Identification and bioinformatics analysis of genes associated with pyroptosis in spinal cord injury of rat and mouse.

The mechanism of spinal cord injury (SCI) is highly complex, and an increasing number of studies have indicated the involvement of pyroptosis in the physiological and pathological processes of secondary SCI. However, there is limited bioinformatics research on pyroptosis-related genes (PRGs) in SCI. This study aims to identify and validate differentially expressed PRGs in the GEO database, perform bioinformatics analysis, and construct regulatory networks to explore potential regulatory mechanisms and therapeutic targets for SCI. We obtained high-throughput sequencing datasets of SCI in rats and mice from the GEO database. Differential analysis was conducted using the "limma" package in R to identify differentially expressed genes (DEGs). These genes were then intersected with previously reported PRGs, resulting in a set of PRGs in SCI. GO and KEGG enrichment analyses, as well as correlation analysis, were performed on the PRGs in both rat and mouse models of SCI. Additionally, a protein-protein interaction (PPI) network was constructed using the STRING website to examine the relationships between proteins. Hub genes were identified using Cytoscape software, and the intersection of the top 5 hub genes in rats and mice were selected for subsequent experimentally validated. Furthermore, a competing endogenous RNA (ceRNA) network was constructed to explore potential regulatory mechanisms. The gene expression profiles of GSE93249, GSE133093, GSE138637, GSE174549, GSE45376, GSE171441_3d and GSE171441_35d were selected in this study. We identified 10 and 12 PRGs in rats and mice datasets respectively. Six common DEGs were identified in the intersection of rats and mice PRGs. Enrichment analysis of these DEGs indicated that GO analysis was mainly focused on inflammation-related factors, while KEGG analysis showed that the most genes were enriched on the NOD-like receptor signaling pathway. We constructed a ceRNA regulatory network that consisted of five important PRGs, as well as 24 miRNAs and 34 lncRNAs. This network revealed potential regulatory mechanisms. Additionally, the three hub genes obtained from the intersection were validated in the rat model, showing high expression of PRGs in SCI. Pyroptosis is involved in secondary SCI and may play a significant role in its pathogenesis. The regulatory mechanisms associated with pyroptosis deserve further in-depth research.

Comprehensive next-generation sequencing reveals double primary colorectal carcinoma missed by diagnostic imaging: A case report.

BACKGROUND: Multiple primary colorectal carcinoma (MPCC) is a rare clinical disease, which is challenging to differentiate from metastatic disease using histopathological methods. Next-generation sequencing (NGS) has been employed to identify multiple primary cancers. CASE SUMMARY: This study a rare case of a 63-year-old male patient diagnosed with MPCC by targeted NGS, which was initially missed by radiological evaluation. The patient was found to have two tumors located on the surface of the colorectum which had distinct genomic alterations. Based on wild-type KRAS detected in the unresected tumor, the patient benefited from the epidermal growth factor receptor (EGFR) inhibitor cetuximab treatment, but developed novel mutations including KIF5B-RET fusion, which provides a possible resistance mechanism to anti-EGFR therapy. CONCLUSION: Our case highlights the necessity of using genetic testing for primary tumor diagnosis and the application of serial plasma circulating tumor DNA profiling for dynamic disease monitoring.

The top 100 most-cited articles on adult spinal deformity: The most popular topics are still sagittal plane parameters and complications.

Purpose: This study aimed to summarize the characteristics of the 100 most-cited articles on adult spinal deformity (ASD) and to analyze past and current research hotspots and trends. Methods: Literature searches (from inception to 28 April 2022) using Web of Science databases were conducted to identify ASD-related articles. The top 100 most-cited articles were collected for further analysis. Meanwhile, author keywords from articles published in the last 5 years were selected for further analysis. Results: The top 100 most-cited articles on ASD were selected from 3,354 papers. The publication year ranged from 1979 to 2017, and all papers were written in English. The citation count among them ranged from 100 to 1,145, and the mean citation number was 215.2. The foremost productive first author was Schwab F. University of Washington had the largest number of publications. The United States of America had the largest number of published articles (n = 84) in this field. Spine was the most popular journal. Complications were the most studied themes. The visualization analysis of author keywords from the literature in the recent 5 years showed that complications, sagittal plane parameters, and surgical techniques are still the research hotspots, and minimally invasive surgery will continue to develop rapidly. Conclusion: Based on a comparative analysis of the results of bibliometric and visualization, complications and sagittal plane parameters are still the major topics of research at present and even later, and minimally invasive surgery has a growth trend in this field of ASD.

The Relationship Between Tumor-Stroma Ratio, the Immune Microenvironment, and Survival in Patients With Spinal Chordoma.

BACKGROUND: Currently, little is known about the clinical relevance of tumor-stroma ratio (TSR) in chordoma and data discussing the relationship between TSR and immune status of chordoma are lacking. OBJECTIVE: To characterize TSR distribution in spinal chordoma, and investigated its correlation with clinicopathologic or immunological features of patients and outcome. METHODS: TSR was assessed visually on hematoxylin and eosin-stained sections from 54 tumor specimens by 2 independent pathologists. Multiplex immunofluorescence was used to quantify the expression levels of microvessel density, Ki-67, Brachyury, and tumor as well as stromal PD-L1. Tumor immunity status including the Immunoscore and densities of tumor-infiltrating lymphocytes (TILs) subtypes were obtained from our published data and reanalyzed. RESULTS: Bland-Altman plot showed no difference between mean TSR derived from the two observers. TSR was positively associated with stromal PD-L1 expression, the Immunoscore and CD3+ as well as CD4+ TILs density, but negatively correlated with tumor microvessel density, Ki-67 index, surrounding muscle invasion by tumor and number of Foxp3+ and PD-1+ TILs. Low TSR independently predicted poor local recurrence-free survival and overall survival. Moreover, patients with low TSR and low Immunoscore chordoma phenotype were associated with the worst survival. More importantly, combined TSR and Immunoscore accurately reflected prognosis and enhanced the ability of TSR or Immunoscore alone for outcome prediction. CONCLUSION: These data reveal the significant impact of TSR on tumor progression and immunological response of patients. Subsequent use of agents targeting the stroma compartment may be an effective strategy to treat chordoma especially in combination with immune-based drugs.

Clinicopathological and Prognostic Characteristics in Extra-Axial Chordomas: An Integrative Analysis of 86 Cases and Comparison With Axial Chordomas.

BACKGROUND: Currently, clinical characteristics and prognostic factors of extra-axial chordoma (EAC) remain poorly understood. OBJECTIVE: To characterize clinicopathological characteristics in a large EAC cohort and investigate their correlation with survival. We also attempted to compare these outcomes with axial chordoma (AC). METHODS: Medline and Embase searches (from inception to February 28, 2018) were conducted to identify eligible studies as per predefined criteria. The local database at our center was also retrospectively reviewed to include additional patients. RESULTS: Forty-three studies from the literature and 86 patients from our local institute were identified, resulting in a total of 86 EAC patients and 75 AC patients for analysis. Overall, EAC had similar characteristics to AC, except for having higher CAM5.2 expression, common lobular growth pattern, and better prognosis. Whereas wide surgical resection was consistently associated with favorable survival in both EAC and AC cohorts on univariate analyses, most parameters showed differential prognostic implications between the 2 groups. Significant prognostic factors for local recurrence-free survival on multivariate analysis included type of surgery in both cohorts and tumor Brachyury expression and adjuvant radiotherapy in AC cohort. Multivariate analysis of overall survival demonstrated that type of surgery, tumor Brachyury expression, and duration of symptoms were significant predictors in the AC cohort, whereas none of the analyzed parameters were predictive of overall survival for the EAC group. CONCLUSION: These data suggest potentially distinct biological behaviors between EAC and AC and may provide useful information to better understand the prognostic characteristics and improve the outcome prediction of EAC patients.

Prognostic Factors in Skull Base Chordoma: A Systematic Literature Review and Meta-Analysis.

OBJECTIVE: Currently, there are a lack of reviews assessing the complete range of prognostic factors in skull base chordoma (SBC). This study aimed to systematically review the published literature on prognostic factors in SBC and establish pooled hazard ratios (HRs) of such factors. METHODS: MEDLINE and Embase searches (inception to April 4, 2017) were conducted. Two reviewers independently selected papers involving SBC prognostic factors, and studied them for methodologic quality and valuable factors. Pooled HRs and 95% confidence intervals (CIs) were calculated. The main end points determined were progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty-two studies with 1754 subjects were included in this systematic review. However, only 18 of the studies provided sufficient data for quantitative synthesis. Preoperative visual deficit (pooled HR, 2.77; 95% CI, 1.57-4.89 for PFS), older patient age (pooled HR, 1.03; 95% CI, 1.1-1.05 for PFS; pooled HR, 1.03; 95% CI, 1.2-1.04 for OS), and nontotal or intralesional tumor resection (pooled HR, 2.01; 95% CI, 1.54-2.62 for PFS; pooled HR, 5.16; 95% CI, 2.27-11.70 for OS) were negative predictors of survival outcomes. However, adjunctive radiotherapy (pooled HR, 0.30; 95% CI, 0.16-0.56) and chondroid chordoma type (pooled HR, 0.5; 95% CI, 0.36-0.69) portended a favorable PFS. In addition, several prognostic biomarkers were promising. CONCLUSIONS: This study demonstrated that several clinicopathologic or molecular parameters are associated with survival up to tumor progression or mortality in SBC patients. However, further methodologically high-quality reports are still required to clarify the effects of these factors.

Inhibition of apoptosis signal-regulating kinase 1 alters the wound epidermis and enhances auricular cartilage regeneration.

Why regeneration does not occur in mammals remains elusive. In lower vertebrates, epimorphic regeneration of the limb is directed by the wound epidermis, which controls blastema formation to promote regrowth of the appendage. Herein, we report that knockout (KO) or inhibition of Apoptosis Signal-regulated Kinase-1 (ASK1), also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5), after full thickness ear punch in mice prolongs keratinocyte activation within the wound epidermis and promotes regeneration of auricular cartilage. Histological analysis showed the ASK1 KO ears displayed enhanced protein markers associated with blastema formation, hole closure and regeneration of auricular cartilage. At seven days after punch, the wound epidermis morphology was markedly different in the KO, showing a thickened stratum corneum with rounded cell morphology and a reduction of both the granular cell layer and decreased expression of filament aggregating protein. In addition, cytokeratin 6 was expressed in the stratum spinosum and granulosum. Topical application of inhibitors of ASK1 (NQDI-1), the upstream ASK1 activator, calcium activated mitogen kinase 2 (KN93), or the downstream target, c-Jun N-terminal kinase (SP600125) also resulted in enhanced regeneration; whereas inhibition of the other downstream target, the p38 α/ß isoforms, (SB203580) had no effect. The results of this investigation indicate ASK1 inhibition prolongs keratinocyte and blastemal cell activation leading to ear regeneration.

Stress-Induced Activation of Apoptosis Signal-Regulating Kinase 1 Promotes Osteoarthritis.

Apoptosis signal-regulated kinase 1 (ASK1) has been shown to affect a wide range of cellular processes including stress-related responses, cytokine and growth factor signaling, cell cycle and cell death. Recently, we reported that lack of ASK1 slowed chondrocyte hypertrophy, terminal differentiation and apoptosis resulting in an increase in trabecular bone formation. Herein, we investigated the role of ASK1 in the pathogenesis of osteoarthritis (OA). Immunohistochemistry performed on articular cartilage samples from patients with OA showed ASK1 expression increased with OA severity. In vitro analysis of chondrocyte hypertrophy, maturation and ASK1 signaling in embryonic fibroblasts from ASK1 knockout (KO) and wild type (WT) mice was examined. Western analysis demonstrated an increase in ASK1 signaling commensurate with chondrogenic maturation during differentiation or in response to stress by the cytokines, tumor necrosis factor alpha or interleukin 1 beta in WT, but not in ASK1 KO embryonic fibroblasts. Surgically induced moderate or severe OA or OA due to natural aging in WT and ASK1 KO mice was assessed by microCT of subchondral bone, immunohistochemistry, histology, and OARSI scoring. Immunohistochemistry, microCT and OARSI scoring all indicated that the lack of ASK1 protected against OA joint degeneration, both in surgically induced OA and in aging mice. We propose that the ASK1 MAP kinase signaling cascade is an important regulator of chondrocyte terminal differentiation and inhibitors of this pathway could be useful for slowing chondrocyte maturation and cell death observed with OA progression. J. Cell. Physiol. 231: 944-953, 2016. © 2015 Wiley Periodicals, Inc.

The significance of removing ruptured intervertebral discs for interbody fusion in treating thoracic or lumbar type B and C spinal injuries through a one-stage posterior approach.

OBJECTIVES: To identify the negative effect on treatment results of reserving damaged intervertebral discs when treating type B and type C spinal fracture-dislocations through a one-stage posterior approach. METHODS: This is a retrospective review of 53 consecutive patients who were treated in our spine surgery center from January 2005 to May 2012 due to severe thoracolumbar spinal fracture-dislocation. The patients in Group A (24 patients) underwent long-segment instrumentation laminectomy with pedicle screw-rod fixators for neural decompression. In Group B (29 patients), the patients underwent long-segment instrumentation laminectomy with pedicle screw-rod fixators for neural decompression evacuating of the ruptured disc and inserting of a bone graft into the evacuated disc space for interbody fusion. The mean time between injury and operation was 4.1 days (range 2-15 days). The clinical, radiologic and complication outcomes were analyzed retrospectively. RESULTS: Periodic follow-ups were carried out until an affirmative union or treatment failure took place. A progressive kyphosis angle larger than 10°, loss of disc height, pseudoarthrosis, recurrence of dislocation or subluxation, or instrument failure before fusion were considered treatment failures. Treatment failures were detected in 13 cases in Group A (failure rate was 54.2%). In Group B, there were 28 cases in which definitive bone fusion was demonstrated on CT scans, and CT scans of the other cases demonstrated undefined pseudoarthrosis without hardware failure. There were statistically significant differences between the two groups (p<0.001 chi-square test). The neurologic recoveries, assessed by the ASIA scoring system, were not satisfactory for the neural deficit patients in either group, indicating there was no significant difference with regard to neurologic recovery between the two groups (p>0.05 Fisher's exact test). CONCLUSION: Intervertebral disc damage is a common characteristic in type B and C spinal fracture-dislocation injuries. The damaged intervertebral disc should be removed and substituted with a bone graft because reserving the damaged disc in situ increases the risk of treatment failure.