SpecReFlow: an algorithm for specular reflection restoration using flow-guided video completion.

Purpose: Specular reflections (SRs) are highlight artifacts commonly found in endoscopy videos that can severely disrupt a surgeon's observation and judgment. Despite numerous attempts to restore SR, existing methods are inefficient and time consuming and can lead to false clinical interpretations. Therefore, we propose the first complete deep-learning solution, SpecReFlow, to detect and restore SR regions from endoscopy video with spatial and temporal coherence. Approach: SpecReFlow consists of three stages: (1) an image preprocessing stage to enhance contrast, (2) a detection stage to indicate where the SR region is present, and (3) a restoration stage in which we replace SR pixels with an accurate underlying tissue structure. Our restoration approach uses optical flow to seamlessly propagate color and structure from other frames of the endoscopy video. Results: Comprehensive quantitative and qualitative tests for each stage reveal that our SpecReFlow solution performs better than previous detection and restoration methods. Our detection stage achieves a Dice score of 82.8% and a sensitivity of 94.6%, and our restoration stage successfully incorporates temporal information with spatial information for more accurate restorations than existing techniques. Conclusions: SpecReFlow is a first-of-its-kind solution that combines temporal and spatial information for effective detection and restoration of SR regions, surpassing previous methods relying on single-frame spatial information. Future work will look to optimizing SpecReFlow for real-time applications. SpecReFlow is a software-only solution for restoring image content lost due to SR, making it readily deployable in existing clinical settings to improve endoscopy video quality for accurate diagnosis and treatment.

Prediction of false-positive PI-RADS 5 lesions on prostate multiparametric MRI: development and internal validation of a clinical-radiological characteristics based nomogram.

BACKGROUND: To develop a risk model including clinical and radiological characteristics to predict false-positive The Prostate Imaging Reporting and Data System (PI-RADS) 5 lesions. METHODS: Data of 612 biopsy-naïve patients who had undergone multiparametric magnetic resonance imaging (mpMRI) before prostate biopsy were collected. Clinical variables and radiological variables on mpMRI were adopted. Lesions were divided into the training and validation cohort randomly. Stepwise multivariate logistic regression analysis with backward elimination was performed to screen out variables with significant difference. A diagnostic nomogram was developed in the training cohort and further validated in the validation cohort. Calibration curve and receiver operating characteristic (ROC) analysis were also performed. RESULTS: 296 PI-RADS 5 lesions in 294 patients were randomly divided into the training and validation cohort (208 : 88). 132 and 56 lesions were confirmed to be clinically significant prostate cancer in the training and validation cohort respectively. The diagnostic nomogram was developed based on prostate specific antigen density, the maximum diameter of lesion, zonality of lesion, apparent diffusion coefficient minimum value and apparent diffusion coefficient minimum value ratio. The C-index of the model was 0.821 in the training cohort and 0.871 in the validation cohort. The calibration curve showed good agreement between the estimation and observation in the two cohorts. When the optimal cutoff values of ROC were 0.288 in the validation cohort, the sensitivity, specificity, PPV, and NPV were 90.6%, 67.9%, 61.7%, and 92.7% in the validation cohort, potentially avoiding 9.7% unnecessary prostate biopsies. CONCLUSIONS: We developed and validated a diagnostic nomogram by including 5 factors. False positive PI-RADS 5 lesions could be distinguished from clinically significant ones, thus avoiding unnecessary prostate biopsy.

GALNT12 suppresses the bone-specific prostate cancer metastasis by activating BMP pathway via the O-glycosylation of BMPR1A.

Bone metastasis caused the majority death of prostate cancer (PCa) but the mechanism remains poorly understood. In this present study, we show that polypeptide N-acetylgalactosaminyltransferase 12 (GALNT12) suppresses bone-specific metastasis of PCa. GALNT12 suppresses proliferation, migration, invasion and cell division ability of PCa cells by activating the BMP pathway. Mechanistic investigations showed that GALNT12 augments the O-glycosylation of BMPR1A then actives the BMP pathway. Activated BMP signaling inhibits the expression of integrin αVß3 to reduce the bone-specific seeding of PCa cells. Furthermore, activated BMP signaling remolds the immune microenvironment by suppressing the STAT3 pathway. Our results of this study illustrate the role and mechanism of GALNT12 in the process of bone metastasis of PCa and identify GALNT12 as a potential therapeutic target for metastatic PCa.

Second generation androgen receptor antagonist, TQB3720 abrogates prostate cancer growth via AR/GPX4 axis activated ferroptosis.

Purpose: Prostate cancer (PCa) poses a great threat to humans. The study aimed to evaluate the potential of TQB3720 in promoting ferroptosis to suppress prostate cancer, providing a theoretical basis for PCa therapy. Methods: PCa cells and nude mice models were divided into TQB3720, enzalutamide (ENZ), and control groups. Sulforhodamine B assay, colony formation assessment, organoids culture system, and the CCK8 assay were used for detecting proliferation. Western blot assay was processed to detect the expression of androgen receptor (AR), ferroptosis, and apoptosis-related genes. Flow cytometry was applied to measure the intracellular ROS levels. ELISA was performed to determine the cellular oxidized glutathione (GSSG) and malondialdehyde (MDA) levels. RT-qPCR was conducted to detect the mRNA expression of genes in AR signaling. BODIPYTM™ 581/591 was processed for detection of intracellular lipid peroxidation levels. The interaction of AR with other translational factor complex proteins was explored using Co-immunoprecipitation (Co-IP), and the chromatin immunoprecipitation (ChIP) assay was performed to detect the binding of AR-involved translational complex to downstream genes promoter. Luciferase reporter assay was conducted to examine the translation activity of GPX4 promoter, and immunohistochemistry (IHC) was conducted to analyze the levels of c-MYC, Ki-67 and AR in TQB3720-treated cancer tissues. Results: Here, we found TQB3720 inhibits the growth of prostate cancer in vitro and in vivo. TQB3720 treatment induced intracellular levels of GSSG and MDA significantly, by which hints AR antagonist caused ferroptosis-related cell death. Moreover, molecular evidence shown TQB3720 regulates downstream of AR signaling by binding AR resulting in inhibition of AR entry into the nucleus. Additional, we also proved that TQB3720 abrogates the interaction between AR and SP1 and leads to decrease GPX4 transcription. Conclusion: TQB3720 promotes ferroptosis in prostate cancer cells by reducing the AR/SP1 transcriptional complex binding to GPX4 promoter. As a result, it is suggested to be a potential drug for clinic prostate cancer treatment.

Small ankyrin 1 (sANK1) promotes docetaxel resistance in castration-resistant prostate cancer cells by enhancing oxidative phosphorylation.

Docetaxel (DTX) plays an important role in treating advanced prostate cancer (PCa). However, nearly all patients receiving DTX therapy ultimately progress to DTX resistance. How to address DTX resistance in PCa remains a key challenge for all urologists. Small ankyrin 1 (sAnk1) is an integral membrane protein in the endoplasmic reticulum. In the present study, we identified that sAnk1 is upregulated in PCa tissues and is positively associated with DTX therapy resistance in PCa. Further investigation demonstrated that overexpression of sAnk1 can significantly increase the DTX-resistant ability of PCa cells in vitro and in vivo. In addition, overexpression of sAnk1 could enhance oxidative phosphorylation (OXPHOS) levels in PCa cells, which was consistent with the higher OXPHOS levels observed in DTX-resistant PCa cells as compared to DTX-sensitive PCa cells. sAnk1 was also found to interact with polypyrimidine-tract-binding protein (PTBP1), an alternative splicing factor, and suppressed PTBP1-mediated alternative splicing of the pyruvate kinase gene (PKM). Thus, overexpression of sAnk1 decreased the ratio of PKM2/PKM1, enhanced the OXPHOS level, and ultimately promoted the resistance of PCa cells to DTX. In summary, our data suggest that sAnk1 enhances DTX resistance in PCa cells.

Low expression of PEBP1P2 promotes metastasis of clear cell renal cell carcinoma by post-transcriptional regulation of PEBP1 and KLF13 mRNA.

BACKGROUND: Pseudogenes play an essential role in tumor occurrence and progression. However, the functions and mechanisms of pseudogenes in clear cell renal cell carcinoma (ccRCC) remain largely elusive. METHODS: We quantified PEBP1P2 expression in ccRCC tissues and cells using fluorescence in situ hybridization and real-time PCR. Besides, we evaluated the role of PEBP1P2 in ccRCC using a lung metastasis model and a transwell assay. Finally, we documented the interactions between PEBP1P2, PEBP1, and KLF13 by performing luciferase, RNA immunoprecipitation, RNA pulldown, and targeted RNA demethylation assays. RESULTS: Low PEBP1P2 expression correlates significantly with advanced stages and poor prognosis in ccRCC patients. Besides, PEBP1P2 overexpression inhibits ccRCC metastasis formation in vivo and in vitro. Interestingly, PEBP1P2 directly interacted with 5-methylcytosine (m5C)-containing PEBP1 mRNA and recruited the YBX1/ELAVL1 complex, stabilizing PEBP1 mRNA. In addition, PEBP1P2 increased KLF13 mRNA levels by acting as a sponge for miR-296, miR-616, and miR-3194. CONCLUSIONS: PEBP1P2 inhibits ccRCC metastasis formation and regulates both PEBP1 and KLF13. Therefore, molecular therapies targeting PEBP1P2 might be an effective treatment strategy against ccRCC and other cancers with low PEBP1P2 levels.

Allosteric activation of the metabolic enzyme GPD1 inhibits bladder cancer growth via the lysoPC-PAFR-TRPV2 axis.

BACKGROUND: Bladder cancer is the most common malignant tumor of the urinary system. Surgical resection and chemotherapy are the two mainstream treatments for bladder cancer. However, the outcomes are not satisfactory for patients with advanced bladder cancer. There is a need to further explore more effective targeted therapeutic strategies. METHODS: Proteomics were performed to compare protein expression differences between human bladder cancer tissues and adjacent normal tissues. The function of GPD1 on bladder cancer cells were confirmed through in vivo and in vitro assays. Transcriptomics and metabolomics were performed to reveal the underlying mechanisms of GPD1. Virtual screening was used to identify allosteric activator of GPD1. RESULTS: Here, we used proteomics to find that GPD1 expression was at low levels in bladder cancer tissues. Further investigation showed that GPD1 overexpression significantly promoted apoptosis in bladder cancer cells. Based on transcriptomics and metabolomics, GPD1 promotes Ca2+ influx and apoptosis of tumor cells via the lysoPC-PAFR-TRPV2 axis. Finally, we performed a virtual screening to obtain the GPD1 allosteric activator wedelolactone and demonstrated its ability to inhibit bladder tumor growth in vitro and in vivo. CONCLUSIONS: This study suggests that GPD1 may act as a novel tumor suppressor in bladder cancer. Pharmacological activation of GPD1 is a potential therapeutic approach for bladder cancer.

circCYP24A1 promotes Docetaxel resistance in prostate Cancer by Upregulating ALDH1A3.

BACKGROUND: Docetaxel (DTX) is the most widely prescribed first-line chemotherapy for advanced prostate cancer (PCa). Unfortunately, DTX resistance invariably emerges, leading to worse prognosis of PCa. Growing evidence has shown that circRNAs had complex spatiotemporal specificity during the tumor development and oncogenesis. This study was designed to investigate the biological functions and possible molecular mechanisms of circRNAs in DTX resistance of PCa. METHODS: circRNAs in established DTX-resistant DU145 cell line were identified by RNA sequencing. Biological function of circCYP24A1 was verified in vitro and in vivo. The potential role of circCYP24A1 in the development of DTX-resistant PCa was investigated via dual-luciferase reporter assays, RIP assays and RNA pull-down assays. Univariate and multivariate logistic regression analyses was used to predict DTX-chemotherapy response based on patients' clinical and biological information. RESULTS: CircCYP24A1 was identified to be upregulated in DTX-resistant DU145 cells. Upregulated circCYP24A1 was found to suppress the DTX chemosensitivity in vitro and in vivo. Furthermore, we found that circCYP24A1 promoted DTX resistance in PCa via regulating ALDH1A3 expression by sponging miR-1301-3p and activating PI3K/AKT/mTOR signaling pathway. Statistical analyses elucidated that circCYP24A1 was an independent risk factor to predict DTX response (OR = 0.165; 95% CI: 0.038-0.723; P = 0.017). CONCLUSIONS: This study demonstrated that circCYP24A played an essential role in DTX resistance in PCa, suggesting that circCYP24A1 could be a promising biomarker to predict DTX response and a potential therapeutic target in PCa patients resistant to DTX chemotherapy.

circDHTKD1 promotes lymphatic metastasis of bladder cancer by upregulating CXCL5.

Lymph node (LN) metastasis is associated with unfavorable prognosis of bladder cancer (BCa). Although lymphangiogenesis is functionally important in LN metastasis of tumors, the potential mechanism in BCa remains unclear. Here, we clarified a regulatory mechanism of circRNA-mediated lymphangiogenesis and LN metastasis in BCa based on next-generation sequencing data. We revealed that circDHTKD1 was positively associated with LN metastasis and significantly upregulated in BCa. By analyzing the co-expression patterns of circDHTKD1 and differentially expressed mRNAs, we identified that circDHTKD1 facilitated lymphangiogenesis by upregulating CXCL5. Mechanistically, circDHTKD1 directly interacted with miR-149-5p, and antagonized the repression of miR-149-5p on CXCL5. Furthermore, circDHTKD1-induced CXCL5 expression recruited and activated neutrophils, which participated in lymphangiogenesis by secreting VEGF-C. Our study supports circDHTKD1 as a promising diagnostic and therapeutic target for LN metastasis in BCa.

Pan-cancer analysis identifies LMNB1 as a target to redress Th1/Th2 imbalance and enhance PARP inhibitor response in human cancers.

BACKGROUND: Emerging evidence suggests that LMNB1 is involved in the development of multiple cancer types. However, there is no study reporting the potential role of LMNB1 in a systematic pan-cancer manner. METHODS: The gene expression level and potential oncogenic roles of LMNB1 in The Cancer Genome Atlas (TCGA) database were analyzed with Tumor Immune Estimation Resource version 2 (TIMER2.0), Gene Expression Profiling Interactive Analysis version 2 (GEPIA2), UALCAN and Sangerbox tools. Pathway enrichment analysis was carried out to explore the possible mechanism of LMNB1 on tumorigenesis and tumor progression. The therapeutic effects of LMNB1 knockdown combined with PARP inhibition on human cancers were further investigated in vitro. RESULTS: LMNB1 upregulation is generally observed in the tumor tissues of most TCGA cancer types, and is verified in kidney renal clear cell carcinoma using clinical specimens of our institute. High level of LMNB1 expression usually predicts poor overall survival and disease free survival for patients with tumors. Mechanically, LMNB1 level is positively correlated with CD4+ Th2 cell infiltration and DNA homologous recombination repair gene expression. In vitro experiments reveal that targeting LMNB1 has a synergistic effect on prostate cancer with PARP inhibitor treatment. CONCLUSIONS: LMNB1 is a biomarker of CD4+ Th2 cell infiltration and DNA homologous recombination repair in human cancers. Blockage of LMNB1 combined with PARP inhibitor treatment could be a promising therapeutic strategy for patients with cancers.

MicroRNA-582-5p regulates cell invasion in bladder cancer through targeting Forkhead Box G1.

Burgeoning evidence shows that microRNAs (miRNAs) are associated with tumorigenesis and progression. However, the alteration and function of many miRNAs in bladder cancer (BCa) are not clear. Here, we explored the regulatory effect of microRNA-582 (miR-582) on cell invasion in BCa and underlying mechanisms. The expression of miR-582 in BCa tissues and cell lines was examined by quantitative real-time PCR (qRT-PCR). The target gene of miR-582 and their binding site were predicted by bioinformatics analysis. Luciferase reporter assay and western blot analysis were performed to confirm miR-582 directly targeting Forkhead Box G1 (FOXG1). The role of miR-582-FOXG1 axis in regulating BCa invasion was evaluated in cell models. The association of miR-582 with clinicopathologic features and prognosis was analyzed. Experimental results indicated that miR-582 was downregulated in BCa tissues and cell lines. Forced miR-582 decreased cell invasion, regulating expression levels of invasion-related proteins, such as MMP2, MMP9 and ZO-1. MiR-582 directly targeted FOXG1 by binding to its 3'UTR. Overexpression of FOXG1 rescued the regulating function in BCa cells induced by miR-582. Moreover, miR-582-FOXG1 axis has obvious clinical relevance with prognosis in BCa patients. Our results indicate that miR-582-FOXG1 axis may act as a key role on cell invasion and serve as a potential prognostic predicted biomarker.

Prediction of Biochemical Recurrence After Radical Prostatectomy Based on Preoperative 68Ga-PSMA-11 PET/CT.

PURPOSE: This study was designed to investigate the prognostic role of preoperative 68Ga-PSMA-11 PET/CT in predicting biochemical recurrence (BCR) of localized prostate cancer (PCa) after radical prostatectomy (RP). METHODS: A total of 77 biopsy-confirmed PCa patients with 68Ga-PSMA-11 PET/CT prior to RP were included. A PSMA-ligand PET/CT-based risk model with SUVmax, maximum diameter of the index tumor and T stage was developed for prediction of 2-year BCR using Cox regression analysis. Also, the efficacy of the developed risk model was compared with European Association of Urology risk stratification (D'Amico) and the Cancer of the Prostate Risk Assessment (CAPRA) score. C-index and calibration plot were used to assess discrimination and calibration with internal validation. RESULTS: With a median follow-up of 25 months, 23 (29.9%) patients experienced BCR within 2 years after RP. Patients experienced BCR had a significant higher PSA at diagnosis (p<0.001), a higher ISUP grade of biopsy (p=0.044), as well as a higher ISUP grade (p=0.001), a higher possibility of T3 diseases (p=0.001) and positive margin (p=0.008) on postoperative pathology. SUVmax, maximum diameter of the index tumor and T stage on preoperative PSMA-ligand PET/CT were significantly associated with BCR (all p<0.01). PSMA-ligand PET/CT-based risk model had a superior discrimination (c-index 78.5%) and good calibration at internal validation. The efficacy of this model in predicting 2-year BCR after RP was better, compared with CAPRA (c-index 66.3%) and D'Amico (c-index 66.2%). The addition of the PSMA-ligand PET/CT-derived variables also improved the efficacy of the existing models in predicting 2-year BCR (C-index of 78.9% for modified CAPRA and 79.3% for modified D'Amico, respectively). CONCLUSION: A PSMA-ligand PET/CT-based risk model showed good efficacy in predicting 2-year BCR after RP, which needed to be validated by further prospective studies.

Can 68Ga-PSMA-11 PET/CT predict pathological upgrading of prostate cancer from MRI-targeted biopsy to radical prostatectomy?

PURPOSE: Prostate-specific membrane antigen (PSMA) positron emission tomography (PSMA-PET) is an ideal tool for staging and restaging of prostate cancer (PCa). This study was designed to investigate the prognostic role of preoperative 68Ga-PSMA-11 PET/CT in predicting pathological upgrading from multiparametric magnetic resonance imaging-targeted biopsy (mpMRI-TB) to final radical prostatectomy (RP) specimens in patients with localized PCa. METHODS: A total of 67 biopsy-confirmed localized PCa patients with mpMRI and 68Ga-PSMA-11 PET/CT prior to RP were included. Clinical and imaging characteristics derived from mpMRI and PET/CT were compared in patients with or without pathological upgrading. Predictors for pathological upgrading were evaluated by using univariate and multivariable analyses. A prediction model was developed based on the identified parameters and validated using internal validation. RESULTS: Pathological upgrading from mpMRI-TB to final RP specimens occurred in 38.8% (26/67) of the patients. Multivariable logistic regression analysis showed SUVmax (OR: 1.223, 95% CI 1.068-1.399, p = 0.003); highest tumor grade at mpMRI-TB, ISUP grade group (ISUP GG) 1 vs. 4 (OR: 0.11, 95% CI 0.000-0.452, p = 0.018) and ISUP GG 2 vs. 4 (OR: 0.16, 95% CI 0.001-0.252, p = 0.003); and multifocality on PET/CT (OR: 9.821, 95% CI 1.438-67.085, p = 0.02) were independent risk factors for pathological upgrading. Our developed prediction model based on the identified parameter showed good calibration at internal validation (mean absolute error = 0.033). CONCLUSION: 68Ga-PSMA-11 PET/CT was found to be an ideal biomarker for the prediction of pathological upgrading from mpMRI-TB to RP, especially for patients with lower tumor grade at mpMRI-TB.