Author Correction: Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper. The original Letter has not been corrected.

Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance.

Treatments that target immune checkpoints, such as the one mediated by programmed cell death protein 1 (PD-1) and its ligand PD-L1, have been approved for treating human cancers with durable clinical benefit. However, many patients with cancer fail to respond to compounds that target the PD-1 and PD-L1 interaction, and the underlying mechanism(s) is not well understood. Recent studies revealed that response to PD-1-PD-L1 blockade might correlate with PD-L1 expression levels in tumour cells. Hence, it is important to understand the mechanistic pathways that control PD-L1 protein expression and stability, which can offer a molecular basis to improve the clinical response rate and efficacy of PD-1-PD-L1 blockade in patients with cancer. Here we show that PD-L1 protein abundance is regulated by cyclin D-CDK4 and the cullin 3-SPOP E3 ligase via proteasome-mediated degradation. Inhibition of CDK4 and CDK6 (hereafter CDK4/6) in vivo increases PD-L1 protein levels by impeding cyclin D-CDK4-mediated phosphorylation of speckle-type POZ protein (SPOP) and thereby promoting SPOP degradation by the anaphase-promoting complex activator FZR1. Loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to increased PD-L1 levels and reduced numbers of tumour-infiltrating lymphocytes in mouse tumours and in primary human prostate cancer specimens. Notably, combining CDK4/6 inhibitor treatment with anti-PD-1 immunotherapy enhances tumour regression and markedly improves overall survival rates in mouse tumour models. Our study uncovers a novel molecular mechanism for regulating PD-L1 protein stability by a cell cycle kinase and reveals the potential for using combination treatment with CDK4/6 inhibitors and PD-1-PD-L1 immune checkpoint blockade to enhance therapeutic efficacy for human cancers.

The combined effect of cohesion and finite size on the collapse of wet granular columns.

The collapse of low-saturation liquid-containing granular materials is prevalent in nature and industrial processes, and understanding the associated transient dynamics is extremely important for exploring such complex flow processes. In this paper, the collapse of a finite-size wet granular column is systematically studied and the determinants affecting its dynamics are analyzed based on the discrete element model for wet particles and the corresponding small-scale experiments. With the aid of parametric analysis, the dimensionless cohesion parameter containing the system size and grain-scale bond number is proposed, and its relevance in characterizing column stability and collapse dynamics of wet granular materials is further confirmed. For the collapse of wet granular columns with a fixed aspect ratio, the initial height contained in the cohesion parameter is verified to be a manifestation of the finite size effect, which is present in a wet granular collapse and is coupled with the cohesive effect. Such a coupling effect is taken into account in our proposed scaling laws that can be applied to uniformly describe the deposit morphology of wet granular columns after collapse.

Prognostic factors for the efficacy of infliximab in patients with luminal fistulizing Crohn's disease.

BACKGROUND: Enteric fistula is one of the penetrating features in Crohn's disease (CD). This study aimed to clarify the prognostic factors for the efficacy of infliximab (IFX) treatment in luminal fistulizing CD patients. METHODS: We retrospectively included 26 cases diagnosed with luminal fistulizing CD hospitalized in our medical center from 2013 to 2021. The primary outcome of our research was defined as death from all causes and undergoing of any relevant abdominal surgery. Kaplan-Meier survival curves were used to describe overall survival. Univariate and multivariate analyses were used to identify prognostic factors. A predictive model was constructed using Cox proportional hazard model. RESULTS: The median follow-up time was 17.5 months (range 6-124 months). The 1- and 2-year surgery-free survival rates were 68.1% and 63.2%, respectively. In the univariate analysis, the efficacy of IFX treatment at 6 months after initiation (P < 0.001, HR 0.23, 95% CI 0.01-0.72) and the existence of complex fistula (P = 0.047, HR 4.11, 95% CI 1.01-16.71) was found significantly related to the overall surgery-free survival, while disease activity at baseline (P = 0.099) also showed predictive potential. The multivariate analysis showed that efficacy at 6 months (P = 0.010) was an independent prognostic factor. The C-index of the model for surgery-free survival was 0.923 (P < 0.001), indicating an acceptable predictive effect. CONCLUSION: Prognostic model including the existence of complex fistula, disease activity at baseline and efficacy of IFX at 6 months may be useful to predict long-term outcome of luminal fistulizing CD patients.

Truncated ERG Oncoproteins from TMPRSS2-ERG Fusions Are Resistant to SPOP-Mediated Proteasome Degradation.

SPOP mutations and TMPRSS2-ERG rearrangements occur collectively in up to 65% of human prostate cancers. Although the two events are mutually exclusive, it is unclear whether they are functionally interrelated. Here, we demonstrate that SPOP, functioning as an E3 ubiquitin ligase substrate-binding protein, promotes ubiquitination and proteasome degradation of wild-type ERG by recognizing a degron motif at the N terminus of ERG. Prostate cancer-associated SPOP mutations abrogate the SPOP-mediated degradation function on the ERG oncoprotein. Conversely, the majority of TMPRSS2-ERG fusions encode N-terminal-truncated ERG proteins that are resistant to the SPOP-mediated degradation because of degron impairment. Our findings reveal degradation resistance as a previously uncharacterized mechanism that contributes to elevation of truncated ERG proteins in prostate cancer. They also suggest that overcoming ERG resistance to SPOP-mediated degradation represents a viable strategy for treatment of prostate cancers expressing either mutated SPOP or truncated ERG.

Impact of renin-angiotensin system inhibitors on outcomes after transcatheter aortic valve replacement: A meta-analysis.

OBJECTIVES: We aimed to evaluate the impact of renin-angiotensin system (RAS) inhibitors on outcomes after transcatheter aortic valve replacement (TAVR). BACKGROUND: The impact of RAS inhibitors on outcomes after TAVR was unclear. METHODS: A systematic review of articles comparing outcomes of patients using and not using RAS inhibitors after TAVR was performed through PubMed, Embase, and Cochrane. Primary outcome was midterm all-cause mortality. Risk ratios (RRs) were calculated with the corresponding 95% confidence interval using random effect models. RESULTS: Five studies with 23,319 patients were included. Patients treated with RAS inhibitors had lower midterm all-cause mortality after TAVR than those without RAS inhibitors in both the unmatched (13.3 vs. 17.2%, RR 0.77, p = .005) and propensity score matched cohorts (13.5 vs 16.2%, RR 0.83, p < .001). Cardiovascular mortality (10.4 vs. 15.6%, RR 0.68, p < .001), rate of heart failure readmission (12.2 vs. 14.5%, RR 0.80, p = .006), and new-onset atrial fibrillation (14.0 vs. 23.7%, RR 0.73, p = .003) were also lower with RAS inhibitors. No difference was found between two groups regarding cerebrovascular events, myocardial infarction, major bleeding, major vascular complications, acute kidney injury, permanent pacemaker implantation, and moderate/severe paravalvular aortic regurgitation. CONCLUSIONS: RAS inhibitors were associated with lower midterm all-cause mortality after TAVR.

Whole-body MRI-based multivariate prediction model in the assessment of bone metastasis in prostate cancer.

PURPOSE: A whole-body MRI (WB-MRI) including T1, short time inversion recovery (STIR), diffusion-weighted imaging (high b value) was applied in our center for the detection of bone metastasis in prostate cancer (PCa) patients. We intended to assess the diagnostic performance of this examination. METHODS: 547 cases of PCa patients with higher risk of metastasis were referred to bone scintigraphy with SPECT/CT (BS + SPECT/CT) and whole-body MRI in Shanghai Changhai Hospital. Best valuable comparator (BVC) was applied for the final diagnosis of metastasis. A panel of radiologists interpreted the results. Decision curve analysis (DCA) and receiver operating characteristic curve (ROC) analysis were applied. RESULTS: Bone metastasis was diagnosed in 110 cases, and others were non-metastatic by BVC. The area under the receiver operating characteristic curve (AUC) was higher in WB-MRI (0.778) than BS + SPECT/CT (0.634, p < 0.001). A WB-MRI-based prediction model was established with AUC of 0.877. Internal validation showed that the predictive model was well-calibrated. The DCA demonstrated that the model had higher net benefit than the BS + SPECT/CT-based model. CONCLUSION: WB-MRI is more effective in identifying metastasis in PCa patients than BS + SPECT/CT. The prediction model combined WB-MRI with clinical parameters may be a promising approach to the assessment of metastasis.

Comparing the prediction of prostate biopsy outcome using the Chinese Prostate Cancer Consortium (CPCC) Risk Calculator and the Asian adapted Rotterdam European Randomized Study of Screening for Prostate Cancer (ERSPC) Risk Calculator in Chinese and European men.

PURPOSE: To externally validate the clinical utility of Chinese Prostate Cancer Consortium Risk Calculator (CPCC-RC) and Asian adapted Rotterdam European Randomized Study of Screening for Prostate Cancer Risk Calculator 3 (A-ERSPC-RC3) for prediction prostate cancer (PCa) and high-grade prostate cancer (HGPCa, Gleason Score ≥ 3 + 4) in both Chinese and European populations. MATERIALS AND METHODS: The Chinese clinical cohort, the European population-based screening cohort, and the European clinical cohort included 2,508, 3,616 and 617 prostate biopsy-naive men, respectively. The area under the receiver operating characteristic curve (AUC), calibration plot and decision curve analyses were applied in the analysis. RESULTS: The CPCC-RC's predictive ability for any PCa (AUC 0.77, 95% CI 0.75-0.79) was lower than the A-ERSPC-RC3 (AUC 0.79, 95% CI 0.77-0.81) in the European screening cohort (p < 0.001), but similar for HGPCa (p = 0.24). The CPCC-RC showed lower predictive accuracy for any PCa (AUC 0.65, 95% CI 0.61-0.70), but acceptable predictive accuracy for HGPCa (AUC 0.73, 95% CI 0.69-0.77) in the European clinical cohort. The A-ERSPC-RC3 showed an AUC of 0.74 (95% CI 0.72-0.76) in predicting any PCa, and a similar AUC of 0.74 (95% CI 0.72-0.76) in predicting HGPCa in Chinese cohort. In the Chinese population, decision curve analysis revealed a higher net benefit for CPCC-RC than A-ERSPC-RC3, while in the European screening and clinical cohorts, the net benefit was higher for A-ERSPC-RC3. CONCLUSIONS: The A-ERSPC-RC3 accurately predict the prostate biopsy in a contemporary Chinese multi-center clinical cohort. The CPCC-RC can predict accurately in a population-based screening cohort, but not in the European clinical cohort.

The characteristics and risk factors of healthcare-seeking men with lower urinary tract symptoms in China: Initial report from the POInT group.

AIMS: To investigate the clinical characteristics of health care-seeking men presenting with lower urinary tract symptoms (LUTS) in China and to reveal risk factors for symptom severity. METHODS: This multicenter, hospital-based, cross-sectional study recruited 1477 eligible male subjects, who were at least 45 years, seeking health care at 9 participating hospitals across the mainland China. The general medical information and subjective symptoms were recorded, followed by the measurement of prostate volume, urodynamic indices, and laboratory tests for kidney function, plus glucose/lipid metabolism. Univariate and multivariate linear regression were employed for the detection of risk factors for symptom severity. RESULTS: The proportion of mild, moderate, and severe LUTS was 14.6%, 32.6%, and 52.8%, respectively, with 62.2% reporting the triple combination of storage, voiding, and postmicturition symptoms. Median prostate volume was 44.6 ml, and 71.1% were experiencing comorbidities. Thirteen independent risk factors for LUTS severity were identified, namely, nocturnal voiding episodes and the presence of straining and weak steam; the triple combination of symptom subtypes; general and nocturia quality of life; Qmax and bladder outlet obstruction index; and numbers of comorbidities, hypertension, estimated glomerular filtration rate, and cholesterol and glycosylated hemoglobin. CONCLUSIONS: The majority of health care-seeking LUTS men present with moderate-to-severe and overlapping symptoms, with a high prevalence of both lower urinary tract dysfunction and systemic comorbidities. The evidence from both urological and nonurological independent risk factors demonstrate the multifactorial nature of LUTS, for which a multidisciplinary management is essential.

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.

A Novel Prediction Tool Based on Multiparametric Magnetic Resonance Imaging to Determine the Biopsy Strategy for Clinically Significant Prostate Cancer in Patients with PSA Levels Less than 50 ng/ml.

PURPOSE: To develop and internally validate nomograms to help choose the optimal biopsy strategy among no biopsy, targeted biopsy (TB) only, or TB plus systematic biopsy (SB). PATIENTS AND METHODS: This retrospective study included a total of 385 patients who underwent magnetic resonance imaging (MRI)-guided TB and/or SB at our institute after undergoing multiparametric MRI (mpMRI) between 2015 and 2018. We developed models to predict clinically significant prostate cancer (csPCa) based on suspicious lesions from a TB result and based on the whole prostate gland from the results of TB plus SB or SB only. Nomograms were generated using logistic regression and evaluated using receiver-operating characteristic (ROC) curve analysis, calibration curves and decision analysis. The results were validated using ROC curve and calibration on 177 patients from 2018 to 2019 at the same institute. RESULTS: In the multivariate analyses, prostate-specific antigen level, prostate volume, and the Prostate Imaging Reporting and Data System score were predictors of csPCa in both nomograms. Age was also included in the model for suspicious lesions, while obesity was included in the model for the whole gland. The area under the curve (AUC) in the ROC analyses of the prediction models was 0.755 for suspicious lesions and 0.887 for the whole gland. Both models performed well in the calibration and decision analyses. In the validation cohort, the ROC curve described the AUCs of 0.723 and 0.917 for the nomogram of suspicious lesions and nomogram of the whole gland, respectively. Also, the calibration curve detected low error rates for both models. CONCLUSION: Nomograms with excellent discriminative ability were developed and validated. These nomograms can be used to select the optimal biopsy strategy for individual patients in the future.

Risk factors for sepsis in patients with struvite stones following percutaneous nephrolithotomy.

PURPOSE: To describe the clinical characteristics of struvite stones and determine the preoperative predictors of sepsis in struvite patients undergoing percutaneous nephrolithotomy (PCNL). METHODS: A retrospective study of patients who underwent PCNL between April 2011 and March 2018 was performed. The data of the struvite stones and non-struvite stones groups were compared following propensity score matching. Subsequently, the struvite stones group was sub-divided for further analysis according to the Sepsis-3 definition: non-sepsis and sepsis groups. RESULTS: After matching based on age, gender, BMI, and number of access tracts, the comparative analysis showed that staghorn calculi and higher Guy's stone score were more frequently observed in non-struvite stone patients (n = 97), while a history of urolithiasis surgery (56.70%), preoperative broad-spectrum antibiotic therapy (53.61%), positive preoperative urine culture (55.67%), and sepsis (35.05%) after surgery were more common in patients (n = 97) with struvite stones (all P values < 0.05). Eighteen (18.56%) patients presented with multidrug-resistant (MDR) bacteriuria. Multivariate analysis demonstrated that the preoperative presence of MDR bacteriuria (OR = 3.203; P = 0.043) and increased serum creatinine (OR = 3.963; P = 0.010) were independent risk predictors of sepsis. The two factors were used to construct a nomogram to predict the probability of sepsis. The nomogram was well calibrated and had moderate discriminative ability (concordance index: 0.711). CONCLUSION: Our study revealed that patients with struvite stones were associated with a significantly high risk of calculi recurrence and sepsis after surgery. The presence of MDR bacteriuria preoperatively was a reliable factor to predict sepsis.

Replicate systematic review and meta-analyses on robotic surgery: a quality appraisal and overlap investigation.

BACKGROUND: The number of publications of systematic reviews and meta-analyses (MAs) on robotic surgery have been increasing, including many investigating the same topic. Their quality and extent of overlap remains unclear. We assessed the quality of the MAs in this area and investigated the extent of their overlap. METHODS: Relevant studies were identified by searching the MEDLINE, EMBASE, and Cochrane Library databases up to August 1, 2017. Reporting and methodological quality levels were assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Assessment of Multiple Systematic Reviews (AMSTAR) checklists. A thorough investigation of the extent of overlap was performed. RESULTS: In total, 90 MAs in 5 surgical subspecialties were included after full-text review. The mean reporting and methodological quality scores were 22.5 (83.2%) and 7.6 (69.2%), respectively. Authors from university-affiliated institutions and the presence of statistician or epidemiologist coauthors were associated with better-reporting quality scores. The topics with the most overlapping MAs (all ≥ 6) were robot-assisted thyroidectomy, prostatectomy, gastrectomy, colectomy, and fundoplication. 36 (40%) of the included MAs cited previous MAs on the same topic. Among the 7 MAs comparing robot-assisted radical prostatectomy to the open procedure, most (6/7) drew the same conclusion. 50 to 86% of MAs on this topic included the same trials as primary studies. CONCLUSION: Conducting multiple overlapping MAs with identical conclusions on the same topic that are of suboptimal quality may be a waste of resource and effort. Authors from university-affiliated institutes and experts in epidemiology and statistics are more likely to conduct MAs that have better quality. More guidelines and registries are needed to avoid overlapping MAs.

Robotic Perineal Radical Prostatectomy: Initial Experience with the da Vinci Si Robotic System.

PURPOSE: To investigate the feasibility and surgical technique of robotic perineal radical prostatectomy (RPRP). MATERIALS AND METHODS: We retrospectively analyzed 6 consecutive patients diagnosed with prostate cancer from December 2018 to May 2019 who underwent RPRP at our center. Perioperative outcomes were recorded for safety and feasibility analysis. RESULTS: Six patients successfully underwent RPRP with no conversion to open procedures. Operative time was 140 (interquartile range [IQR] 123.75-148.75) min, console time was 70 (IQR 62.5-70) min, with an estimated blood loss of 125 (IQR 100-187.5) mL. Patients were discharged 2 days postoperatively (IQR range 1-3) with pelvic drainages removed. The Foley catheter was removed 2 weeks after surgery. Postoperative pathology revealed 5 patients with locally advanced disease (apical margin-positive prostate cancer [pT3a]bNx). Two patients had a positive surgical margin (33.3%). No complications of Clavien grade 3 and above were recorded; 1 patient had a delay in wound-healing of 1 week. Postoperative continence was achieved for 2 patients immediately after Foley catheter removal, 2 recovered 1-month postoperatively, and 1 recovered within 3 months, and 1 still had mild incontinence at the latest follow-up 1-month postoperatively. CONCLUSION: RPRP is a safe and feasible alternative for the transperitoneal route in selected patients. Further investigation is required to assess its oncological and quality-of-life results.

Outcomes of Evolut R Versus CoreValve After Transcatheter Aortic Valve Implantation: A Meta-Analysis.

BACKGROUND: Superiority of the new-generation, self-expanding Evolut R compared with the first-generation CoreValve on outcomes after transcatheter aortic valve implantation (TAVI) is unclear. This meta-analysis sought to investigate the outcomes of Evolut R vs CoreValve after TAVI. METHODS: A systematic review of studies comparing outcomes of Evolut R and CoreValve after TAVI was performed through PubMed, EMBASE and Cochrane Library. Crude risk ratios (RRs) were calculated with 95% confidence intervals using a random effects model. Outcomes of interest were mortality, myocardial infarction (MI), stroke or transient ischaemic attack (TIA), severe bleeding, acute kidney injury (AKI), major vascular complications (MVC), permanent pacemaker implantation (PPI), moderate or severe paravalvular regurgitation (PVR), and device failure. RESULTS: Six studies involving 11,530 patients (4,597 receiving Evolut R and 6,933 receiving CoreValve) were included. There was no significant difference in 30-day all-cause mortality between Evolut R and CoreValve (3.4% vs 5.0%, p = 0.10). The incidence of MI (0.2% vs 0.5%, p = 0.02), AKI (6.0% vs 9.2%, p = 0.001), moderate or severe PVR (6.4% vs 8.0%, p = 0.04), and device failure (3.5% vs 5.2%, p = 0.04) were significantly lower in Evolut R than CoreValve. There were trends toward less severe bleeding (7.2% vs 8.8%, p = 0.05) and PPI (18.6% vs 20.8%, p = 0.05) in Evolut R. The rates of stroke or TIA and MVC were similar between the two prostheses. CONCLUSIONS: Compared with CoreValve, Evolut R did not reduce 30-day all-cause mortality, but significantly improved periprocedural complications after TAVI.

Investigation of adolescents' developmental stages in deductive reasoning: An application of a specialized confirmatory mixture IRT approach.

In this paper, we propose a specialized confirmatory mixture IRT model to analyze complex cognitive assessment data that is designed to evaluate adolescents' developmental stages in deductive reasoning. The model is specified for the following purposes: (1) to measure multiple deductive reasoning traits, (2) to identify adolescents' differential developmental stages based on their ability levels in the multiple dimensions, (3) to quantify the differences in dimension-specific performance between developmental stages, and (4) to examine the difficulty levels of test design factors. A Bayesian estimation of the model is described. The overall goodness-of-fit of the model is assessed as well as its parameter recovery to validate the application of the model to the data.

Prognostic value of differentially methylated gene profiles in bladder cancer.

DNA methylation can regulate gene expression and is pivotal in the occurrence and development of bladder cancer. In this study, we analyzed whole-genome DNA methylation on the basis of data from The Cancer Genome Atlas to select epigenetic biomarkers predictive of survival and further understand the molecular mechanisms underlying methylation patterns in bladder cancer. We identified 540 differentially methylated genes between tumor and normal tissues, including a number of independent prognostic factors based on univariate analysis. Genes (MIR6732, SOWAHC, SERPINI1, OR10W1, OR7G3, AIM1, and ZFAND5) were integrated to establish a risk model for prognostic assessment based on multivariate Cox analysis. The methylation of SOWAHC was negatively correlated with its messenger RNA expression, and together these were significantly correlated with prognosis. This study took advantage of high-throughput data mining to provide new bioinformatics evidence and ideas for further study into the pathogenesis and prognosis of bladder cancer.

Prostate Cancer-associated SPOP mutations enhance cancer cell survival and docetaxel resistance by upregulating Caprin1-dependent stress granule assembly.

BACKGROUND: The gene encoding the E3 ubiquitin ligase substrate-binding adaptor SPOP is frequently mutated in primary prostate cancer, but how SPOP mutations contribute to prostate cancer pathogenesis remains poorly understood. Stress granules (SG) assembly is an evolutionarily conserved strategy for survival of cells under stress, and often upregulated in human cancers. We investigated the role of SPOP mutations in aberrant activation of the SG in prostate cancer and explored the relevanve of the mechanism in therapy resistance. METHODS: We identified SG nucleating protein Caprin1 as a SPOP interactor by using the yeast two hybrid methods. A series of functional analyses in cell lines, patient samples, and xenograft models were performed to investigate the biological significance and clinical relevance of SPOP regulation of SG signaling in prostate cancer. RESULTS: The cytoplasmic form of wild-type (WT) SPOP recognizes and triggers ubiquitin-dependent degradation of Caprin1. Caprin1 abundance is elevated in SPOP-mutant expressing prostate cancer cell lines and patient specimens. SPOP WT suppresses SG assembly, while the prostate cancer-associated mutants enhance SG assembly in a Caprin1-dependent manner. Knockout of SPOP or expression of prostate cancer-associated SPOP mutants conferred resistance to death caused by SG inducers (e.g. docetaxel, sodium arsenite and H2O2) in prostate cancer cells. CONCLUSIONS: SG assembly is aberrantly elevated in SPOP-mutated prostate cancer. SPOP mutations cause resistance to cellular stress induced by chemtherapeutic drug such as docetaxel in prostate cancer.

Clinical Benefit of Sorafenib Combined with Paclitaxel and Carboplatin to a Patient with Metastatic Chemotherapy-Refractory Testicular Tumors.

Testicular cancer is one of the few tumor types that have not yet benefited from targeted therapy. Still no new active agents for treating this cancer have been identified over the past 15 years. Once patients are refractory to cisplatin-based chemotherapy, they will be expected to die from testicular cancer. This report describes a 21-year-old man who was refractory to chemotherapy and immunotherapy. Whole exome sequencing and low-depth whole genome sequencing confirmed the KRAS gene amplification, which may lead to the tumor cells' progression and proliferation. After discussion at the molecular tumor board, the patient was offered paclitaxel, carboplatin, and sorafenib (CPS) based on a phase III clinical trial of melanoma with KRAS gene copy gains. After treatment with CPS, the patient achieved excellent curative effects. Because of a nearly 50% frequency of KRAS amplification in chemotherapy-refractory testicular germ cells, CPS regimen may provide a new therapy, but it still warrants further validation in clinical studies. KEY POINTS: Chemotherapy-refractory testicular cancer has a very poor prognosis resulting in a lack of effective targeted therapies. KRAS gene amplification occurs in nearly 20% of testicular cancer and 50% of chemotherapy-refractory testicular cancer. KRAS amplification may activate the MAPK signaling pathway, and inhibition of MAPK by sorafenib combined with paclitaxel and carboplatin could be a viable option based on a phase III clinical trial of melanoma.To the authors' knowledge, this is the first report of response to sorafenib-based combination targeted therapy in a patient with chemotherapy-refractory testicular cancer.Clinical genomic profiling can confirm copy number variation of testicular cancer and provide insights on therapeutic options.