into 4 groups (n=6) by using a computer algorithm-generated random digital, including control, DSS model, mesalazine, and CSCC groups. A DSS-induced colitis mice model was established to determine the effects of CSCC by recording colonic weight, colonic length, index of colonic weight, and histological colonic score. The variations in ILC3s were assessed by immunofluorescence and flow cytometry. The results of gut microbiota and SCFAs were acquired by 16s rDNA and gas chromatography-mass spectrometry (GC-MS) analysis. The expression levels of NCR+ ILC3-, CCR6+ Nkp46- (Lti) ILC3-, and ILCreg-specific markers were detected by enzyme-linked immunosorbent assay, and real-time quantitative polymerase chain reaction and Western blot, respectively.@*RESULTS@#The main components of CSCC were matrine, ammothamnine, Sophora flavescens neoalcohol J, and Sophora oxytol U. After 7 days of treatment, CSCC significantly alleviated colitis by promoting the reproduction of intestinal probiotics manifested as upregulation of the abundance of Bacteroidetes species and specifically the Bacteroidales_S24-7 genus (P<0.05). Among the SCFAs, the content of butyric acid increased the most after CSCC treatment. Meanwhile, compared with the model group, Lti ILC3s and its biomarkers were significantly downregulated and NCR+ ILC3s were significantly elevated in the CSCC group (P<0.01). Further experiments revealed that ILC3s were differentiated from Lti ILC3s to NCR+ ILC3s, resulting in interleukin-22 production which regulates gut epithelial barrier function.@*CONCLUSION@#CSCC may exert a therapeutic effect on UC by improving the gut microbiota, promoting metabolite butyric acid production, and managing the ratio between NCR+ ILC3s and Lti ILC3s.

Biocompatible Nano-Hydroxyapatites Regulate Macrophage Polarization.

Research on regulation of the immune microenvironment based on bioactive materials is important to osteogenic regeneration. Hydroxyapatite (HAP) is believed to be a promising scaffold material for dental and orthopedic implantation due to its ideal biocompatibility and high osteoconductivity. However, any severe inflammation response can lead to loosening and fall of implantation, which cause implant failures in the clinic. Morphology modification has been widely studied to regulate the host immune environment and to further promote bone regeneration. Here, we report the preparation of nHAPs, which have uniform rod-like shape and different size (200 nm and 400 nm in length). The morphology, biocompatibility, and anti-inflammatory properties were evaluated. The results showed that the 400 nm nHAPs exhibited excellent biocompatibility and osteoimmunomodulation, which can not only induce M2-phenotype macrophages (M2) polarization to decrease the production of inflammatory cytokines, but also promote the production of osteogenic factor. The reported 400 nm nHAPs are promising for osteoimmunomodulation in bone regeneration, which is beneficial for clinical application of bone defects.

Immune-Related Biomarkers Associated with Lung Metastasis from the Colorectal Cancer Microenvironment.

Immune-associated biomarkers can predict lung metastases from colorectal cancer. Differentially expressed genes (DEGs) were screened from sample data extracted from gene expression omnibus (GEO) database. The DEGs were screened from the lung metastasis (LM) and primary cancer (PC) groups of the Moffitt Cancer Center cohort dataset. Then, the tumor immune microenvironment and abundance of immune cell infiltration analyses were performed, and the immune-related DEGs were retrieved. In addition, the transcription factor (TF)-miRNA-mRNA network was constructed and enrichment analyses of the immune-related DEGs and upregulated and downregulated DEGs were carried out. Then, the protein-protein interaction (PPI) network was conducted and the drug-gene interaction was predicted. A total of 268 DEGs were screened. The Immune_Score of samples in the LM group was significantly higher compared with the PC group. The infiltration ratio of M0 macrophages and M2 macrophages of samples was higher than others. A total of 54 immune-related DEGs in M0 macrophages were screened. Moreover, the TF-miRNA-mRNA network was constructed among 8 miRNA-mRNA and 50 TF-mRNA, and the secreted phosphoprotein 1 was regulated by 12 TFs, and the oxidized low-density lipoprotein receptor 1 was regulated by 3 miRNAs and 3 TFs. The TF SAM pointed domain containing ETS TF was also a downregulated DEG. The Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the DEGs in the TF-miRNA-mRNA network were mainly involved in the interleukin-7 signaling pathway and cell adhesion molecules. In total, 23 protein interactions in this PPI network of M0 macrophage cells were involved in 27 mRNAs. There were 38 drug-gene interactions of immune-related DEGs of M0 macrophage cells predicted to contain 34 small molecule drugs and 8 mRNAs. Finally, the CON cohort dataset verified that the infiltration ratio of M0 and M2 macrophages of the samples was higher.

Research on mechanism of salidroside activating HIF-1 a signaling pathway to promote MOB proliferation / 中国药理学通报

Aim To explore the effeet of salidroside (SAL) on proliferation of osteoblasts and its possible mechanism by using mouse primary osteoblasts ( MOB) as the research object.Methods Alkaline phosphatase ( ALP) staining was used to identify the extracted primary cells.MTT was used to detect the effect of SAL on the proliferation.RT-PCR, Western blot, ELISA were used to investigate the molecular mechanism of SAL.Results The extracted cells generated black-brown deposits by ALP staining, which were shown to be osteoblasts clearly.SAL promoted the pro liferation of MOB.Meanwhile, SAL could up-regulate the mRNA and protein expression levels of hypoxia-inducible factor-lcx ( HIF-1 ex), vascular endothelial growth factor ( VEGF ) , angiopoietin-like protein 4 (ANGPTL4) and interleukin 6 ( IL-6 ) , which were down-regulated by using the HIF-lex blocker YC-1.Conclusions SAL could promote the proliferation of MOB through HIF-1 a/VEGF, ANGPTL4, IL-6 signaling pathway.

Validation of compound C19 as a glutaminase C inhibitor / 药学学报

The mitochondrial enzyme glutaminase C (GAC) is highly expressed in a variety of cancer cells, resulting in increased glutamine metabolism and cancer development. Therefore, GAC has become a potential target for anti-tumor drug development. However, current GAC inhibitors shared similar structural characteristics, few new scaffolds were reported. By conducting a prokaryotic Escherichia coli expression system, human GAC protein of high-purity was obtained through lysozyme digestion combined with ultrasound dissociation, and cobalt magnetic beads purification, Moreover, we performed studies to validate interaction between small molecules and GAC protein through thermal shift assay, drug affinity responsive target stability assay, protein crosslinking and GAC enzyme activity detection. Meanwhile, a comprehensive small molecule-protein interaction confirmation and systematic pharmacodynamic study in vitro were carried out on compound C19, which was a reported GAC inhibitor screened from the Enamine database. Results showed that C19 directly bind to GAC protein, disturbed GAC tetramers formation, and inhibited its enzyme catalytic activity. By interfering GAC function, C19 dose-dependently suppressed GAC-mediated glutamine metabolism, reduced glutamate in cancer cells, and thus alleviated A549 and NCI-H1299 non-small cell lung cancer cell growth. Together, C19 was identified as a lead compound, providing a new strategy for the structural design of drugs targeting GAC.

A multicenter prospective randomized controlled study on the timing of laparoscopic cholecystectomy after percutaneous transhepatic gallbladder drainage for grade Ⅱ-Ⅲ acute cholecystitis / 中华肝胆外科杂志

Objective:To study the optimal timing of laparoscopic cholecystectomy (LC) after percutaneous transhepatic gallbladder drainage (PTGBD) for grade Ⅱ-Ⅲ acute cholecystitis.Methods:A multicenter, single blind and randomized controlled study was conducted at Shanghai Fifth People's Hospital Affiliated to Fudan University, Shanghai Pudong Hospital, and Shanghai Minhang District Central Hospital from October 2018 to September 2021. Patients who underwent LC after PTGBD were divided 1∶1 into the early group and the late group. LC was performed 4-6 weeks after PTGBD in the early group and 7-8 weeks after PTGBD in the late group. Gender, age, AC grade, complications after PTGBD, body mass index, complications before LC, operation time of LC, intraoperative bleeding, total treatment cost, conversion rate to open surgery and complications after LC were compared between the two groups. The 36-Item Short Form Health Survey (SF-36) before and after LC was also compared.Results:Of 248 patients who were eligible for the study, there were 52 males and 196 females, with ages ranging from 18 to 89 years, and mean ±s.d. of (52.5 ± 20.2) years. There were 126 patients in the early group and 122 patients in the late group. There were no significant differences in gender, age, AC grade, body mass index and complications before LC between the two groups (all P>0.05). The preoperative score of SF-36 in the early group was significantly better than that in late group, and the complications of PTGBD in the late group were significantly higher than the early group (both P<0.05). The operation time and total treatment cost of the early group were significantly less than those of the late group (37.2±12.8 min vs. 48.5±19.7 min, 20 856±2 136 yuan vs. 2 2207±2 049 yuan) (both P<0.05). The intraoperative bleeding volume of LC in the early group was [ M( Q1, Q3)] 40 (40, 60) ml and the late group was [ M( Q1, Q3)] 35 (25, 40) ml. The difference was also significant ( P<0.05). There was no significant differences in the conversion rates to open surgery, complications and SF-36 scores after LC between the two groups (all P>0.05). Conclusion:LC should be performed 4-6 weeks after PTGBD for grade Ⅱ-Ⅲ acute cholecystitis. Although the amount of intraoperative bleeding was higher, the operation time was shorter, the burden on patients was reduced and there was more rapid recovery.

A study of the effectiveness of nucleos(t)ide analogues in the treatment of HBeAg- positive chronic hepatitis B with normal alanine aminotransferase and high level of HBV DNA / 中华肝脏病杂志

Objective: To investigate the effectiveness of nucleos(t)ide analogues in the treatment of HBeAg-positive chronic hepatitis B with normal alanine aminotransferase and high level of HBV DNA. Methods: Treatment-naïve chronic hepatitis B patients who were followed up at the Center of Infectious Diseases, West China Hospital of Sichuan University from January 2019 to January 2020 were selected as subjects. Demographic characteristics, the results of laboratory examination before treatment and one year after treatment were retrospectively collected. Patients were divided into tenofovir dipivoxil (TDF) and propofol fumurate tenofovir (TAF) treatment group according to different types of medication. The changes of serum HBV DNA level, HBeAg serological conversion and HBsAg quantitative level were analyzed and compared between the two groups. Results: A total of 38 cases were enrolled. Among them, there were 16 and 22 cases in the TDF and TAF group, respectively. There was no statistically significant difference in demographic characteristics, baseline HBV DNA levels and HBsAg quantitative levels between the two groups. Virological response was achieved in 60.5% (23/38) of patients after one year of antiviral therapy. Serum HBV DNA levels below the lower limit of detection [68.2% (15/22) vs. 50.0% (8/16), P=0.258] and higher HBeAg seroconversion rate [18.2%] (4/22) vs. 6.3% (1/16), P=0.374] was obtained in TAF than TDF group; however, there was no statistically significant differences between the two. Serum HBsAg quantitative level was significantly reduced with TDF and TAF treatment. In addition, alanine aminotransferase elevation was reduced in TAF than TDF treated group. Multivariate logistic regression analysis showed that patient age was an independent predictor of a virological response to antiviral therapy. Conclusion: HBeAg-positive CHB patients with normal alanine aminotransferase, and high HBV DNA level can obtain better curative effect after TDF and TAF treatment.

Clinical value of routine contrast esophagram in the diagnosis of anastomotic leakage for three-incision esophagectomy with cervical anastomosis / 中华外科杂志

Objective: To examine the clinical value of routine contrast esophagram (RCE) for the diagnosis of anastomotic leakage (AL) after three-incision esophagectomy with cervical anastomosis. Methods: Clinical data of 1 022 patients with esophageal cancer who underwent McKeown three-incision esophagectomy with cervical anastomosis from January 2015 to December 2019 at Department of Minimally Invasive Esophageal Surgery, Tianjin Medical University Cancer Hospital and Institute were analyzed retrospectively. There were 876 males and 146 females, aging(M(IQR)) 48(16) years (range: 36 to 84 years). There were 253 patients (24.8%) with neoadjuvant therapy, and 817 patients (79.9%) with minimally invasive esophagectomy. According to the diagnosis and treatment habits of the attending surgeons, 333 patients were included in the RCE group, and RCE was performed on the 7th day postoperative, while 689 patients were included in the non-RCE group, and RCE was performed when the patients had suspicious symptoms. Taking clinical symptoms, RCE, CT, endoscopy and other methods as reference to the diagnosis of AL, the sensitivity and specificity were used to analyze and evaluate the efficacy of RCE for the diagnosis of AL. The data were compared by U test or χ² test between groups. Results: The incidence rate of AL after three-incision esophagectomy was 7.34% (75/1 022), including 30 cases in the RCE group and 45 cases in the non-RCE group (9.0%(30/333) vs. 6.5%(45/689), χ²=2.027, P=0.155). The diagnostic time of AL was 9(5) days postoperative (range: 4 to 30 days). Among them, 23 cases showed cervical leakages, 50 cases showed intro-thoracic leakages, and 2 cases both cervical and intro-thoracic leakages. The diagnostic time of patients with intro-thoracic leakages was longer than that of cervical leakages (10(4) days vs. 6(3) days, Z=-2.517, P=0.012). Among the 333 patients in the RCE group, 16 cases of RCE indicated leakages including 11 cases of true positive and 5 cases determined to be false positive, while 317 cases indicated no abnormalities including 19 cases developed leakages. The sensitivity and specificity of RCE to detect AL were 36.7%(11/30) and 98.3%(298/333), respectively. The Youden-index was 0.35, and the diagnostic accuracy was 92.8%(309/333). The positive and negative predictive value were 11/16 and 94.0%(298/317), respectively. Conclusions: Routine contrast esophagram after three-incision esophagectomy with cervical anastomosis has low sensitivity and high specificity in the diagnosis of AL. The diagnostic time of AL is the 9th day after surgery. It is necessary to prolong the observation time clinically, and combine RCE with CT, endoscopy and other inspection methods for diagnosis.

The application and insight of single-stage posterior total en bloc spondylectomy treatment on L 5 vertebrae spine tumors / 中华骨科杂志

Objective:To investigate the feasibility and technical points of single posterior total spine resection for L 5 vertebrae tumors, evaluate the effectiveness and safety of the technique, and propose a comprehensive treatment model for L 5 tumors on this basis. Methods:A retrospective analysis was performed on the data of 13 patients with L 5 vertebrae tumor who were treated by total en bloc spondylectomy (TES) through single-stage posterior approach from January 2014 to September 2021, including 4 males and 9 females. The age range was 21-65 years, with an average age of 33.85±14.24 years. Imaging examination showed isolated tumors of L 5 vertebrae without other metastases. All patients were treated with a single posterior L 5 vertebrae tumor TES by adjusting the curvature of lumbar lordosis, and the lumbar nerve root was fully dissociated. The vertebra with tumor was removed entirely and lumbar stability reconstruction via a pedicle screw system. Various parameters, including operative time, blood loss, complications, preoperative and postoperative spine sagittal parameters, Japanese Orthopaedic Association scores (JOAs), tumor control and outcome, were listed and analyzed. Results:Preoperative pathological diagnosis of 13 patients was mainly primary bone tumor including giant cell tumor in 7 cases, and invasive hemangioma, epithelioid hemangioma, aneurysmal bone cyst, chordoma, plasma cell myeloma and bone metastasis of breast cancer in 1 case. The mean operative time was 333.23±99.48 min (range 175-480 min), and the mean intraoperative blood loss was 1 407.69±676.49 ml (range 300-2 800 ml). There were no serious perioperative complications during the perioperative period. The mean follow-up was 54.92±19.29 months (range 28-84 months). JOAs improved from 13.85±3.86 points before operation to 24.31±2.16 points at 6 months after operation, and the difference was statistically significant ( t=8.19, P<0.001). Postoperative delayed wound healing occurred in 2 case. 2 patients showed numbness of the left lower limb, and 1 patient had slightly reduced plantar flexion movement. Conclusion:Single posterior TES is a good surgical method for the treatment of isolated L 5 vertebrae tumors. Although this technique is difficult, it can reduce surgical wounds and postoperative complications and good functional and oncology prognosis can be achieved.

NIR-triggered drug delivery system for chemo-photothermal therapy of posterior capsule opacification.

Posterior capsule opacification (PCO) is the most common complication after cataract surgery and is likely to cause the second loss of vision. Pharmacological PCO prophylaxis has been proved to be effective, yet no clinical option is available due to the lack of a suitable mode of administration. In this work, we propose a unique concept of NIR dual-triggered drug release from black phosphorus (BP)-based implantable intraocular lens (IOL) for controlled drug release and chemo-photothermal combination therapy of PCO. Here, IOL is used as a "reservoir" of doxorubicin-loaded black phosphorus (BP-DOX), and BP is used as NIR activation agent for controlled drug release and photothermal therapy. This BP-DOX integrated IOL, namely BP-DOX@IOL, shows the characteristics of good transmittance, good mechanical property, NIR dual-triggered drug release behaviors, and excellent photothermal efficacy. In vivo studies reveal that there is no PCO occurrence in rabbits' model by using BP-DOX@IOL combined NIR irradiation, which exhibits distinct superiority on inhibiting PCO than the control group (100% PCO occurrence) 28 days post-surgery. This novel IOL drug delivery system would be a promising strategy for the future clinical application for PCO prophylaxis and treatment.

3D-printed titanium implant combined with interleukin 4 regulates ordered macrophage polarization to promote bone regeneration and angiogenesis.

AIMS: The use of 3D-printed titanium implant (DT) can effectively guide bone regeneration. DT triggers a continuous host immune reaction, including macrophage type 1 polarization, that resists osseointegration. Interleukin 4 (IL4) is a specific cytokine modulating osteogenic capability that switches macrophage polarization type 1 to type 2, and this switch favours bone regeneration. METHODS: IL4 at concentrations of 0, 30, and 100 ng/ml was used at day 3 to create a biomimetic environment for bone marrow mesenchymal stromal cell (BMMSC) osteogenesis and macrophage polarization on the DT. The osteogenic and immune responses of BMMSCs and macrophages were evaluated respectively. RESULTS: DT plus 30 ng/ml of IL4 (DT + 30 IL4) from day 3 to day 7 significantly (p < 0.01) enhanced macrophage type 2 polarization and BMMSC osteogenesis compared with the other groups. Local injection of IL4 enhanced new bone formation surrounding the DT. CONCLUSION: DT + 30 IL4 may switch macrophage polarization at the appropriate timepoints to promote bone regeneration. Cite this article: Bone Joint Res 2021;10(7):411-424.

Prognostic Factors and Survival Prediction of Pediatric Glioblastomas: A Population-Based Study.

AIM: To identify the risk factors for pediatric glioblastomas (GBMs), and to develop an effective prediction model to estimate the survival rate for these patients. MATERIAL AND METHODS: Pediatric patients with GBM were extracted from the Surveillance, Epidemiology, and End Results database. Kaplan-Meier analyses were performed for overall survival. Significant prognostic factors were identified using univariate and multivariate Cox regression analyses. A nomogram model was also established. RESULTS: A total of 378 pediatric patients with GBM were included in our study. The multivariate Cox analysis revealed that age at diagnosis (HR, 1.67; 95% CI, 1.19-2.35; p=0.003), tumor site (infratentorial vs. supratentorial: HR, 1.44; 95% CI, 1.03-2.03; p=0.035), surgery (gross total resection [GTR] vs. no surgery: HR, 0.53; 95% CI, 0.36-0.77, p < 0.001), and chemotherapy (HR, 0.56; 95% CI, 0.42-0.74; p < 0.001) were independent prognostic factors of overall survival for pediatric GBMs. Additionally, we found that patients with tumors located in the infratentorial region (p < 0.001) tended to receive conservative treatments. Moreover, our nomogram model showed favorable discriminative ability. CONCLUSION: At the population level, we found that older children and tumors located in the infratentorial region were associated with poor survival, while both GTR and chemotherapy were associated with improved survival. There was no association between radiotherapy and survival outcomes. Moreover, a nomogram with good performance was constructed to predict the overall survival of these patients.

Nitric Oxide-Driven Nanomotor for Deep Tissue Penetration and Multidrug Resistance Reversal in Cancer Therapy.

Poor permeation of therapeutic agents and multidrug resistance (MDR) in solid tumors are the two major challenges that lead to the failure of the current chemotherapy methods. Herein, a zero-waste doxorubicin-loaded heparin/folic acid/l-arginine (HFLA-DOX) nanomotor with motion ability and sustained release of nitric oxide (NO) to achieve deep drug penetration and effective reversal of MDR in cancer chemotherapy is designed. The targeted recognition, penetration of blood vessels, intercellular penetration, special intracellular distribution (escaping from lysosomes and accumulating in Golgi and nucleus), 3D multicellular tumor spheroids (3D MTSs) penetration, degradation of tumor extracellular matrix (ECM), and reversal of MDR based on the synergistic effects of the motion ability and sustained NO release performance of the NO-driven nanomotors are investigated in detail. Correspondingly, a new chemotherapy mode called recognition-penetration-reversal-elimination is proposed, whose effectiveness is verified by in vitro cellular experiments and in vivo animal tumor model, which can not only provide effective solutions to these challenges encountered in cancer chemotherapy, but also apply to other therapy methods for the special deep-tissue penetration ability of a therapeutic agent.

Interleukin-4 assisted calcium-strontium-zinc-phosphate coating induces controllable macrophage polarization and promotes osseointegration on titanium implant.

Titanium (Ti) and its alloys are believed to be promising scaffold materials for dental and orthopedic implantation due to their ideal mechanical properties and biocompatibility. However, the host immune response always causes implant failures in the clinic. Surface modification of the Ti scaffold is an important factor in this process and has been widely studied to regulate the host immune response and to further promote bone regeneration. In this study, a calcium-strontium-zinc-phosphate (CSZP) coating was fabricated on a Ti implant surface by phosphate chemical conversion (PCC) technique, which modified the surface topography and element constituents. Here, we envisioned an accurate immunomodulation strategy via delivery of interleukin (IL)-4 to promote CSZP-mediated bone regeneration. IL-4 (0 and 40 ng/mL) was used to regulate immune response of macrophages. The mechanical properties, biocompatibility, osteogenesis, and anti-inflammatory properties were evaluated. The results showed that the CSZP coating exhibited a significant enhancement in surface roughness and hydrophilicity, but no obvious changes in proliferation or apoptosis of bone marrow mesenchymal stem cells (BMMSCs) and macrophages. In vitro, the mRNA and protein expression of osteogenic related factors in BMMSCs cultured on a CSZP coating, such as ALP and OCN, were significantly higher than those on bare Ti. In vivo, there was no enhanced bone formation but increased macrophage type 1 (M1) polarization on the CSZP coating. IL-4 could induce M2 polarization and promote osteogenesis of BMMSCs on CSZP in vivo and in vitro. In conclusion, the CSZP coating is an effective scaffold for BMMSCs osteogenesis, and IL-4 presents the additional advantage of modulating the immune response for bone regeneration on the CSZP coating in vivo.