Necroptosis-related lncRNA-based novel signature to predict the prognosis and immune landscape in soft tissue sarcomas.

BACKGROUND: Necroptosis-related long noncoding RNAs (lncRNAs) play crucial roles in cancer initiation and progression. Nevertheless, the role and mechanism of necroptosis-related lncRNAs in soft tissue sarcomas (STS) is so far unknown and needs to be explored further. METHODS: Clinical and genomic data were obtained from the UCSC Xena database. All STS patients' subclusters were performed by unsupervised consensus clustering method based on the prognosis-specific lncRNAs, and then assessed their survival advantage and immune infiltrates. In addition, we explored the pathways and biological processes in subclusters through gene set enrichment analysis. At last, we established the necroptosis-related lncRNA-based risk signature (NRLncSig) using the least absolute shrinkage and selection operator (LASSO) method, and explored the prediction performance and immune microenvironment of this signature in STS. RESULTS: A total of 911 normal soft tissue samples and 259 STS patients were included in current study. 39 prognosis-specific necroptosis-related lncRNAs were selected. Cluster 2 had a worse survival than the cluster 1 and characterized by different immune landscape in STS. A worse outcome in the high-risk group was observed by survival analysis and indicated an immunosuppressive microenvironment. The ROC curve analyses illustrated that the NRLncSig performing competitively in prediction of prognosis for STS patients. In addition, the nomogram presents excellent performance in predicting prognosis, which may be more beneficial towards STS patients' treatment. CONCLUSIONS: Our result indicated that the NRLncSig could be a good independent predictor of prognosis, and significantly connected with immune microenvironment, thereby providing new insights into the roles of necroptosis-related lncRNAs in STS.

Development and verification of a novel immunogenic cell death-related signature for predicting the prognosis and immune infiltration in triple-negative breast cancer.

BACKGROUND: Insufficient understanding of the pathogenesis and tumor immunology of triple-negative breast cancer (TNBC) has limited the development of immunotherapy. The importance of tumor microenvironment (TME) in immunotyping, prognostic assessment and immunotherapy efficacy of cancer has been emphasized, however, potential immunogenic cell death (ICD) related genes function in TME of TNBC has been rarely investigated. AIMS: To initially explore the role and related mechanisms of ICD in TNBC, especially the role played in the TME of TNBC, and to identify different relevant subtypes based on ICD, and then develop an ICD-related risk score to predict each TNBC patient TME status, prognosis and immunotherapy response. METHODS AND RESULTS: In this study, we identified distinct ICD-related modification patterns based on 158 TNBC cases in the TCGA-TNBC cohort. We then investigated the possible correlation between ICD-related modification patterns and TME cell infiltration characteristics in TNBC. By using univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analysis, we created a risk scoring system (ICD score) to quantifiably evaluate the impact of ICD-related modification patterns in individual TNBC patient. Two different ICD-related modification patterns were found with significant differences in immune infiltration. Lower ICD score was correlated with higher immune infiltration, tumor mutational burden and significantly enriched in immune-related pathways, indicating a strong ability to activate immune response, which might account for relatively favorable prognosis of TNBC patients and could serve as a predictor to select suitable candidates for immunotherapy. We used two independent cohorts, GSE58812 cohort and Metabric cohort to validate prognosis and immunohistochemistry for preliminary in vitro validation. CONCLUSION: This study evidenced that the ICD-related modification patterns might exert pivotal roles in the immune infiltration landscape of TNBC and ICD score might act as potential predictors of prognostic assessment and immunotherapy response. This research provides unique insights for individualize immune treatment strategies and promising immunotherapy candidates screening.

The association between brominated flame retardants exposure with bone mineral density in US adults: A cross-sectional study of the national health and nutrition examination survey (NHANES) 2005-2014.

BACKGROUND AND AIMS: Exposure to brominated flame retardants (BFRs) has been widely confirmed to impair the normal functioning of the human body system. However, there is a paucity of study on the effects of serum BFRs on bone mineral density (BMD). This study aims to investigate the relationship between exposure to BFRs and BMD in a nationally representative sample of U.S. adults. METHODS: 3079 participants aged between 20 and 80 years with complete data were included in the study. Serum levels of BFRs were measured using automated liquid-liquid extraction and subsequent sample clean-up. The BMD of all participants were assessed by DXA examinations. Generalize linear model, Restricted cubic spline (RCS), subgroup, weighted quantile sum (WQS) and bayesian kernel machine regression (BKMR) were used to estimate the association between serum BFRs and BMD. RESULTS: Multivariate linear regression analyses revealed that, after adjusting for covariates, PBB153 was significantly associated with TF-BMD (ß = 0.0177, 95%CI: 0.0103-0.0252), FN-BMD (ß = 0.009, 95%CI: 0.0036-0.0145), TS-BMD (ß = 0.0081, 95%CI: 0.0013-0.015) and L1-BMD (ß = 0.0144, 95%CI: 0.0075-0.0213). However, the associations lose their statistical significance after further adjustment for sex. BFRs exhibited S-shaped or line-plateau dose-response curves with BMD. In subgroup analyses, BFRs were significantly associated with BMD in participants who were younger than 55 years, female, overweight (BMI >25 kg/m2), and less alcohol consumption. In WQS and BKMR analyses, the effects of BFRs mixtures on BMD differed by sex, and PBDE153, PBDE209 and PBB153 had the highest weights in the WQS regression model. CONCLUSION: This study showed that serum BFRs negatively predicted BMD in men, but not in women or the general population. PBDE153, PBDE209, and PBB153 were significant BMD factors, especially in younger, overweight, and less alcohol consumption individuals.

Exploring the biological behavior and underlying mechanism of KITLG in triple-negative breast cancer.

The tyrosine-kinase receptor that is specified by the KIT locus is demarcated by KITLG. This multifaceted factor is instrumental during in-utero germ and neural cell maturation and hematopoiesis, ostensibly reflecting its role in facilitating cell migration. Concurrently, KITLG is prone to a mutation in germ cell tumors, entailing a presumed connection to tumorigenesis. Despite this, the intricacies of its function in breast cancer and the relevant mechanisms remain elusive. Multiple independent databases depict a consistently low expression of KITLG within tissues affected by triple-negative breast cancers (TNBC), a trend strongly coupled with reduced survival rates. Interestingly, non-triple-negative breast cancers exhibit a markedly high expression of KITLG compared to the norm. An initial analysis of the GEO database speculates that KITLG may serve as an oncogene suppressor in TNBC, hinting at varied roles for KITLG isoforms within this disease context. In conclusion, our preliminary analysis offers valuable insights into the role and expression pattern of KITLG in TNBC. We provide evidence supporting its consideration as a promising new prognostic marker, thereby potentially enriching therapeutic strategies for TNBC. Indeed, given the limited advances in molecularly targeted therapy for TNBC, a significant need exists for a more precise therapeutic approach and a comprehensive understanding of its inherent mechanisms of action.

Immunological role and prognostic value of the SKA family in pan-cancer analysis.

Background: The spindle and kinetochore associated (SKA) complex, which plays important roles in proper chromosome segregation during mitosis by maintaining the stabilization of kinetochore-spindle microtubule attachment during mitosis, has recently been reported to exert regulatory effects on the initiation and progression of various human cancer types. Nevertheless, the prognostic significance and immune infiltration of the SKA family across cancers have not been well elucidated. Methods: Using data from three large public datasets, including The Cancer Genome Atlas, Genotype-Tissue Expression, and Gene Expression Omnibus databases, a novel scoring system (termed the SKA score) was developed to quantify the SKA family level across cancers. We then evaluated the prognostic impact of the SKA score on survival and assessed the effect of the SKA score on immunotherapy at the pan-cancer level using multiomics bioinformatic analyses. The correlation of the SKA score and the tumor microenvironment (TME) was also explored in depth. Potential small molecular compounds and chemotherapeutic agents were assessed by CTRP and GDSC analyses. Immunohistochemistry was performed to verify the expression of the SKA family genes. Results: Our results demonstrated a close correlation between the SKA score and tumor development and prognosis in multiple cancers. The SKA score was positively related to cell cycle pathways and DNA replication across cancers, such as E2F targets, the G2M checkpoint, MYC targets V1/V2, mitotic spindles and DNA repair. Additionally, the SKA score was negatively related to the infiltration of various immune cells with antitumor effects in the TME. In addition, the potential value of the SKA score was identified to predict immunotherapy response for melanoma and bladder cancer. We also demonstrated a correlation between SKA1/2/3 and the response to drug treatment across cancers and the promising potential of the SKA complex and its genes as therapeutic targets in cancer. Immunohistochemistry demonstrated that the expression differences of SKA1/2/3 were significant between the breast cancer group and the paracancerous group. Conclusion: The SKA score plays a critical role in 33 cancer types and is highly related to tumor prognosis. Patients with elevated SKA scores have a clear immunosuppressive TME. The SKA score may serve as a predictor for patients receiving anti-PD-1/L1 therapy.

Construction of a novel signature and prediction of the immune landscape in gastric cancer based on necroptosis-related genes.

Necroptosis, a type of programmed cell death, has become a potential therapeutic target for solid tumors. Nevertheless, the potential roles of necroptosis-related genes (NRGs) in gastric cancer (GC) remain unknown. The objective of the present study was to create a necroptosis-related prognostic signature that can provide more accurate assessment of prognosis in GC. Using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data, we identified differentially expressed NRGs. Univariate analysis and Lasso regression were performed to determine the prognostic signature. Risk scores were calculated and all GC patients were divided into high- and low-risk score group according to the median risk score value. The robustness of this signature was externally validated with data from GSE84437 cohort (n = 431). Survival analysis revealed high-risk score patients had a worse prognosis. Results evidenced that the signature was an independent prognosis factor for survival. Single-sample sequence set enrichment analysis (ssGSEA) exhibited different enrichment of immune cells and immune-related pathways in the two risk groups. Furthermore, a predictive nomogram was generated and showed excellent predictive performance based on discrimination and calibration. In addition, the risk score positively correlated with tumor mutational burden and was associated with sensitivity to multiple anti-cancer drugs. Overall, our work demonstrates a close relationship between necroptosis and the prognosis of GC. The signature we constructed with potential clinical application value, can be used for prognosis prediction and being a potential therapeutic responses indicator in GC patients.

Comparative Physiology and Transcriptome Analysis of Young Spikes in Response to Late Spring Coldness in Wheat (Triticum aestivum L.).

Late spring coldness (LSC) is critical for wheat growth and development in the Huang-Huai valleys of China. However, little is known about the molecular mechanisms for young spikes responding to low temperature (LT) stress during anther connective tissue formation phase (ACFP). To elucidate the molecular mechanisms associated with low temperature, we performed a comparative transcriptome analysis of wheat cultivars Xinmai26 (XM26: cold-sensitive) and Yannong19 (YN19: cold-tolerant) using RNA-seq data. Over 4000 differently expressed genes (DEGs) were identified under low temperature conditions (T1: 4°C) and freezing conditions (T2: -4°C) compared with control (CK: 16°C). The number of DEGs associated with two cultivars at two low temperature treatments (T1: 4°C and T2: -4°C) were 834, 1,353, 231, and 1,882 in four comparison groups (Xinmai26-CK vs. Xinmai26-T1, Xinmai26-CK vs. Xinmai26-T2, Yannong19-CK vs. Yannong19-T1, and Yannong19-CK vs. Yannong19-T2), respectively. Furthermore, to validate the accuracy of RNA-seq, 16 DEGs were analyzed using quantitative real-time RT-PCR. Several transcriptome changes were observed through Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway functional enrichment analysis in plant hormone signal transduction, circadian rhythm-plant, and starch and sucrose metabolism under low temperature. In addition, 126 transcription factors (TFs), including AP2-ERF, bHLH, WRKY, MYB, HSF, and members of the bZIP family, were considered as cold-responsive. It is the first study to investigate DEGs associated with low temperature stress at the transcriptome level in two wheat cultivars with different cold resistance capacities. Most likely, the variations in transcription factors (TFs) regulation, and starch and sucrose metabolism contribute to different cold resistance capacities in the two cultivars. Further, physiological activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT) enzymes, malondialdehyde (MDA), soluble sugar (SS), and sucrose contents were evaluated to investigate the negative impacts of low temperature in both cultivars. These findings provide new insight into the molecular mechanisms of plant responses to low temperature and potential candidate genes that required for improving wheat's capacity to withstand low temperature stress.

Effects of Low Temperature Stress on Source-Sink Organs in Wheat and Phosphorus Mitigation Strategies.

The 21st century presents many challenges to mankind, including climate change, fast growing human population, and serious concerns over food security. Wheat is a leading cereal crop that largely fulfills the global food needs. Low temperature stress accompanied by nutrient-starved soils is badly disrupting the source-sink relationship of wheat, thus causing an acute decline in final yield and deteriorating the grain quality. This review paper aimed to understand how low temperature stress affects wheat source-sink organs (i.e., leaves, roots, and spikes) and how phosphorus application reliefs in alleviating its harmful consequences. Also, we discussed mitigation strategies to enhance wheat capacity to adapt to varying temperature extremes and made rational recommendations based on modern agronomic and breeding approaches. Therefore, this study is likely to establish a solid foundation for improving the tolerance to low temperature stress and to improve its phosphorus utilization efficiency in wheat.

Identification and validation of a hypoxia-related prognostic signature in clear cell renal cell carcinoma patients.

ABSTRACT: Increasing evidence has shown that hypoxia is closely related to the development, progression, and prognosis of clear cell renal cell carcinoma (ccRCC). Nevertheless, reliable prognostic signatures based on hypoxia have not been well-established. This study aimed to establish a hypoxia-related prognostic signature and construct an optimized nomogram for patients with ccRCC.We accessed hallmark gene sets of hypoxia, including 200 genes, and an original RNA seq dataset of ccRCC cases with integrated clinical information obtained by mining the Cancer Genome Atlas database and the International Cancer Genome Consortium (ICGC) database. Univariate Cox regression analysis and multivariate Cox proportional hazards regression were performed to identify prognostic hub genes and further established prognostic model as well as visualized the nomogram. External validation of the optimized nomogram was performed in independent cohorts from the ICGC database.ANKZF1, ETS1, PLAUR, SERPINE1, FBP1, and PFKP were selected as prognostic hypoxia-related hub genes, and the prognostic model effectively distinguishes high-risk and low-risk patients with ccRCC. The results of receiver operating characteristic curve, risk plots, survival analysis, and independent analysis suggested that RiskScore was a useful tool and independent predictive factor. A novel prognosis nomogram optimized via RiskScore showed its promising performance in both the Cancer Genome Atlas-ccRCC cohort and an ICGC-ccRCC cohort.Our study reveals that the differential expressions of hypoxia-related genes are associated with the overall survival of patients with ccRCC. The prognostic model we established showed a good predictive and discerning ability in ccRCC patients. The novel nomogram optimized via RiskScore exhibited a promising predictive ability. It may be able to serve as a visualized tool for guiding clinical decisions and selecting effective individualized treatments.

MiRNA-based model for predicting the TMB level in colon adenocarcinoma based on a LASSO logistic regression method.

ABSTRACT: Some patients with advanced colon adenocarcinoma (COAD) are not sensitive to radiotherapy and chemotherapy, and as such, immunotherapy has become the most popular option for these patients. However, different patients respond differently to immunotherapy. Tumor mutational burden (TMB) has been used as a predictor of the response of advanced COAD patients to immunotherapy. A high TMB typically indicates that the patient's immune system will respond well to immunotherapy. In addition, while microRNAs (miRNA) have been shown to play an important role in treatment responses associated with the immune system, the relationship between miRNA expression levels and TMB has not been clarified in COAD.We downloaded miRNA data and mutational files of COAD from the Cancer Genome Atlas database. Differentially expressed miRNAs were screened in the training group, and miRNAs used to construct the model were further identified using the LASSO logistic regression method. After building the miRNA-based model, we explored the correlation between the model and TMB. The model was verified by a receiver operating characteristic curve, and the correlation between it and 3 widely used immune checkpoints (programmed death receptor-1, programmed death-ligand 1, and cytotoxic T-lymphocyte associated protein-4) was explored. Functional enrichment analysis of the selected miRNAs was performed, and these respective miRNA target genes were predicted using online tools.Our results showed that a total of 32 differentially expressed miRNAs were used in the construction of the model. The accuracies of the models of the 2 datasets (training and test sets) were 0.987 and 0.934, respectively. Correlation analysis showed that the correlation of the model with programmed death-ligand 1 and cytotoxic T-lymphocyte associated protein-4, as well as TMB, was high, but there was no correlation with programmed death receptor-1. The results of functional enrichment analysis indicated that these 32 miRNAs were involved in many immune-related biological processes and tumor-related pathways.Therefore, this study demonstrated that differentially expressed miRNAs can be used to predict the TMB level, which can help identify advanced COAD patients who will respond well to immunotherapy. The miRNA-based model may be used as a tool to predict the TMB level in patients with advanced COAD.

PLCG2 as a potential indicator of tumor microenvironment remodeling in soft tissue sarcoma.

ABSTRACT: The tumor microenvironment (TME) plays an important role in the occurrence and development of soft tissue sarcoma (STS). A number of studies have shown that to inhibit tumor growth, the TME can be remodeled into an environment unsuitable for tumor proliferation. However, a lack of understanding exists regarding the dynamic regulation of TME.In this study, we used CIBERSORT and ESTIMATE calculation methods from the Cancer Genome Atlas (TCGA) database to calculate the proportion of tumor infiltrating immune cells (TICs) and the number of immune and stromal components in 263 STS samples. Differential expression genes (DEGs) shared by Immune Score and Stromal Score were obtained via difference analysis. Univariate Cox regression analysis and construction of protein-protein interaction (PPI) networks were applied to the DEGs.Through intersection analysis of univariate COX and PPI, PLCG2 was determined as the indicator. Further analysis showed that PLCG2 expression was positively correlated with the survival of STS patients. Gene set enrichment analysis (GSEA) showed that genes in the highly expressed PLCG2 group were enriched in immune-related activities. In the low-expression PLCG2 group, genes were enriched in the E2F, G2M, and MYC pathways. Difference analysis and correlation analysis showed that CD8+ T cells, gamma delta T cells, monocytes, and M1 macrophages were positively correlated with PLCG2 expression, indicating that PLCG2 may represent the immune status of TME.Therefore, the level of PLCG2 may aid in determining the prognosis of STS patients, especially the status of TME. These data provide additional insights into the remodeling of TME.

Over-expression of CEP55 Predicts Favorable Prognosis in Colorectal Cancer Patients With Lymph Node Involvement.

BACKGROUND/AIM: To characterize the potential roles of CEP55 in colorectal cancer development and assess its eligibility as a prognostic diagnosis tool for colorectal cancer. PATIENTS AND METHODS: Immunohistochemical (IHC) analysis of CEP55 immunoreactivity in 166 cancer specimens from colorectal cancer patients. RESULTS: CEP55 was not found to statistically significantly affect different patient clinical parameters. Multivariate analysis illustrated that patients with N stage (1+2) colorectal cancer and high CEP55 expression had a significantly lower five-year survival rate than patients with N stage (1+2) colorectal cancer and low CEP55 expression. CONCLUSION: There is a correlation between CEP55 and advanced N-stage colorectal cancer. Thus, CEP55 may be a potential diagnostic biomarker for colorectal cancer patients.

Nomogram for predicting overall survival in stage II-III colorectal cancer.

PURPOSE: The overall survival (OS) of patients diagnosed with stage II-III colorectal cancer (CRC) can vary greatly, even between patients with the same tumor stage. We aimed to design a nomogram to predict OS in resected, stage II-III CRC and stratify patients with CRC into different risk groups. PATIENTS AND METHODS: Based on data from 873 patients with CRC, we used univariate Cox regression analysis to select the significant prognostic features, which were subjected to the least absolute shrinkage and selection operator (LASSO) regression algorithm for feature selection. Cross-validation was used to confirm suitable tuning parameters (λ) for LASSO logistic regression. Then, the nomogram was used to estimate 3- and 5-year OS based on the multivariable Cox regression model. The survival curves of the two groups were produced using the Kaplan-Meier method. Risk group stratification was performed to assess the predictive capacity of the nomogram. RESULTS: Preoperative mean platelet volume, preoperative platelet distribution width, monocytes, and postoperative adjuvant chemotherapy were identified as independent prognostic factors by LASSO regression and integrated for the construction of the nomogram. The nomogram provided good discrimination, with C-indices of 0.67 and 0.69 for the training and validation sets, respectively. Calibration plots illustrated excellent agreement between the nomogram predictions and actual observations for 3- and 5-year OS. Moreover, a significant difference in OS was shown between patients stratified into different risk groups (P < .001). CONCLUSION: We constructed and validated an original predictive nomogram for OS in patients with CRC after surgery, facilitating physicians to appraise the individual survival of postoperative patients accurately and identify high-risk patients who need more aggressive treatment and follow-up strategies.

A nomogram to predict vascular invasion before resection of colorectal cancer.

Vascular invasion (VI) is an important feature for systemic recurrence and an indicator for the application of adjuvant therapy in colorectal cancer (CRC). Preoperative knowledge of VI is important in determining whether adjuvant therapy is necessary, as well as the adequacy of surgical resection. In the present study, a predictive nomogram for VI in patients with CRC was constructed. The prediction model consisted of 664 eligible patients with CRC, who were divided into a training set (n=468) and a validation set (n=196). Data were collected between August 2013 and April 2018. The feature selection model was established using the least absolute shrinkage and selection operator regression model. Multivariable logistic regression analysis was used to construct the predictive nomogram. The performance of the nomogram was evaluated by calibration, discrimination and clinical usefulness. Differentiation, computed tomography (CT)-based on N stage (CT N stage), hemameba and tumor distance from the anus (cm) were integrated into the nomogram. The nomogram exhibited good discrimination, with an area under the curve (AUC) of 0.731 and good calibration. Application of the nomogram in the validation cohort showed acceptable discrimination, with an AUC of 0.710 and good calibration. Decision curve analysis revealed that the nomogram was clinically useful. These findings suggests, to the best of our knowledge, that this may be the first nomogram for individual preoperative prediction of VI in patients with CRC, which may promote preoperative optimization strategies for this selected group of patients.