Single-cell and spatial transcriptomics reveal metastasis mechanism and microenvironment remodeling of lymph node in osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor and is highly prone to metastasis. OS can metastasize to the lymph node (LN) through the lymphatics, and the metastasis of tumor cells reestablishes the immune landscape of the LN, which is conducive to the growth of tumor cells. However, the mechanism of LN metastasis of osteosarcoma and remodeling of the metastatic lymph node (MLN) microenvironment is not clear. METHODS: Single-cell RNA sequencing of 18 samples from paracancerous, primary tumor, and lymph nodes was performed. Then, new signaling axes closely related to metastasis were identified using bioinformatics, in vitro experiments, and immunohistochemistry. The mechanism of remodeling of the LN microenvironment in tumor cells was investigated by integrating single-cell and spatial transcriptomics. RESULTS: From 18 single-cell sequencing samples, we obtained 117,964 cells. The pseudotime analysis revealed that osteoblast(OB) cells may follow a differentiation path from paracancerous tissue (PC) → primary tumor (PT) → MLN or from PC → PT, during the process of LN metastasis. Next, in combination of bioinformatics, in vitro and in vivo experiments, and immunohistochemistry, we determined that ETS2/IBSP, a new signal axis, might promote LN metastasis. Finally, single-cell and spatial dissection uncovered that OS cells could reshape the microenvironment of LN by interacting with various cell components, such as myeloid, cancer-associated fibroblasts (CAFs), and NK/T cells. CONCLUSIONS: Collectively, our research revealed a new molecular mechanism of LN metastasis and clarified how OS cells influenced the LN microenvironment, which might provide new insight for blocking LN metastasis.

Single-cell RNA sequencing reveals the immune microenvironment landscape of osteosarcoma before and after chemotherapy.

Chemotherapy, a primary treatment for osteosarcoma (OS), has limited knowledge regarding its impact on tumor immune microenvironment (TIME). Here, tissues from 6 chemotherapy-naive OS patients underwent single-cell RNA sequencing (scRNA-seq) and were analyzed alongside public dataset (GSE152048) containing 7 post-chemotherapy OS tissues. CD45+ (PTPRC+) cells were used for cell clustering and annotation. Changes in immune cell composition pre- and post-chemotherapy were characterized. Totally, 28,636 high-quality CD45+ (PTPRC+) cells were extracted. Following chemotherapy, the proportions of regulatory T cells (Tregs) and activated CD8 T cells decreased, while CD8 effector T cells increased. GO analysis indicated that differentially expressed genes (DEGs) in T cells were associated with cell activation, adaptive immune response, and immune response to tumor cells. Furthermore, the proportions of plasma cells increased, while naive B cells decreased. B cell surface receptors expression was upregulated, and GO analysis revealed DEGs of B cells were mainly enriched in B cell-mediated immunity and B cell activation. Moreover, M2 polarization of macrophages was suppressed post-chemotherapy. Overall, this study elucidates chemotherapy remodels the OS TIME landscape, triggering immune heterogeneity and enhancing anti-tumor properties.

Development and validation of neutrophil extracellular traps-derived signature to predict the prognosis for osteosarcoma patients.

Neutrophil extracellular traps (NETs) have been reported to be crucial in tumorigenesis and malignant progression. However, their prognostic significance, association with tumor immune microenvironment (TIME), and therapeutic response in osteosarcoma (OS) stills remain unclear. Hence, TARGET and GSE21257 cohorts were included for analysis. Single-sample gene set enrichment analysis (ssGSEA) and weighted gene co-expression network analysis (WGCNA) were conducted to extract NETs-derived genes. Subsequently, the NETs score (NETScore) model, consisting of 4 signature genes, was established and validated with the least absolute shrinkage and selection operator (LASSO) and Cox regression analysis. Our results indicated that NETScore has satisfactory predictability of the patient's overall survival, with AUC values at 1-, 3- and 5-year in the training cohort of 0.798, 0.792 and 0.804, respectively; similar prominent prediction performance was obtained in three validation cohorts. Further, real-time quantitative PCR (RT-qPCR) assay was conducted to determine the expression of signature genes in human osteoblasts and OS cells. Besides, NETScore and clinical factors (age, gender, metastatic status) were integrated to construct a nomogram. C-index and AUC values at 1-, 3-, and 5-year were above 0.800, displaying robust predictive performance. Patients with high and low NETScore had different immune statuses and drug sensitivity. Meanwhile, several positive regulatory immune function pathways, including T cell proliferation, activation and migration, were significantly suppressed among patients with high NETScore. Summarily, we established a novel NETScore that can accurately predict OS patients' prognosis, which correlated closely with the immune landscape and therapeutic response and might help to guide clinical decision-making.

Efficacy of quadratus lumborum block on postoperative pain and side effects in patients who underwent urological surgery: A meta-analysis.

BACKGROUND: Ultrasound-guided quadratus lumborum block (QLB) is considered a novel nerve block for postoperative pain control. However, its efficacy after urological surgery remains unclear. OBJECTIVES: The purpose of the current meta-analysis was to evaluate the effects of the QLB block versus control (placebo or no injection) on postoperative pain and other adverse outcomes after urological surgery, providing extensive evidence of whether quadratus lumborum block is suitable for pain management after urological surgery. STUDY DESIGN: Systematic review with meta-analysis of randomized clinical trials. METHODS: We searched PubMed, Cochrane Library, Embase, Web of Science, and ClinicalTrials.gov to collect studies investigating the effects of QLB on analgesia after urological surgery. The primary outcomes included visual analog scale (VAS) at rest and during movement, 24-h postoperative morphine consumption, and the incidence of postoperative nausea and vomiting (PONV). RESULTS: Overall, 13 randomized controlled trials (RCTs) were reviewed, including 751 patients who underwent urological surgery. The QLB group exhibited a lower VAS score postoperatively at rest or on movement at 0, 6, 12, and 24 h, with less 24-h postoperative morphine consumption and lower incidence of PONV. LIMITATIONS: Although the result is stable, heterogeneity exists in the current research. CONCLUSIONS: QLB exhibited a favorable effect of postoperative analgesia with reduced postoperative complications at rest or during movement after urological surgery. However, it is still a novel technology at a primary stage, which needs further research to develop.

Effects of Ultrasound-Guided Transversus Thoracic Muscle Plane Block on Postoperative Pain and Side Effects: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The effects of the transversus thoracic muscle plane (TTP) block on postoperative pain have become increasingly controversial. This meta-analysis compared the effects of the TTP block versus no block on postoperative analgesia and side effects to determine whether this new technique is a reliable alternative for pain management. PubMed, Cochrane Library, Embase, Web of Science, ClinicalTrials.gov, China National Knowledge Infrastructure, Chongqing VIP information, and Wanfang Data were searched for clinical studies investigating the analgesic effect of the TTP block compared to controls. The primary outcomes included the postoperative pain scores at rest and during movement, morphine consumption in 24 hours, and the rate of postoperative nausea and vomiting (PONV). Eleven randomized controlled trials (RCTs), including 682 patients, were reviewed. The meta-analysis showed that the TTP block significantly could reduce the pain scores at 0 (at rest: mean difference [MD], -2.28; 95% CI: -2.67 to -1.90) (during movement: MD: -2.09, 95% CI: -2.62 to -1.56) and 12 hours (at rest: -1.42, 95% CI: -2.03 to -0.82) (during movement: MD: -2.13, 95% CI: -2.80 to -1.46) after surgery, 24-hour postoperative analgesic consumption (MD: -23.18, 95% CI: -33.71 to -12.66), and the incidence of PONV (odds ratio, 0.36, 95% CI: 0.15-0.88). Furthermore, the trial sequence analysis confirmed the result of less 24-hour postoperative analgesic consumption in the TTP block group. As a novel technique, the TTP block exhibited a superior postoperative analgesic effect during the early postoperative period. Nevertheless, additional well-designed RCTs are needed.

Human Urinary Kallidinogenase Pretreatment Inhibits Myocardial Inflammation and Apoptosis after Coronary Microembolization by Activating PI3K/Akt/FoxO1 Axis.

BACKGROUND: As a fatal cardiovascular complication, coronary microembolization (CME) results in severe cardiac dysfunction and arrhythmia associated with myocardial inflammation and apoptosis. Human urinary kallidinogenase (HUK) can provide a protective function for cardiomyocytes by improving microcirculation. However, the therapeutic effects and underlying mechanisms of HUK in CME-induced myocardial injury remain unclear. AIMS: We evaluated the effect of HUK on cardiac protection in a rat model of CME and whether it could restrain myocardial inflammation and apoptosis, and alleviate CME-induced myocardial injury. METHODS: We established the CME model by injecting 42 µm inert plastic microspheres into the left ventricle of rats in advance, then the rats were randomly and equally divided into CME, CME + HUK (the dose of HUK at 0.016 PNA/kg/day), CME + HUK + LY (the dose of LY294002 at 10 mg/kg, 30 minutes before modeling), and Sham operation groups. Cardiac function, the serum levels of myocardial injury biomarkers, myocardial inflammation and apoptosis-related genes were measured; and the myocardial histopathological examination was performed at 12 h after the operation. RESULTS: The results revealed that HUK effectively reducing myocardial inflammation, apoptosis, and myocardial infarction area; and improving CME-induced cardiac injury by activating the PI3K/Akt/FoxO1 axis. In addition, these cardioprotective effects can be reduced by the PI3K specific inhibitor LY294002, suggesting that the aforementioned protective effects may be related to activation of the PI3K/Akt/FoxO1 axis. CONCLUSIONS: HUK seems to control inflammatory infiltration and cardiomyocyte apoptosis significantly to improve CME-induced cardiac injury via regulating the PI3K/Akt/FoxO1 axis.

Inflammation and Oxidative Stress Role of S100A12 as a Potential Diagnostic and Therapeutic Biomarker in Acute Myocardial Infarction.

Acute myocardial infarction (AMI) is one of the most serious cardiovascular diseases with high morbidity and mortality. Numerous studies have indicated that S100A12 may has an essential role in the occurrence and development of AMI, and in-depth studies are currently lacking. The purpose of this study is to investigate the effect of S100A12 on inflammation and oxidative stress and to determine its clinical applicability in AMI. Here, AMI datasets used to explore the expression pattern of S100A12 in AMI were derived from the Gene Expression Omnibus (GEO) database. The pooled standard average deviation (SMD) was calculated to further determine S100A12 expression. The overlapping differentially expressed genes (DEGs) contained in all included datasets were recognized by the GEO2R tool. Then, functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, were carried out to determine the molecular function of overlapping DEGs. Gene set enrichment analysis (GSEA) was conducted to determine unrevealed mechanisms of S100A12. Summary receiver operating characteristic (SROC) curve analysis and receiver operating characteristic (ROC) curve analysis were carried out to identify the diagnostic capabilities of S100A12. Moreover, we screened miRNAs targeting S100A12 using three online databases (miRWalk, TargetScan, and miRDB). In addition, by comprehensively using enzyme-linked immunosorbent assay (ELISA), real-time quantitative PCR (RT-qPCR), Western blotting (WB) methods, etc., we used the AC16 cells to validate the expression and underlying mechanism of S100A12. In our study, five datasets related to AMI, GSE24519, GSE60993, GSE66360, GSE97320, and GSE48060 were included; 412 overlapping DEGs were identified. Protein-protein interaction (PPI) network and functional analyses showed that S100A12 was a pivotal gene related to inflammation and oxidative stress. Then, S100A12 overexpression was identified based on the included datasets. The pooled standard average deviation (SMD) also showed that S100A12 was upregulated in AMI (SMD = 1.36, 95% CI: 0.70-2.03, p = 0.024). The SROC curve analysis result suggested that S100A12 had remarkable diagnostic ability in AMI (AUC = 0.90, 95% CI: 0.87-0.92). And nine miRNAs targeting S100A12 were also identified. Additionally, the overexpression of S100A12 was further confirmed that it maybe promote inflammation and oxidative stress in AMI through comprehensive in vitro experiments. In summary, our study suggests that overexpressed S100A12 may be a latent diagnostic biomarker and therapeutic target of AMI that induces excessive inflammation and oxidative stress. Nine miRNAs targeting S100A12 may play a crucial role in AMI, but further studies are still needed. Our work provides a positive inspiration for the in-depth study of S100A12 in AMI.

Combining Single-Cell and Transcriptomic Data Revealed the Prognostic Significance of Glycolysis in Pancreatic Cancer.

Background: Pancreatic cancer (PC), the most common fatal solid malignancy, has a very dismal prognosis. Clinical computerized tomography (CT) and pathological TNM staging are no longer sufficient for determining a patient's prognosis. Although numerous studies have suggested that glycolysis is important in the onset and progression of cancer, there are few publications on its impact on PC. Methods: To begin, the single-sample gene set enrichment analysis (ssGSEA) approach was used to quantify the glycolysis pathway enrichment fraction in PC patients and establish its prognostic significance. The genes most related to the glycolytic pathway were then identified using weighted gene co-expression network analysis (WGCNA). The glycolysis-associated prognostic signature in PC patients was then constructed using univariate Cox regression and lasso regression methods, which were validated in numerous external validation cohorts. Furthermore, we investigated the activation of the glycolysis pathway in PC cell subtypes at the single-cell level, performed a quasi-time series analysis on the activated cell subtypes and then detected gene changes in the signature during cell development. Finally, we constructed a decision tree and a nomogram that could divide the patients into different risk subtypes, according to the signature score and their different clinical characteristics and assessed the prognosis of PC patients. Results: Glycolysis plays a risky role in PC patients. Our glycolysis-related signature could effectively discriminate the high-risk and low-risk patients in both the trained cohort and the independent externally validated cohort. The survival analysis and multivariate Cox analysis indicated this gene signature to be an independent prognostic factor in PC. The prognostic ROC curve analysis suggested a high accuracy of this gene signature in predicting the patient prognosis in PC. The single-cell analysis suggested that the glycolytic pathway may be more activated in epithelial cells and that the genes in the signature were also mainly expressed in epithelial cells. The decision tree analysis could effectively identify patients in different risk subgroups, and the nomograms clearly show the prognostic assessment of PC patients. Conclusion: Our study developed a glycolysis-related signature, which contributes to the risk subtype assessment of patients with PC and to the individualized management of patients in the clinical setting.

MAIP1-Related Tumor Immune Infiltration: As a Potential Prognostic Biomarker for Esophageal Cancer.

Background: Esophageal cancer (EC), a common malignant tumor of digestive tract, is also one of the most deadly cancers. Accumulating studies have shown that the initiating and progressing multiple human diseases were closely related to the expression of MAIP. However, the specific roles and mechanisms of MAIP1 in EC remain incompletely defined. Purpose: This study aims to determine the clinical significance of MAIP1 in EC and explores its potential molecular mechanisms regulating tumor immune infiltration. Methods: We obtained RNA-seq datasets and corresponding clinical data for EC patients from the Cancer Genome Atlas (TCGA) database via the UCSC Xena browser to extract MAIP1 expression and plot survival curves to determine their prognosis. Based on the differential expression of MAIP1, EC patients were divided into high and low group to investigate the mechanism of MAIP1 in EC. In addition, the single sample gene set enrichment analysis (ssGSEA) quantified the expression of various immune cell signature marker genes and assessed the degree of immune infiltration in EC. Results: In the TCGA-EC cohort, the overexpression of MAIP1 was observed in tumor tissues compared to normal tissues (p = 0.0038). Overall survival analysis showed that EC patients with the overexpression of MAIP1 presented a lower overall survival and worse prognosis (p = 0.004). Enrichment analysis revealed that the differential genes (DEGs) between high and low group are involved in biological functions such as extracellular matrix and organization extracellular structure. The results of ssGSEA showed that DCs, iDCs, macrophages, mast cells, and NK cells were significantly different in MAIP1high and MAIP1low groups, and all showed high expression in the MAIP1low group. Conclusion: We proposed that MAIP1 overexpression was associated with poor prognosis and tumor immune infiltration in EC. At present, there are few MAIP1-related tumor immune infiltration studies in EC, and further investigation is needed.

Clinical Value for Diagnosis and Prognosis of Signal Sequence Receptor 1 (SSR1) and Its Potential Mechanism in Hepatocellular Carcinoma: A Comprehensive Study Based on High-Throughput Data Analysis.

OBJECTIVE: Hepatocellular Carcinoma (HCC) has the characteristics of high incidence and poor prognosis. However, the underlying mechanism of HCC has not yet been fully elucidated. This study aims to investigate the potential mechanism and clinical significance of signal sequence receptor (SSR1) in HCC through bioinformatics methods. METHODS: Four online (GEPIA, TIMER, TCGA, and GEO) databases were used to explore the expression level of SSR1 in HCC. The summary receiver operating characteristic (SROC) analysis and standardized mean difference (SMD) calculation were performed further to detect its diagnostic ability and expression level. The Human Protein Atlas (HPA) database was applied to verify the level of SSR1 protein expression. Chi-square test and Fisher's exact test were carried out to determine the clinical relevance of SSR1 expression. KM survival analysis, univariate and multivariate COX regression analyses were employed to explore the prognostic impact of SSR1. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Gene set enrichment analysis (GSEA) were implemented to reveal the underlying mechanism of SSR1. Quantitative Real-Time Polymerase Chain Reaction (QRT-PCR) was used to verify the expression of SSR1 in HCC. RESULTS: SSR1 was significantly overexpressed in HCC (SMD=1.25, P=0.03) and had the moderate diagnostic ability (AUC=0.84). SSR1 expression was significantly correlated with T stage, Gender, Pathologic stage (All P<0.05). Patients with high SSR1 expression had shorter overall survival (OS). Univariate and multivariate Cox regression analyses showed that high SSR1 expression was an independent risk factor for poor prognosis. KEGG analysis showed that SSR1-related genes were enriched in the cell cycle, DNA replication, and TGF-beta signaling pathway. GSEA analysis also shows that the high expression of SSR1 is related to the activation of the above three signal pathways. qRT-PCR showed that the SSR1 expression in HCC was significantly higher than the Peri-carcinoma tissue (PHCC) and the corresponding normal liver tissue. CONCLUSION: SSR1 expression was significantly up-regulated, and it had the potential as a biomarker for the diagnosis and prognosis of HCC. It was very likely to participate in the occurrence and development of HCC by regulating the cell cycle. In summary, our study comprehensively analyzed the clinical value of SSR1 and also conducted a preliminary study on its potential mechanism, which will provide inspiration for the in-depth study of SSR1 in HCC.

Overexpression of CXCR7 is a Novel Indicator for Enzalutamide Resistance in Castration-Resistant Prostate Cancer Patients.

BACKGROUND: To evaluate whether the overexpression of chemokine receptor-7 (CXCR7) in prostatic tissues obtained from men with Castration-Resistant Prostate Cancer (CRPC) is associated with resistance to enzalutamide (Enza). METHODS: Based on the inclusion criteria of CRPC in EAU guidelines, all eligible patients treated in our hospital from January 2015 to December 2019 were included. Cases underwent radical prostatectomy, docetaxel-based chemotherapy, or new endocrine therapies (including Enza or abiraterone), and cases with severe cardiopulmonary disease or other malignant tumors were excluded. After immunohistochemical staining for CXCR7 expression in prostatic biopsy tissues, all enrolled cases were divided into two groups, namely, the CXCR7-positive group and the CXCR7-negative group. And then, PSA response to Enza treatment was recorded in detail and comparatively analyzed. In addition, the Cox proportional hazard modeling and the Kaplan-Meier analysis were used to determine PSA progression-free survival (PSAP-FS) and clinical or radiographic progression-free survival (CRP-FS) in this cohort. RESULTS: A total of 79 CRPC individuals were enrolled and evaluated in this study. Median follow-up durations were 24 months (range, 12-42) in the CXCR7-positive group (n = 47) and 28.5 months (range, 12-42) in the CXCR7-negative group (n = 32). The patients with lower CXCR7 expression showed much better PSA response to Enza treatment. There was 84.4% of CXCR7- cases showing decreasing PSA response, while there were 71.4% in the CXCR7/1+ group and 31.2% in the CXCR7/2+ group, respectively. All patients in the CXCR7/3+ group showed increasing PSA response to Enza treatment. And the percentage of patients whose PSA decreased over 50% is significantly higher in the CXCR7-negative group than in the CXCR7-positive group (68.8% vs. 8.5%, P < 0.001), and the percentage of patients whose PSA decreased over 90% is also remarkably higher in the CXCR7-negative group (43.8% vs. 0, P < 0.001). The Kaplan-Meier analysis demonstrated that the oncologic outcomes of CXCR7-negative patients were improved much significantly by Enza treatment in comparison with those of CXCR7-positive patients. Significantly increased median PSAP-FS (21 months vs. 6 months, P < 0.0001) and CRP-FS (27 months vs. 9 months, P < 0.0001) were obtained in the CXCR7-negative group. The further stratified analysis in all CXCR7-positive patients demonstrated that the patients with higher CXCR7 expression showed much worse outcome. The median time of PSAP-FS was 21 months in the CXCR7/1+ group, 9 months in the CXCR7/2+ group, and 6 months in the CXCR7/3+ group, while the median time of CRP-FS was 21 months in the CXCR7/1+ group, 12 months in the CXCR7/2+ group, and 6 months in the CXCR7/3+ group, respectively. CONCLUSION: Overexpression of CXCR7 induced by an AR antagonist in CRPC patients displays much better treatment response to Enza. CXCR7 might be a novel therapeutic target gene for CRPC patients.

Clinical Significance and Potential Role of LSM4 Overexpression in Hepatocellular Carcinoma: An Integrated Analysis Based on Multiple Databases.

Background: Hepatocellular carcinoma (HCC) is a solid tumor with high recurrence rate and high mortality. It is crucial to discover available biomarkers to achieve early diagnosis and improve the prognosis. The effect of LSM4 in HCC still remains unrevealed. Our study is dedicated to exploring the expression of LSM4 in HCC, demonstrating its clinical significance and potential molecular mechanisms. Methods: Clinical information and LSM4 expression values of HCC were obtained from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Survival analysis and receiver operating characteristic (ROC) curve analysis were applied to evaluate the prognostic and diagnostic significance of LSM4. Calculating pooled standardized mean difference (SMD) and performing summary receiver operating characteristic (sROC) curve analysis to further determine its expression status and diagnostic significance. LSM4-related co-expressed genes (CEGs) were obtained and explored their clinical significance in HCC. LSM4-associated pathways were identified through Gene set enrichment analysis (GSEA). Results: Up-regulated LSM4 was detected in HCC tissues (SMD = 1.56, 95% CI: 1.29-1.84) and overexpressed LSM4 had excellent distinguishing ability (AUC = 0.91, 95% CI: 0.88-0.93). LSM4 was associated with clinical stage, tumor grade, and lymph node metastasis status (p < 0.05). Survival analysis showed that high LSM4 expression was related to poor overall survival (OS) of HCC patients. Cox regression analysis suggested that high LSM4 expression may be an independent risk factor for HCC. We obtained nine up-regulated CEGs of LSM4 in HCC tissues, and six CEGs had good prognostic and diagnostic significance. GSEA analysis showed that up-regulated LSM4 was closely related to the cell cycle, cell replication, focal adhesion, and several metabolism-associated pathways, including fatty acid metabolism. Conclusion: Overexpressed LSM4 may serve as a promising diagnostic and prognostic biomarker of HCC. Besides, LSM4 may play a synergistic effect with CEGs in promoting the growth and metastasis of HCC cells via regulating crucial pathways such as cell cycle, focal adhesion, and metabolism-associated pathways.

Adjuvant chemotherapy after radical nephroureterectomy improves the survival outcome of high-risk upper tract urothelial carcinoma patients with cardiovascular comorbidity.

This prospective randomized comparative trial study aimed to evaluate the therapeutic outcomes of radical nephroureterectomy and adjuvant chemotherapy (ACT) used in combination in high risk upper tract urothelial carcinoma (UTUC) patients with cardiovascular comorbidity. Based on the inclusion criteria of high-risk UTUC in EAU guidelines (updated in 2014), all eligible patients treated in our hospital from January 2014 to March 2018 were included, and cases with late disease, renal dysfunction, severe cardiopulmonary disease or other malignant tumors were excluded. The cases were randomized into two groups based on treatment regimen. Multivariate analyses were performed to analyze the influencing factors of survival outcome in the enrolled patients. The Cox proportional-hazards model and the Kaplan-Meier method were employed to assess progression free survival (PFS), overall survival (OS) and cancer specific survival (CSS). In addition, the potential adverse effects of chemotherapy were actively monitored. A total of 176 high-risk UTUC individuals with cardiovascular comorbidity were enrolled and evaluated in this study. Median follow-up durations were 30 months (range 6-54) in the RNU (n = 82) group and 36 months (range 6-54) in the RNU + ACT (n = 94) group. Multivariable analysis indicated that peri-operative cardiovascular events risk grade was independent prognostic factor for OS. Tumor size was independent prognostic factor for PFS and CSS. BMI and lymphovacular invasion were significant predictors of PFS. Clinical stage, lymph node involvement, and tumor grade were significant predictors of PFS, OS and CSS in these patients. Especially, chemotherapy was helpful in improving PFS [P < 0.001, HR = 6.327 (5.115-7.793)], OS [P = 0.013, HR = 2.336 (1.956-2.883)] and CSS [P = 0.008, HR = 3.073 (2.533-3.738)]. Kaplan-Meier analysis demonstrated that the oncologic outcomes of RNU treated high-risk UTUC patients were improved much significantly by ACT, including PFS [P = 0.0033, HR = 3.78 (3.13-4.55)], OS [P = 0.0397, HR = 1.39 (1.01-1.75)] and CSS [P = 0.0255, HR = 1.26 (1.07-1.45)]. Further analysis of the lymph node positive subgroup showed that the median time of oncologic events was enhanced in RNU + ACT treated individuals in comparison with the RNU group, including PFS (11.4 months vs. 31.9 months, P = 0.0018), OS (26.8 months vs. 36.3 months, P = 0.0255) and CSS (28.2 months vs. 39.3 months, P = 0.0197). In the T3/4 cohort, significantly increased median PFS (13.9 months vs. 36.3 months, P = 0.0217), OS (20.6 months vs. 32.2 months, P = 0.0183) and CSS (21.9 months vs. 38.4 months, P = 0.0226) were obtained in the combination group. Additionally, no severe adverse events (over grade 4) associated with chemotherapy were detected in the RNU + ACT group. In conclusion, ACT after radical surgery has statistically significant therapeutic effects on PFS, OS and CSS in high-risk UTUC patients with cardiovascular comorbidity.

The evaluation of nocturia in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia and the analysis of the curative effect after medical or placebo therapy for nocturia: a randomized placebo-controlled study.

BACKGROUND: To study nocturia in patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) after medical or placebo treatment. METHODS: Patients with LUTS suggestive of BPH from several community clinics were included. Patients completed the International Prostate Symptom Score (I-PSS) questionnaire and a 3-day voiding diary. Urinalysis, prostate-specific antigen (PSA) measurement, and prostate ultrasonography were performed. Nocturnal polyuria (NP) was defined as a nocturnal urine fraction exceeding one third of the daily urine output in elderly men. A total of 148 outpatients were randomized to drug treatment (tamsulosin) or placebo treatment. After 8 weeks of treatment, they were re-evaluated using a 3-day voiding diary, PSA measurement, prostate volume (PV), I-PSS, etc. RESULTS: The average I-PSS score was 20.3, storage symptom score was 11.7, voiding symptom score was 8.6, quality of life (QoL) score was 3.7, PV was 40.4 ± 19.4 ml, and nocturnal urine volume (NUV) was 845.7 ± 339.0 ml. The mean frequency of nocturia was 2.3 ± 1.1 per day, and 94% of the patients had a nocturia frequency of more than two times per day. Of these patients, 76.5% had NP. A significant correlation was found between NUV and the amount of water intake at night and 4 h before sleep (r = 0.419,P = 0.002; r = 0.302,P = 0.031). Eighty patients were randomized to drug treatment (tamsulosin) and 68 patients were randomized to placebo treatment. The I-PSS score was 16.8 ± 4.9 to 19.3 ± 5.0 (p = 0.002), the storage symptom score was 10.3 ± 3.4 to 10.7 ± 3.4 (p = 0.007), and the voiding symptom score was 7.5 ± 2.4 to 8.6 ± 2.3 (p = 0.003). The frequency of daytime urination was 7.5 ± 2.6 to 8.1 ± 2.6 (p = 0.002), maximum urine volume (ml) was 372.8 ± 103.3 to 302.8 ± 119.3 (p = 0.007), and morning urine volume (ml) was 280.5 ± 111.7 to 259.5 ± 100.7 (p = 0.003). However, the frequency of nocturia score was 2.8 ± 0.7 to 3.0 ± 0.6 (p = 0.306) and the nocturnal urine volume (ml) was 800.7 ± 323.0 to 845.7 ± 303.5 (p = 0.056), which did not change significantly. There were significant differences between the NP and non-NP groups in the duration of LUTS, first voided urine volume, daytime urination frequency, and the amount of water intake at night and 4 h before sleep. CONCLUSIONS: Among the symptoms of LUTS, the improvement rates for nocturia were the lowest after medical treatment for BPH. The α-blockers did not improve nocturia, which was a common symptom accompanying LUTS suggestive of BPH. Our results showed that the prevalence of NP was 76.5% and that NP was significantly related to the amount of water intake during the evening and before sleep. TRIAL REGISTRATION: ISRCTN registry, Trial registration number (TRN): ISRCTN85509614 , Date of registration: 30/10/2018. This trial was registered retrospectively.

Long-term oncologic outcomes of radiotherapy combined with maximal androgen blockade for localized, high-risk prostate cancer.

BACKGROUND: To assess the oncologic outcomes of radiation therapy (RT) combined with maximal androgen blockade (MAB) and prostate-specific antigen (PSA) kinetics in patients with localized, high-risk prostate carcinoma (PCa). METHODS: Three-hundred twenty individuals with localized PCa who underwent RT + MAB in 2001-2015 were evaluated retrospectively. All patients had received 36 months of MAB therapy and 45 Gy of pelvic irradiation, plus a dose-escalated external beam radiation therapy (DE-EBRT) boost to 76~81 Gy (MAB + EBRT group), or a low-dose-rate prostate permanent brachytherapy (LDR-PPB) boost to 110 Gy with I-125 (MAB + EBRT + PPB group). RESULTS: Follow-up median is 90 months, ranging from 12 to 186 months; 117 (36.6%) and 203 (63.4%) cases underwent MAB + EBRT and MAB + EBRT + PPB, respectively. Multivariate Cox regression showed that the PPB regimen and PSA kinetics were positive indicators of oncologic outcomes. Compared with MAB + EBRT, MAB + EBRT + PPB remarkably improved PSA kinetics more pronouncedly: PSA nadir (1.3 ± 0.7 vs 0.11 ± 0.06 ng/mL); time of PSA decrease to nadir (7.5 ± 1.8 vs 3.2 ± 2.1 months); PSA doubling time (PSADT; 15.6 ± 4.2 vs 22.6 ± 6.1 months); decrease in PSA (84.6 ± 6.2% vs 95.8 ± 3.4%). Additionally, median times of several important oncologic events were prolonged in the MAB + EBRT + PPB group compared with the MAB + EBRT group: overall survival (OS; 12.3 vs 9.1 years, P < 0.001), biochemical recurrence-free survival (BRFS; 9.8 vs 6.5 years, P < 0.001), skeletal-related event (SRE; 10.4 vs 8.2 years, P < 0.001), and cytotoxic chemotherapy (CCT; 11.6 vs 8.8 years, P = 0.007). CONCLUSION: MAB + EBRT + PPB is extremely effective in patients with localized, high-risk PCa, indicating that PPB may play a synergistic role in improving PSA kinetics and independently predicts oncologic outcomes.

ß­catenin nuclear translocation induced by HIF­1α overexpression leads to the radioresistance of prostate cancer.

Hypoxia-inducible factor­1α (HIF­1α) is known to play crucial roles in tumor radioresistance; however, the molecular mechanisms responsible for the promotion of tumor radioresistance by HIF­1α remain unclear. ß­catenin is known to be involved in the metastatic potential of prostate cancer (PCa). In this study, to investigate the role of HIF­1α and ß­catenin in the radioresistance of PCa, two PCa cell lines, LNCaP and C4­2B, were grouped as follows: Negative control (no treatment), HIF­1α overexpression group (transfected with HIF­1α overexpression plasmid) and ß­catenin silenced group (transfected with HIF­1α plasmids and ß­catenin-shRNA). Cell proliferation, cell cycle, cell invasion and radiosensitivity were examined under normal or hypoxic conditions. In addition, radiosensitivity was examined in two mouse PCa models (the LNCaP orthotopic BALB/c-nu mice model and the C4­2B subcutaneous SCID mice model). Our results revealed that in both the LNCaP and C4­2B cells, transfection with HIF­1α overexpression plasmid led to an enhanced ß­catenin nuclear translocation, while ß­catenin silencing inhibited ß­catenin nuclear translocation. The enhanced ß­catenin nuclear translocation induced by HIF­1α overexpression resulted in an enhanced cell proliferation and cell invasion, an altered cell cycle distribution, decreased apoptosis, and improved non­homologous end joining (NHEJ) repair under normal and irradiation conditions. Similar results were observed in the animal models. HIF­1α overexpression enhanced ß­catenin nuclear translocation, which led to the activation of the ß­catenin/NHEJ signaling pathway and increased cell proliferation, cell invasion and DNA repair. These results thus suggest that HIF­1α overexpression promotes the radioresistance of PCa cells.

Evaluation of perioperative prophylaxis with fosfomycin tromethamine in ureteroscopic stone removal: an investigator-driven prospective, multicenter, randomized, controlled study.

PURPOSE: To compare efficacy, safety, and cost-effectiveness of fosfomycin tromethamine with other standard-of-care antibiotics in patients undergoing ureteroscopic lithotripsy. METHODS: This study was a prospective, multicenter, randomized, controlled trial. Eligible patients scheduled for ureteroscopic lithotripsy were randomly assigned to receive either fosfomycin (fosfomycin group, N = 101 patients) or standard-of-care antibiotic therapy as prophylaxis (control group, N = 115 patients). The incidence of infectious complications and adverse events was analyzed between the two groups, as well as the cost-benefit analysis. RESULTS: The incidence of infections following lithotripsy was 3.0% in the fosfomycin group and 6.1% in the control group (p > 0.05). Only asymptomatic bacteriuria was reported in fosfomycin group. In the control group was reported asymptomatic bacteriuria (3.5%), fever (0.9%), bacteremia (0.9%), and genitourinary infection (0.9%). The rate of adverse events was very low, with no adverse event reported in the fosfomycin group and only one in the control group (forearm phlebitis). The average cost per patient of antibiotic therapy with fosfomycin was 151.45 ± 8.62 yuan (22.7 ± 1.3 USD), significantly lower compared to the average cost per patient of antibiotics used in the control group 305.10 ± 245.95 yuan (45.7 ± 36.9 USD; p < 0.001). CONCLUSIONS: Two oral doses of 3 g fosfomycin tromethamine showed good efficacy and safety and low cost in perioperative prophylaxis of infections following ureteroscopic stone removal.

Spirometric prediction equations and the relationship between metabolic syndrome and spirometric parameters from an island in Fujian, China.

BACKGROUND: We investigated risk factors for decreased lung function among Chinese island residents (≥30 years) to determine the relationship between metabolic syndrome (MS) and decreased lung function. METHODS: From October 17, 2011 to November 1, 2011, 2607 residents aged ≥30 years who lived on the Huangqi Peninsula of Fujian were enlisted by random cluster sampling. They completed a questionnaire designed according to the Burden of Obstructive Lung Disease (BOLD) questionnaire, and underwent physical examination, blood test, and lung function evaluation. We constructed spirometric prediction equations for forced vital capacity (FVC) and forced expiratory volume in one second (FEV1), determined the lower limits of normal for FVC, FEV1 and FEV1/FVC, and examined the relationship between lung function and MS. RESULTS: Prediction equations for normal island residents were as follows: FVC (L) = -0.023 × age (years) + 0.042 × height (cm) + 0.641 × weight (kg) - 3.607 (males); FVC (L) = -0.017 × age (years) + 0.030 × height (cm) + 0.009 × weight (kg) - 1.741 (females); FEV1 (L) = -0.023 × age (years) + 0.040 × height (cm) + 0.010 × weight (kg) - 2.999 (males); FEV1 (L) = -0.017 × age (years) + 0.026 × height (cm) + 0.007 × weight (kg) -1.135 (females). The odds ratio for MS for increased risk of decreased FVC was 4.623 (95%CI =3.626-5.894, P<0.001), and for increased risk of decreased FEV1 was 3.043 (95%CI =2.447-3.785, P<0.001). CONCLUSIONS: MS is a risk factor for decreased lung function in island residents ≥30 years old.

Pituitary tumor-transforming gene 1 regulates invasion of prostate cancer cells through MMP13.

It is critical to understand the molecular mechanisms underlying the migration and invasiveness of prostate cancer (PC) for improving the outcome of therapy. A relationship of pituitary tumor-transforming gene 1 (Pttg1) and matrix metalloproteinase 13 (MMP13) in PC as well as their roles in the metastases of PC has not been studied. Here, we reported significantly higher levels of Pttg1 and MMP13 in the resected PC specimens, compared to the adjacent normal prostate tissue from the same patient. Interestingly, Pttg1 and MMP13 levels strongly correlated with each other. In vitro, Pttg1 activated MMP13, which determined PC cell invasiveness. However, Pttg1 levels were not significantly affected by MMP13. Furthermore, the Pttg1-activated MMP13 in PC cells was significantly suppressed by inhibition of PI3k/Akt, but not ERK/MAPK or JNK pathways. Together, our data suggest that Pttg1 may increase PC cell metastasis by MMP13, and highlight Pttg1/MMP13 axis as a promising therapeutic target for PC treatment.

[Prognostic value of PSA kinetics in locally advanced prostate cancer treated by maximal androgen blockade combined with brachytherapy].

OBJECTIVE: To evaluate the effect of post-treatment PSA kinetics on the prognosis of prostate cancer (PCa). METHODS: We retrospectively reviewed the clinical data of 114 cases of locally advanced PCa treated by maximal androgen blockade (MAB) combined with brachytherapy, and analyzed the association of the changes in PSA kinetics with the prognosis of the patients. RESULTS: The median survival time of the patients was 81 (15 - 144) months, with 1-, 3- and 5-year survival rates of 91. 23%, 78.07% and 68.42% , respectively. Univariate analysis indicated that the baseline PSA level, PSA nadir, the time of PSA decreasing to nadir, PSA doubling time, and the extent of PSA declining were all predictive factors for the survival time of the PCa patients. Multivariate analysis demonstrated that PSA nadir, the time of PSA decreasing to nadir, and the extent of PSA declining were three independent prognostic factors, which prolonged the long-term survival of the patients by 1.7, 3.2 and 6.8 times, respectively. CONCLUSION: For locally advanced PCa treated by MAB combined with brachytherapy, PSA nadir <1 micro g/L, the time to nadir <3 months, and the extent of PSA declining >96% are independent prognostic factors.