Publications by authors named "Tianxin Lin"

131 Publications

An Artificial Intelligence System for the Detection of Bladder Cancer via Cystoscopy: A Multicenter Diagnostic Study.

J Natl Cancer Inst 2021 Sep 2. Epub 2021 Sep 2.

Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

Background: Cystoscopy plays an important role in bladder cancer (BCa) diagnosis and treatment, but its sensitivity needs improvement. Artificial intelligence has shown promise in endoscopy, but few cystoscopic applications have been reported. We report a Cystoscopy Artificial Intelligence Diagnostic System (CAIDS) for BCa diagnosis.

Methods: In total, 69,204 images from 10,729 consecutive patients from six hospitals were collected and divided into training, internal validation, and external validation sets. The CAIDS was built using a pyramid scene parsing network and transfer learning. A subset (n = 260) of the validation sets was used for a performance comparison between the CAIDS and urologists for complex lesion detection. The diagnostic accuracy, sensitivity, specificity, and positive and negative predictive values and 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method.

Results: The diagnostic accuracies of the CAIDS were 0.977 (95% CI = 0.974-0.979) in the internal validation set and 0.990 (95% CI = 0.979-0.996), 0.982 (95% CI = 0.974-0.988), 0.978 (95% CI = 0.959-0.989), and 0.991 (95% CI = 0.987-0.994) in different external validation sets. In the CAIDS versus urologists' comparisons, the CAIDS showed high accuracy and sensitivity (accuracy = 0.939, 95% CI = 0.902-0.964; and sensitivity = 0.954, 95% CI = 0.902-0.983) with a short latency of 12 s, much more accurate and quicker than the expert urologists.

Conclusions: The CAIDS achieved accurate BCa detection with a short latency. The CAIDS may provide many clinical benefits, from increasing the diagnostic accuracy for BCa, even for commonly misdiagnosed cases such as flat cancerous tissue (carcinoma in situ), to reducing the operation time for cystoscopy.
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http://dx.doi.org/10.1093/jnci/djab179DOI Listing
September 2021

Tumor-derived exosomal BCYRN1 activates WNT5A/VEGF-C/VEGFR3 feedforward loop to drive lymphatic metastasis of bladder cancer.

Clin Transl Med 2021 Jul;11(7):e497

Department of Urology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, P. R. China.

Background: Patients with lymph node (LN) metastatic bladder cancer (BCa) present with extremely poor prognosis. BCa-derived exosomes function as crucial bioactive cargo carriers to mediate the signal transduction in tumor microenvironment triggering tumor metastasis. However, the mechanisms underlying exosome-mediated LN metastasis in BCa are unclear.

Methods: We conducted the high-throughput sequencing to explore the expression profile of long noncoding RNA (lncRNA) in urinary exosomes (urinary-EXO) from patients with BCa and further evaluated the clinical relevance of exosomal lncRNA BCYRN1 in a larger 210-case cohort. The functional role of exosomal BCYRN1 was evaluated through the migration and tube formation assays in vitro and the footpad-popliteal LN metastasis model in vivo. RNA pull-down assays, luciferase assays, and actinomycin assays were conducted to detect the regulatory mechanism of exosomal BCYRN1.

Results: LncRNA BCYRN1 was substantially upregulated in urinary-EXO from patients with BCa, and associated with the LN metastasis of BCa. We demonstrated that exosomal BCYRN1 markedly promoted tube formation and migration of human lymphatic endothelial cells (HLECs) in vitro and lymphangiogenesis and LN metastasis of BCa in vivo. Mechanistically, BCYRN1 epigenetically upregulated WNT5A expression by inducing hnRNPA1-associated H3K4 trimethylation in WNT5A promoter, which activated Wnt/β-catenin signaling to facilitate the secretion of VEGF-C in BCa. Moreover, exosomal BCYRN1 was transmitted to HLECs to stabilize the VEGFR3 mRNA and thus formed an hnRNPA1/WNT5A/VEGFR3 feedforward regulatory loop, ultimately promoting the lymphatic metastasis of BCa. Importantly, blocking VEGFR3 with specific inhibitor, SAR131675 significantly impaired exosomal BCYRN1-induced the LN metastasis in vivo. Clinically, exosomal BCYRN1 was positively associated with the shorter survival of BCa patients and identified as a poor prognostic factor of patients.

Conclusion: Our results uncover a novel mechanism by which exosomal BCYRN1 synergistically enhances VEGF-C/VEGFR3 signaling-induced lymphatic metastasis of BCa, indicating that BCYRN1 may serve as an encouraging therapeutic target for patients with BCa.
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http://dx.doi.org/10.1002/ctm2.497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288020PMC
July 2021

Targeting WD repeat domain 5 enhances chemosensitivity and inhibits proliferation and programmed death-ligand 1 expression in bladder cancer.

J Exp Clin Cancer Res 2021 Jun 21;40(1):203. Epub 2021 Jun 21.

Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107th Yanjiangxi Road, Guangzhou, China.

Background: Chemotherapy and/or immunotherapy are first-line treatments for advanced muscle-invasive bladder cancer (BCa), but the unsatisfactory objective response rate to these treatments yields poor 5-year patient survival. Discovery of therapeutic targets essential for BCa maintenance is critical to improve therapy response in clinic. This study evaluated the role of targeting WD repeat domain 5 (WDR5) with the small molecule compound OICR-9429 and whether it could be used to treat bladder cancer.

Methods: We analysed the expression and clinical prognosis of WDR5 in a TCGA cohort. The pharmacological role of OICR-9429 was further investigated in vitro and in vivo. RNA sequencing, western blot, and chromatin immunoprecipitation (ChIP) were utilized to explored the mechanism underlying OICR-9429-induced WDR5 inhibition.

Results: First, we found that WDR5 expression was upregulated in BCa and was associated with histologic grade, metastasis status, histologic subtype, and molecular subtype. High WDR5 expression level was also correlated with shorter overall survival (OS) in BCa. The WDR5 inhibitor OICR-9429 reduced cell viability by decreasing H3K4me3 levels but not WDR5 levels in T24, UM-UC-3, and TCCSUP BCa cells. OICR-9429 suppressed the proliferation of BCa cells by blocking the G1/S phase transition. Next, OICR-9429 enhanced apoptosis and chemosensitivity to cisplatin in BCa cells. In addition, OICR-9429 independently inhibited the motility and metastatic behaviour of BCa cells. In vivo experiments further revealed that OICR-9429 suppressed tumour growth, enhanced chemosensitivity, and reduced the toxicity of cisplatin in BCa. Notably, WDR5 was positively correlated with programmed death-ligand 1 (PD-L1) expression, and OICR-9429 suppressed immune evasion by blocking PD-L1 induced by IFN-γ. Mechanistically, some cell cycle-, antiapoptosis-, DNA repair-, metastasis-, and immune evasion-related genes, including BIRC5, XRCC2, CCNB1, CCNE2, PLK1, AURKA, FOXM1, and PD-L1 were identified to be directly regulated by OICR-9429 in a H3K4me3-dependent manner.

Conclusions: Our novel finding is that the WDR5 inhibitor, OICR-9429, suppressed proliferation, metastasis and PD-L1-based immune evasion while enhancing apoptosis and chemosensitivity to cisplatin in BCa by blocking the WDR5-MLL complex mediating H3K4me3 in target genes. Hence, our findings offer insight into a multipotential anticancer compound, OICR-9429, which enhances the antitumour effect of cisplatin or immunotherapy in BCa.
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http://dx.doi.org/10.1186/s13046-021-01989-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215817PMC
June 2021

A multicenter study to develop a non-invasive radiomic model to identify urinary infection stone in vivo using machine-learning.

Kidney Int 2021 Jun 12. Epub 2021 Jun 12.

Department of Pharmacy, the First People's Hospital of Kashi Prefecture, Affiliated Kashi Hospital of Sun Yat-Sen University, Kashi, People's Republic of China. Electronic address:

Urolithiasis is a common urological disease, and treatment strategy options vary between different stone types. However, accurate detection of stone composition can only be performed in vitro. The management of infection stones is particularly challenging with yet no effective approach to pre-operatively identify infection stones from non-infection stones. Therefore, we aimed to develop a radiomic model for preoperatively identifying infection stones with multicenter validation. In total, 1198 eligible patients with urolithiasis from three centers were divided into a training set, an internal validation set, and two external validation sets. Stone composition was determined by Fourier transform infrared spectroscopy. A total of 1316 radiomic features were extracted from the pre-treatment Computer Tomography images of each patient. Using the least absolute shrinkage and selection operator algorithm, we identified a radiomic signature that achieved favorable discrimination in the training set, which was confirmed in the validation sets. Moreover, we then developed a radiomic model incorporating the radiomic signature, urease-producing bacteria in urine, and urine pH based on multivariate logistic regression analysis. The nomogram showed favorable calibration and discrimination in the training and three validation sets (area under the curve [95% confidence interval], 0.898 [0.840-0.956], 0.832 [0.742-0.923], 0.825 [0.783-0.866], and 0.812 [0.710-0.914], respectively). Decision curve analysis demonstrated the clinical utility of the radiomic model. Thus, our proposed radiomic model can serve as a non-invasive tool to identify urinary infection stones in vivo, which may optimize disease management in urolithiasis and improve patient prognosis.
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http://dx.doi.org/10.1016/j.kint.2021.05.031DOI Listing
June 2021

A urine-based DNA methylation assay to facilitate early detection and risk stratification of bladder cancer.

Clin Epigenetics 2021 Apr 26;13(1):91. Epub 2021 Apr 26.

AnchorDx Medical Co., Ltd, Unit 502, 3rd Luoxuan Road, International Bio-Island, Guangzhou, 510300, China.

Background: Current non-invasive tests have limited sensitivities and lack capabilities of pre-operative risk stratification for bladder cancer (BC) diagnosis. We aimed to develop and validate a urine-based DNA methylation assay as a clinically feasible test for improving BC detection and enabling pre-operative risk stratifications.

Methods: A urine-based DNA methylation assay was developed and validated by retrospective single-center studies in patients of suspected BC in Cohort 1 (n = 192) and Cohort 2 (n = 98), respectively. In addition, a prospective single-center study in hematuria patient group (Cohort 3, n = 174) was used as a second validation of the model.

Results: The assay with a dual-marker detection model showed 88.1% and 91.2% sensitivities, 89.7% and 85.7% specificities in validation Cohort 2 (patients of suspected BC) and Cohort 3 (patients of hematuria), respectively. Furthermore, this assay showed improved sensitivities over cytology and FISH on detecting low-grade tumor (66.7-77.8% vs. 0.0-22.2%, 0.0-22.2%), Ta tumor (83.3% vs. 22.2-41.2%, 44.4-52.9%) and non-muscle invasive BC (NMIBC) (80.0-89.7% vs. 51.5-52.0%, 59.4-72.0%) in both cohorts. The assay also had higher accuracies (88.9-95.8%) in diagnosing cases with concurrent genitourinary disorders as compared to cytology (55.6-70.8%) and FISH (72.2-77.8%). Meanwhile, the assay with a five-marker stratification model identified high-risk NMIBC and muscle invasive BC with 90.5% sensitivity and 86.8% specificity in Cohort 2.

Conclusions: The urine-based DNA methylation assay represents a highly sensitive and specific approach for BC early-stage detection and risk stratification. It has a potential to be used as a routine test to improve diagnosis and prognosis of BC in clinic.
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http://dx.doi.org/10.1186/s13148-021-01073-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072728PMC
April 2021

A deep-learning pipeline for the diagnosis and discrimination of viral, non-viral and COVID-19 pneumonia from chest X-ray images.

Nat Biomed Eng 2021 06 15;5(6):509-521. Epub 2021 Apr 15.

Department of Medical Imaging and Deptartment of Cardiology, Xiangya Hospital, Central South University, Changsha, China.

Common lung diseases are first diagnosed using chest X-rays. Here, we show that a fully automated deep-learning pipeline for the standardization of chest X-ray images, for the visualization of lesions and for disease diagnosis can identify viral pneumonia caused by coronavirus disease 2019 (COVID-19) and assess its severity, and can also discriminate between viral pneumonia caused by COVID-19 and other types of pneumonia. The deep-learning system was developed using a heterogeneous multicentre dataset of 145,202 images, and tested retrospectively and prospectively with thousands of additional images across four patient cohorts and multiple countries. The system generalized across settings, discriminating between viral pneumonia, other types of pneumonia and the absence of disease with areas under the receiver operating characteristic curve (AUCs) of 0.94-0.98; between severe and non-severe COVID-19 with an AUC of 0.87; and between COVID-19 pneumonia and other viral or non-viral pneumonia with AUCs of 0.87-0.97. In an independent set of 440 chest X-rays, the system performed comparably to senior radiologists and improved the performance of junior radiologists. Automated deep-learning systems for the assessment of pneumonia could facilitate early intervention and provide support for clinical decision-making.
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http://dx.doi.org/10.1038/s41551-021-00704-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611049PMC
June 2021

WD repeat domain 5 promotes chemoresistance and Programmed Death-Ligand 1 expression in prostate cancer.

Theranostics 2021 4;11(10):4809-4824. Epub 2021 Mar 4.

Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.

Advanced prostate cancer (PCa) has limited treatment regimens and shows low response to chemotherapy and immunotherapy, leading to poor prognosis. Histone modification is a vital mechanism of gene expression and a promising therapy target. In this study, we characterized WD repeat domain 5 (WDR5), a regulator of histone modification, and explored its potential therapeutic value in PCa. We characterized specific regulators of histone modification, based on TCGA data. The expression and clinical features of WDR5 were analyzed in two dependent cohorts. The functional role of WDR5 was further investigated with siRNA and OICR-9429, a small molecular antagonist of WDR5, and . The mechanism of WDR5 was explored by RNA-sequencing and chromatin immunoprecipitation (ChIP). WDR5 was overexpressed in PCa and associated with advanced clinicopathological features, and predicted poor prognosis. Both inhibition of WDR5 by siRNA and OICR-9429 could reduce proliferation, and increase apoptosis and chemosensitivity to cisplatin and . Interestingly, targeting WDR5 by siRNA and OICR-9429 could block IFN-γ-induced PD-L1 expression in PCa cells. Mechanistically, we clarified that some cell cycle, anti-apoptosis, DNA repair and immune related genes, including AURKA, CCNB1, E2F1, PLK1, BIRC5, XRCC2 and PD-L1, were directly regulated by WDR5 and OICR-9429 in H3K4me3 and c-Myc dependent manner. These data revealed that targeting WDR5 suppressed proliferation, enhanced apoptosis, chemosensitivity to cisplatin and immunotherapy in PCa. Therefore, our findings provide insight into OICR-9429 is a multi-potency and promising therapy drug, which improves the antitumor effect of cisplatin or immunotherapy in PCa.
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http://dx.doi.org/10.7150/thno.55814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978315PMC
August 2021

SUMOylation promotes extracellular vesicle-mediated transmission of lncRNA ELNAT1 and lymph node metastasis in bladder cancer.

J Clin Invest 2021 04;131(8)

Department of Urology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China.

Small ubiquitin-like modifier (SUMO) binding (termed SUMOylation) emerged as the inducer for the sorting of bioactive molecules into extracellular vesicles (EVs), triggering lymphangiogenesis and further driving tumor lymph node (LN) metastasis, but the precise mechanisms remain largely unclear. Here, we show that bladder cancer (BCa) cell-secreted EVs mediated intercellular communication with human lymphatic endothelial cells (HLECs) through transmission of the long noncoding RNA ELNAT1 and promoted lymphangiogenesis and LN metastasis in a SUMOylation-dependent manner in both cultured BCa cell lines and mouse models. Mechanistically, ELNAT1 induced UBC9 overexpression to catalyze the SUMOylation of hnRNPA1 at the lysine 113 residue, which mediated recognition of ELNAT1 by the endosomal sorting complex required for transport (ESCRT) and facilitated its packaging into EVs. EV-mediated ELNAT1 was specifically transmitted into HLECs and epigenetically activated SOX18 transcription to induce lymphangiogenesis. Importantly, blocking the SUMOylation of tumor cells by downregulating UBC9 expression markedly reduced lymphatic metastasis in EV-mediated, ELNAT1-treated BCa in vivo. Clinically, EV-mediated ELNAT1 was correlated with LN metastasis and a poor prognosis for patients with BCa. These findings highlight a molecular mechanism whereby the EV-mediated ELNAT1/UBC9/SOX18 regulatory axis promotes lymphangiogenesis and LN metastasis in BCa in a SUMOylation-dependent manner and implicate ELNAT1 as an attractive therapeutic target for LN metastatic BCa.
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http://dx.doi.org/10.1172/JCI146431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262506PMC
April 2021

Lymphatic metastasis of bladder cancer: Molecular mechanisms, diagnosis and targeted therapy.

Cancer Lett 2021 05 18;505:13-23. Epub 2021 Feb 18.

Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China. Electronic address:

Bladder cancer is the most common and lethal cancer of the urinary system. Lymphatic metastasis is the primary and main metastatic type of bladder cancer, leading to an extremely poor prognosis in patients. Therefore, a better understanding of molecular mechanisms may provide potential targets for the diagnosis and treatment of lymphatic metastasis in bladder cancer. Herein, we summarize the current knowledge of molecular mechanisms of the lymphatic metastasis in bladder cancer, including lymphangiogenesis and its regulators, noncoding RNAs, and microenvironment-associated molecules. Novel radiomics and genomics approaches have substantially improved the preoperative diagnostic accuracy of lymph node metastasis in patients with bladder cancer. Newly discovered targets may lead to promising therapeutic strategies for clinical intervention in lymphatic metastasis of bladder cancer. More basic and translational studies need to be conducted to further clarify the molecular mechanisms, and identify predictive markers and therapeutic targets of lymphatic metastasis for bladder cancer patients.
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http://dx.doi.org/10.1016/j.canlet.2021.02.010DOI Listing
May 2021

Development and validation of a PD-L1/PD-1/CD8 axis-based classifier to predict cancer survival of upper tract urothelial carcinoma after radical nephroureterectomy.

Cancer Immunol Immunother 2021 Sep 19;70(9):2657-2668. Epub 2021 Feb 19.

Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen (Zhongshan) University, Guangzhou, 510120, People's Republic of China.

The expression status of programmed cell death-ligand 1/programmed cell death 1 (PD-L1/PD-1) and the infiltration of CD8 T cells in tumor tissues are considered to be related to immunotherapy efficacy and patient prognosis. The purpose of this study is to clarify the prognostic value of the PD-L1/PD-1/CD8 axis, and to develop and validate a comprehensive scoring system based on multiple immune variables to predict cancer survival of upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). The immunohistochemical method was used to detect the expression of PD-L1, PD-1, and CD8 in cancer tissues of UTUC patients after RNU. Then, an immunoscore was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression model in the training cohort (n = 120), and it was verified in the validation cohort (n = 54). We found that infiltration of PD-L1 immune cells (ICs), stromal PD-1 tumor-infiltrating lymphocytes (TILs), and intratumoral CD8 TILs was associated with poor overall survival (OS). The immunoscore based on the three immune variables further divided the patients into low- and high-risk groups, and there was a significant difference in the survival rate. A nomogram was constructed by combining tumor-node-metastasis (TNM) stage and immunoscore, and the area under the curve of the receiver-operating characteristic (ROC) (0.78) for predicting 5-year mortality was better than that of the TNM stage (0.70) and immunoscore (0.76). Our results show that the PD-L1/PD-1/CD8 axis-based classifier have potential clinical application to predict cancer survival of UTUC patients after RNU.
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http://dx.doi.org/10.1007/s00262-020-02827-xDOI Listing
September 2021

Corrigendum to "Circular RNA circPICALM sponges miR-1265 to inhibit bladder cancer metastasis and influence FAK phosphorylation": [EBioMedicine 48 (2019) 316-331].

EBioMedicine 2021 Feb 30;64:103226. Epub 2021 Jan 30.

Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-sen Memorial Hospital, SunYat-sen University, Guangzhou, China. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2021.103226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851770PMC
February 2021

Long-Term Oncologic Outcomes After Laparoscopic and Robotic Tumor Enucleation for Renal Cell Carcinoma.

Front Oncol 2020 14;10:595457. Epub 2021 Jan 14.

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

Objectives: Tumor enucleation (TE) optimizes parenchymal preservation with promising short-term oncologic outcomes compared with standard partial nephrectomy (SPN). However, researches/literatures about long-term oncologic outcomes for TE after minimally invasive surgery are scarce. We aim to analyze long-term oncologic outcomes after laparoscopic and robotic tumor enucleation for renal cell carcinoma (RCC).

Patients And Methods: We retrospectively analyzed 146 patients who underwent TE with either laparoscopic or robotic approach for localized RCC in our center. Local recurrence, cancer specific survival (CSS), recurrence free survival (RFS), and overall survival (OS) were the main outcomes. Survival curves were generated using a Kaplan-Meier method. Perioperative outcomes and pathological outcomes were also analyzed.

Results: Overall, 98 male and 48 female patients were eligible for the study. The median tumor size was 3.4 cm with a median R.E.N.A.L. score of seven. Warm ischemia was used in 143 patients with a median ischemia time of 20 min and three patients had zero ischemia. Five patients (3.4%) had major complications (> Clavien IIIa) and only two were related to urinary system. The median global glomerular filtration rate (GFR) preserved after surgery was 93%. Pseudocapsule invasion was reported in 50 tumors (34%) and positive surgical margins were found in 3/146 (2.1%) tumors. At a median follow-up of 66 months, local recurrence happened in two patients (1.4%), and systemic recurrence happened in six patients (4.2%). The 5-year CSS, RFS, OS were 95.7, 89.6, and 91.9%, and the 10-year CSS, RFS, OS were 93.8, 89.6, and 90.0%, respectively.

Conclusion: This study indicates that tumor enucleation with laparoscopic or robotic approach in experienced hands for the treatment of RCC appears oncologically safe with a median follow-up of more than 5 years. Prospective studies with more patients and longer follow-up will be required to further evaluate oncologic safety after TE.
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http://dx.doi.org/10.3389/fonc.2020.595457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841649PMC
January 2021

Correction for: Circ-BPTF promotes bladder cancer progression and recurrence through the miR-31-5p/RAB27A axis.

Aging (Albany NY) 2021 01 28;13(2):3162-3164. Epub 2021 Jan 28.

Department of Urology, Sun Yat-Sen Memorial Hospital Sun Yat-Sen University, Guangzhou, PR, China.

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http://dx.doi.org/10.18632/aging.202597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880377PMC
January 2021

Prognostic role of stromal tumor-infiltrating lymphocytes in locally advanced upper tract urothelial carcinoma: A retrospective multicenter study (TSU-02 study).

Oncoimmunology 2021 01 4;10(1):1861737. Epub 2021 Jan 4.

Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing, China.

Locally advanced upper urinary tract urothelial carcinoma (UTUC) exhibits high recurrence and metastasis rates even after radical nephroureterectomy. Adjuvant immunotherapy can be a reasonable option, and a simple, low-cost, and effective biomarker is further needed. Stromal tumor-infiltrating lymphocytes (sTILs) has been demonstrated as a prognostic and predictive biomarker in various tumor types, but not yet in locally advanced UTUC. In this multicenter, real-world and retrospective study, we tried to investigate the prognostic role of sTIL and its correlation with the PD-L1/PD-1/CD8 axis by reviewing the clinicopathologic variables of 398 locally advanced UTUC patients at four high-volume Chinese medical centers. sTIL density was evaluated with standardized methodology on H&E sections, and patients were stratified by the cutoff of sTIL (50%). Results showed that high sTIL indicated improved survival (CSS, = .022; RFS, = .015; DFS, = .004), and was an independent predictor of better CSS (, 0.577; 95% CI, 0.391-0.851; = .006), RFS (, 0.613; 95% CI 0.406-0.925; = .020) and DFS (, 0.609; 95% CI, 0.447-0.829; = .002). A strongly positive correlation between sTIL density and the expression level of PD-1/PD-L1/CD8 axis was observed. We also found that aristolochic acid (AA) exposure was associated with increased sTIL and elevated PD-L1 expression, indicating that AA-related UTUC might be a distinct subgroup with unique tumor microenvironment characteristics. Our results show that sTIL can be an easily acquired biomarker for prognostic stratification in locally advanced UTUC.
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http://dx.doi.org/10.1080/2162402X.2020.1861737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801121PMC
January 2021

Corrigendum to "Polypyrimidine tract binding protein 1 promotes lymphatic metastasis and proliferation of bladder cancer via alternative splicing of MEIS2 and PKM." [Canc. Lett. 449 (2019) 31-44].

Cancer Lett 2021 Mar 31;500:292-293. Epub 2020 Dec 31.

Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. Electronic address:

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http://dx.doi.org/10.1016/j.canlet.2020.12.027DOI Listing
March 2021

Correction to: circRIP2 accelerates bladder cancer progression via miR-1305/Tgf-β2/smad3 pathway.

Mol Cancer 2021 Jan 2;20(1). Epub 2021 Jan 2.

The Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.

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http://dx.doi.org/10.1186/s12943-020-01284-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7777397PMC
January 2021

Correction to: Circular RNA circ-ZKSCAN1 inhibits bladder cancer progression through miR-1178-3p/p21 axis and acts as a prognostic factor of recurrence.

Mol Cancer 2020 Oct 12;19(1):148. Epub 2020 Oct 12.

Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107.W. Yanjiang Road, Guangzhou, Guangdong, 510120, People's Republic of China.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s12943-020-01265-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549201PMC
October 2020

Depression and prostate cancer risk: A Mendelian randomization study.

Cancer Med 2020 12 7;9(23):9160-9167. Epub 2020 Oct 7.

Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, P. R. China.

Background: The association between depression and prostate carcinogenesis has been reported in observational studies but the causality from depression on prostate cancer (PCa) remained unknown. We aimed to assess the causal effect of depression on PCa using the two-sample Mendelian randomization (MR) method.

Methods: Two sets of genetics instruments were used for analysis, derived from publicly available genetic summary data. One was 44 single-nucleotide polymorphisms (SNPs) robustly associated with major depressive disorder (MDD) and the other was two SNPs related with depressive status as ever depressed for a whole week. Inverse-variance weighted method, weighted median method, MR-Egger regression, MR Pleiotropy RESidual Sum, and Outlier test were used for MR analyses.

Results: No evidence for an effect of MDD on PCa risk was found in inverse-variance weighted (OR: 1.12, 95% CI: 0.97-1.30, p = 0.135), MR-Egger (OR 0.89, 95% CI: 0.29-2.68, p = 0.833), and weighted median (OR: 1.08, 95% CI: 0.92-1.27, p = 0.350). Also, no strong evidence for an effect of depressive status on PCa incidence was found using the inverse-variance weighted method (OR 0.72, 95% CI: 0.35-1.47, p = 0.364).

Conclusions: The large MR analysis indicated that depression may not be causally associated with a risk of PCa.
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http://dx.doi.org/10.1002/cam4.3493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724297PMC
December 2020

Macroscopic somatic clonal expansion in morphologically normal human urothelium.

Science 2020 10;370(6512):82-89

Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China.

Knowledge of somatic mutation accumulation in normal cells, which is essential for understanding cancer development and evolution, remains largely lacking. In this study, we investigated somatic clonal events in morphologically normal human urothelium (MNU; epithelium lining the bladder and ureter) and identified macroscopic clonal expansions. Aristolochic acid (AA), a natural herb-derived compound, was a major mutagenic driving factor in MNU. AA drastically accelerates mutation accumulation and enhances clonal expansion. Mutations in MNU were widely observed in chromatin remodeling genes such as and but rarely in , , and mutations were found to be common in urothelial cells, regardless of whether the cells experience exogenous mutagen exposure. Copy number alterations were rare and largely confined to small-scale regions, along with copy-neutral loss of heterozygosity. Single AA-associated clones in MNU expanded to a scale of several square centimeters in size.
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http://dx.doi.org/10.1126/science.aba7300DOI Listing
October 2020

NONO Inhibits Lymphatic Metastasis of Bladder Cancer via Alternative Splicing of SETMAR.

Mol Ther 2021 01 5;29(1):291-307. Epub 2020 Sep 5.

Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Department of Urology, The Affiliated Kashi Hospital, Sun Yat-sen University, Kashi, China. Electronic address:

Bladder cancer patients with lymph node (LN) metastasis have an extremely poor prognosis and no effective treatment. The alternative splicing of precursor (pre-)mRNA participates in the progression of various tumors. However, the precise mechanisms of splicing factors and cancer-related variants in LN metastasis of bladder cancer remain largely unknown. The present study identified a splicing factor, non-POU domain-containing octamer-binding protein (NONO), that was significantly downregulated in bladder cancer tissues and correlated with LN metastasis status, tumor stage, and prognosis. Functionally, NONO markedly inhibited bladder cancer cell migration and invasion in vitro and LN metastasis in vivo. Mechanistically, NONO regulated the exon skipping of SETMAR by binding to its motif, mainly through the RRM2 domain. NONO directly interacted with splicing factor proline/glutamine rich (SFPQ) to regulate the splicing of SETMAR, and it induced metastasis suppression of bladder cancer cells. SETMAR-L overexpression significantly reversed the metastasis of NONO-knockdown bladder cancer cells, both in vitro and in vivo. The further analysis revealed that NONO-mediated SETMAR-L can induce H3K27me3 at the promotor of metastatic oncogenes and inhibit their transcription, ultimately resulting in metastasis suppression. Therefore, the present findings uncover the molecular mechanism of lymphatic metastasis in bladder cancer, which may provide novel clinical markers and therapeutic strategies for LN-metastatic bladder cancer.
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http://dx.doi.org/10.1016/j.ymthe.2020.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791011PMC
January 2021

Serum CCL27 predicts the response to Bacillus Calmette-Guerin immunotherapy in non-muscle-invasive bladder cancer.

Oncoimmunology 2020 06 27;9(1):1776060. Epub 2020 Jun 27.

Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China.

The prediction of the response to Bacillus Calmette-Guerin (BCG) can help identify non-muscle-invasive bladder cancer (NMIBC) patients that may be better served with alternative therapy. Several cytokine profiles present promising results, but they are difficult to use in clinical practice. In this prospective, longitudinal study, we tried to identify reliable serum cytokines/chemokines to predict the response to BCG using samples collected before and during BCG induction therapy. We used the Bio-plex multiplex assays to identify potential BCG failure-related serum cytokines/chemokines in the discovery set (n = 13). After screening, we identified CCL27 as the top candidate biomarker for predicting the response to BCG ( = .003). In the validation set, we found that the AUC of the baseline CCL27 was 0.730 (95% CI 0.515-0.945, = .040) along with 67% sensitivity, 78% specificity. The changes from baseline to last timepoint can also distinguish BCG responders from non-responders (AUC: 0.726, 95% CI 0.474-0.979, = .044). Moreover, the combination score of serum CCL27 (CS), based on the baseline and changes of CCL27, could further improve the predictive accuracy with an AUC of 0.897 (95% CI 0.790-1.000, < .001). The correlations between CCL27 and local/systemic immunologic parameters were further analyzed. The level of serum CCL27 was strongly correlated with regulatory T cells (Tregs) in the tumor microenvironment ( = .002), indicating that CCL27 may promote the recruitment of Tregs into the tumor microenvironment. Our results show that serum CCL27 may represent a practical and reliable marker for the prediction of the response to BCG in NMIBC.
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http://dx.doi.org/10.1080/2162402X.2020.1776060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458591PMC
June 2020

Clinical Characteristics, Treatment Strategy, and Outcomes of Primary Large Cell Neuroendocrine Carcinoma of the Bladder: A Case Report and Systematic Review of the Literature.

Front Oncol 2020 28;10:1291. Epub 2020 Jul 28.

Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

The aim of this study was to review the clinicopathologic characteristics, treatments, and outcomes of patients with primary large cell neuroendocrine carcinoma of the bladder (LCNEC). We report one patient diagnosed with primary pure LCNEC of the bladder in Sun Yat-sen Memorial Hospital. In addition, we performed a systematic literature review, in April 2020, on case report and case series of LCNEC of the bladder. The clinicopathologic characteristics, treatments and outcomes of this rare disease were analyzed. A total of 39 patients were included in our analysis (1 case from our institution and 38 cases from the literature). Most patients (79.5%) were male. The average age at the surgery for the patients is 61.5 years (range 19-85 years). The most common symptom was hematuria ( = 20, 76.9%). Almost all patients (38, 97.4%) underwent surgery, with 26 (66.7%) receiving multimodality therapy. Out of 24 patients with available data, regional or distant recurrences developed in 14 patients (58.3%). The median overall survival of the patients was 11.5 months, with 1- and 3-year survival rates of 54.0 and 21.4%, respectively. In the survival analysis, theT1-2 tumors ( = 0.025), no distant metastases at diagnosis ( = 0.001), and multimodality therapy ( = 0.017) were associated with better overall survival (OS). LCNEC of the bladder is an extremely rare neoplasm. The available data suggest that the disease has an aggressive natural history with poor prognosis. Early pathologic stage and multimodality treatment may be important factors in determining prognosis.
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http://dx.doi.org/10.3389/fonc.2020.01291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399333PMC
July 2020

Urine DNA methylation assay enables early detection and recurrence monitoring for bladder cancer.

J Clin Invest 2020 12;130(12):6278-6289

Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China.

BACKGROUNDCurrent methods for the detection and surveillance of bladder cancer (BCa) are often invasive and/or possess suboptimal sensitivity and specificity, especially in early-stage, minimal, and residual tumors.METHODSWe developed an efficient method, termed utMeMA, for the detection of urine tumor DNA methylation at multiple genomic regions by MassARRAY. We identified the BCa-specific methylation markers by combined analyses of cohorts from Sun Yat-sen Memorial Hospital (SYSMH), The Cancer Genome Atlas (TCGA), and the Gene Expression Omnibus (GEO) database. The BCa diagnostic model was built in a retrospective cohort (n = 313) and validated in a multicenter, prospective cohort (n = 175). The performance of this diagnostic assay was analyzed and compared with urine cytology and FISH.RESULTSWe first discovered 26 significant methylation markers of BCa in combined analyses. We built and validated a 2-marker-based diagnostic model that discriminated among patients with BCa with high accuracy (86.7%), sensitivity (90.0%), and specificity (83.1%). Furthermore, the utMeMA-based assay achieved a great improvement in sensitivity over urine cytology and FISH, especially in the detection of early-stage (stage Ta and low-grade tumor, 64.5% vs. 11.8%, 15.8%), minimal (81.0% vs. 14.8%, 37.9%), residual (93.3% vs. 27.3%, 64.3%), and recurrent (89.5% vs. 31.4%, 52.8%) tumors. The urine diagnostic score from this assay was better associated with tumor malignancy and burden.CONCLUSIONUrine tumor DNA methylation assessment for early diagnosis, minimal, residual tumor detection and surveillance in BCa is a rapid, high-throughput, noninvasive, and promising approach, which may reduce the burden of cystoscopy and blind second surgery.FUNDINGThis study was supported by the National Key Research and Development Program of China and the National Natural Science Foundation of China.
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http://dx.doi.org/10.1172/JCI139597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685755PMC
December 2020

Correction to: Invasion-related circular RNA circFNDC3B inhibits bladder cancer progression through the miR-1178-3p/G3BP2/SRC/FAK axis.

Mol Cancer 2020 08 10;19(1):124. Epub 2020 Aug 10.

Department of Urology and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107th Yanjiangxi Road, Yuexiu District, Guangzhou, 510120, China.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s12943-020-01241-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416400PMC
August 2020

Survival after radical cystectomy for bladder cancer: Multicenter comparison between minimally invasive and open approaches.

Asian J Urol 2020 Jul 14;7(3):291-300. Epub 2020 Jun 14.

Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

Objective: To investigate oncological outcomes in patients with bladder cancer who underwent minimally invasive radical cystectomy (MIRC) or open radical cystectomy (ORC).

Methods: We identified patients with bladder cancer who underwent radical cystectomy (RC) in 13 centers of the Chinese Bladder Cancer Consortium (CBCC). Perioperative outcomes were compared between MIRC and ORC. The influence of surgical approaches on overall survival (OS) and cancer-specific survival (CSS) in the entire study group and subgroups classified according to pathologic stage or lymph node (LN) status was assessed with the log-rank test. Multivariable Cox proportional hazard models were used to evaluate the association among OS, CSS and risk factors of interest.

Results: Of 2 098 patients who underwent RC, 1 243 patients underwent MIRC (1 087 laparoscopic RC and 156 robotic-assisted RC, respectively), while 855 patients underwent ORC. No significant differences were noted in positive surgical margin rate and 90-day postoperative mortality rate. MIRC was associated with less estimated blood loss, more LN yield, higher rate of neobladder diversion, longer operative time, and longer length of hospital stay. There was no significant difference in OS and CSS according to surgical approaches (=0.653, and 0.816, respectively). Subgroup analysis revealed that OS and CSS were not significantly different regardless of the status of extravesical involvement or LN involvement. Multivariable Cox regression analyses showed that the surgical approach was not a significant predictor of OS and CSS.

Conclusions: Our study showed that MIRC was comparable to conventional ORC in terms of OS and CSS.
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http://dx.doi.org/10.1016/j.ajur.2020.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385523PMC
July 2020

Clinically Applicable AI System for Accurate Diagnosis, Quantitative Measurements, and Prognosis of COVID-19 Pneumonia Using Computed Tomography.

Cell 2020 06 4;181(6):1423-1433.e11. Epub 2020 May 4.

The First People's Hospital of Yunnan Province, Kunmin, China.

Many COVID-19 patients infected by SARS-CoV-2 virus develop pneumonia (called novel coronavirus pneumonia, NCP) and rapidly progress to respiratory failure. However, rapid diagnosis and identification of high-risk patients for early intervention are challenging. Using a large computed tomography (CT) database from 3,777 patients, we developed an AI system that can diagnose NCP and differentiate it from other common pneumonia and normal controls. The AI system can assist radiologists and physicians in performing a quick diagnosis especially when the health system is overloaded. Significantly, our AI system identified important clinical markers that correlated with the NCP lesion properties. Together with the clinical data, our AI system was able to provide accurate clinical prognosis that can aid clinicians to consider appropriate early clinical management and allocate resources appropriately. We have made this AI system available globally to assist the clinicians to combat COVID-19.
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http://dx.doi.org/10.1016/j.cell.2020.04.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196900PMC
June 2020
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