PPP1R14A is Associated with Immunotherapy Resistance in Head and Neck Squamous Cell Carcinoma Identified by Single-Cell and Bulk RNA-Sequencing.

Objective To identify nivolumab resistance-related genes in patients with head and neck squamous cell carcinoma (HNSCC) using single-cell and bulk RNA-sequencing data. Methods The single-cell and bulk RNA-sequencing data downloaded from the Gene Expression Omnibus database were analyzed to screen out differentially expressed genes (DEGs) between the nivolumab resistant and nivolumab sensitive patients using R software. The Least Absolute Shrinkage Selection Operator (LASSO) regression and Recursive Feature Elimination (RFE) algorithm were performed to identify key genes associated with nivolumab resistance. Functional enrichment of DEGs was analyzed with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. The relationships of key genes with immune cell infiltration, differentation trajectory, dynamic gene expression profiles, and ligand-receptor interaction were explored. Results We found 83 DEGs. They were mainly enriched in T-cell differentiation, PD-1 and PD-L1 checkpoint pathways, and T-cell receptor pathways. In six key genes identified using machine learning algorithms, only PPP1R14A gene was differentially expressed between the nivolumab resistant and nivolumab sensitive groups both before and after immunotherapy (P < 0.05). The high PPP1R14A gene expression group had lower immune score (P < 0.01), higher expression of immunosuppressive factors (such as PDCD1, CTLA4, and PDCD1LG2) (r > 0, P < 0.05), lower differentiation of infiltrated immune cells (P < 0.05), and a higher degree of interaction between HLA and CD4 (P < 0.05). Conclusions PPP1R14A gene is closely associated with resistance to nivolumab in HNSCC patients. Therefore, PPP1R14A may be a target to ameliorate nivolumab resistance of HNSCC patients.

Inflammatory Myofibroblastic Tumor of the Sciatic Nerve Mimicking Lumbar Disc Herniation: A Diagnostic Challenge.

Inflammatory myofibroblastic tumors (IMTs), which involve the proliferation of fibroblastic-myofibroblastic cells mixed with inflammatory infiltrates, are exceedingly rare in the extremities. There are no reported IMTs involving the sciatic nerve. This type of involvement may cause entrapment of the sciatic nerve, whose symptoms may mimic lumbar disc herniation (LDH), especially when it occurs in patients with lumbar degenerative disc disease. We describe the case of a 40-year-old male with lumbar degenerative disc disease accompanied by IMT involving the sciatic nerve whose symptoms mimicked LDH and posed a diagnostic challenge. We showed the course of the disease as well as the systematic imaging manifestations of IMTs involving the sciatic nerve and discussed their therapeutic management.

Trilobolide-6-O-isobutyrate exerts anti-tumor effects on cholangiocarcinoma cells through inhibiting JAK/STAT3 signaling pathway.

Trilobolide-6-O-isobutyrate exhibits significant antitumor effects on cholangiocarcinoma (CCA) cells by effectively inhibiting the JAK/STAT3 signaling pathway. This study aims to investigate the mechanisms underlying the antitumor properties of trilobolide-6-O-isobutyrate, and to explore its potential as a therapeutic agent for CCA. This study illustrates that trilobolide-6-O-isobutyrate efficiently suppresses CCA cell proliferation in a dose- and time-dependent manner. Furthermore, trilobolide-6-O-isobutyrate stimulates the production of reactive oxygen species, leading to oxidative stress and initiation of apoptosis via the activation of the mitochondrial pathway. Data from xenograft tumor assays in nude mice confirms that TBB inhibits tumor growth, and that there are no obvious toxic effects or side effects in vivo. Mechanistically, trilobolide-6-O-isobutyrate exerts antitumor effects by inhibiting STAT3 transcriptional activation, reducing PCNA and Bcl-2 expression, and increasing P21 expression. These findings emphasizes the potential of trilobolide-6-O-isobutyrate as a promising therapeutic candidate for the treatment of CCA.

Corrigendum: Study of quality of life and its correlated factors in patients after lumbar fusion for lumbar degenerative disc disease.

[This corrects the article DOI: 10.3389/fsurg.2022.939591.].

RARγ promotes the invasion and metastasis of thyroid carcinoma by activating the JAK1-STAT3-CD24/MMPs axis.

The nuclear receptor superfamily RAR is generally considered to play a crucial role in the development of tumors by regulating the transcription of target genes. Nevertheless, whether RARγ performs tumor-promoting or tumor-suppressing functions and its specific mechanism in thyroid carcinoma (TC) remain unknown. Here, our study demonstrated that RARγ was abnormally overexpressed in TC tissues compared with normal thyroid tissues. Moreover, RARγ expression was remarkably correlated with cell phenotypes such as cell proliferation, migration and invasion. Mechanistically, RARγ knockdown effectively decreased the phosphorylation levels of JAK1 and STAT3, leading to decreased expression of the membrane protein CD24. In a coculture system, TC cells with high levels of CD24 in the membrane were more likely to escape phagocytosis by macrophages via the combination of CD24 with the inhibitory receptor Siglec-10 in the membrane of macrophages. In contrast, the ability of macrophages to engulf TC cells was notably elevated through exogenous addition of CD24 antibody. Collectively, our study revealed a previously undiscovered molecular mechanism of RARγ in promoting the development of TC, shedding light on RARγ as a promising therapeutic target for TC.

The Antibacterial Effect, Biocompatibility, and Osteogenesis of Vancomycin-Nanodiamond Composite Scaffold for Infected Bone Defects.

Purpose: The repair and treatment of infected bone defects (IBD) is a common challenge faced by orthopedic clinics, medical materials science, and tissue engineering. Methods: Based on the treatment requirements of IBD, we utilized multidisciplinary knowledge from clinical medicine, medical materials science, and tissue engineering to construct a high-efficiency vancomycin sustained-release system with nanodiamond (ND) and prepare a composite scaffold. Its effect on IBD treatment was assessed from materials, cytology, bacteriology, and zoology perspectives. Results: The results demonstrated that the Van-ND-45S5 scaffold exhibited an excellent antibacterial effect, biocompatibility, and osteogenesis in vitro. Moreover, an efficient animal model of IBD was established, and a Van-ND-45S5 scaffold was implanted into the IBD. Radiographic and histological analyses and bone repair-related protein expression, confirmed that the Van-ND-45S5 scaffold had good biocompatibility and osteogenic and anti-infective activities in vivo. Conclusion: Collectively, our findings support that the Van-ND-45S5 scaffold is a promising new material and approach for treating IBD with good antibacterial effects, biocompatibility, and osteogenesis.

Topoisomerase â ¡α Gene as a Marker for Prognostic Prediction of Hepatocellular Carcinoma: A Bioinformatics Analysis.

Objective To investigate the expression of topoisomeraseⅡα (TOP2α) in hepatocellular carcinoma (HCC) and its role in predicting prognosis of HCC patients. Methods We used HCC-related datasets in UALCAN, HCCDB, and cBioPortal databases to analyze the expression and mutation of TOP2α and its co-expressed genes in HCC tissues. GO function and KEGG pathway enrichment of TOP2α and its co-expressed genes were identified. The TIMER database was used to analyze infiltration levels of immune cells in HCC. The impacts of TOP2α and its co-expression genes and the infiltrated immune cells on the survival of HCC patients were assayed by Kaplan-Meier plotter analysis. Results TOP2α and its co-expression genes were highly expressed in HCC (P< 0.001) and detrimental to overall survival of HCC patients (P< 0.001). TOP2α and its co-expression genes were mainly involved in cell mitosis and proliferation, and cell cycle pathway (ID: hsa04110, P = 0.001945). TOP2α and its co-expression genes were mutated in HCC and the mutations were significantly detrimental to overall survival (P = 0.0247) and disease-free survival (P = 0.0265) of HCC patients. High TOP2α expression was positively correlated with the infiltration of B cell (r = 0.459, P< 0.01), CD8+ T cell (r = 0.312, P< 0.01), CD4+ T cell (r = 0.370, P< 0.01), macrophage (r = 0.459, P< 0.01), neutrophil (r = 0.405, P< 0.01), and dendritic cell (r = 0.473, P< 0.01) in HCC. The CD8+ T cell infiltration significantly prolonged the 3- and 5-year survival of HCC patients (all P< 0.05), and CD4+ T cell infiltration significantly shortened the 3-, 5-, and 10-year survival of HCC patients (all P< 0.05). ConclusionTOP2α may be an oncogene, which was associated with poor prognosis of HCC patients and could be used as a biomarker for the prognostic prediction of HCC.

Study of quality of life and its correlated factors in patients after lumbar fusion for lumbar degenerative disc disease.

Background: In the present work, we aimed to explore the correlated factors of quality of life in patients receiving lumbar fusion for lumbar degenerative disc disease (DDD) in China. Methods: A total of 180 patients treated with lumbar fusion were included in the present study. Their general demographic characteristics, Visual Analog Scale (VAS) scores, Japanese Orthopedic Association (JOA) scores, Simplified Coping Style Questionnaire (SCSQ), Social Support Questionnaire (SSQ), and Medical Outcomes Study Short Form 36 (MOS SF-36) were collected and evaluated preoperatively and at 1 year postoperatively. Results: There were significant improvements in scores of VAS, JOA, and quality of life of patients from preoperation to 1-year postoperation after lumbar fusion. Marital status, with or without children, education level, economic pressure, and social support had significant predictive effects on the physical health of patients undergoing lumbar fusion. Marital status, education level, and economic pressure had significant predictive effects on the mental health of patients undergoing lumbar fusion. Conclusions: Factors correlated with the physical health of patients after lumbar fusion included positive coping style, negative coping style, social support, age, education level (high school college), disease duration (5-10), suffering from other diseases (combined with two or more other disease) and the number of surgical segments (double and three or more). Factors correlated with the mental health included negative coping style, social support, age, education level (middle school and high school college) and the number of surgical segments (double and three or more). The results verify that these factors were correlated to the patient's quality of life after lumbar fusion. Emphasizing and selectively intervening these correlated factors can further improve the quality of life in patients receiving lumbar fusion for lumbar degenerative disc disease.

Application of a modified surgical position in anterior approach for total cervical artificial disc replacement.

BACKGROUND: Total cervical artificial disc replacement (TDR) has been considered a safe and effective alternative surgical treatment for cervical spondylosis and degenerative disc disease that have failed to improve with conservative methods. Positioning the surgical patient is a critical part of the procedure. Appropriate patient positioning is crucial not only for the safety of the patient but also for optimizing surgical exposure, ensuring adequate and safe anesthesia, and allowing the surgeon to operate comfortably during lengthy procedures. The surgical posture is the traditional position used in anterior cervical approach; in general, patients are in a supine position with a pad under their shoulders and a ring-shaped pillow under their head. AIM: To investigate the clinical outcomes of the use of a modified surgical position versus the traditional surgical position in anterior approach for TDR. METHODS: In the modified position group, the patients had a soft pillow under their neck, and their jaw and both shoulders were fixed with wide tape. The analyzed data included intraoperative blood loss, position setting time, total operation time, and perioperative blood pressure and heart rate. RESULTS: Blood pressure and heart rate were not significantly different before and after body positioning in both groups (P > 0.05). Compared with the traditional position group, the modified position group showed a statistically significantly longer position setting time (P < 0.05). However, the total operation time and intraoperative blood loss were significantly reduced in the modified position group compared with the traditional position group (P < 0.05). CONCLUSION: The clinical outcomes indicated that total operation time and intraoperative blood loss were relatively lower in the modified position group than in the traditional position group, thus reducing the risks of surgery while increasing the position setting time. The modified surgical position is a safe and effective method to be used in anterior approach for TDR surgery.

In vitro and in vivo evaluation of calcium phosphate composite scaffolds containing BMP-VEGF loaded PLGA microspheres for the treatment of avascular necrosis of the femoral head.

Avascular necrosis of the femoral head (ANFH) is difficult to treat due to high pressure and hypoxia, and reduced levels of growth factors such as bone morphogenetic protein (BMP), and vascular endothelial growth factor (VEGF). We generated a novel calcium phosphate (CPC) composite scaffold, which contains BMP-VEGF-loaded poly-lactic-co-glycolic acid (PLGA) microspheres (BMP-VEGF-PLGA-CPC). The BMP-VEGF-loaded microspheres have an encapsulation efficiency of 89.15% for BMP, and 78.55% for VEGF. The BMP-VEGF-PLGA-CPC scaffold also demonstrated a porosity of 62% with interconnected porous structures, and pore sizes of 219 µm and compressive strength of 6.60 MPa. Additionally, bone marrow mesenchymal stem cells (BMSCs) were seeded on scaffolds in vitro. Further characterization showed that the BMP-VEGF-PLGA-CPC scaffolds were biocompatible and enhanced osteogenesis and angiogenesis in vitro. Using a rabbit model of ANFH, BMP-VEGF-PLGA-CPC scaffolds were implanted into the bone tunnels of core decompression in the femoral head for 6 and 12 weeks. Radiographic and histological analysis demonstrated that the BMP-VEGF-PLGA-CPC scaffolds exhibited good biocompatibility, and osteogenic and angiogenic activity in vivo. These results indicate that the BMP-VEGF-PLGA-CPC scaffold may improve the therapeutic effect of core decompression surgery and be used as a treatment for ANFH.

IL-17A enhances ADAMTS-7 expression through regulation of TNF-α in human nucleus pulposus cells.

ADMATS-7 is known to play an important role in the pathogenesis of various diseases, including cartilaginous diseases. IL-17A is an inflammatory cytokine detected in degenerative disc tissues. However, the interplay between IL-17A and ADMATS-7 in human disc degeneration is still unknown. Samples collected from 50 patients were divided into three groups according to MRI degeneration grading system score. Immunohistochemistry, RT-PCR and western Blotting were used to investigate the expression of ADAMTS-7 in NP tissues. Furthermore, a rat disc degeneration model was established, and the expression level of ADAMTS-7 was assayed using immunohistochemistry, RT-PCR and western Blotting. The human NP cells were cultured in the presence and absence of IL-17A stimulation. RNA extracts were collected, and real-time PCR was performed to determine the expression of ADAMTS-7. Moreover, ADAMTS-7 concentrations were detected in human NP cell culture supernatants by ELISA. After culturing NP cells with IL-17A (with or without Etanercept), ADAMTS-7 levels were detected in each group. ADAMTS-7 expression was dramatically elevated in both human and rat degenerative NP tissues compared with normal controls. The RT-PCR and ELISA results revealed that IL-17A could enhance the production of ADAMTS-7, while ADAMTS-7 expression dramatically decreased in the IL-17A + Etanercept group in comparison to the IL-17A alone group. Our results indicate the presence of ADAMTS-7 in human NP cells and imply its potential role in disc degeneration. Additionally, our results indicate that IL-17A induced ADAMTS-7 expression via TNF-α, which may form a molecular axis in human NP cells.

The biocompatibility of calcium phosphate cements containing alendronate-loaded PLGA microparticles in vitro.

The composite of poly-lactic-co-glycolic acid (PLGA) and calcium phosphate cements (CPC) are currently widely used in bone tissue engineering. However, the properties and biocompatibility of the alendronate-loaded PLGA/CPC (APC) porous scaffolds have not been characterized. APC scaffolds were prepared by a solid/oil/water emulsion solvent evaporation method. The morphology, porosity, and mechanical strength of the scaffolds were characterized. Bone marrow mesenchymal stem cells (BMSCs) from rabbit were cultured, expanded and seeded on the scaffolds, and the cell morphology, adhesion, proliferation, cell cycle and osteogenic differentiation of BMSCs were determined. The results showed that the APC scaffolds had a porosity of 67.43 ± 4.2% and pore size of 213 ± 95 µm. The compressive strength for APC was 5.79 ± 1.21 MPa, which was close to human cancellous bone. The scanning electron microscopy, cell counting kit-8 assay, flow cytometry and ALP activity revealed that the APC scaffolds had osteogenic potential on the BMSCs in vitro and exhibited excellent biocompatibility with engineered bone tissue. APC scaffolds exhibited excellent biocompatibility and osteogenesis potential and can potentially be used for bone tissue engineering.

Biocompatibility and osteogenesis of calcium phosphate composite scaffolds containing simvastatin-loaded PLGA microspheres for bone tissue engineering.

By utilizing a modified solid/oil/water (s/o/w) emulsion solvent evaporation technique, calcium phosphate composite scaffolds containing simvastatin-loaded PLGA microspheres (SIM-PLGA-CPC) were prepared in this study. We characterized the morphology, encapsulation efficiency and in vitro drug release of SIM-loaded PLGA microspheres as well as the macrostructure, pore size, porosity and mechanical strength of the scaffolds. Rabbit bone mesenchymal stem cells (BMSCs) were seeded onto SIM-PLGA-CPC scaffolds, and the proliferation, morphology, cell cycle and differentiation of BMSCs were investigated using the cell counting kit-8 (CCK-8) assay, scanning electron microscopy (SEM), flow cytometry, alkaline phosphatase (ALP) activity and alizarin red S staining, respectively. The results revealed that SIM-PLGA-CPC scaffolds were biocompatible and osteogenic in vitro. To determine the in vivo biocompatibility and osteogenesis of the scaffolds, both pure PLGA-CPC scaffolds and SIM-PLGA-CPC scaffolds were implanted in rabbit femoral condyles and microradiographically and histologically investigated. SIM-PLGA-CPC scaffolds exhibited good biocompatibility and could improve the efficiency of new bone formation. All these results suggested that the SIM-PLGA-CPC scaffolds fulfilled the basic requirements of bone tissue engineering scaffold and possessed application potentials in orthopedic surgery.

Clinical and radiographic evaluation of cervical disk replacement: a retrospective study.

Studies have shown the effectiveness of cervical disk replacement. However, clinical outcomes, particularly by radiographic assessment during the 36-month follow-up visit, have not been reported for cervical disk replacement with Mobi-C (LDR, Austin, Texas) disk prostheses. A retrospective study was conducted at 10 centers across China and included 65 patients who underwent single-level Mobi-C disk prosthesis replacement from October 2009 to July 2010. Clinical and radiographic data were collected before replacement, 7 days postoperatively, and 1, 3, 6, 12, 24, and 36 months postoperatively. Clinical and neurologic outcomes were assessed by the Japanese Orthopaedic Association (JOA) score, visual analog scale (VAS), Neck Disability Index (NDI), and Odom's criteria. Static and dynamic radiographs were measured to determine intervertebral height and range of motion (ROM) of the cervical spine, the functional spinal unit, the treated segment, and adjacent segments. JOA, VAS, and NDI scores showed statistically significant improvement 36 months after replacement (P<.05). The ROM of the cervical spine, functional spinal unit, treated segment, and adjacent segments did not show a significant difference before and after replacement (P>.05). The intervertebral height of the treated segment increased significantly, and the intervertebral height of adjacent segments showed no statistical significance between time points and at follow-up. Clinical outcomes indicated that Mobi-C artificial cervical disk replacement is reliable. Radiographic data showed that it plays a role in reconstruction or maintenance of intervertebral height and ROM of the cervical spine, functional spinal unit, treated segment, and adjacent segments after Mobi-C cervical disk replacement.

A prospective, randomised, controlled multicentre study comparing cervical disc replacement with anterior cervical decompression and fusion.

PURPOSE: Total cervical artificial disc replacement (TDR) simulates normal disc structure, thus avoiding the drawbacks of anterior cervical decompression and fusion (ACDF). This prospective, randomized, controlled and multicentre study aimed to evaluate clinical and radiographic outcomes by comparing cervical disc replacement using Mobi-C disc prostheses with ACDF. METHODS: This prospective, randomized, controlled and multicentre study consisted of 111 patients undergoing single-level Mobi-C disc prosthesis replacement (TDR group, n = 55) or ACDF (n = 56) from February 2008 to November 2009 at 11 medical centres across China. Patients were assessed before surgery, at seven days postoperation and one, three, six, 12, 24, 36 and 48 months postoperation. Clinical and neurological outcome was determined by measuring the Japanese Orthopaedic Association (JOA) scores, visual analogue scale (VAS) and Neck Disability Index (NDI). Static and dynamic radiographs were obtained of the cervical curvature, the functional spinal unit (FSU) angle and range of motion (ROM) of the cervical spine, FSU angle and treated and adjacent segments. RESULTS: A total of 111 patients were included and randomly assigned to either Mobi-C disc prosthesis replacement or ACDF. JOA, VAS and NDI showed statistically significant improvements 48 months after surgery (P < 0.05). ROM, FSU angle, treated segment and adjacent segments in the Mobi-C group were not significantly different before and after replacement (p > 0.05). ROM in the ACDF group was significantly reduced at one month and remained so throughout the follow-up. By 48-months, more ACDF patients required secondary surgery (four of 56 patients). CONCLUSIONS: Although ACDF may increase the risk of additional surgery, clinical outcomes indicated that both Mobi-C artificial cervical disc replacement and ACDF were reliable. Radiographic data showed that ROM of the cervical spine, FSU angle and treated and adjacent segments were relatively better reconstructed and maintained in the Mobi-C group compared with those in the ACDF group.