Diagnosis and management of urinary bladder paragangliomas: A Sino-American-European retrospective observational study.

OBJECTIVE: Paragangliomas of the urinary bladder (UBPGLs) are rare neuroendocrine tumours and pose a diagnostic and surgical challenge. It remains unclear what factors contribute to a timely presurgical diagnosis. The purpose of this study is to identify factors contributing to missing the diagnosis of UBPGLs before surgery. DESIGN, PATIENTS AND MEASUREMENTS: A total of 73 patients from 11 centres in China, and 51 patients from 6 centres in Europe and 1 center in the United States were included. Clinical, surgical and genetic data were collected and compared in patients diagnosed before versus after surgery. Logistic regression analysis was used to identify clinical factors associated with initiation of presurgical biochemical testing. RESULTS: Among all patients, only 47.6% were diagnosed before surgery. These patients were younger (34.0 vs. 54.0 years, p < .001), had larger tumours (2.9 vs. 1.8 cm, p < .001), and more had a SDHB pathogenic variant (54.7% vs. 11.9%, p < .001) than those diagnosed after surgery. Patients with presurgical diagnosis presented with more micturition spells (39.7% vs. 15.9%, p = .003), hypertension (50.0% vs. 31.7%, p = .041) and catecholamine-related symptoms (37.9% vs. 17.5%, p = .012). Multivariable logistic analysis revealed that presence of younger age (<35 years, odds ratio [OR] = 6.47, p = .013), micturition spells (OR = 6.79, p = .007), hypertension (OR = 3.98, p = .011), and sweating (OR = 41.72, p = .013) increased the probability of initiating presurgical biochemical testing. CONCLUSIONS: Most patients with UBPGL are diagnosed after surgery. Young age, hypertension, micturition spells and sweating are clues in assisting to initiate early biochemical testing and thus may establish a timely presurgical diagnosis.

[68Ga]Ga­LNC1007 PET/CT in the evaluation of renal cell carcinoma: comparison with 2-[18F]FDG/[68Ga]Ga-PSMA PET/CT.

PURPOSE: To compare the potential efficiency of [68Ga]Ga-LNC1007 with 2-[18F]FDG/[68Ga]Ga-PSMA PET/CT for detecting renal cell carcinoma (RCC) and to explore parameters derived from [68Ga]Ga-LNC1007 PET/CT for discriminating pathological characteristics in RCC. METHODS: Twenty-five RCC patients confirmed by pathology were enrolled in this prospective study. The maximum standardized uptake value (SUVmax), mean SUV (SUVmean), gross tumor volume (GTV) and total lesion-tracer (TL-tracer) of lesions were calculated from the corresponding PET/CT images. Pathological characteristics included World Health Organization/International Society of Urological Pathology (WHO/ISUP) grade and adverse pathological features (tumor necrosis or sarcomatoid or rhabdoid feature). RESULTS: [68Ga]Ga-LNC1007 PET/CT showed a higher detection rate for primary lesions than 2-[18F]FDG and [68Ga]Ga-PSMA (LNC1007 vs. FDG: 13/17 vs. 4/17, P = 0.005; LNC1007 vs. PSMA: 9/11 vs. 6/11, P = 0.361). [68Ga]Ga-LNC1007 PET/CT showed higher SUVmax (6.6 vs. 3.7, P = 0.005), SUVmean (4.1 vs. 2.3, P = 0.001) and TBR (2.6 vs. 1.7, P = 0.011) compared with 2-[18F]FDG PET/CT, and it also showed higher TBR (2.9 vs. 0.5, P = 0.003), TBR-delay (2.8 vs. 0.3, P = 0.003), GTV (84.1 vs. 42.9, P = 0.003) and TL-tracer (442.7 vs. 235.8, P = 0.008) compared with [68Ga]Ga-PSMA PET/CT. SUVmax and TBR derived from [68Ga]Ga-LNC1007 PET/CT could effectively differentiate WHO/ISUP grade (3-4 vs. 1-2) and adverse pathological features (positive vs. negative) (SUVmax: AUC 0.81, P = 0.04; AUC 0.80, P = 0.033; TBR: AUC 0.84, P = 0.026; AUC 0.85, P = 0.014). The SUVmax was positively correlated with the FAP expression, integrin αvß3 expression and the total expression of FAP and integrin αvß3 (r = 0.577, P = 0.006, r = 0.701, P < 0.001, and r = 0.702, P < 0.001, respectively). CONCLUSION: [68Ga]Ga-LNC1007 is a promising tracer for RCC imaging and can effectively identify aggressive pathological characteristics of RCC.

Heart failure classification using deep learning to extract spatiotemporal features from ECG.

BACKGROUND: Heart failure is a syndrome with complex clinical manifestations. Due to increasing population aging, heart failure has become a major medical problem worldwide. In this study, we used the MIMIC-III public database to extract the temporal and spatial characteristics of electrocardiogram (ECG) signals from patients with heart failure. METHODS: We developed a NYHA functional classification model for heart failure based on a deep learning method. We introduced an integrating attention mechanism based on the CNN-LSTM-SE model, segmenting the ECG signal into 2 to 20 s long segments. Ablation experiments showed that the 12 s ECG signal segments could be used with the proposed deep learning model for superior classification of heart failure. RESULTS: The accuracy, positive predictive value, sensitivity, and specificity of the NYHA functional classification method were 99.09, 98.9855, 99.033, and 99.649%, respectively. CONCLUSIONS: The comprehensive performance of this model exceeds similar methods and can be used to assist in clinical medical diagnoses.

Integrative Analysis Developing and Validating Potential Candidate Biomarkers for Cancer Stemness Features of Pan-Renal Cell Carcinoma.

In our study, 49 key genes significantly associated with renal cell carcinoma (RCC) stemness were obtained. Next, we developed a molecular prognostic signature associated with stemness features of pan-RCC. The difference in overall survival (OS) between the high- and low-risk groups was statistically significant (p < .05). The area under the receiver operating characteristic curve for 1-year OS, 5-year OS, and 10-year OS was 0.759, 0.712, and 0.918, respectively. The results of validation in The Cancer Genome Atlas cohort and International Cancer Genome Consortium cohort revealed the predictive capability of this signature. Furthermore, we selected three genes and further validation showed that these three hub genes were potential hub biomarkers for pan-RCC stemness features.

A novel CD8+ T cell-related gene signature for predicting the prognosis and immunotherapy efficacy in bladder cancer.

OBJECTIVE: To identify CD8+ T cell-related molecular clusters and establish a novel gene signature for predicting the prognosis and efficacy of immunotherapy in bladder cancer (BCa). METHODS: Transcriptome and clinical data of BCa samples were obtained from the Cancer Genome Atlas (TCGA) and GEO databases. The CD8+ T cell-related genes were screened through the CIBERSORT algorithm and correlation analysis. Consensus clustering analysis was utilized to identified CD8+ T cell-related molecular clusters. A novel CD8+ T cell-related prognostic model was developed using univariate Cox regression analysis and Lasso regression analysis. Internal and external validations were performed and the validity of the model was validated in a real-world cohort. Finally, preliminary experimental verifications were carried out to verify the biological functions of SH2D2A in bladder cancer. RESULTS: A total of 52 CD8+ T cell-related prognostic genes were screened and two molecular clusters with notably diverse immune cell infiltration, prognosis and clinical features were developed. Then, a novel CD8+ T cell-related prognostic model was constructed. The patients with high-risk scores exhibited a significantly worse overall survival in training, test, whole TCGA and validating cohort. The AUC was 0.766, 0.725, 0.739 and 0.658 in the four cohorts sequentially. Subgroup analysis suggested that the novel prognostic model has a robust clinical application for selecting high-risk patients. Finally, we confirmed that patients in the low-risk group might benefit more from immunotherapy or chemotherapy, and validated the prognostic model in a real-world immunotherapy cohort. Preliminary experiment showed that SH2D2A was capable of attenuating proliferation, migration and invasion of BCa cells. CONCLUSIONS: CD8+ T cell-related molecular clusters were successfully identified. Besides, a novel CD8+ T cell-related prognostic model with an excellent predictive performance in predicting survival rates and immunotherapy efficacy of BCa was developed.

[Research progress on chemical constituents and pharmacological activities of halogenated sesquiterpenes from natural sources].

Halogenated sesquiterpenes are important derivatives of sesquiterpenes, referring to chemical components of sesquiterpenes that contain halogens such as chlorine, bromine, and iodine. Halogenated sesquiterpenes have attracted attention from researchers in China and abroad because of their diverse structures, unique halogen elements, and extensive pharmacological activities. Studies have shown that halogenated sesquiterpenes exhibit significant antimicrobial, anti-inflammatory, anticancer, insecticidal, hypoglycemic, and enzyme inhibitory activities. In order to better explore the potential pharmaceutical value of halogenated sesquiterpenes, this paper reviewed the structural characteristics and pharmacological activities of halogenated sesquiterpenes in the past two decades, aiming to provide references for further research and development of this class of compounds.

Driver mutations in ADGRL3 are involved in the evolution of ependymoma.

Although there have been recent advances in the molecular pathology of ependymomas, little is known about the underlying molecular evolution during its development. Here, we assessed the clinical, pathological and molecular evolutionary process of ependymoma recurrence in a 9-year-old patient who had seven recurrences of supratentorial ependymoma and died from intracranial multiregional recurrences at the age of 19 years old. Whole-genome sequencing (WGS) of 7 tumor samples (1 primary and 6 subsequent recurrent tumors) was performed to elucidate the mutation landscape and identify potential driver mutations for tumor evolution. The genetic profiles of the seven tumor specimens showed significant heterogeneity and suggested a highly branched evolutionary pattern. The mutational signatures and chromothripsis changed with treatments. Strikingly, adhesion G protein-coupled receptor L3 (ADGRL3, also known as Latrophilins 3, LPNH3) was found to be consistently mutated during the entire disease process. However, Sanger sequencing of other 78 ependymoma patients who underwent surgery at our institution showed no genetic alteration of ADGRL3, as found in the present case. The mRNA levels of ADGRL3 were significantly lower in ependymomas (n = 36), as compared with normal brain tissue (n = 3). Grade III ependymomas had the lowest ADGRL3 expression. Moreover, ependymomas with lower mRNA level of ADGRL3 had shorter overall survival. Our findings, therefore, demonstrate a rare evolutionary process of ependymoma involving ADGRL3.

Radiographic analysis of dynamic lumbar motion during the five-repetition sit-to-stand test in degenerative lumbar spondylolisthesis.

BACKGROUND: To investigate the mechanisms of low back pain triggered by the five-repetition sit-to-stand test (5R-STS test) in degenerative lumbar spondylolisthesis (DLS) from radiographic perspective, as well as to determine the most useful diagnostic modalities in the evaluation of segmental instability. METHODS: We retrospectively performed a study of 78 patients (23 men and 55 women) with symptomatic DLS at L4/5 in our institution between April 2020 and December 2021. Each patient was assessed by using the 5R-STS test and received a series of radiographs including the upright standing, normal sitting, standing flexion-extension radiographs, and supine sagittal MR images. Enrolled patients were divided into two groups based on the 5R-STS test score: severe group and mild group. Translational and angular motion was determined by comparing normal sitting radiograph (N) with upright standing radiograph (U) (Combined, NU), flexion/extension radiographs (FE) as well as normal sitting radiograph (N) with a supine sagittal MR image (sMR) (Combined, N-sMR). RESULTS: Overall, 78 patients were enrolled, and there were 31(39.7%) patients in group S and 47(60.3%) patients in group M, with an average age of 60.7 ± 8.4 years. The normal sitting radiograph demonstrated the maximum slip percentage (SP) and the highest kyphotic angle both in group S and group M. Compared with group M, group S revealed significantly higher SP in the normal sitting position (24.1 vs 19.6; p = 0.002). The lumbar slip angular in group S with a sitting position was significantly higher than that in group M (-5.2 vs -1.3; p < 0.001). All patients in group S had objective functional impairment (OFI) and 28 patients of them were diagnosed with lumbar instability by using the combination of normal sitting radiograph (N) and supine sagittal MR image (sMR) (Combined, N-sMR). CONCLUSION: DLS patients with positive sign of the 5R-STS test is a distinct subgroup associated with lumbar instability. The modality of the combination of normal sitting radiograph (N) and supine sagittal MR image (sMR) had a significant advantage in terms of the ability to identify segmental instability.

Analysis of lumbar lateral instability on upright left and right bending radiographs in symptomatic patients with degenerative lumbar spondylolisthesis.

BACKGROUND: To evaluate lumbar mobility in various positions using upright left and right bending radiographs in patients with degenerative lumbar spondylolisthesis (DLS), as well as to assess the impact of lateral instability on patient-reported outcomes. METHODS: This study retrospectively reviewed a consecutive series of patients with DLS between January 2019 and October 2020. The enrolled patients were divided into two groups: the lateral instability group (group L) and non-lateral instability group (group NL). Translational and angular motion in both sagittal and coronal planes and patient-reported outcomes were compared between the two groups. RESULTS: There were 104 (59.8%) patients in group L and 70 (40.2%) patients in group NL, with an average age of 60.6 ± 7.8 years. Patients with a right bending posture in group L had a higher slip percentage (14.2 ± 7.4% vs 9.2 ± 3.2%, p = 0.01) and slip angle (6.3 ± 1.5° vs 2.2 ± 0.8°, p = 0.021). Compared with group NL, group L demonstrated significantly larger angular motion in the coronal plane (2.4 ± 1.3° vs 1.0 ± 0.7°, p = 0.008). Patients with lateral instability had worse preoperative back pain (6.1 ± 1.6 vs 2.7 ± 1.9, p = 0.01) and Oswestry Disability Index (ODI) scores (37.7 ± 5.5 vs 25.6 ± 2.6, p = 0.002). In terms of pain characteristics, group L was characterized by pain when getting out of a car, when rising from a chair, and when climbing stairs (all p values < 0.05). CONCLUSION: Lumbar lateral instability, that is, increased mobility in the coronal plane on lateral bending radiographs, translational and/or angular, correlates to more pronounced patient related symptoms in degenerative L4-5 spondylolisthesis. The existence of lumbar lateral instability leads to worse impacts on patient-reported outcomes when patients change their positions including getting out of a car, rising from a chair, and climbing stairs.

Optimal dose of perineural dexmedetomidine to prolong analgesia after brachial plexus blockade: a systematic review and Meta-analysis of 57 randomized clinical trials.

BACKGROUND AND OBJECTIVES: Peripheral injection of dexmedetomidine (DEX) has been widely used in regional anesthesia to prolong the duration of analgesia. However, the optimal perineural dose of DEX is still uncertain. It is important to elucidate this characteristic because DEX may cause dose-dependent complications. The aim of this meta-analysis was to determine the optimal dose of perineural DEX for prolonged analgesia after brachial plexus block (BPB) in adult patients undergoing upper limb surgery. METHOD: A search strategy was created to identify suitable randomized clinical trials (RCTs) in Embase, PubMed and The Cochrane Library from inception date to Jan, 2021. All adult patients undergoing upper limb surgery under BPB were eligible. The RCTs comparing DEX as an adjuvant to local anesthetic (LA) with LA alone for BPB were included. The primary outcome was duration of analgesia for perineural DEX. Secondary outcomes included visual analog scale (VAS) in 12 and 24 h, consumption of analgesics in 24 h, and adverse events. RESULTS: Fifty-seven RCTs, including 3332 patients, were identified. The subgroup analyses and regression analyses revealed that perineural DEX dose of 30-50 µg is an appropriate dosage. With short-/intermediate-acting LAs, the mean difference (95% confidence interval [CI]) of analgesia duration with less than and more than 60 µg doses was 220.31 (153.13-287.48) minutes and 68.01 (36.37-99.66) minutes, respectively. With long-acting LAs, the mean differences (95% CI) with less than and more than 60 µg doses were 332.45 (288.43-376.48) minutes and 284.85 (220.31-349.39) minutes. CONCLUSION: 30-50 µg DEX as adjuvant can provides a longer analgesic time compared to LA alone and it did not increase the risk of bradycardia and hypotension.

Development and validation of hub genes for lymph node metastasis in patients with prostate cancer.

Lymph node metastasis is one of the most important independent risk factors that can negatively affect the prognosis of prostate cancer (PCa); however, the exact mechanisms have not been well studied. This study aims to better understand the underlying mechanism of lymph node metastasis in PCa by bioinformatics analysis. We analysed a total of 367 PCa cases from the cancer genome atlas database and performed weighted gene co-expression network analysis to explore some modules related to lymph node metastasis. Gene Ontology analysis and pathway enrichment analysis were conducted for functional annotation, and a protein-protein interaction network was built. Samples from the International Cancer Genomics Consortium database were used as a validation set. The turquoise module showed the most relevance with lymph node metastasis. Functional annotation showed that biological processes and pathways were mainly related to activation of the processes of cell cycle and mitosis. Four hub genes were selected: CKAP2L, CDCA8, ERCC6L and ARPC1A. Further validation showed that the four hub genes well-distinguished tumour and normal tissues, and they were good biomarkers for lymph node metastasis of PCa. In conclusion, the identified hub genes facilitate our knowledge of the underlying molecular mechanism for lymph node metastasis of PCa.

Up-regulation of LIMK1 expression in prostate cancer is correlated with poor pathological features, lymph node metastases and biochemical recurrence.

This study aimed to explore the association between LIM domain kinase 1 (LIMK1) expression in prostate cancer (PCa) tissues with advanced pathological features, lymph node metastases and biochemical recurrence. A total of 279 PCa specimens from patients who underwent radical prostatectomy and 50 benign prostatic hyperplasia (BPH) specimens were collected to construct tissue microarray, which were subjected to immunohistochemical staining for LIMK1 expression subsequently. Logistic and Cox regression analysis were used to evaluate the relationship between LIMK1 expression and clinicopathological features of patients with PCa. Immunohistochemical staining assay demonstrated that LIMK1 expression was significantly higher in PCa than BPH specimens (77.1% vs 26.0%; P < .001). LIMK1 expression was significantly higher in positive lymph node specimens than corresponding PCa specimens (P = .002; P < .001). Up-regulation of LIMK1 was associated with prostate volume, prostate-specific antigen, prostate-specific antigen density, Gleason score, T stage, lymph node metastases, extracapsular extension and seminal vesicle invasion, and positive surgical margin. Multivariate logistic regression analysis demonstrated that LIMK1 was an independent risk factor for PCa lymph node metastasis (P < .05). Multivariate Cox regression analysis revealed that the up-regulation of LIMK1 was an independent risk factor for biochemical recurrence. Kaplan-Meier analysis indicated that up-regulation LIMK1 was associated with shortened biochemical-free survival (BFS) after radical prostatectomy (P < .001). In conclusion, LIMK1 was significantly up-regulated in PCa and positive lymph node specimens and correlated with lymph node metastasis and shortened BFS of PCa. The underlying molecular mechanism of LIMK1 in PCa should be further evaluated.

Dual antivascular function of human fibulin-3 variant, a potential new drug discovery strategy for glioblastoma.

The ECM protein EFEMP1 (fibulin-3) is associated with all types of solid tumor through its cell context-dependent dual function. A variant of fibulin-3 was engineered by truncation and mutation to alleviate its oncogenic function, specifically the proinvasive role in glioblastoma multiforme (GBM) cells at stem-like state. ZR30 is an in vitro synthesized 39-kDa protein of human fibulin-3 variant. It has a therapeutic effect in intracranial xenograft models of human GBM, through suppression of epidermal growth factor receptor/AKT and NOTCH1/AKT signaling in GBM cells and extracellular MMP2 activation. Glioblastoma multiforme is highly vascular, with leaky blood vessels formed by tumor cells expressing endothelial cell markers, including CD31. Here we studied GBM intracranial xenografts, 2 weeks after intratumoral injection of ZR30 or PBS, by CD31 immunohistochemistry. We found a 70% reduction of blood vessel density in ZR30-treated xenografts compared with that of PBS-treated ones. Matrigel plug assays showed the effect of ZR30 on suppressing angiogenesis. We further studied the effect of ZR30 on genes involved in endothelial transdifferentiation (ETD), in 7 primary cultures derived from 3 GBMs under different culture conditions. Two GBM cultures formed mesh structures with upregulation of ETD genes shortly after culture in Matrigel Matrix, and ZR30 suppressed both. ZR30 also downregulated ETD genes in two GBM cultures with high expression of these genes. In conclusion, multifaceted tumor suppression effects of human fibulin-3 variant include both suppression of angiogenesis and vasculogenic mimicry in GBM.

Skp2 modulates proliferation, senescence and tumorigenesis of glioma.

BACKGROUND: Gliomas represent the largest class of primary central nervous system neoplasms, many subtypes of which exhibit poor prognoses. Surgery followed by radiotherapy and chemotherapy has been used as a standard strategy but yielded unsatisfactory improvements in patient survival outcomes. The S-phase kinase protein 2 (Skp2), a critical component of the E3-ligase SCF complex, has been documented in tumorigenesis in various cancer types but its role in glioma has yet to be fully clarified. In this study, we investigated the function of Skp2 in the proliferation, stem cell maintenance, and drug sensitivity to temozolomide (TMZ) of glioma. METHODS: To investigate the role of Skp2 in the prognosis of patients with glioma, we first analyzed data in databases TCGA and GTEx. To further clarify the effect of Skp2 on glioma cell proliferation, we suppressed its level in glioblastoma (GBM) cell lines through knockdown and small molecule inhibitors (lovastatin and SZL-P1-41). We then detected cell growth, colony formation, sphere formation, drug sensitivity, and in vivo tumor formation in xenograft mice model. RESULTS: Skp2 mRNA level was higher in both low-grade glioma and GBM than normal brain tissues. The knockdown of Skp2 increased cell sensitivity to TMZ, decreased cell proliferation and tumorigenesis. In addition, Skp2 level was found increased upon stem cells enriching, while the knockdown of Skp2 led to reduced sphere numbers. Downregulation of Skp2 also induced senescence. Repurposing of lovastatin and novel compound SZL-P1-41 suppressed Skp2 effectively, and enhanced glioma cell sensitivity to TMZ in vitro and in vivo. CONCLUSION: Our data demonstrated that Skp2 modulated glioma cell proliferation in vitro and in vivo, stem cell maintenance, and cell sensitivity to TMZ, which indicated that Skp2 could be a potential target for long-term treatment.

Transferrin receptor 1 targeted optical imaging for identifying glioma margin in mouse models.

OBJECTIVE: Optical molecular imaging technology that indiscriminately detects intracranial glioblastoma (GBM) can help neurosurgeons effectively remove tumor masses. Transferrin receptor 1 (TfR 1) is a diagnostic and therapeutic target in GBM. A TfR 1-targeted peptide, CRTIGPSVC (CRT), was shown to cross the blood brain barrier (BBB) and accumulate at high levels in GBM tissues. In this study, we synthesized a TfR 1-targeted near-infrared fluorescent (NIRF) probe, Cy5-CRT, for identifying the GBM tissue margin in mouse models. METHODS: We initially confirmed the overexpression of TfR 1 in GBM and the tumor-specific homing ability of Cy5-CRT in subcutaneous and orthotopic GBM mouse models. We then examined the feasibility of Cy5-CRT for identifying the tumor margin in orthotopic GBM xenografts. Finally, we compared Cy5-CRT with the clinically used fluorescein sodium in identifying tumor margins. RESULTS: Cy5-CRT specifically accumulated in GBM tissues and detected the tumor burden with exceptional contrast in mice with orthotopic GBM, enabling fluorescence-guided GBM resection under NIRF live imaging conditions. Importantly, Cy5-CRT recognized the GBM tissue margin more clearly than fluorescein sodium. CONCLUSIONS: The TfR 1-targeted optical probe Cy5-CRT specifically differentiates tumor tissues from the surrounding normal brain with high sensitivity, indicating its potential application for the precise surgical removal of GBM.

Bioinformatics Analysis of the Expression of Key Long Intergenic Non-Protein Coding RNA Genes in Bladder Cancer.

BACKGROUND Evidence indicates that there is an important role for long non-coding RNAs (lncRNA) in numerous cellular processes and that lncRNAs dysregulation contributes to tumor progression. Improved insight into the molecular characteristics of bladder cancer is required to predict outcomes and to develop a new rationale for targeted therapeutic strategies. Bioinformatics methods, including functional enrichment and network analysis combined with survival analysis, are required to process a large volume of data to obtain further information about differentially expressed genes (DEGs) in bladder cancer. This study aimed to explore the role of lncRNAs and their regulation network in bladder cancer. MATERIAL AND METHODS We analyzed bladder cancer data by The Cancer Genome Atlas profiling to identify differentially expressed lncRNAs in bladder cancer. The genes involved in the circlncRNAnet database were evaluated using Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), evolutionary relationship analysis, and protein-protein interaction (PPI) networks. RESULTS Two new lncRNAs, ADAMTS9-AS1 and LINC00460, were shown to be differentially expressed in bladder cancer. Patients were divided into 2 groups (high expression and low expression) according to their median expression values. The overall survival and disease-free survival of patients with high ADAMTS9-AS1 bladder cancer were significantly shorter; the expression of LINC00460 had no significant correlation with survival. GO and KEGG analysis of the 2 lncRNA-related genes revealed that these lncRNAs played a vital role in tumorigenesis. Bioinformatics analysis showed that key genes related to LINC00460, including CXCL, CCL, and CSF2, may be related to the development of bladder cancer. The low expression of ADAMTS9-AS1 may influence the survival rate of bladder cancer with the hub gene as a target. CONCLUSIONS LncRNA, including LINC00460 and ADAMTS9-AS1, might play a crucial role in the biosynthesis network of bladder cancer. Differential expression results of ADAMTS9-AS1 suggests it may be correlated with a worse prognosis and a shorter survival time. We outlined the biosynthesis network that regulates lncRNAs in bladder cancer. Further experimental data is needed to validate our results.

Identification of key genes and pathways in benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is one of the most common causes of lower urinary tract symptoms (LUTS) in elderly man. However, the underlying molecular mechanisms of BPH have not been completely elucidated. We identified the key genes and pathways by using analysis of Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using edgeR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed for the DEGs by Database for Annotation, Visualization and Integrated Discovery (DAVID) database and ConsensusPathDB, respectively. Then, protein-protein interaction (PPI) networks were established by the Search Tool for the Retrieval of Interacting Genes (STRING) database and visualized by Cytoscape software. Finally, we identified 660 DEGs ultimately including 268 upregulated genes and 392 downregulated genes. GO analysis revealed that DEGs were mainly enriched in extracellular exosome, identical protein binding, mitochondrial adenosine triphosphate (ATP) synthesis coupled proton transport, extracelluar matrix, focal adhesion, cytosol, Golgi apparatus, cytoplasm, protein binding, and Golgi membrane. Focal adhesion pathway, FoxO signaling pathway, and autophagy pathway were selected. Ubiquitin-conjugating enzyme E2 C (UBE2C), serine/threonine kinase (AKT1), mitogen-activated protein kinase 1 (MAPK1), cyclin B1 (CCNB1), polo-like kinase 1 (PLK1) were filtrated as the hub genes according to the degree of connectivity from the PPI network. The five hub genes including UBE2C, AKT1, MAPK1, CCNB1, PLK1 may play key roles in the pathogenesis of benign prostatic hyperplasia (BPH). Focal adhesion pathway, FoxO signaling pathway, and autophagy pathway may be crucial for the progression of BPH.

Identification of key DNA methylation-driven genes in prostate adenocarcinoma: an integrative analysis of TCGA methylation data.

BACKGROUND: Prostate cancer (PCa) remains the second leading cause of deaths due to cancer in the United States in men. The aim of this study was to perform an integrative epigenetic analysis of prostate adenocarcinoma to explore the epigenetic abnormalities involved in the development and progression of prostate adenocarcinoma. The key DNA methylation-driven genes were also identified. METHODS: Methylation and RNA-seq data were downloaded for The Cancer Genome Atlas (TCGA). Methylation and gene expression data from TCGA were incorporated and analyzed using MethylMix package. Methylation data from the Gene Expression Omnibus (GEO) were assessed by R package limma to obtain differentially methylated genes. Pathway analysis was performed on genes identified by MethylMix criteria using ConsensusPathDB. Gene Ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were also applied for the identification of pathways in which DNA methylation-driven genes significantly enriched. The protein-protein interaction (PPI) network and module analysis in Cytoscape software were used to find the hub genes. Two methylation profile (GSE112047 and GSE76938) datasets were utilized to validate screened hub genes. Immunohistochemistry of these hub genes were evaluated by the Human Protein Atlas. RESULTS: A total of 553 samples in TCGA database, 32 samples in GSE112047 and 136 samples in GSE76938 were included in this study. There were a total of 266 differentially methylated genes were identified by MethylMix. Plus, a total of 369 differentially methylated genes and 594 differentially methylated genes were identified by the R package limma in GSE112047 and GSE76938, respectively. GO term enrichment analysis suggested that DNA methylation-driven genes significantly enriched in oxidation-reduction process, extracellular exosome, electron carrier activity, response to reactive oxygen species, and aldehyde dehydrogenase [NAD(P)+] activity. KEGG pathway analysis found DNA methylation-driven genes significantly enriched in five pathways including drug metabolism-cytochrome P450, phenylalanine metabolism, histidine metabolism, glutathione metabolism, and tyrosine metabolism. The validated hub genes were MAOB and RTP4. CONCLUSIONS: Methylated hub genes, including MAOB and RTP4, can be regarded as novel biomarkers for accurate PCa diagnosis and treatment. Further studies are needed to draw more attention to the roles of these hub genes in the occurrence and development of PCa.

[Impact of the degrees of intravesical prostatic protrusion on the recovery of urinary continence after radical prostatectomy].

OBJECTIVE: To investigate the influence of the degrees of intravesical prostatic protrusion (IPP) on the recovery of urinary continence after radical prostatectomy. METHODS: We retrospectively analyzed the clinical data on 212 patients diagnosed with prostate cancer by biopsy and treated by laparoscopic radical prostatectomy by the same surgeon. Based on the degrees of IPP measured by MRI, we divided the patients into an IPP ≤ 10 mm group (n = 146) and an IPP > 10 mm group (n = 66) and determined the factors influencing the recovery of urinary continence by univariate and multivariate logistic regression analyses. RESULTS: At 1, 3, 6 and 12 months after surgery, the urinary continence rates of the patients were 32.5%, 50.5%, 82.1% and 91%, respectively. Univariate analysis indicated that the factors influencing the recovery of urinary continence included IPP, body mass index (BMI), bladder neck preservation (BNP), neurovascular bundle preservation (NVBP) and clinical tumor (T) stage at 3 months (P < 0.05 or P < 0.01), age, IPP, BMI, BNP and clinical T stage at 6 months (P < 0.05 or P < 0.01), and age, IPP, BMI, BNP, NVBP and clinical T stage at 12 months (P < 0.05), while multivariate logistic regression analysis showed the independent influencing factors to be IPP > 10 mm (P < 0.001), BMI ≥ 25 kg/m2 (P = 0.004) and BNP (P = 0.032) at 3 months, and IPP and BMI at 6 months (both P < 0.01) and 12 months (P < 0.01 and P = 0.033). CONCLUSIONS: IPP > 10 mm and BMI ≥ 25 kg/m2 are independent factors influencing the long-term recovery of urinary continence after radical prostatectomy.

Characterization of naturally occurring pentacyclic triterpenes as novel inhibitors of deubiquitinating protease USP7 with anticancer activity in vitro.

Deubiquitinating protease USP7 is a promising therapeutic target for cancer treatment, and interest in developing USP7 inhibitors has greatly increased. In the present study, we reported a series of natural pentacyclic triterpenes with USP7 inhibitory activity in vitro. Among them, both the ursane triterpenes and oleanane triterpenes were more active than the lupine triterpenes, whereas ursolic acid was the most potent with IC50 of 7.0±1.5 µmol/L. Molecular docking studies showed that ursolic acid might occupy the ubiquitin binding pocket of USP7, with the 17-carboxyl group and 3-hydroxyl group playing a vital role in the USP7-ursolic acid interaction. Using the cellular thermal shift assay, we demonstrated that ursolic acid interacted with USP7 in RPMI8226 human myeloma cells. Ursolic acid dose-dependently inhibited the proliferation of the myeloma cells with IC50 of 6.56 µmol/L, accompanied by reductions in USP7 substrates such as MDM2, UHRF1 and DNMT1. Overexpression of USP7 partially, but significantly attenuated ursolic acid-induced cell death as well as downregulation of MDM2, UHRF1 and DNMT1. In conclusion, we demonstrate for the first time that pentacyclic triterpenes represent a novel scaffold for developing USP7 inhibitors and that USP7 inhibition contributes to the anti-cancer effect of ursolic acid.