BLCA prognostic model creation and validation based on immune gene-metabolic gene combination.

BACKGROUND: Bladder cancer (BLCA) is a prevalent urinary system malignancy. Understanding the interplay of immunological and metabolic genes in BLCA is crucial for prognosis and treatment. METHODS: Immune/metabolism genes were extracted, their expression profiles analyzed. NMF clustering found prognostic genes. Immunocyte infiltration and tumor microenvironment were examined. Risk prognostic signature using Cox/LASSO methods was developed. Immunological Microenvironment and functional enrichment analysis explored. Immunotherapy response and somatic mutations evaluated. RT-qPCR validated gene expression. RESULTS: We investigated these genes in 614 BLCA samples, identifying relevant prognostic genes. We developed a predictive feature and signature comprising 7 genes (POLE2, AHNAK, SHMT2, NR2F1, TFRC, OAS1, CHKB). This immune and metabolism-related gene (IMRG) signature showed superior predictive performance across multiple datasets and was independent of clinical indicators. Immunotherapy response and immune cell infiltration correlated with the risk score. Functional enrichment analysis revealed distinct biological pathways between low- and high-risk groups. The signature demonstrated higher prediction accuracy than other signatures. qRT-PCR confirmed differential gene expression and immunotherapy response. CONCLUSIONS: The model in our work is a novel assessment tool to measure immunotherapy's effectiveness and anticipate BLCA patients' prognosis, offering new avenues for immunological biomarkers and targeted treatments.

Identification and validation of a novel cuproptosis-related lncRNA gene signature to predict prognosis and immune response in bladder cancer.

PURPOSE: Bladder cancer (BCa) is one of the most common malignant tumors in the urogenital system, characterized by the high recurrence rate, mortality rate and poor prognosis. Based on cuproptosis-related long noncoding RNAs (CRLs), this study set out to create a prediction signature to evaluate the prognosis of patients with BCa. METHODS: RNA-seq data including CRLs and related clinicopathological data were gathered from The Cancer Genome Atlas (TCGA) database (n = 428). The predictive signature was constructed after correlation analysis. Subsequently, relying on the analyzed data from the TCGA database and our sample collection, we examined and verified the connections between CRLs model and important indexes included prognosis, route and functional enrichment, tumor immune evasion, tumor mutation, and treatment sensitivity. RESULTS: Patients in the high-risk group had lower overall survival (OS) than that of low-risk group. Compared with clinicopathological variables, CRLs features have better predictive value according to receiver operating characteristic (ROC) curve. The expression level of CRLs was highly associated with the tumor progress, tumor microenvironment and tumor immune escape. Additionally, we identified that the mutation of TP53, TTN, KMT2D and MUC16 gene were founded in patients with BCa. Lapatinib, pazopanib, saracatinib, gemcitabine, paclitaxel and palenolactone had good antitumor effects for BCa patients in the high-risk group (all P < 0.001). CONCLUSION: This study revealed the effects of CRLs on BCa and further established CRLs model, which can be used in clinic for predicting prognosis, immunological response and treatment sensitivity inpatient with BCa.

Molecular Cluster Mining of Adrenocortical Carcinoma via Multi-Omics Data Analysis Aids Precise Clinical Therapy.

Adrenocortical carcinoma (ACC) is a malignancy of the endocrine system. We collected clinical and pathological features, genomic mutations, DNA methylation profiles, and mRNA, lncRNA, microRNA, and somatic mutations in ACC patients from the TCGA, GSE19750, GSE33371, and GSE49278 cohorts. Based on the MOVICS algorithm, the patients were divided into ACC1-3 subtypes by comprehensive multi-omics data analysis. We found that immune-related pathways were more activated, and drug metabolism pathways were enriched in ACC1 subtype patients. Furthermore, ACC1 patients were sensitive to PD-1 immunotherapy and had the lowest sensitivity to chemotherapeutic drugs. Patients with the ACC2 subtype had the worst survival prognosis and the highest tumor-mutation rate. Meanwhile, cell-cycle-related pathways, amino-acid-synthesis pathways, and immunosuppressive cells were enriched in ACC2 patients. Steroid and cholesterol biosynthetic pathways were enriched in patients with the ACC3 subtype. DNA-repair-related pathways were enriched in subtypes ACC2 and ACC3. The sensitivity of the ACC2 subtype to cisplatin, doxorubicin, gemcitabine, and etoposide was better than that of the other two subtypes. For 5-fluorouracil, there was no significant difference in sensitivity to paclitaxel between the three groups. A comprehensive analysis of multi-omics data will provide new clues for the prognosis and treatment of patients with ACC.

Identification of Novel Pyroptosis-Related Gene Signatures to Predict Prostate Cancer Recurrence.

Prostate cancer (PCa) is a common malignant type of urogenital tract tumor with poor prognosis. Despite therapeutic advances, the recurrence and mortality rates of PCa have continued to increase with poor prognoses. Pyroptosis, also known as inflammatory cell necrosis, is a recently identified type of programmed cell death that can regulate the invasiveness, differentiation, proliferation, and metastasis of tumor cells; thus, it has a profound effect on the prognosis of patients with tumors. However, the relationship between pyroptosis and PCa remains unclear. We first identified 25 pyroptosis-related genes (PRGs) that were differentially expressed between PCa tissues and matched normal tissues in The Cancer Genome Atlas (TCGA) cohort. Based on the expression levels of 25 PRGs, PCa patients were clearly divided into two clusters and 17 PRGs were found to be significantly different between the two clusters, suggesting probable roles for these genes in the progression and recurrence of PCa. Therefore, the GSE40272 dataset with recurrence follow-up information was used to verify their value. Univariate analysis suggested that 5/17 genes were associated with recurrence, the number of genes did not decrease after least absolute shrinkage and selection operator (LASSO) regression analysis, and 5 PRGs constituted the risk score formula. Low-risk and high-risk subgroups identified using the recurrence model showed different disease-free survival (DFS) times (P<0.001) and the risk score of five PRGs was a factor of independence for recurrence in patients with PCa. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested that these pathways, and comprising PRGs might be closely related to carcinogenesis and invasion of tumors, tumor microenvironment, and immune response. In conclusion, the expression signatures of PRGs play an important role in predicting PCa recurrence.

CXCR3 antagonist AMG487 ameliorates experimental autoimmune prostatitis by diminishing Th1 cell differentiation and inhibiting macrophage M1 phenotypic activation.

BACKGROUND: Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) is an inflammatory immune disease that is characterized by infiltrating inflammatory cells in the prostate and pelvic or by perineal pain. Receptor CXCR3modulates immune and inflammatory responses; however, the effects of CXCR3 antagonist AMG487 in the context of CP/CPPS are unknown. Therefore, we investigated the effect of AMG487 in experimental autoimmune prostatitis (EAP) mice and explored the potential functional mechanisms. METHODS: The EAP model was induced by intradermally injecting a mixture of prostate antigens and complete Freund's adjuvant on Days 0 and 28. To evaluate the effect of AMG487 on EAP mice, treatment with AMG487 and vehicle solution was conducted for the indicated period. Then, procedures were performed, including behavioral test, to evaluate the pain response to stimulation before the mice were killed and a histological assessment to evaluate the inflammation after the mice were killed. Immunofluorescence, flow cytometry, and Western blot assay were used to analyze the functional phenotype and regulation mechanism of AMG487 on T helper type 1 (Th1) cells and macrophages. RESULTS: We found high expression of CXCR3 in human benign prostate tissues with inflammation and EAP mice. The elevated CXCR3 in prostate tissues correlates with the severity of inflammation. CXCR3 antagonist AMG487 treatment ameliorated the inflammatory changes and the pelvic pain of EAP mice. AMG487 inhibits Th1 cell differentiation through the IL-12/STAT4pathway and inhibits pro-inflammatory M1 macrophages through the lipopolysaccharide/NF-κB p65signaling. AMG487 could inhibit the secretion of inflammatory mediators in EAP mice. CONCLUSION: CXCR3 antagonist AMG487 could ameliorate the inflammatory changes and the pelvic pain of EAP mice by diminishing Th1 cell differentiation and inhibiting macrophage M1 phenotypic activation. Thus, the results imply that AMG487 has the potential as an effective therapeutic agent in the prevention and treatment of EAP.

Application of Contrast-Enhanced Ultrasonography (CEUS) in the Assessment of Kidney Wound Recovery After Nephron-Sparing Surgery.

PURPOSE: To investigate feasibility, repeatability and usefulness of contrast-enhanced ultrasonography (CEUS) in the assessment of kidney wound recovery after laparoscopic nephron-sparing surgery (LNSS) or robot-assisted nephron-sparing surgery (RANSS) and preliminarily research the clinical factors associated with the length of extravasation (LOE). PATIENTS AND METHODS: From April 2019 to January 2020, 130 patients that underwent LNSS or RANSS in our hospital were included, and 90 patients (90/130) received CEUS examinations each one day from the postoperative day 1. The discovery of the cessation of contrast medium extravasation from the renal wound was the primary endpoint named "ultrasonic healing", and LOE ranged from the day of surgery to "ultrasonic healing". Patient, tumor, perioperative factors and LOE were collected. Univariate analysis and multivariate linear regression analysis were applied for the determination of factors associated with LOE. RESULTS: The average postoperative LOE was 1.76 days (standard deviation, 1.115; 95% confidence interval: 1.52-1.99). Ultrasonic healing within three days was observed in 95.6% patients (86/90). Univariable and multivariable analyses showed that R and A components in R.E.N.A.L. nephrometry score were associated with LOE. Anterior location and R component score of 2 (tumor size>4cm) were related to longer LOE than posterior location and R score of 1 (tumor size<4cm). The incidence of complications in patients with LOE over one day was higher than those with LOE of one day. CONCLUSION: CEUS was feasible, repeatable and useful in the assessment of kidney wound recovery. Tumor size and location were related to LOE after minimally invasive nephron-sparing surgery (MINSS). Length of stay after MINSS within three days might be relatively safe.

CaMK4-dependent phosphorylation of Akt/mTOR underlies Th17 excessive activation in experimental autoimmune prostatitis.

Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) is a complicated syndrome characterized by genitourinary pain in the absence of bacterial infection. Th17 cell-driven autoimmunity has been proposed as a cause of CP/CPPS. However, the factors that promote Th17-driven autoimmunity in experimental autoimmune prostatitis (EAP) and the molecular mechanisms are still largely unknown. Here, we showed that Th17 cells were excessively activated, and blockade of IL-17A could effectively ameliorate various symptoms in EAP. Furthermore, we revealed that calcium/calmodulin-dependent kinase Ⅳ (CaMK4), especially Thr196 p-CaMK4 was increased in the Th17 cells of the EAP group, which were activated by intracellular cytosolic Ca2+ . Pharmacologic and genetic inhibition of CaMK4 decreased the proportion of Th17 cells, and the protein and mRNA level of IL-17A, IL-22, and RORγt. The phosphorylation of CaMK4 was dependent on the increase in intracellular cytosolic Ca2+ concentration in Th17 cells. A mechanistic study demonstrated that inhibition of CaMK4 reduced IL-17A production by decreasing the phosphorylation of Akt-mTOR, which was well accepted to positively regulate Th17 differentiation. Collectively, our results demonstrated that Ca2+ -CaMK4-Akt/mTOR-IL-17A axis inhibition may serve as a promising therapeutic strategy for CP/CPPS.

Baicalin suppresses the cell cycle progression and proliferation of prostate cancer cells through the CDK6/FOXM1 axis.

The aim of this study was to investigate the effects and mechanisms of baicalin against prostate cancer cell growth and cell cycle progression. A human prostate cancer cell line LNCaP was engrafted into nude mice, and the oncogenicity of LNCaP cells was analyzed. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay was used to measure LNCaP and PC3 proliferation capability. CDK6 mRNA level was detected using qRT-PCR. Western blotting was performed to assess the levels of cell cycle-associated proteins. In addition, cell cycle and apoptosis were analyzed using flow cytometry. Baicalin significantly decreased the expression of cell cycle-associated proteins. Furthermore, baicalin showed an observable effect on proliferation, cell cycle progression and apoptosis in LNCaP and PC3 cells. Upregulation of CDK6 and FOXM1 reversed the effect of baicalin. CDK6- and FOXM1-mediated cell growth attenuated the protective effect of baicalin in prostate cancer. This study presented an understanding of the role and mechanism of baicalin in prostate cancer cells, providing a new target and therapies for the prevention and treatment of prostate cancer.

MicroRNA expression profile in chronic nonbacterial prostatitis revealed by next-generation small RNA sequencing.

MicroRNAs (miRNAs) are considered to be involved in the pathogenic initiation and progression of chronic nonbacterial prostatitis (CNP); however, the comprehensive expression profile of dysregulated miRNAs, relevant signaling pathways, and core machineries in CNP have not been fully elucidated. In the current research, CNP rat models were established through the intraprostatic injection of carrageenan into the prostate. Then, next-generation sequencing was performed to explore the miRNA expression profile in CNP. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) bioinformatical analyses were conducted to reveal the enriched biological processes, molecular functions, and cellular components and signaling pathways. As a result, 1224, 1039, and 1029 known miRNAs were annotated in prostate tissues from the blank control (BC), normal saline injection (NS), and carrageenan injection (CAR) groups (n = 3 for each group), respectively. Among them, 84 miRNAs (CAR vs BC) and 70 miRNAs (CAR vs NS) with significantly different expression levels were identified. Compared with previously reported miRNAs with altered expression in various inflammatory diseases, the majority of deregulated miRNAs in CNP, such as miR-146b-5p, miR-155-5p, miR-150-5p, and miR-139-5p, showed similar expression patterns. Moreover, bioinformatics analyses have enriched mitogen-activated protein kinase (MAPK), cyclic adenosine monophosphate (cAMP), endocytosis, mammalian target of rapamycin (mTOR), and forkhead box O (FoxO) signaling pathways. These pathways were all involved in immune response, which indicates the critical regulatory role of the immune system in CNP initiation and progression. Our investigation has presented a global view of the differentially expressed miRNAs and potential regulatory networks containing their target genes, which may be helpful for identifying the novel mechanisms of miRNAs in immune regulation and effective target-specific theragnosis for CNP.

The association of HIF-1α expression with clinicopathological significance in prostate cancer: a meta-analysis.

BACKGROUND: Hypoxia-inducible factor-1α (HIF-1α) plays an important role in tumor growth, invasion, and metastasis. The aim of this study was to perform a meta-analysis to explore the association of HIF-1α expression with clinicopathological significance in patients with prostate cancer (PCa). METHODS: A detailed literature search was made in PubMed, Embase, Cochrane Library, China Biology Medicine disc (CBM), and China National Knowledge Infrastructure (CNKI) up to August 21, 2017. Odds ratios (ORs) with 95% CIs were calculated to evaluate the strength of the correlations. Analysis of pooled data was performed using Review Manager 5.3 software. RESULTS: Eventually, 14 studies were identified and involved in this meta-analysis. The rate of HIF-1α protein expression was significantly higher in PCa than in nonmalignant prostate tissues (OR=12.01, 95% CI: 8.22-17.55, P<0.00001). Similar results were found in different subgroups. There were significant differences between HIF-1α expression and clinicopathological significance. The expression of HIF-1α protein was significantly associated with Gleason score (Gleason ≥7 vs Gleason <7: OR=3.58, 95% CI: 2.35-5.46, P<0.00001). The frequency of HIF-1α protein expression was significantly higher in T3-T4 stages than in T1-T2 stages of PCa (OR=3.70, 95% CI: 1.53-8.96, P=0.004). The expression of HIF-1α protein was significantly associated with the presence of lymph node and/or bone metastasis of PCa (metastasis positive vs negative: OR=7.07, 95% CI: 4.08-12.25, P<0.00001). CONCLUSION: Taken together, our findings have demonstrated the certain associations of HIF-1α expression with an increased risk and clinicopathological significance in PCa patients, indicating that HIF-1α may serve as a valuable biomarker for diagnosing PCa and monitoring the progression.

Pigmented perivascular epithelioid cell tumor (PEComa) arising from kidney: A case report.

INTRODUCTION: Perivascular epithelioid cell tumor (PEComa) is a mesenchymal neoplasm composed of perivascular epithelioid cells with clear to eosinophilic cytoplasm. Pigmented PEComa arising from kidney is extraordinarily rare and sometimes can exhibit aggressive biological behavior. CASE REPORT: We present here a rare case of pigmented renal PEComa in a 46-year-old female. The patient had complained of lumbago complicated with nausea and vomiting for 2 weeks and therefore was referred to our department. An enhanced computed scan revealed a 4 × 3 × 3 cm round-like mass in the lower pole of right kidney with inhomogeneous enhancement. The tumor cells immunestained was positive for HMB-45, focally positive for c-Kit (CD117), and negative for vimentin, S-100, AE1/AE3, CK-7, CK-18, CD-10, RCC antigen, CgA, DOG-1, EMA, smooth muscle actin, and synaptophysin. We successfully performed 3-dimensional laparoscopic resection of the neoplasm, which was then diagnosed as pigmented PEComa by postoperative pathology. No further growing lesion or metastasis was observed during a 1-year follow-up. CONCLUSION: This case report shows that pigmented renal PEComa is often presented as a renal mass with nonspecific symptoms and imaging features. The gold diagnosis of renal pigmented PEComa is mainly based on the combination of histopathology and immunohistochemistry. Complete resection by 3-dimensional laparoscopic nephron-sparing surgery can be an effective therapeutic management.

Mixed epithelial and stromal tumor of the kidney: a rare case report and review of the literatures.

Mixed epithelial and stromal tumor of the kidney (MESTK) is a rare complex renal neoplasm composed of a mixture of cystic and solid components. Until date only few cases of MESTK have been reported. We present here a rare case of MESTK that was diagnosed in a 56-year-old female. The patients were referred to our hospital due to a mass on the right kidney identified incidentally in a routine physical examination. A pre-operative diagnosis of cystic renal cell carcinoma was made and a right radical nephrectomy was carried out. Macroscopically, a cystic tumor was noticed in the upper portion of the right kidney. Various-sized cysts accompanied by multiple cysts and few solid areas were observed. Immunohistochemically, various epithelial markers as well as stromal markers were identified. Taken together with all the immunohistochemical results and morphological pattern of the tumor, a diagnosis of MESTK was made. MESTK is relatively rare and generally benign. However, it is difficult to distinguish between benign or malignant tumors according to the current radiological method. Therefore a complete resection of the tumor by partial or radical nephrectomy is suggested.