Tertiary lymphoid structures in cancer: immune mechanisms and clinical implications.

Cancer is a major cause of death globally, and traditional treatments often have limited efficacy and adverse effects. Immunotherapy has shown promise in various malignancies but is less effective in tumors with low immunogenicity or immunosuppressive microenvironment, especially sarcomas. Tertiary lymphoid structures (TLSs) have been associated with a favorable response to immunotherapy and improved survival in cancer patients. However, the immunological mechanisms and clinical significance of TLS in malignant tumors are not fully understood. In this review, we elucidate the composition, neogenesis, and immune characteristics of TLS in tumors, as well as the inflammatory response in cancer development. An in-depth discussion of the unique immune characteristics of TLSs in lung cancer, breast cancer, melanoma, and soft tissue sarcomas will be presented. Additionally, the therapeutic implications of TLS, including its role as a marker of therapeutic response and prognosis, and strategies to promote TLS formation and maturation will be explored. Overall, we aim to provide a comprehensive understanding of the role of TLS in the tumor immune microenvironment and suggest potential interventions for cancer treatment.

Integrative analysis of TROAP with molecular features, carcinogenesis, and related immune and pharmacogenomic characteristics in soft tissue sarcoma.

Soft tissue sarcoma (STS) is an uncommon malignancy that often carries a grim prognosis. Trophinin-associated protein (TROAP) is augmented in a variety of tumors and can affect tumor proliferation. Nevertheless, the prognostic value and specific functions of TROAP in STS are still vague. Herein, we display that TROAP exhibits an augmented trend in STS, and its elevation correlates with a poor prognosis of STS. Furthermore, its reduction is related to increased immune cell infiltration, enhanced stroma, and elevation of immune activation. Meanwhile, the TROAP-derived genomic signature is validated to predict patient prognosis, immunotherapy, and drug response reliably. A nomogram constructed based on age, metastatic status, and a TROAP-derived risk score of an STS individual could be used to quantify the survival probability of STS. In addition, in vitro experiments have demonstrated that TROAP is overexpressed in STS, and the downregulation of TROAP could affect the proliferation, migration, metastasis, and cell cycle of STS cells. In summary, the TROAP expression is elevated in STS tissues and cells, which is related to the poor prognosis and malignant biological behaviors of STS. It could act as a potential prognostic biomarker for diagnosis and treatment of STS.

Integrative profiling analysis reveals prognostic significance, molecular characteristics, and tumor immunity of angiogenesis-related genes in soft tissue sarcoma.

Background: Soft tissue sarcoma (STS) is a class of malignant tumors originating from mesenchymal stroma with a poor prognosis. Accumulating evidence has proved that angiogenesis is an essential hallmark of tumors. Nevertheless, there is a paucity of comprehensive research exploring the association of angiogenesis-related genes (ARGs) with STS. Methods: The ARGs were extracted from previous literature, and the differentially expressed ARGs were screened for subsequent analysis. Next, the least absolute shrinkage and selection operator (LASSO) and Cox regression analyses were conducted to establish the angiogenesis-related signature (ARSig). The predictive performance of the novel ARSig was confirmed using internal and external validation, subgroup survival, and independent analysis. Additionally, the association of the ARSig with the tumor immune microenvironment, tumor mutational burden (TMB), and therapeutic response in STS were further investigated. Notably, we finally conducted in vitro experiments to verify the findings from the bioinformatics analysis. Results: A novel ARSig is successfully constructed and validated. The STS with a lower ARSig risk score in the training cohort has an improved prognosis. Also, consistent results were observed in the internal and external cohorts. The receiver operating characteristic (ROC) curve, subgroup survival, and independent analysis further indicate that the novel ARSig is a promising independent prognostic predictor for STS. Furthermore, it is proved that the novel ARSig is relevant to the immune landscape, TMB, immunotherapy, and chemotherapy sensitivity in STS. Encouragingly, we also validate that the signature ARGs are significantly dysregulated in STS, and ARDB2 and SRPK1 are closely connected with the malignant progress of STS cells. Conclusion: In sum, we construct a novel ARSig for STS, which could act as a promising prognostic factor for STS and give a strategy for future clinical decisions, immune landscape, and personalized treatment of STS.

Integration analysis based on fatty acid metabolism robustly predicts prognosis, dissecting immunity microenvironment and aiding immunotherapy for soft tissue sarcoma.

Background: Soft tissue sarcoma (STS) is a highly malignant tumor with a dismal prognosis. Presently, the dysregulation of fatty acid metabolism has received increasing attention in tumor research, but fewer reports are relevant to STS. Methods: Based on fatty acid metabolism-related genes (FRGs), a novel risk score for STS was developed utilizing univariate analysis and least absolute shrinkage selection operator (LASSO) Cox regression analyses in the STS cohort, which were further validated using the external validation cohort from other databases. Furthermore, independent prognostic analysis, C-index, ROC curves, and nomogram were carried out to investigate the predictive performance of fatty acid-related risk scores. We also analysed the differences in enrichment pathways, the immune microenvironment, gene mutations, and immunotherapy response between the two distinct fatty acid score groups. Moreover, the real-time quantitative polymerase chain reaction (RT-qPCR) was used to further verify the expression of FRGs in STS. Results: A total of 153 FRGs were retrieved in our study. Next, a novel fatty acid metabolism-related risk score (FAS) was constructed based on 18 FRGs. The predictive performance of FAS was also verified in external cohorts. In addition, the independent analysis, C-index, ROC curve, and nomograph also revealed that FAS could serve as an independent prognostic factor for the STS patients. Meanwhile, our results demonstrated that the STS cohort in two distinct FAS groups had different copy number variations, immune cell infiltration, and immunotherapy responses. Finally, the in vitro validation results demonstrated that several FRGs included in the FAS exhibited abnormal expression in STS. Conclusion: Altogether, our work comprehensively and systematically clarifies fatty acid metabolism's potential roles and clinical significance in STS. The novel individualized score based on fatty acid metabolism may be provided as a potential marker and treatment strategy in STS.

The emerging applications and advancements of Raman spectroscopy in pediatric cancers.

Although the survival rate of pediatric cancer has significantly improved, it is still an important cause of death among children. New technologies have been developed to improve the diagnosis, treatment, and prognosis of pediatric cancers. Raman spectroscopy (RS) is a non-destructive analytical technique that uses different frequencies of scattering light to characterize biological specimens. It can provide information on biological components, activities, and molecular structures. This review summarizes studies on the potential of RS in pediatric cancers. Currently, studies on the application of RS in pediatric cancers mainly focus on early diagnosis, prognosis prediction, and treatment improvement. The results of these studies showed high accuracy and specificity. In addition, the combination of RS and deep learning is discussed as a future application of RS in pediatric cancer. Studies applying RS in pediatric cancer illustrated good prospects. This review collected and analyzed the potential clinical applications of RS in pediatric cancers.

Development of a prognostic Neutrophil Extracellular Traps related lncRNA signature for soft tissue sarcoma using machine learning.

Background: Soft tissue sarcoma (STS) is a highly heterogeneous musculoskeletal tumor with a significant impact on human health due to its high incidence and malignancy. Long non-coding RNA (lncRNA) and Neutrophil Extracellular Traps (NETs) have crucial roles in tumors. Herein, we aimed to develop a novel NETsLnc-related signature using machine learning algorithms for clinical decision-making in STS. Methods: We applied 96 combined frameworks based on 10 different machine learning algorithms to develop a consensus signature for prognosis and therapy response prediction. Clinical characteristics, univariate and multivariate analysis, and receiver operating characteristic curve (ROC) analysis were used to evaluate the predictive performance of our models. Additionally, we explored the biological behavior, genomic patterns, and immune landscape of distinct NETsLnc groups. For patients with different NETsLnc scores, we provided information on immunotherapy responses, chemotherapy, and potential therapeutic agents to enhance the precision medicine of STS. Finally, the gene expression was validated through real-time quantitative PCR (RT-qPCR). Results: Using the weighted gene co-expression network analysis (WGCNA) algorithm, we identified NETsLncs. Subsequently, we constructed a prognostic NETsLnc signature with the highest mean c-index by combining machine learning algorithms. The NETsLnc-related features showed excellent and stable performance for survival prediction in STS. Patients in the low NETsLnc group, associated with improved prognosis, exhibited enhanced immune activity, immune infiltration, and tended toward an immunothermal phenotype with a potential immunotherapy response. Conversely, patients with a high NETsLnc score showed more frequent genomic alterations and demonstrated a better response to vincristine treatment. Furthermore, RT-qPCR confirmed abnormal expression of several signature lncRNAs in STS. Conclusion: In conclusion, the NETsLnc signature shows promise as a powerful approach for predicting the prognosis of STS. which not only deepens our understanding of STS but also opens avenues for more targeted and effective treatment strategies.

Comprehensive analysis of a novel cuproptosis-related lncRNA signature associated with prognosis and tumor matrix features to predict immunotherapy in soft tissue carcinoma.

Background: A crucial part of the malignant processes of soft tissue sarcoma (STS) is played by cuproptosis and lncRNAs. However, the connection between cuproptosis-related lncRNAs (CRLs) and STS is nevertheless unclear. As a result, our objective was to look into the immunological activity, clinical significance, and predictive accuracy of CRLs in STS. Methods: The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, respectively, provided information on the expression patterns of STS patients and the general population. Cuproptosis-related lncRNA signature (CRLncSig) construction involved the univariate, multivariate, and least absolute shrinkage and selection operator Cox regression analysis. The predictive performance of the CRLncSig was evaluated using a serial analysis. Further research was done on the connections between the CRLncSig and the tumor immune milieu, somatic mutation, immunotherapy response, and chemotherapeutic drug susceptibility. Notably, an in vitro investigation served to finally validate the expression of the hallmark CRLs. Results: A novel efficient CRLncSig composed of seven CRLs was successfully constructed. Additionally, the low-CRLncSig group's prognosis was better than that of the high-CRLncSig group's based on the new CRLncSig. The innovative CRLncSig then demonstrated outstanding, consistent, and independent prognostic and predictive usefulness for patients with STS, according to the evaluation and validation data. The low-CRLncSig group's patients also displayed improved immunoreactivity phenotype, increased immune infiltration abundance and checkpoint expression, and superior immunotherapy response, whereas those in the high-CRLncSig group with worse immune status, increased tumor stemness, and higher collagen levels in the extracellular matrix. Additionally, there is a noticeable disparity in the sensitivity of widely used anti-cancer drugs amongst various populations. What's more, the nomogram constructed based on CRLncSig and clinical characteristics of patients also showed good predictive ability. Importantly, Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) demonstrated that the signature CRLs exhibited a significantly differential expression level in STS cell lines. Conclusion: In summary, this study revealed the novel CRLncSig could be used as a promising predictor for prognosis prediction, immune activity, tumor immune microenvironment, immune response, and chemotherapeutic drug susceptibility in patients with STS. This may provide an important direction for the clinical decision-making and personalized therapy of STS.

Molecular characterization of immunogenic cell death indicates prognosis and tumor microenvironment infiltration in osteosarcoma.

Introduction: Osteosarcoma (OS) is a highly aggressive bone malignancy with a poor prognosis, mainly in children and adolescents. Immunogenic cell death (ICD) is classified as a type of programmed cell death associated with the tumor immune microenvironment, prognosis, and immunotherapy. However, the feature of the ICD molecular subtype and the related tumor microenvironment (TME) and immune cell infiltration has not been carefully investigated in OS. Methods: The ICD-related genes were extracted from previous studies, and the RNA expression profiles and corresponding data of OS were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus database. The ICD-related molecular subtypes were classed by the "ConsensusclusterPlus" package and the construction of ICD-related signatures through univariate regression analysis. ROC curves, independent analysis, and internal validation were used to evaluate signature performance. Moreover, a series of bioinformatic analyses were used for Immunotherapy efficacy, tumor immune microenvironments, and chemotherapeutic drug sensitivity between the high- and low-risk groups. Results: Herein, we identified two ICD-related subtypes and found significant heterogeneity in clinical prognosis, TME, and immune response signaling among distinct ICD subtypes. Subsequently, a novel ICD-related prognostic signature was developed to determine its predictive performance in OS. Also, a highly accurate nomogram was then constructed to improve the clinical applicability of the novel ICD-related signature. Furthermore, we observed significant correlations between ICD risk score and TME, immunotherapy response, and chemotherapeutic drug sensitivity. Notably, the in vitro experiments further verified that high GALNT14 expression is closely associated with poor prognosis and malignant progress of OS. Discussion: Hence, we identified and validated that the novel ICD-related signature could serve as a promising biomarker for the OS's prognosis, chemotherapy, and immunotherapy response prediction, providing guidance for personalized and accurate immunotherapy strategies for OS.

The regulatory role and therapeutic application of pyroptosis in musculoskeletal diseases.

Pyroptosis is a controlled form of inflammatory cell death characterized by inflammasome activation, pore formation, and cell lysis. According to different caspases, pyroptosis can be divided into canonical, non-canonical, and other pathways. The role of pyroptosis in disease development has been paid more attention in recent years. The trigger factors of pyroptosis are often related to oxidative stress and proinflammatory substances, which coincide with the pathological mechanism of some diseases. Pyroptosis directly leads to cell lysis and death, and the release of cytosolic components and proinflammatory cytokines affects cell activity and amplifies the inflammatory response. All the above are involved in a series of basic pathological processes, such as matrix degradation, fibrosis, and angiogenesis. Since these pathological changes are also common in musculoskeletal diseases (MSDs), emerging studies have focused on the correlations between pyroptosis and MSDs in recent years. In this review, we first summarized the molecular mechanism of pyroptosis and extensively discussed the differences and crosstalk between pyroptosis, apoptosis, and necrosis. Next, we elaborated on the role of pyroptosis in some MSDs, including osteoarthritis, rheumatoid arthritis, osteoporosis, gout arthritis, ankylosing spondylitis, intervertebral disc degeneration, and several muscle disorders. The regulation of pyroptosis could offer potential therapeutic targets in MSDs treatment. Herein, the existing drugs and therapeutic strategies that directly or indirectly target pyroptosis pathway components have been discussed in order to shed light on the novel treatment for MSDs.

Integrated Analysis of TME and Hypoxia Identifies a Classifier to Predict Prognosis and Therapeutic Biomarkers in Soft Tissue Sarcomas.

Soft tissue sarcoma (STS) is one of the rarest but most aggressive cancer. It is important to note that intratumoral hypoxia and tumor microenvironment (TME) infiltration play a significant role in the growth and therapeutic resistance of STS. The goal of this study was therefore to determine whether linking hypoxia-related parameters to TME cells could provide a more accurate prediction of prognosis and therapeutic response. An analysis of 109 hypoxia-related genes and 64 TME cells was conducted in STS. Hypoxia-TME classifier was constructed based on 6 hypoxia prognostic genes and 8 TME cells. As a result, we evaluated the prognosis, tumor, and immune characteristics, as well as the effectiveness of therapies in Hypoxia-TME-defined subgroups. The Lowplus group showed a better prognosis and therapeutic response than any other subgroup. It is possible to unravel these differences based on immune-related molecules and somatic mutations in tumors. Further validation of Hypoxia-TME was done in an additional cohort of 225 STS patients. Additionally, we identified five key genes through differential analysis and RT-qPCR, namely, ACSM5, WNT7B, CA9, MMP13, and RAC3, which could be targeted for therapy. As a whole, the Hypoxia-TME classifier demonstrated a pretreatment predictive value for prognosis and therapeutic outcome, providing new approaches to therapy strategizing for patients.

The emerging role of pyroptosis in pediatric cancers: from mechanism to therapy.

Pediatric cancers are the driving cause of death for children and adolescents. Due to safety requirements and considerations, treatment strategies and drugs for pediatric cancers have been so far scarcely studied. It is well known that tumor cells tend to progressively evade cell death pathways, which is known as apoptosis resistance, one of the hallmarks of cancer, dominating tumor drug resistance. Recently, treatments targeting nonapoptotic cell death have drawn great attention. Pyroptosis, a newly specialized form of cell death, acts as a critical physiological regulator in inflammatory reaction, cell development, tissue homeostasis and stress response. The action in different forms of pyroptosis is of great significance in the therapy of pediatric cancers. Pyroptosis could be induced and consequently modulate tumorigenesis, progression, and metastasis if treated with local or systemic therapies. However, excessive or uncontrolled cell death might lead to tissue damage, acute inflammation, or even cytokine release syndrome, which facilitates tumor progression or recurrence. Herein, we aimed to describe the molecular mechanisms of pyroptosis, to highlight and discuss the challenges and opportunities for activating pyroptosis pathways through various oncologic therapies in multiple pediatric neoplasms, including osteosarcoma, neuroblastoma, leukemia, lymphoma, and brain tumors.

Identification of cuproptosis-related lncRNA prognostic signature for osteosarcoma.

Background: Copper is an indispensably mineral element involved in various metabolic processes and functions in the active sites of many metalloproteins. Copper dysregulation is associated with cancers such as osteosarcoma (OS), the most common primary bone malignancy with invasiveness and metastasis. However, the causality between cuproptosis and OS remains elusive. We aim to identify cuproptosis-related long non-coding RNAs (lncRNAs) for osteosarcomatous prognosis, immune microenvironment response, and immunotherapy. Methods: The Person correlation and differential expression analysis were used to identify differentially expressed cuproptosis-related lncRNAs (CRLs). The univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis were performed to construct the CRL signature. The Kaplan-Meier (K-M) survival analysis, receiver operating characteristic (ROC) curve, internal validation, independent prognostic analysis, and nomograph were used to evaluate the prognostic value. The functional enrichment, tumor microenvironment, immunotherapy and chemotherapy response between the two distinct groups were further explored using a series of algorithms. The expression of signature CRLs was verified by real-time quantitative polymerase chain reaction (RT-qPCR) in OS cell lines. Results: A novel CRL signature consisting of four CRLs were successfully identified. The K-M survival analysis indicated that the OS patients in the low-risk groups had a better prognosis than that in the high-risk group. Then, the ROC curve and subgroup survival analysis confirmed the prognostic evaluation performance of the signature. Equally, the independent prognostic analysis demonstrated that the CRL signature was an independently predicted factor for OS. Friends analysis determined the hub genes that played a critical role in differentially expressed genes between two distinct risk groups. In addition, the risk score was related to immunity status, immunotherapy response, and chemotherapeutic drug sensitivity. Finally, the expression of these signature CRLs detected by RT-qPCR was consistent with the bioinformatic analysis results. Conclusion: In summary, our study confirmed that the novel CRL signature could effectively evaluate prognosis, tumor immune microenvironment, and immunotherapy response in OS. It may benefit for clinical decision-making and provide new insights for personalized therapeutics.

A bibliometric and visualization analysis of glucocorticoid-induced osteoporosis research from 2012 to 2021.

Introduction: Glucocorticoid-induced osteoporosis (GIOP) is the most common cause of secondary osteoporosis. Although many studies related to GIOP have been published, there was no bibliometric analysis in this field. This study aimed to investigate the research trends on GIOP by using bibliometric analysis. Materials and Methods: All data were collected from the Web of Science Core Collection (WoSCC). All original research articles regarding GIOP from 2012 to 2021 were retrieved. CiteSpace was used to analyze the distribution of countries, institutions, journals, authors, and keywords. We revealed hotspots and trends in the field by drawing co-occurrence keyword maps and identifying burst keywords. Results: From 2012 to 2021, 685 relevant articles were published, with a peak in 2018 in the annual number of publications. China and McMaster University were the leading country and institution in this field with 208 and 12 publications, respectively. Osteoporosis International was the journal with the most studies, while Journal of Bone and Mineral Research was the most cited journal. "Bone mineral density", "fracture", "postmenopausal women", "prevention" and "therapy" were the most high-frequency keywords, while "bone mineral density", "bisphosphonate" and "metabolism" were the top high-centrality keywords. Conclusion: The results from this bibliometric study provided insight into the status and research trends in GIOP of the past decade, which could help researchers quickly determine the current hotspots and frontier trends in this field.

Long-term macrolide treatment for the prevention of acute exacerbations in COPD: a systematic review and meta-analysis.

BACKGROUND: Acute exacerbation of COPD (AECOPD) is associated with an increased hospitalization and mortality. Azithromycin and erythromycin are the recommended drugs to reduce the risk of exacerbations. However, the most suitable duration of therapy and drug-related adverse events are still a matter of debate. The aim of this meta-analysis was to assess the current evidence regarding the efficacy and safety of long-term macrolide treatment for COPD. MATERIALS AND METHODS: We comprehensively searched PubMed, Embase, the Cochrane Library, and the Web of Science and performed a systematic review and cumulative meta-analysis of all randomized controlled trials (RCTs) and retrospective studies. RESULTS: Eleven RCTs and one retrospective study including a total of 2,151 cases were carried out. Long-term macrolide treatment significantly reduced the total number of cases with one or more exacerbations (OR=0.40; 95% CI=0.24-0.65; P<0.01) and the rate of exacerbations per patient per year (risk ratio [RR]=0.60; 95% CI=0.45-0.78; P<0.01). Subgroup analyses showed that the minimum duration for drug efficacy for both azithromycin and erythromycin therapy was 6 months. In addition, macrolide therapy could improve the St George Respiratory Questionnaire (SGRQ) total score (P<0.01) but did not achieve the level of clinical significance. The frequency of hospitalizations was not significantly different between the treatment and control groups (P=0.50). Moreover, chronic azithromycin treatment was more likely to increase adverse events (P<0.01). CONCLUSION: Prophylactic azithromycin or erythromycin treatment has a significant effect in reducing the frequency of AECOPD in a time-dependent manner. However, long-term macrolide treatment could increase the occurrence of adverse events and macrolide resistance. Future large-scale, well-designed RCTs with extensive follow-up are required to identify patients in whom the benefits outweigh risks.