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Non‐invasive screening for bladder cancer is crucial for treatment and postoperative follow‐up. This study combines digital microfluidics (DMF) technology with fluorescence lifetime imaging microscopy (FLIM) for urine analysis and introduces a novel non‐invasive bladder cancer screening technique. Initially, the DMF was utilized to perform preliminary screening and enrichment of urine exfoliated cells from 54 participants, followed by cell staining and FLIM analysis to assess the viscosity of the intracellular microenvironment. Subsequently, a deep learning residual convolutional neural network was employed to automatically classify FLIM images, achieving a three‐class prediction of high‐risk (malignant), low‐risk (benign), and minimal risk (normal) categories. The results demonstrated a high consistency with pathological diagnosis, with an accuracy of 91% and a precision of 93%. Notably, the method is sensitive for both high‐grade and low‐grade bladder cancer cases. This highly accurate non‐invasive screening method presents a promising approach for bladder cancer screening with significant clinical application potential. [ABSTRACT FROM AUTHOR]

Patients with impaired left ventricular (LV) function can develop LV thrombus, a potentially life‐threatening condition due to risk of stroke and embolization. Conventional treatment with vitamin K antagonists (VKAs; e.g., warfarin) puts patients at risk of bleeding, and the use of direct oral anticoagulants (DOACs) appears promising, although data are scant. We searched the published English language literature for randomized controlled trials (RCTs) comparing DOACs with VKAs in LV thrombus. End points were failure to resolve, thromboembolic events (stroke, embolism), bleeding, or any adverse event (composite of thromboembolism or bleeding), or all‐cause death. Data were pooled and analyzed in hierarchical Bayesian models. In three eligible RCTs, 141 patients were studied during an average of 4.6 months (53.8 patient‐years; n = 71 assigned to DOAC, n = 70 assigned to VKA). A similar number of patients in each treatment arm demonstrated failure to resolve (DOAC: 14/71 vs. VKA: 15/70) and death events (3/71 vs. 4/70). However, patients on DOACs suffered fewer strokes/thromboembolic events (1/71 vs. 7/70; log odds ratio [OR], −2.02 [95% credible interval (CI95), −4.53 to −0.31]) and fewer bleeding events (2/71 vs. 9/70; log OR, −1.62 [CI95, −3.43 to −0.26]), leading to fewer patients on DOACs with any adverse event versus VKAs (3/71 vs. 16/70; log OR, −1.93 [CI95, −3.33 to −0.75]). In conclusion, pooled analysis of RCT data favors DOACs over VKAs in patients with LV thrombus in terms of both efficacy and safety. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the narrow‐sense validity of polygenic risk score (PRS) for prostate cancer (PCa) in a Chinese prostate biopsy cohort. We performed an observational prospective study with 2640 men who underwent prostate biopsy. Germline DNA samples were genotyped and PRS was calculated for each subject using 17 PCa risk‐associated genetic variants. Additional GWAS data of the ChinaPCa dataset was also used to compliment the evaluation process. The mean PRS was 1.02 in patients with negative biopsy results, which met the baseline benchmark. The mean PRS was significantly higher in the PCa cases (1.32 vs. 1.02, p = 5.56 × 10−17). Significant dose–response associations between PRS values and odds ratios for PCa were observed. However, the raw calibration slope was 0.524 and the average bias score between the observed risk and uncorrected PRS value was 0.307 in the entire biopsy cohort. After applying a correction factor derived from a training set, the corrected calibration slope improved to 1.002 in a testing set. Similar and satisfied results were also seen in the ChinaPCa dataset and two datasets combined, while the calibration results were inaccurate when the calibration process were performed mutually between two different study populations. In conclusion, assessing the narrow‐sense validity of PRS is necessary prior to its clinical implementation for accurate individual risk assessment. [ABSTRACT FROM AUTHOR]

Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy. Recent studies have discovered a pivotal role of the intratumoral microbiota in various cancers, yet it remains elusive in ACC. Here, we explored the intratumoral microbiome data derived from in silico identification, further validated in an in‐house cohort by bacterial 16S rRNA fluorescence in situ hybridization and lipopolysaccharide staining. Unsupervised clustering determined two naturally distinct clusters of the intratumoral microbiome in ACC, which was associated with overall survival. The incorporation of microbial signatures enhanced the prognostic performance of the clinical stage in an immunity‐dependent manner. Genetic and transcriptomic association analyses identified significant upregulation of the cell cycle and p53 signaling pathways associated with microbial signatures for worsened prognosis. Our study not only supports the presence of intratumoral bacteria but also implies a prognostic and biological role of intratumoral microbiota in ACC, which can advance a better understanding of the biology of ACC. Highlights: Adrenocortical carcinoma (ACC) harbors intratumoral microbes.The intratumoral microbiome is associated with prognosis in ACC.The intratumoral microbiota might correlate with genomic events, immune status and specific carcinogenic pathways. [ABSTRACT FROM AUTHOR]

Background: Recurrence and metastasis of bladder cancer are major factors affecting patient prognosis. Endoscopic cryoablation achieved a better clinical outcome among clinical patients and could be synergistic with ICIs. Thus, this study aimed to evaluate the immunological mechanism of cryoablation for bladder cancer to reveal the therapeutic mechanism. Methods: We systematically reviewed the clinical prognosis of patients underwent cryoablation at Huashan Hospital in these first‐in‐human studies (ChiCTR‐INR‐17013060). Murine models were constructed to explore cryoablation‐induced tumour‐specific immunity, which was further confirmed by primary bladder tumour organoids and autologous lymphocytes cocultured system. Results: Cryoablation improved progression‐free survival and recurrence‐free survival respectively. Assessment of murine models after cryoablation confirmed microenvironment remodelling and tumour‐specific T cells expansion. Enhanced antitumour effects were found after coculture of organoids with autologous lymphocytes collected from post‐cryoablation. We also demonstrated cryoablation‐induced tumour elimination required IFNGR expression on tumour cells. In addition, a long‐lasting antitumour memory response is achieved by cryoablation and could be enhanced after combination with ICIs. Conclusions: This study revealed endoscopic cryoablation is an efficient and safe therapy for bladder tumour treatment. The tumour‐specific immune responses induced by cryoablation could reduce tumour recurrence and metastasis. [ABSTRACT FROM AUTHOR]

Background: Cryotherapy is a prevalent percutaneous ablative therapy for solid tumors. Here, we report a novel device using liquid nitrogen for endoscopic cryotherapy of bladder cancer. Methods: In this multicenter, randomized, parallel controlled, Phase 2 trial, we compared endoscopic balloon cryoablation (EBCA) with a single instillation (SI) of pirarubicin after transurethral resection (TUR). Eligible participants were randomly assigned (1:1) to the TUR‐EBCA or TUR‐SI group. Repeat TUR or tissue biopsies were performed to evaluate residual tumor at 4 to 6 weeks after primary treatment. The primary end point was the local control rate. The secondary end points included the tumor upgrading/upstaging, catheter indwelling duration, and adverse events. Results: In total, 205 patients received EBCA or SI after TUR between November 2017 and September 2020, of whom 163 completed all the required interventions. In the per‐protocol set, the local control rate was 91.5% (75/82) in TUR‐EBCA group compared with 76.5% (61/81) in TUR‐SI group (risk difference, 15%; 95% CI, 0.03–0.27, p <.001), meeting the criteria for noninferiority. Similar results were found in the modified intention‐to‐treat analysis. Tumor upgrading/upstaging was found in five patients from the TUR‐SI group. There was no significant difference in the catheter indwelling duration (5.1 vs. 5.2 days, p =.76) or serious adverse event rate (3.0% vs. 3.9%, p =.52). The median follow‐up time of post hoc analysis was 31 (range, 15–50) months. Patients in the TUR‐EBCA group had a better recurrence‐free survival and progression‐free survival. Conclusion: EBCA is a safe and effective adjuvant therapy with TUR for non–muscle‐invasive bladder cancer. Plain language summary: This is the first randomized trial that evaluated endoscopic cryotherapy after transurethral resection (TUR) of bladder tumors. The efficacy and safety analysis shows endoscopic balloon cryoablation (EBCA) is a promising alternative.Results report that EBCA is not inferior to a single instillation of intravesical chemotherapy in eliminating residual bladder tumor. Further analysis with ∼3 years' median follow‐up suggested a better prognosis in patients who received EBCA after TUR. This is the first multicenter randomized controlled trial of endoscopic cryotherapy for intraluminal malignancies. Endoscopic balloon cryoablation is a promising choice for bladder cancer. [ABSTRACT FROM AUTHOR]

Recent studies identified Midkine (MDK) as playing a key role in immune regulation. In this study, we aimed to discover the clinical significance and translational relevance in prostate cancer (PCa). We retrospectively analyzed 759 PCa patients who underwent radical prostatectomy from Huashan Hospital, Fudan University (training cohort, n = 369) and Chinese Prostate Cancer Consortium (validation cohort, n = 390). A total of 325 PCa patients from The Cancer Genome Atlas (TCGA) database (external cohort) were analyzed for exploration. Immune landscape and antitumor immunity were assessed through immunohistochemistry and flow cytometry. Patient‐derived explant culture system was applied for evaluating the targeting potential of MDK. We found that intratumoral MDK expression correlated with PCa progression, which indicated an unfavorable biochemical recurrence (BCR)‐free survival for postoperative PCa patients. Addition of MDK expression to the postoperative risk assessment tool CAPRA‐S could improve its prognostic value. Tumors with MDK abundance characterized the tumor‐infiltrating CD8+ T cells with less cytotoxicity production and increased immune checkpoint expression, which were accompanied by enriched immunosuppressive contexture. Moreover, MDK inhibition could reactivate CD8+ T cell antitumor immunity. MDK mRNA expression negatively correlated with androgen receptor activity signature and positively associated with radiotherapy‐related signature. In conclusion, intratumoral MDK expression could serve as an independent prognosticator for BCR in postoperative PCa patients. MDK expression impaired the antitumor function of CD8+ T cells through orchestrating an immunoevasive microenvironment, which could be reversed by MDK inhibition. Moreover, tumors with MDK enrichment possessed potential sensitivity to postoperative radiotherapy while resistance to adjuvant hormonal therapy of PCa. MDK could be considered as a potential therapeutic target for PCa. [ABSTRACT FROM AUTHOR]

Our knowledge of the coordination of intergenerational inheritance and offspring metabolic reprogramming by gastrointestinal endocrine factors is largely unknown. Here, we showed that secretin (SCT), a brain‐gut peptide, is downregulated by overnutrition in pregnant mice and women. More importantly, genetic loss of SCT in the maternal gut results in undesirable phenotypes developed in offspring including enhanced high‐fat diet (HFD)‐induced obesity and attenuated browning of inguinal white adipose tissue (iWAT). Mechanistically, loss of maternal SCT represses iWAT browning in offspring by a global change in genome methylation pattern through upregulation of DNMT1. SCT functions to facilitate ubiquitination and degradation of DNMT1 by activating AMPKα, which contributes to the observed alteration of DNMT1 in progeny. Lastly, we showed that SCT treatment during pregnancy can reduce the development of obesity and improve glucose tolerance and insulin resistance in offspring of HFD‐fed females, suggesting that SCT may serve as a novel biomarker or a strategy for preventing metabolic diseases. Synopsis: Maternal secretin promotes white adipose tissue browning in the offspring by inducing a global change in genome methylation pattern through the DNA methyltransferase DNMT1. Genetic loss of secretin in the maternal gut results in disrupted glucose and lipid homeostasis in the offspring.Maternal secretin promotes white adipose tissue browning in the offspring.Depletion of maternal SCT leads to an AMPKAα dependent increase in DNMT1 protein levels in the white adipose tissue of the offspring.Maternal secretin reprograms white adipose tissue methylation of the offspring. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is one of the most common health‐related issues in the male individuals of western countries. Icaritin (ICT) is a traditional Chinese herbal medicine that exhibits antitumor efficacy in variety of cancers including PCa. However, the precise function and detailed molecular mechanism of ICT in the regression of PCa remain unclear. Ubiquitin‐conjugating enzyme E2C (UBE2C) is an anaphase‐promoting complex/cyclosome (APC/C)‐specific ubiquitin conjugating enzyme, which acts as an oncogene in PCa progression. The function of ICT in PCa was investigated in transgenic adenocarcinoma mouse prostate (TRAMP) mice using survival analysis, hematoxylin and eosin (HE) staining, TUNEL assay, and immunohistochemistry and in human PCa cell lines using various molecular techniques and functional assays including plasmid construction and transfection. Bioinformatic analyses were performed to identify the interaction between miRNA and UBE2C via the TargetScan algorithm. We demonstrated that ICT inhibited the development and progression of PCa in TRAMP mice by improving the survival rate and tumor differentiation. Furthermore, we found that ICT could significantly inhibit cell proliferation and invasion and induce apoptosis in PCa cells. Consistently, downregulation of UBE2C suppressed the proliferation and invasion of PCa cells. Moreover, a luciferase reporter assay confirmed that UBE2C was a direct target of miR‐381‐3p. Meanwhile, ICT simultaneously downregulated UBE2C expression and upregulated miR‐381‐3p levels in human PCa cells. Altogether, our findings provide a strong rationale for the clinical application of ICT as a potential oncotherapeutic agent against PCa via a novel molecular mechanism of regulating the miR‐381‐3p/UBE2C pathway. [ABSTRACT FROM AUTHOR]

Atomic force microscope (AFM) has been widely used in the biological field owing to its high sensitivity (subnanonewton), high spatial resolution (nanometer), and adaptability to physiological environments. Nowadays, force volume (FV) and peakforce quantitative nanomechanical (QNM) are two distinct modes of AFM used in biomechanical research. However, numerous studies have revealed an extremely confusing phenomenon that FV mode has a significant difference with QNM in determining the mechanical properties of the same samples. In this article, for the case of human benign prostatic hyperplasia cells (BPH) and two cancerous prostate cells with different grades of malignancy (PC3 and DU145), the differences were compared between FV and QNM modes in detecting mechanical properties. The results show measured Young's modulus of the same cells in FV mode was much lower than that obtained by QNM mode. Combining experimental results with working principles of two modes, it is indicated that surface adhesion is highly suspected to be a critical factor resulting in the measurement difference between two modes. To further confirm this conjecture, various weight ratios of polydimethylsiloxane (PDMS) were assessed by two modes, respectively. The results show that the difference of Young's modulus measured by two modes increases with the surface adhesion of PDMS, confirming that adhesion is one of the significant elements that lead to the measurement difference between FV and QNM modes. [ABSTRACT FROM AUTHOR]

Circular RNA UVRAG (circUVRAG), a type of non‐coding RNA, is derived and cyclized by part of the exon from the UVRAG gene. However, the role of circUVRAG in bladder cancer (BLCA) has not been reported. The purpose of the present study was therefore to characterize the role of circUVRAG in BLCA. Bioinformatics analysis showed interactive relationships among circUVRAG, microRNA‐223 (miR‐223), and fibroblast growth factor receptor 2 (FGFR2). Quantitative real‐time PCR was used to detect the expression of circUVRAG in BLCA cell lines. UM‐UC‐3 cells were stably transfected with siRNA against circUVRAG, and cell proliferation and migration ability were tested using the CCK8 assay, clone formation, and Transwell assays in vitro. Tumor xenograft formation and metastasis were determined using nude mice. Fluorescence in situ hybridization was used to confirm the subcellular localization of circUVRAG, and the luciferase reporter assay was used to confirm the relationships among circUVRAG, miR‐223, and FGFR2. Results showed that circUVRAG was upregulated in BLCA cell lines. Downregulation of circUVRAG expression suppressed proliferation and metastasis both in vitro and in vivo. Downregulation of circUVRAG suppressed FGFR2 expression by "sponging" miR‐223, which was confirmed by rescue experiments and luciferase reporter assay. Overall, the results showed that downregulation of circUVRAG suppressed the aggressive biological phenotype of BLCA. Taken together, silencing circular RNA UVRAG inhibited bladder cancer growth and metastasis by targeting the miR‐223/FGFR2 axis, which may provide a potential biomarker and therapeutic target for the management of BLCA. This study found that silencing circular RNA UVRAG inhibited bladder cancer growth and metastasis by targeting the miR‐223/FGFR2 axis, which may provide a potential biomarker and therapeutic target for the management of BLCA. [ABSTRACT FROM AUTHOR]

This study was to evaluate the risk factors of infectious complications after percutaneous nephrolithotomy (PCNL) and build a prediction tool for postoperative complications based on the risk factors. A total of 110 male (67.1%) and 54 female (32.9%) patients who underwent PCNL for renal stones between 2010 and 2014 in our institute were included. A detailed clinical information and laboratory results were obtained from patients. Systemic inflammatory response syndrome (SIRS) and postoperative fever were recorded after PCNL surgery. In all, 45 cases (27.4%) developed SIRS and fever was observed in 20 cases (12.2%). In multivariate analysis, stone size (odds ratio, OR = 1.471, p=0.009) and urine white blood cell (WBC) (OR = 1.001, p=0.007) were related to the development of SIRS. Stone size (OR = 1.644, p=0.024), urine WBC (OR = 1.001, p=0.002) and serum albumin (OR = 0.807, p=0.021) were associated with postoperative fever. We concluded that patients with larger stone size and preoperative urinary tract infection might have a higher risk of developing SIRS and fever after operation, while a high-normal level of serum albumin might be the protective factor for postoperative fever. [ABSTRACT FROM AUTHOR]

Notch signaling was associated with a variety of cancers but was not comprehensively studied in clear-cell renal cell carcinoma (ccRCC). We have in this study studied the genetic alteration (mutation and copy number variance) of Notch gene set in the Cancer Genome Atlas (TCGA) Kidney Renal Clear Cell Carcinoma (KIRC) database. We found that Notch pathway was frequently altered in ccRCC. The Notch gene set was genetically altered in 182 (44%) of the 415 ccRCC patients. CNV was the predominant type of alteration in most genes. Alterations in KAT2B and MAML1 occurred in 13% and 19% of patients, respectively, both of which were functionally active in ccRCC. Deletion of VHL was exclusively found in cases with Notch alteration. Overall survival was longer in ccRCC patients with altered-Notch pathway. The median survival was 90.41 months in Notch-altered cases and 69.15 in Notch-unaltered cases ( P = 0.0404). The median disease free time was 89.82 months in Notch-altered cases and 77.27 months in in Notch-unaltered cases ( P = 0.935). Conclusively, Notch signaling was altered in almost half of the ccRCC patients and copy number variances in MAML1 and KAT2B were predominant changes. These findings broadened our understanding of the role of Notch in ccRCC. © 2015 BioFactors, 42(1):41-48, 2016 [ABSTRACT FROM AUTHOR]

Objectives: To explore whether asymptomatic inflammatory prostatitis is associated with prostatic enlargement beyond that of benign prostatic hyperplasia patients without asymptomatic inflammatory prostatitis, and whether asymptomatic inflammatory prostatitis affects long-term outcomes of transurethral resection of the prostate. Methods: The present study involved 106 benign prostatic hyperplasia patients who underwent transurethral resection of the prostate. Clinical and pathological parameters were compared between those with benign prostatic hyperplasia associated with asymptomatic inflammatory prostatitis and those with benign prostatic hyperplasia alone. Results: A total of 55 patients (52%) were found to have benign prostatic hyperplasia and asymptomatic inflammatory prostatitis, whereas 51 patients (48%) had benign prostatic hyperplasia alone. The prostate volume of the benign prostatic hyperplasia/ asymptomatic inflammatory prostatitis group was significantly larger than the benign prostatic hyperplasia alone group: 68.1 cm3 (interquartile range 45.7-86.3) versus 44.1 cm3 (interquartile range 30.9-72.1), P = 0.036. In terms of histopathological analysis, benign prostatic hyperplasia/asymptomatic inflammatory prostatitis patients were more likely to show mild (53%), focal (67%) and stromal (40%) prostatic inflammation in our study. Furthermore, statistically significant differences of International Prostate Symptom Score were found 3 years after transurethral resection of the prostate, with benign prostatic hyperplasia/asymptomatic inflammatory prostatitis patients reporting higher (worse) scores than benign prostatic hyperplasia alone patients (P = 0.025). Conclusions: Chronic prostatic inflammatory process might progressively conduce to benign prostatic hyperplasia development, which can also result in prostate enlargement and worsen long-term postoperative International Prostate Symptom Scores. Multicenter studies with larger cohorts and longer follow-up periods are required to confirm these findings. [ABSTRACT FROM AUTHOR]