Endoplasmic reticulum stress-related genes as prognostic and immunogenic biomarkers in prostate cancer.

BACKGROUND: The metastasis and aggressive nature of prostate cancer (PCa) has become a major malignancy related threat that concerns men's health. The efficacy of immune monotherapy against PCa is questionable due to its lymphocyte-suppressive nature. METHOD: Endoplasmic reticulum stress- (ERS-) and PCa-prognosis-related genes were obtained from the Molecular Signatures Database and the Cancer Genome Atlas database. The expression, prognosis and immune infiltration values of key genes were explored by "survival R package", "rms", "xCELL algorithm", and univariate-multivariate Cox and LASSO regression analyses. The "consensus cluster plus R package" was used for cluster analysis. RESULT: As ERS-related genes, ERLIN2 and CDK5RAP3 showed significant expressional, prognostic and clinic-pathologic values. They were defined as the key genes significantly correlated with immune infiltration and response. The nomogram was constructed with T-stage and primary treatment outcome, and the risk-prognostic model was constructed in the following way: Riskscore = (- 0.1918) * ERLIN2 + (0.5254) * CDK5RAP3. Subsequently, prognostic subgroups based on key genes classified the high-risk group as a pro-cancer subgroup that had lower mutation rates of critical genes (SPOP and MUC16), multiple low-expression immune-relevant molecules, and differences in macrophages (M1 and M2) expressions. Finally, ERLIN2 as an anti-oncogene and CDK5RAP3 as a pro-oncogene were further confirmed by cell phenotype assays and immunohistochemistry. CONCLUSION: We identified ERLIN2 and CDK5RAP3 as ERS-related genes with important prognostic and immunologic values, and classified patients between high- and low-risk subgroups, which provided new prognostic markers, immunotherapeutic targets, and basis for prognostic assessments.

GAD1 contributes to the progression and drug resistance in castration resistant prostate cancer.

BACKGROUND: Prostate cancer is currently the second most lethal malignancy in men worldwide due to metastasis and invasion in advanced stages. Studies have revealed that androgen deprivation therapy can induce stable remission in patients with advanced prostate cancer, although most patients will develop castration-resistant prostate cancer (CRPC) in 1-2 years. Docetaxel and enzalutamide improve survival in patients with CRPC, although only for a short time, eventually patients develop primary or secondary resistance, causing disease progression or biochemical relapse. METHODS: The gene expression profiles of docetaxel-sensitive or -resistant prostate cancer cell lines, namely GSE33455, GSE36135, GSE78201, GSE104935, and GSE143408, were sequentially analyzed for differentially expressed genes and progress-free interval significance. Subsequently, the overall survival significance and clinic-pathological features were analyzed by the R package. The implications of hub genes mutations, methylation in prostate cancer and the relationship with the tumor immune cell infiltration microenvironment were assessed with the help of cBioPortal, UALCAN and TISIDB web resources. Finally, effects of the hub genes on the progression and drug resistance in prostate cancer were explored using reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, cell phenotype, and drug sensitivity. RESULT: Glutamate decarboxylase 1 (GAD1) was tentatively identified by bioinformatic analysis as an hub gene for the development of drug resistance, including docetaxel and enzalutamide, in prostate cancer. Additionally, GAD1 expression, mutation and methylation were significantly correlated with the clinicopathological features and the tumor immune microenvironment. RT-PCR, immunohistochemistry, cell phenotype and drug sensitivity experiments further demonstrated that GAD1 promoted prostate cancer progression and decreased the therapeutic effect of docetaxel or enzalutamide. CONCLUSION: This research confirmed that GAD1 was a hub gene in the progression and development of drug resistance in prostate cancer. This helped to explain prostate cancer drug resistance and provides new immune-related therapeutic targets and biomarkers for it.

Current status and perspectives of non-coding RNA and phase separation interactions.

Phase separation refers to a phenomenon in which different components of a cell collide and fuse with each other to form droplets such that some components are encapsulated within the droplet and some are blocked outside. It is prevalent in eukaryotic cells and is closely related to genome assembly and transcriptional regulation, enabling multiple biological functions. With the development of high-throughput sequencing technologies, several non-coding RNAs (ncRNAs) have been shown to play an important role in epigenetic regulation of gene expression in addition to their roles at the transcriptional and post-transcriptional levels. In addition, some ncRNAs are involved in the formation of membraneless organelles (MLOs), the regulation of genomic stability and stress response through phase separation. Notably, phase separation can also affect the biogenesis, processing and maturation of ncRNAs. This review summarizes recent discoveries related to the relationship between ncRNAs and phase separation, providing new perspectives to guide future interventions.

Correlation between TCM Constitutional Types and Lung Carcinoma in Various Geographical Areas: A Systematic Review and Meta-Analysis.

Background: Lung carcinoma is a serious disorder that negatively influences the quality of life of sufferers. Despite the growing number of investigations into the management and prognosis of lung carcinoma, few research studies have been conducted to demonstrate the association between TCM constitution and lung carcinoma. Methods: We searched PubMed, EMBASE, Science Net, Cochrane Library, China National Knowledge Infrastructure, VIP database, Wanfang database, and China Biomedical Literature Database for Chinese and English versions until January 31, 2021. We also manually searched for Chinese lung cancer, Chinese physical medicine, Chinese medical trial registries, and unpublished surveys or references. The literature was screened against inclusive and exclusive criteria, and two investigators' results were independently summarized. The primary outcome was a ratio of body type. Single-group rates were meta-analyzed using Stata 14.0 statistical software, bias was estimated by funnel plotting, and sources of heterogeneity were evaluated by subgroup and sensitivity examinations. Results: 18 randomized controlled trials were totally included to compare the single-group ratio and 95% confidence interval of nine constitution types of lung cancer, namely, mild constitution (ES = 0.12, 95% CI (0.08, 0.15), P < 0.0001), Qi deficiency constitution (ES = 0.20, 95% CI (0.15, 0.26), P < 0.0001), Qi depression constitution (ES = 0.09, 95% CI (0.07, 0.12), P < 0.0001), damp-heat constitution (ES = 0.05, 95% CI (0.03, -0.06), P < 0.0001), phlegm dampness constitution (ES = 0.05, 95% CI (0.03, -0.06), P < 0.0001), special constitution (ES = 0.01, 95% CI (0.01, 0.02), P=0.993), blood stasis constitution (ES = 0.05, 95% CI (0.04, 0.07), P < 0.0001), Yang deficiency constitution (ES = 0.16, 95% CI (0.12, 0.19), P < 0.0001), and Yin deficiency constitution (MD = 0.15, 95% CI (0.11, 0.18), P < 0.0001). Conclusion: This study showed that Qi deficiency, Yang deficiency, and Yin vacuity were the predominant types of physical conditions of lung cancer cases.

Urine Exosomal AMACR Is a Novel Biomarker for Prostate Cancer Detection at Initial Biopsy.

Objectives: The aim of this study is to identify and validate urine exosomal AMACR (UE-A) as a novel biomarker to improve the detection of prostate cancer (PCa) and clinically significant PCa (Gleason score ≥ 7) at initial prostate biopsy. Methods: A total of 289 first-catch urine samples after the digital rectal exam (DRE) were collected from patients who underwent prostatic biopsy, and 17 patients were excluded due to incomplete clinical information. Urine exosomes were purified, and urinary exosomal AMACR (UE-A) was measured by enzyme-linked immunosorbent assay (ELISA). The diagnostic performance of UE-A was evaluated by receiver operating characteristic (ROC) analysis, decision curve analysis (DCA), and waterfall plots. Results: The expression of AMACR in PCa and csPCa was significantly higher than that in BPH and non-aggressive (p < 0.001). The UE-A presented good performance in distinguishing PCa from BPH or BPH plus non-significant PCa (nsPCa) from csPCa with an area under the ROC curve (AUC) of 0.832 and 0.78, respectively. The performance of UE-A was further validated in a multi-center cohort of patients with an AUC of 0.800 for detecting PCa and 0.749 for detecting csPCa. The clinical utility assessed by DCA showed that the benefit of patients using UE-A was superior to PSA, f/t PSA, and PSAD in both the training cohort and the validation cohort in terms of all threshold probabilities. Setting 95% sensitivity as the cutoff value, UE-A could avoid 27.57% of unnecessary biopsies, with only 4 (1.47%) csPCa patients missed. Conclusions: We demonstrated the great performance of UE-A for the early diagnosis of PCa and csPCa. UE-A could be a novel non-invasive diagnostic biomarker to improve the detection of PCa and csPCa.

Inflammatory Immune-Associated eRNA: Mechanisms, Functions and Therapeutic Prospects.

The rapid development of multiple high-throughput sequencing technologies has made it possible to explore the critical roles and mechanisms of functional enhancers and enhancer RNAs (eRNAs). The inflammatory immune response, as a fundamental pathological process in infectious diseases, cancers and immune disorders, coordinates the balance between the internal and external environment of the organism. It has been shown that both active enhancers and intranuclear eRNAs are preferentially expressed over inflammation-related genes in response to inflammatory stimuli, suggesting that enhancer transcription events and their products influence the expression and function of inflammatory genes. Therefore, in this review, we summarize and discuss the relevant inflammatory roles and regulatory mechanisms of eRNAs in inflammatory immune cells, non-inflammatory immune cells, inflammatory immune diseases and tumors, and explore the potential therapeutic effects of enhancer inhibitors affecting eRNA production for diseases with inflammatory immune responses.

Characterization and function of biomarkers in sunitinib-resistant renal carcinoma cells.

OBJECTIVE: Sunitinib is a first-line drug in the treatment of metastatic renal cell carcinoma, but patients will inevitably develop drug resistance after 6-15 months of systematic treatment, which seriously affects the prognosis in KIRC. METHODS: During the study, the Gene Expression Omnibus (GEO) database was used to perform a systematic bioinformatics analysis,so that we could determine the genes (DEGs) which are differentially expressed between sunitinib-sensitive and sunitinib-resistant RCC (SRRC) cells. RESULTS: A total of 31 DEGs were identified. Gene ontology (GO) was used to analyze the function of DEGS. These DEGs were found mainly enriched in organic aniontransmembrane transporter. The Cytohubba plug-in, STRING database and Cytoscape software were involved to construct a protein-protein interaction (PPI) network, and the pivot genes were identified by single-gene and multi-gene Cox regression analysis. Finally, DDX58 and MX2 were identified as prognostic genes. Survival analysis was performed by using prognostic nomogram, prognostic histogram and GEPIA database to verify the relationship between DDX58 and MX2 expression and survival. The relationship between the two pivot genes and the prognosis of patients was further verified by using the KM survival analyses and Time Dependency ROC curve analyses from TCGA database. Immunohistochemical analyses confirmed that, in tumor tissues and normal tissues, DDX58 and MX2 were differentially expressed. The expression of these two genes have relationship with the immune checkpoint. CONCLUSIONS: This study provides insights into the molecular mechanisms of SRRC, as well as the selection of therapeutic and prognostic biomarkers for SRRC.

Metastatic Immune-Related Genes for Affecting Prognosis and Immune Response in Renal Clear Cell Carcinoma.

Background: In renal clear cell carcinoma, a common cancer of the urinary system, 25-30% patients are metastatic at initial diagnosis and 20-30% patients have a tendency of recurrence and metastasis after local surgery. With the rapid development of tumor immunology, immune agents have brought new directions to tumor therapy. However, no relevant studies have explored the role of immune-related genes in kidney cancer metastasis. Methods: Co-expressed metastatic immune-related differentially expressed genes (mIR-DEGs) were screened by GSE12606, GSE47352, and immunorelated genes. Then, differential expression analysis, prognostic analysis, and univariate and multivariate Cox regression analysis in KIRC were performed to determine independent prognostic factors associated, and the risk prognostic model was established. The correlation of hub mIR-DEGs with clinicopathological factors, immune invasion, and immune checkpoints was analyzed, and the expression of hub mIR-DEGs and their effect on tumor were re-evaluated by OCLR scores in KIRC. Results: By comprehensive bioassay, we found that FGF17, PRKCG, SSTR1, and SCTR were mIR-DEGs with independent prognostic values, which were significantly associated with clinicopathological factors and immune checkpoint-related genes. The risk prognostics model built on this basis had good predictive potential. In addition, targeted small molecule drugs, including calmidazolium and sulfasalazine, were predicted for mIR-DEGs. Further experimental results were consistent with the bioinformatics analysis. Conclusion: This study preliminarily confirmed that FGF17, PRKCG, SSTR1, and SCTR were targeted genes affecting renal cancer metastasis and related immune responses and can be used as potential therapeutic targets and prognostic biomarkers for renal cancer. Preliminary validation found that PRKCG and SSTR1 were consistent with predictions.

Association Between Preoperative Blood Glucose Level and Hospital Length of Stay in Patients With Kidney Stones Undergoing Percutaneous Nephrolithotomy.

AIM: To assess the effect of preoperative blood glucose (POBG) levels on the length of stay (LOS) in patients with kidney stones undergoing percutaneous nephrolithotomy (PCNL). METHODS: We conducted a retrospective study of patients who underwent PCNL at the Zhongda Hospital of Southeast University from 2013 to 2019. The relationship between POBG level and LOS was investigated by dose-response analysis curves of restricted cubic spline function. RESULTS: We included 310 patients and divided them into three groups (<5.04, 5.04 to <6.88, ≥6.88 mmol/L) according to the POBG levels. Patients with POBG levels ≥6.88 mmol/L (adjusted odds risk [aOR] 1.67; 95% CI 0.83-3.33) had a 67% higher risk of LOS > 2 weeks than patients with POBG levels <5.04 mmol/L. A positive dose-response analysis curve was observed between POBG and the adjusted risk of LOS >2 weeks. Similar results were observed in the subgroups analysis. CONCLUSION: We demonstrated that higher POBG levels were significantly associated with longer LOS in patients with kidney stones undergoing PCNL.