Unveiling the atlas of associations between 1,400 plasma metabolites and 24 tumors: Mendelian randomization analyses.

Background: Association between plasma metabolites and pan-cancer remains controversial. Herein, we performed a two-sample Mendelian randomization (MR) analysis to verify whether there is a causal relationship between the two and to point the way for cancer metabolism research. Methods: In our research, we downloaded 1,400 plasma metabolites from a large genome-wide association study (GWAS). We also obtained GWAS summary statistics for 24 types of cancers from the publicly available GWAS database, totaling 5,003,410 European individuals. We mainly used the fixed/random-effects inverse variance-weighted (IVW) method for two-sample MR analysis. Results: In a combined sample of 291,202 cancer cases and 4,712,208 controls, a total of 55 plasma metabolites were identified as causally associated with nine types of cancer as a result of our MR analysis [P<0.05, false discovery rate (FDR) <0.2], including methionine sulfone, gamma-glutamylcitrulline, alliin, tetradecanedioate, hexadecanedioate, glutarate, ceramide, linolenoylcarnitine, hydroxypalmitoyl sphingomyelin, 1-palmitoyl-2-linoleoyl-glycerylphosphorylcholine (1-palmitoyl-2-linoleoyl-GPC), 3-acetylphenol sulfate, retinol (vitamin a) to linoleoyl-arachidonoyl-glycerol (18:2 to 20:4) ratio, etc. Reverse MR analysis revealed a causal relationship between lung cancer and the only plasma metabolite, 1-palmitoyl-2-linoleoyl-GPC (P<0.05, FDR <0.2). Conclusions: Our study provides a comprehensive atlas of cancer-related plasma metabolites, offering possible targets for cancer detection, as well as a reference for future research on tumorigenesis mechanisms and therapeutic targets.

UPCARE: Urinary Extracellular Vesicles-Derived Prostate Cancer Assessment for Risk Evaluation.

In the quest for efficient tumor diagnosis via liquid biopsy, extracellular vesicles (EVs) have shown promise as a source of potential biomarkers. This study addresses the gap in biomarker efficacy for predicting clinically significant prostate cancer (csPCa) between the Western and Chinese populations. We developed a urinary extracellular vesicles-based prostate score (EPS) model, utilizing the EXODUS technique for EV isolation from 598 patients and incorporating gene expressions of FOXA1, PCA3, and KLK3. Our findings reveal that the EPS model surpasses prostate-specific antigen (PSA) testing in diagnostic accuracy within a training cohort of 234 patients, achieving an area under the curve (AUC) of 0.730 compared to 0.659 for PSA (p = 0.018). Similarly, in a validation cohort of 101 men, the EPS model achieved an AUC of 0.749, which was significantly better than PSA's 0.577 (p < 0.001). Our model has demonstrated a potential reduction in unnecessary prostate biopsies by 26%, with only a 3% miss rate for csPCa cases, indicating its effectiveness in the Chinese population.

Integrated bioinformatics investigation of adenylyl cyclase family co-expression network in bladder cancer followed by preliminary validation of member 2 (ADCY2) in tumorigenesis and prognosis.

Background: The adenylyl cyclase (ADCY) gene family encodes enzymes responsible for the synthesis of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP), which comprises nine transmembrane isoforms (ADCYs 1-9). Although ADCYs correlate with intracellular signalling and tumorigenesis in different malignancies, their roles in bladder cancer remain unclear. Methods: Utilizing the bladder urothelial carcinoma (BLCA) dataset from The Cancer Genome Atlas (TCGA), we employed the R package 'limma' to identify differential genes. Subsequent correlation analysis with corresponding clinical data was conducted. Prognostic significance of ADCY family genes was assessed through survival analysis. Univariate and multivariate Cox regression determined ADCY2 as a potential independent risk factor for BLCA. Validation was performed using immunohistochemistry results from independent cohorts. Additionally, we delved into the mechanism of genetic variations, methylation modifications, and signalling pathways of ADCY family genes. Evaluation of their role in the immune microenvironment was achieved through R packages single-sample gene set enrichment analysis (ssGSEA), CIBERPORT, and ESTIMATE. Results: Cases of bladder cancer were retrieved from TCGA, and the transcriptionally differentially expressed members of ADCY were identified (members 2, 4, and 5). Genomic alteration, epigenomic modification, clinicopathological characteristics and clinical survival were systematically investigated. A co-expression network was established based on the intersection of correlated genes, which was centred around ADCY2, ADCY4, and ADCY5. Enrichment analysis revealed that correlated genes were involved in epithelial-mesenchymal transition (EMT). The ADCY2 was selected as the most representative biomarker for prognosis in bladder cancer. Bladder tumour with higher ADCY2 expression had higher prognostic risk and worse survival outcomes. Moreover, ADCY2 was correlated with classic immune checkpoints, and a better responsiveness to immunotherapy was exhibited in high-expression subsets. To ameliorate universality of the conclusion, our study also included several real-world cohorts into the preliminary validation, using datasets from the Gene Expression Omnibus (GEO; GSE13507), tissue microarray (TMA) with 80 bladder cancer inclusion and clinical trial IMvigor210, which were associated with immunotherapy sensitivity, prognosis, and common biomarker presentation. Conclusions: Our study reveals that ADCY family has prognostic value in patients with bladder cancer; the ADCY2 is a prominent prognostic biomarker. The bioinformatics analyses and validation provide direction for further functional and mechanistic studies on the screened members of ADCY family.

The application and influence of "Small Private Online Course" based on flipped classroom teaching model in the course of fundamental operations in surgery in China.

To investigate the effect of "Small Private Online Course" (SPOC) based on flipped classroom teaching model on the students in the course of fundamental operations in surgery. A prospective study. 8-year program students (juniors) majored in clinical medicine in Navy medical university. The mastery of theoretical knowledge and operational skill of the students, the comparison of final test examination score between traditional teaching method and "SPOC + flipped classroom" model and the feedback completed by students. Our study found that SPOC + flipped classroom could significantly increase the efficacy of the class and enhance the ability of the students compared with the traditional method. The new teaching model could have a positive influence for medical students on their basic knowledge and operational skill.

Integrative transcriptome and proteome analyses of clear cell renal cell carcinoma develop a prognostic classifier associated with thrombus.

Clear cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) is associated with poor prognosis. Our integrative analyses of transcriptome and proteome reveal distinctive molecular features of ccRCC with VTT, and yield the development of a prognostic classifier to facilitate ccRCC molecular subtyping and treatment. The RNA sequencing and mass spectrometry were performed in normal-tumor-thrombus tissue triples of five ccRCC patients. Statistical analysis, GO and KEGG enrichment analysis, and protein-protein interaction network construction were used to interpret the transcriptomic and proteomic data. A six-gene-based classifier was developed to predict patients' survival using Cox regression, which was validated in an independent cohort. Transcriptomic analysis identified 1131 tumorigenesis-associated differentially expressed genes (DEGs) and 856 invasion-associated DEGs. Overexpression of transcription factor EGR2 in VTT indicated its important role in tumor invasion. Furthermore, proteomic analysis showed 597 tumorigenesis-associated differentially expressed proteins (DEPs) and 452 invasion-associated DEPs. The invasion-associated DEPs showed unique enrichment in DNA replication, lysine degradation, and PPAR signaling pathway. Integration of transcriptome and proteome reveals 142 tumorigenesis-associated proteins and 84 invasion-associated proteins displaying changes consistent with corresponding genes in transcriptomic profiling. Based on their different expression patterns among normal-tumor-thrombus triples, RAB25 and GGT5 were supposed to play a consistent role in both tumorigenesis and invasion processes, while SHMT2 and CADM4 might play the opposite roles in tumorigenesis and thrombus invasion. A prognostic classifier consisting of six DEGs (DEPTOR, DPEP1, NAT8, PLOD2, SLC7A5, SUSD2) performed satisfactorily in predicting survival of ccRCC patients (HR = 4.41, P < 0.001), which was further validated in an independent cohort of 40 cases (HR = 5.52, P = 0.026). Our study revealed the transcriptomic and proteomic profiles of ccRCC patients with VTT, and identified the distinctive molecular features associated with VTT. The six-gene-based prognostic classifier developed by integrative analyses may facilitate ccRCC molecular subtyping and treatment.

Sustainable functional urethral reconstruction improves early urinary continence after robot-assisted radical prostatectomy: a randomised controlled trial.

OBJECTIVE: To evaluate the impact of sustainable functional urethral reconstruction (SFUR) on early recovery of urinary continence (UC) after robot-assisted radical prostatectomy. PATIENTS AND METHODS: Overall, 96 patients with primary prostate cancer were randomised into the SFUR or standard group (n = 48 each). The primary outcome was the 1-month UC recovery. Secondary outcomes included short-term (≤3 months) UC recovery, urinary function, micturition-related bother, perioperative complications, and oncological outcomes. Kaplan-Meier curves and Cox proportional hazard models were used to assess the 3-month UC recovery. Generalised estimating equations were used to compare postoperative urinary function and micturition-related bother. RESULTS: The 1-month UC recovery rates, median 24-h pad weights, and median operative time in the SFUR and standard groups were 73% and 49% (P = 0.017), 0 and 47 g (P = 0.001), and 125 and 103 min (P = 0.025), respectively. The UC recovery rates in the SFUR vs standard groups were 53% vs 23% at 1 week (P = 0.003), 53% vs 32% at 2 weeks (P = 0.038), and 93% vs 77% at 3 months (P = 0.025). The median time to UC recovery in the SFUR and standard groups was 5 and 34 days, respectively (log-rank P = 0.006); multivariable Cox regression supported this result (hazard ratio 1.73, 95% confidence interval 1.08-2.79, P = 0.024). Similar results were observed when UC was defined as 0 pads/day. Urinary function (P = 0.2) and micturition-related bother (P = 0.8) were similar at all follow-up intervals. The perioperative complication rates, positive surgical margin rates, and 1-year biochemical recurrence-free survival were comparable between both groups (all P > 0.05). CONCLUSION: SFUR resulted in earlier UC recovery without compromising postoperative urinary function. Long-term validation and multicentre studies are required to confirm the results of this novel technique.

Propensity-matched pair analysis of safety and efficacy between laparoscopic and open radical nephrectomy for the treatment of large renal masses (>10 cm): a retrospective cohort study.

Background: Open radical nephrectomy (ORN) is a practical procedure for treating patients with large renal carcinomas >10 cm in size, and few studies have focused on feasibility and safety of laparoscopic radical nephrectomy (LRN). The current study was to assess the safety and effectiveness of LRN and ORN in large renal carcinoma patients by propensity matched pair analysis. Methods: In this cohort study, a retrospective review of radical nephrectomy data from October 2010 to October 2018 at Changhai Hospital was conducted. Patients with renal carcinomas >10 cm in size by pre-operative images were included. Patients' demographics including age, gender, body mass index (BMI), tumor size, operation time, hospitalization days, etc. were collected. Renal tumor patients undergoing LRN or ORN were match-paired by gender, BMI, age, and tumor size. Peri-operative outcomes including estimated blood loss and complications were compared. The follow-up contents included survival time, disease progression, and cause of death, and cancer-specific and progression-free survival were estimated via Kaplan-Meier curve analysis. Results: Among 92 patients with clinical T2b renal masses, 37 pairs were matched. The average tumor sizes of the LRN and ORN groups were 11.37±0.30 and 11.67±0.33 cm (P=0.375), respectively. The average operating time for LRN was slightly longer (204.32±11.17 vs. 192.78±8.50 min, P=0.414). Estimated blood loss (EBL) (336.49±63.58 mL for LRN vs. 545.95±74.52 mL for ORN, P=0.036), the length of postoperative stay [6.0 (5.0-9.0) for LRN vs. 9.0 (6.0-11.5) days for ORN, P=0.015], and removal time of the drainage tube [4.0 (3.0-5.0) days for LRN vs. 5.0 (4.0-6.0) for ORN, P<0.001] were less than in the LRN group. The pathological subtype and Fuhrman grade were comparable. Both groups were followed up for a similar period, and no difference was observed in 5-year survival rates. Conclusions: Considering the conversion rates and overall complication rates, it seems that LRN for large renal carcinomas demonstrated equivalent peri-operative safety and effectiveness compared with ORN, with no adverse effects on midterm oncological outcomes.

A morphology-based nephrometry score to predict pathological upstaging to T3 renal cell carcinoma.

Background: Patients with clinical T1-2 renal cell carcinoma (RCC) upstaging to pathological T3 showed worse survival prognosis than those without upstaging. We aimed to develop and validate a morphology-based nephrometry scoring system for predicting pathological upstaging to T3 of RCC. Methods: We retrospectively reviewed 200 patients with clinical T1-2 RCC who underwent surgical treatment. The nephrometry scores were measured through preoperative computed tomography images. The risk factors of pathological upstaging were identified by logistic regression models. The predictive accuracy of a novel morphology-based nephrometry scoring system (M-Index), was compared with R.E.N.A.L (radius, exophytic/endophytic, nearness, anterior/posterior, location), PADUA (preoperative aspects and dimensions used for an anatomic classification), DAP (diameter, axial, polar) and C-Index scores. Results: The upstaging rate of the population was 17% (34 out of 200 patients). The upstaging and non-upstaging groups were comparable in terms of age, gender ratio, body mass index, tumor laterality, and pathological type, while the upstaging group tended to have large tumor diameter, irregular tumor morphology, inner tumor location, and short polar and axial distance. Large tumor diameter refers to larger than 5 cm, while irregular tumor morphology refers to not regular shapes such as round, oval, or lobular. Univariate and multivariate logistic regression analyses showed that tumor morphology [odds ratio (OR) 3.26, 95% confidence interval (CI): 1.79-5.97] and tumor rim location (OR 2.95, 95% CI: 1.16-7.46) were independent risk factors for pathological upstaging. The receiver operating characteristic curve and decision curve analysis (DCA) demonstrated the novel M-Index based on tumor morphology and rim location outperformed R.E.N.A.L, PADUA, DAP, and C-Index in the prediction of pathological upstaging (area under curve 0.756 vs. 0.728 vs. 0.641 vs. 0.661 vs. 0.743). Conclusions: Consisting of fewer non-complex parameters, the M-Index is an intuitive and practical tool with satisfactory predictive power for pathological upstaging to T3 in RCC patients undergoing surgery.

KDM6B is an androgen regulated gene and plays oncogenic roles by demethylating H3K27me3 at cyclin D1 promoter in prostate cancer.

Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, plays oncogenic or antitumoral roles in malignant tumors depending on the type of tumor cell. However, how this histone modifier affects the progression of prostate cancer (PCa) is still unknown. Here we analyzed sequenced gene expression data and tissue microarray to explore the expression features and prognostic value of KDM6B in PCa. Further, we performed in vitro cell biological experiments and in vivo nude mouse models to reveal the biological function, upstream and downstream regulation mechanism of KDM6B. In addition, we investigated the effects of a KDM6B inhibitor, GSK-J4, on PCa cells. We showed that KDM6B overexpression was observed in PCa, and elevated KDM6B expression was associated with high Gleason Score, low serum prostate-specific antigen level and shorted recurrence-free survival. Moreover, KDM6B prompted proliferation, migration, invasion and cell cycle progression and suppressed apoptosis in PCa cells. GSK-J4 administration could significantly suppress the biological function of KDM6B in PCa cells. KDM6B is involved in the development of castration-resistant prostate cancer (CRPC), and combination of MDV3100 plus GSK-J4 is effective for CRPC and MDV3100-resistant CRPC. Mechanism exploration revealed that androgen receptor can decrease the transcription of KDM6B and that KDM6B demethylates H3K27me3 at the cyclin D1 promoter and cooperates with smad2/3 to prompt the expression of cyclin D1. In conclusion, our study demonstrates that KDM6B is an androgen receptor regulated gene and plays oncogenic roles by promoting cyclin D1 transcription in PCa and GSK-J4 has the potential to be a promising agent for the treatment of PCa.

Novel Long Non-coding RNA lncAMPC Promotes Metastasis and Immunosuppression in Prostate Cancer by Stimulating LIF/LIFR Expression.

Long non-coding RNAs (lncRNAs) participate in the development and progression of prostate cancer (PCa). We aimd to identify a novel lncRNA, named lncRNA activated in metastatic PCa (lncAMPC), and investigate its mechanisms and clinical significance in PCa. First, the biological capacity of lncAMPC in PCa was demonstrated both in vitro and in vivo. The lncAMPC was overexpressed in tumor tissue and urine of metastatic PCa patients and promoted PCa tumorigenesis and metastasis. Then, a mechanism study was conducted to determine how the lncAMPC-activated pathway contributed to PCa metastasis and immunosuppression. In the cytoplasm, lncAMPC upregulated LIF expression by sponging miR-637 and inhibiting its activity. In the nucleus, lncAMPC enhanced LIFR transcription by decoying histone H1.2 away from the upstream sequence of the LIFR gene. The lncAMPC-activated LIF/LIFR expressions stimulated the Jak1-STAT3 pathway to simultaneously maintain programmed death-ligand 1 (PD-L1) protein stability and promote metastasis-associated gene expression. Finally, the prognostic value of the expression of lncAMPC and its downstream genes in PCa patients was evaluated. High LIF/LIFR levels indicated shorter biochemical recurrence-free survival among patients who underwent radical prostatectomy. Therefore, the lncAMPC/LIF/LIFR axis plays a critical role in PCa metastasis and immunosuppression and may serve as a prognostic biomarker and potential therapeutic target.

The previously uncharacterized lncRNA APP promotes prostate cancer progression by acting as a competing endogenous RNA.

Long noncoding RNAs (lncRNAs) promote cell proliferation, migration, invasion and castration resistance in prostate cancer (PCa). Understanding the inherited molecular mechanisms by which lncRNAs contribute to the progression of PCa to a lethal disease could have an important impact on cancer detection, diagnosis and prognosis. In our study, PCa-associated lncRNA transcripts from RNA-seq data were identified and screened via bioinformatics analysis, NCBI annotations and literature review. We identified a novel lncRNA, lncAPP (lncRNA activated in PCa progression), which activates in PCa progression and is expressed in primary tumor tissues and urine samples of patients with localized or advanced PCa. Urinary-based lncAPP is a promising biomarker for predicting PCa progression. In vitro and in vivo studies demonstrated that lncAPP enhanced cell proliferation and promoted migration and invasion. The underlying mechanism of lncRNA was investigated by RNA immunoprecipitation, dual-luciferase reporter system assay, etc. Upregulation of lncAPP promoted cell migration and invasion via competitively binding miR218 to facilitate ZEB2/CDH2 expression. In addition, in vivo subcutaneous tumor xenograft models and tail intravenously injection metastatic models were constructed to evaluate lncRNA function. Targeting lncAPP/miR218 axis in cell lines and tumor xenografts restrained tumor progression properties both in vitro and in vivo. These results establish that lncAPP/miR218 axis plays a critical role in PCa progression, and they also suggest new strategies to prevent tumor progression for therapeutic purposes.

Transurethral seminal vesiculoscopy for recurrent hemospermia: experience from 419 cases.

We summarized our experience in transurethral seminal vesiculoscopy (TSV) for recurrent hemospermia by introducing surgical techniques, intraoperative findings, and treatment outcomes. TSV was performed in 419 patients with an initial diagnosis of persistent hemospermia at Shanghai Changhai Hospital (Shanghai, China) from May 2007 to November 2015. TSV was successfully performed in 381 cases (90.9%). Hemospermia was alleviated or disappeared in 324 (85.0%) patients by 3 months after surgery. Common intraoperative manifestations were bleeding, obstruction or stenosis, mucosal lesions, and calculus. Endoscopic presentation of the ejaculatory duct orifice and the verumontanum was categorized into four types, including 8 (1.9%), 32 (7.6%), 341 (81.4%), and 38 (9.1%) cases in Types A, B, C, and D, respectively. TSV is an effective and safe procedure in the management of seminal tract disorders. This study may help other surgeons to become familiar with and improve this procedure. However, further multicentric clinical trials are warranted to validate these findings.

Cross-cultural Adaptation and Validation of the Simplified Chinese Version of the Knee Outcome Survey Activities of Daily Living Scale.

PURPOSE: To perform a cross-cultural adaptation and translation of the original version of the Activities of Daily Living Scale of the Knee Outcome Survey into Simplified Chinese and validate of the Simplified Chinese version. METHODS: The original version was translated and cross-culturally adapted into Simplified Chinese according to the guidelines and the recommendations of the American Academy of Orthopaedic Surgeons Outcome Committee. A total of 213 patients (96 male, 117 female) were selected to participate in our investigation. The inclusion criteria were as follows: 18 years of age and older, able to speak Chinese Mandarin and read Simplified Chinese, and referred to physical therapy for evaluation and treatment for a knee disorder. The exclusion criteria were as follows: patients who had disorders or impairments involving both knees, patients who had other conditions that could affect lower extremity function, patients with physical therapy related to the knee in the previous 1 month, and patients with psychological problems. Each participant was asked to complete the Knee Outcome Survey Activities of Daily Living Scale (KOS-ADLS), International Knee Documentation Committee Subjective Knee Form, Western Ontario and McMaster Universities Osteoarthritis Index, and Short Form 36 forms and to provide baseline demographic data. Each participant completed the KOS-ADLS twice on 2 nonconsecutive days for reliability evaluation. A portion of the participants (n = 161) finished the KOS-ADLS a third time 4 weeks after physical treatment to test responsiveness. RESULTS: The original version of the KOS-ADLS was well adapted and translated into Simplified Chinese. Simplified Chinese of KOS-ADLS was shown to have good internal consistency (Cronbach's alpha = 0.855 to 0.929), great test-retest reliability (intraclass correlation coefficient = 0.935 to 0.961), high construct validity as we hypothesized (significant correlations with Short Form 36 subscales, Western Ontario and McMaster Universities Osteoarthritis Index, and International Knee Documentation Committee Subjective Knee Form), and high responsiveness (standard response means = 0.97 to 1.23, standard effect size = 0.81 to 0.91). CONCLUSIONS: Simplified Chinese of KOS-ADLS was shown to have good reliability, validity, and responsiveness for use in patients with knee disorders in China. LEVEL OF EVIDENCE: Level II, testing of previously developed diagnostic criteria in a series of consecutive patients with universally applied gold standard.