CT features based preoperative predictors of aggressive pathology for clinical T1 solid renal cell carcinoma and the development of nomogram model.

BACKGROUND: We aimed to identify preoperative predictors of aggressive pathology for cT1 solid renal cell carcinoma (RCC) by combining clinical features with qualitative and quantitative CT parameters, and developed a nomogram model. METHODS: We conducted a retrospective study of 776 cT1 solid RCC patients treated with partial nephrectomy (PN) or radical nephrectomy (RN) between 2018 and 2022. All patients underwent four-phase contrast-enhanced CT scans and the CT parameters were obtained by two experienced radiologists using region of interest (ROI). Aggressive pathology was defined as patients with nuclear grade III-IV; upstage to pT3a; type II papillary renal cell carcinoma (pRCC), collecting duct or renal medullary carcinoma, unclassified RCC or sarcomatoid/rhabdoid features. Univariate and multivariate logistic analyses were used to determine significant predictors and develop the nomogram model. To evaluate the accuracy and clinical utility of the nomogram model, we used the receiver operating characteristic (ROC) curve, calibration plot, decision curve analysis (DCA), risk stratification, and subgroup analysis. RESULTS: Of the 776 cT1 solid RCC patients, 250 (32.2%) had aggressive pathological features. The interclass correlation coefficient (ICC) of CT parameters accessed by two reviewers ranged from 0.758 to 0.982. Logistic regression analyses showed that neutrophil-to-lymphocyte ratio (NLR), distance to the collecting system, CT necrosis, tumor margin irregularity, peritumoral neovascularity, and RER-NP were independent predictive factors associated with aggressive pathology. We built the nomogram model using these significant variables, which had an area under the curve (AUC) of 0.854 in the ROC curve. CONCLUSIONS: Our research demonstrated that preoperative four-phase contrast-enhanced CT was critical for predicting aggressive pathology in cT1 solid RCC, and the constructed nomogram was useful in guiding patient treatment and postoperative follow-up.

Tumor margin irregularity degree is an important preoperative predictor of adverse pathology for clinical T1/2 renal cell carcinoma and the construction of predictive model.

PURPOSE: To explore the critical role of the tumor margin irregularity degree (TMID) of renal tumors in predicting adverse pathology of patients with clinical T1/2 (cT1/2) renal cell carcinoma (RCC). METHODS: A total of 821 patients with cT1/2 RCC undergoing nephrectomy in the Second Hospital of Tianjin Medical University between January 2017 and December 2020 were reviewed. The tumor margin irregularity (TMI) was classified into renal mass with locally raised protrusion and smooth margin called 'lobular', sharply and unsmooth nodular margin called 'spiculation', blurred margins between tumor and renal parenchyma or a completely irregular and non-elliptical shape. The ratio between the number of irregular cross-sections (X) and the number of total cross-sections from top to bottom occupied (Y) was defined as TMID (X/Y). The logistic regression was performed to determine the independent predictors of adverse pathology, and the Kaplan-Meier curve and log-rank test were used to analyze the survival outcomes. RESULTS: Among 821 cT1/2 RCC patients, 245 (29.8%) had adverse pathology. The results of the univariate and multivariate logistic regressions showed that the age, tumor size, hemoglobin, and TMID were the independent predictors of adverse pathology. Incorporation of TMID could increase the discrimination of the predictive model with the area under curve (AUC) of ROC curves increasing from 0.725 to 0.808. Patients with adverse pathology or higher TMID both had significantly shorter recurrence-free survival (RFS). CONCLUSION: The nomogram model incorporated with TMID for predicting adverse pathology could increase its discrimination, calibration, and clinical application values, compared with the models without TMID.

Analysis of Variable Frequency Stimulation Sacral Neuromodulation for Different Genders: A Chinese Multicentric Prospective Clinical Study.

AIM: Sacral neuromodulation (SNM) is widely recognized as the essential treatment modality for patients suffering from various lower urinary tract disorders, particularly overactive bladder (OAB). This prospective study recruited patients who underwent variable frequency SNM treatment at six Chinese medical centers, aiming to evaluate the gender-specific effects of this intervention and provide precise guidance on its application for clinical management. METHODS: This prospective study was managed by Beijing Hospital, and six Chinese medical centers participated in this prospective research. Inclusion and exclusion criteria were established to screen patients based on the indication for SNM. During the research, all patients were required to record 72-h voiding diaries, urgency scores, and visual analogue scale (VAS) scores to reflect their disease symptoms. Additionally, subjective questionnaire surveys such as OAB symptom score (OABSS) and quality-of-life (Qol) score were recorded to reflect the patients' quality of life and treatment satisfaction. RESULTS: In this study, 52 patients (male patients: 25; female patients: 27) with OAB symptoms agreed to undergo variable frequency stimulation SNM therapy and finally convert to Stage II. Regarding the baseline outcomes, no significant differences were observed between the male and female groups. In terms of postoperative indicators, male patients showed a greater improvement in Qol scores compared to their female counterparts (20.06 ± 13.12 vs. 40.83 ± 26.06, p = 0.005). The results from VAS scores indicated that pain remission was more pronounced in male patients than in female patients (0.31 ± 0.87 vs. 1.67 ± 2.16, p = 0.02). Importantly, there was a statistically significant disparity in urinary urgency between males and females (male patients: 1.19 ± 1.56; female patients: 2.17 ± 1.52, p = 0.04). CONCLUSIONS: In our study, we found that variable frequency SNM treatment yielded sex-specific differences in therapeutic effects, with male patients having a better outcome in some metrics. This suggests that a patient's sex may influence when variable frequency SNM is used, and in the patient's follow-up. TRIAL REGISTRATION: ClinicalTrials.gov identifier: ChiCTR2000036677.

Development and validation of a nomogram to predict recurrence for clinical T1/2 clear cell renal cell carcinoma patients after nephrectomy.

OBJECTIVE: To develop and validate a nomogram for predicting recurrence-free survival (RFS) for clinical T1/2 (cT1/2) clear cell renal cell carcinoma (ccRCC) patients after nephrectomy. METHODS: Clinicopathological and survival data from 1289 cT1/2 ccRCC patients treated at the Second Hospital of Tianjin Medical University between 2017 and 2020 were included. Cox regression analysis was used to identify independent risk factors in 902 and 387 ccRCC patients in the training and validation cohorts, respectively, and construct the nomogram. The performance of the nomogram was assessed through calibration plots, time-dependent receiver operating characteristic (ROC) curves, C-index (concordance-index), and decision curve analysis (DCA). Kaplan-Meier curves were used to evaluate the probability of RFS in patients with different recurrence risks. RESULTS: Age, tumor size, surgical approach, Fuhrman grade, and pT3a upstage were identified as independent predictors of RFS. The area under the curve (AUC) for the 3-year and 5-year RFS ROC curves were 0.791 and 0.835 in the training cohort, and 0.860 and 0.880 in the validation cohort. The DCA and calibration plots demonstrated the optimal application and excellent accuracy of the nomogram for predicting 3-year and 5-year RFS. Kaplan-Meier curves revealed significant differences in RFS among the three risk groups in both the training and validation cohorts. Clinically, the developed nomogram provides a more precise tool for risk stratification, enabling tailored postoperative management and surveillance strategies, ultimately aiming to improve patient outcomes. CONCLUSIONS: We developed a nomogram for predicting RFS in cT1/2 ccRCC patients after nephrectomy with high accuracy. The clinical implementation of this nomogram can significantly enhance clinical decision-making, leading to improved patient outcomes and optimized resource utilization in the management of ccRCC.

Letter to the Editor: clinical utility of urine DNA for noninvasive detection and minimal residual disease monitoring in urothelial carcinoma.

Current methods for the early detection and minimal residual disease (MRD) monitoring of urothelial carcinoma (UC) are invasive and/or possess suboptimal sensitivity. We developed an efficient workflow named urine tumor DNA multidimensional bioinformatic predictor (utLIFE). Using UC-specific mutations and large copy number variations, the utLIFE-UC model was developed on a bladder cancer cohort (n = 150) and validated in The Cancer Genome Atlas (TCGA) bladder cancer cohort (n = 674) and an upper tract urothelial carcinoma (UTUC) cohort (n = 22). The utLIFE-UC model could discriminate 92.8% of UCs with 96.0% specificity and was robustly validated in the BLCA_TCGA and UTUC cohorts. Furthermore, compared to cytology, utLIFE-UC improved the sensitivity of bladder cancer detection (p < 0.01). In the MRD cohort, utLIFE-UC could distinguish 100% of patients with residual disease, showing superior sensitivity compared to cytology (p < 0.01) and fluorescence in situ hybridization (FISH, p < 0.05). This study shows that utLIFE-UC can be used to detect UC with high sensitivity and specificity in patients with early-stage cancer or MRD. The utLIFE-UC is a cost-effective, rapid, high-throughput, noninvasive, and promising approach that may reduce the burden of cystoscopy and blind surgery.

TEAD3 inhibits the proliferation and metastasis of prostate cancer via suppressing ADRBK2.

TEAD3 acts as a transcription factor in many tumors to promote tumor occurrence and development. But in prostate cancer (PCa), it appears as a tumor suppressor gene. Recent studies have shown that this may be related to subcellular localization and posttranslational modification. We found that TEAD3 was down-expressed in PCa. Immunohistochemistry of clinical PCa specimens confirmed that TEAD3 expression was the highest in benign prostatic hyperplasia (BPH) tissues, followed by primary PCa tissues, and the lowest in metastatic PCa tissues, and its expression level was positively correlated with overall survival. MTT assay, clone formation assay, and scratch assay confirmed that overexpression of TEAD3 could significantly inhibit the proliferation and migration of PCa cells. Next-generation sequencing results indicated that Hedgehog (Hh) signaling pathway was significantly inhibited after overexpression of TEAD3. Rescue assays suggested that ADRBK2 could reverse the proliferation and migration ability caused by overexpression of TEAD3. TEAD3 is downregulated in PCa and associated with poor patient prognosis. Overexpression of TEAD3 inhibits the proliferation and migration ability of PCa cells via restraining the mRNA level of ADRBK2. These results indicate that TEAD3 was down-expressed in PCa patients and was positively correlated with a high Gleason score and poor prognosis. Mechanistically, we found that the upregulation of TEAD3 inhibits the proliferation and metastasis of prostate cancer by inhibiting the expression of ADRBK2.

Adenoviral Vector for Enhanced Prostate Cancer Specific Transferrin Conjugated Drug Targeted Therapy.

Prostate cancer (PCa) is one of the leading causes of death for men worldwide. Unlike some other types of cancer, there is a lack of targeted therapy for prostate cancer patients that can kill cancer cells but do much less damage to the normal tissue. In this paper, we report on an adenoviral vector enhanced prostate cancer specific transferrin conjugated drug targeted therapy. In particular, a functional PCa-specific gene probe is introduced to drive and up-regulate the transferrin receptor expression on the PCa via adenoviral vector. As a result, significantly enhanced accumulation of nanoscale transferrin-doxorubicin (Tf-DOX) protein drug conjugates and concomitant notably elevated PCa tumor inhibition are observed. This conceptual strategy provides the proof-of-concept for the targeted therapy of PCa that is highly desired but not yet developed.

DNA-repair status should be assessed in treatment-emergent neuroendocrine prostate cancer before platinum-based therapy.

OBJECTIVES: This study sought to provide contemporary data from a multi-institution with respect to DNA-repair genes (DRGs) status and its impact on effects of platinum-based chemotherapy in treatment-emergent neuroendocrine prostate cancer (t-NEPC), for which little data exist. PATIENTS AND METHODS: All patients were retrospectively collected with eligible biopsied tissues for targeted next generation sequencing (NGS). The main outcomes were radiologic progression-free survival and overall survival according to Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Among the 43 NEPC patients, 13/43 (30%) harbored homozygous deletions, deleterious mutations, or both in DRGs. Eleven patients (11/13, 85%) with DRGs aberrations had effective response, including 7 patients with BRCA1/2 defects and 2 with mismatch repair-deficient caused by MSH2 alterations. While significantly fewer responders (30%) were detected in patients without DRGs aberrations (odds ratio = 12.83, p = 0.003). Compared with patients without genomic DRGs aberrations, the hazard ratio (HR) for radiologic progression in those with DRGs defects was 0.42 (95% confidence interval [CI]: 0.19-0.93), and the HR for death was 0.65 (95% CI: 0.24-1.72). The most common adverse event of Grade 3 or 4 was anemia, as noted in 7 patients (16%). CONCLUSION: The DRGs status is therapeutically meaningful in t-NEPC. Given the potential responses to platinum-based chemotherapy, our findings support the clinical use of NGS in t-NEPC patients to identify DRGs aberrations.

Prognostic implication and immunotherapy response prediction of a costimulatory molecule signature in kidney renal clear cell carcinoma.

Costimulatory molecules were considered to be promising and important targets in immunotherapy for various cancers. The present study was intended for generating a costimulatory molecule signature in kidney renal clear cell carcinoma (KIRC), to investigate prognostic implication, elucidate immune atlas, and predict immunotherapy response. All the KIRC samples from the TCGA were randomly divided into the training dataset and the testing dataset in the ratio of 7:3. The Cox and least absolute shrinkage and selection operator (LASSO) regression analysis were used to identify 7 key costimulatory molecules which were associated with prognosis and construct a costimulatory molecule prognostic index (CMsPI), which was validated by internal and external datasets and an independent cohort. Patients in the high-CMsPI group had high mortality. Mutation analysis showed the most common mutational genes and variant types. Immune analysis demonstrated CD8+ T cells were infiltrated at a high level in the high-CMsPI group. In combination of analysis of the immune relevant gene signature and the biomarkers of immunotherapy, we may infer there were more dysfunctional CD8+ T cells in the high-CMsPI group, and the patients of this group were less sensitive to immunotherapy. A nomogram was constructed, and the concordance index was 0.77 (95% CI: 0.74-0.79). Three key signaling pathways were identified to facilitate tumor progression. The CMsPI can be regarded as a promising biomarker for predicting individual prognosis and assessing immunotherapy response in KIRC patients.

Identification of LAT/ZAP70 characterized immune subtypes of prostate cancer.

BACKGROUND: While immunotherapy has shown potent efficacy in clinical practices, patient selection to receive checkpoint blockade is still challenging in prostate cancer (PCa). LAT and ZAP70 functions in lymphocyte activation and plays a critical role in T cell receptor (TCR) signal transduction. However, PCa genomic and clinical data regarding the role of LAT and ZAP70 are limited. We aim to identify and characterize LAT/ZAP70 defined subtypes of PCa. METHODS: We elaborated the TCGA PCa data and metastatic castration-resistant prostate cancer (mCRPC) RNA-seq data bioinformatic analysis and systematically elucidated the role of intra-tumoral expressed LAT and ZAP70 in the progression-free survival and immunotherapeutic-related signals. LAT/ZAP70-associated immune infiltration was evaluated using bioinformatic tools. Immunohistochemical staining of serial sections was used to confirm the expression and distribution of LAT, ZAP70 and androgen receptor (AR) in PCa tissues. RESULTS: Specifically, LAT and ZAP70 revealed increased expressions in PCa when compared to normal tissues and positively associated with intra-tumoral immune cells infiltration. LAT/ZAP70 defined immune-high early-stage PCa revealed higher TP53 mutation frequency and poor prognosis. Transcriptome analysis indicated immune-related signals and CTLA4 expression were highly enhanced in immune-high PCa parallel with higher protein level of MYC and lower AR expression. In mCRPC, LAT/ZAP70 defined immune-high patients also revealed upregulated immune related signals, higher CTLA4 expression and DNA repair deficiency. CONCLUSION: LAT/ZAP70 defined immune-high PCa linked to immune infiltration and predicts poor prognosis. Immune-high PCa may receive effective response from immune checkpoint inhibitor parallel with systemic treatment.

C1QBP regulates apoptosis of renal cell carcinoma via modulating xanthine dehydrogenase (XDH) mediated ROS generation.

Background: Complement component 1 Q subcomponent binding protein (C1QBP) plays a vital role in the progression and metabolism of cancer. Studies have shown that xanthine dehydrogenase (XDH)-derived reactive oxygen species (ROS) accelerates tumor growth, and also induces mutations or produces cytotoxic effects concurrently. However, the role of C1QBP in metabolism, oxidative stress, and apoptosis of renal cell carcinoma (RCC) cells have not yet been explored. Methods: Metabolomics assay was applied to investigate the role of C1QBP in RCC metabolism. C1QBP knockdown and overexpression cells were established via lentiviral infection and subjected to apoptosis and ROS assay in vitro. RNA stability assay was applied to characterize the mechanism of C1QBP regulating XDH transcription. In vivo, orthotopic tumor xenografts assay was performed to investigate the role of C1QBP in RCC progression. Results: Metabolomics investigation revealed that C1QBP dramatically diminished the hypoxanthine content in RCC cells. C1QBP promoted the mRNA and protein expression of hypoxanthine catabolic enzyme XDH. Meanwhile, C1QBP may affect XDH transcription by regulating the mRNA level of XDH transcriptional stimulators IL-6, TNF-α, and IFN-γ. Moreover, the expression of C1QBP and XDH was lower in RCC tumors compared with the tumor-associated normal tissues, and their down-regulation was associated with higher Fuhrman grade. C1QBP significantly increased ROS level, apoptosis, and the expression of apoptotic proteins such as cleaved caspase-3 and bax/bcl2 via regulating XDH. Conclusion: C1QBP promotes the catabolism of hypoxanthine and elevates the apoptosis of RCC cells by modulating XDH-mediated ROS generation.

One-Stage Flexible Ureteroscopy during Single-Tract Percutaneous Nephrolithotomy in the Treatment of Parallel Calyceal Stones.

INTRODUCTION: The aim of this study was to compare the clinical safety and efficiency between one-stage flexible ureteroscopy (FURS) during single-tract percutaneous nephrolithotomy (PCNL) and multi-tract PCNL in the treatment of parallel calyceal stones. METHODS: One hundred and twenty-five patients who had calyceal stones parallel to puncture channel from March 2017 to January 2021 were enrolled and assigned into two groups. Seventy cases received the treatment of FURS combined with single-tract PCNL under the oblique supine position (the Combined group), and 55 cases had multi-tract PCNL procedure under the prone position (the Multi-tract group). Demographic characteristics, clinical information, and surgical outcomes were analyzed. RESULTS: Demographic variables and stone characteristics did not show statistical difference between the two groups. Compared with the Multi-tract group, there were longer operation time (p = 0.021), shorter postoperative hospitalization days (p = 0.003), smaller postoperative hemoglobin drop (p = 0.002), less incidence of moderate and severe postoperative pain (p = 0.001), and postoperative perirenal hematoma (p = 0.012) in the Combined group. No significant difference was found in the stone-free rate (SFR) and postoperative fever between the two groups (p = 0.880 and p = 0.324). More patients needed postoperative intervening embolization in the Multi-tract group (p = 0.048). DISCUSSION/CONCLUSIONS: For most patients with parallel calyceal stones, one-stage FURS combined with single-tract PCNL procedure was a safer procedure for the reduction of complications and could achieve a comparative SFR compared to the multi-tract PCNL.

LncRNA PCAT1 activates AKT and NF-κB signaling in castration-resistant prostate cancer by regulating the PHLPP/FKBP51/IKKα complex.

In PTEN-deficient prostate cancers, AKT signaling may be activated upon suppression of androgen receptor signaling. Activation of AKT as well as NF-κB signaling involves a key regulatory protein complex containing PHLPP, FKBP51 and IKKα. Here, we report a critical role of lncRNA PCAT1 in regulating the PHLPP/FKBP51/IKKα complex and progression of castration-resistant prostate cancer (CRPC). Using database queries, bioinformatic analyses, as well as RIP and RNA pull-down assays, we discovered and validated that the lncRNA-PCAT1 perturbs the PHLPP/FKBP51/IKKα complex and activates AKT and NF-κB signaling. Expression of lncRNA-PCAT1 is positively linked to CRPC progression. PCAT1 binds directly to FKBP51, displacing PHLPP from the PHLPP/FKBP51/IKKα complex, leading to activation of AKT and NF-κB signaling. Targeting PCAT1 restores PHLPP binding to FKBP1 leading to suppression of AKT signaling. Preclinical study in a mouse model of CRPC suggests therapeutic potential by targeting lncRNA PCAT1 to suppress CRPC progression. Together, the newly identified PCAT1/FKBP51/IKKα complex provides mechanistic insight in the interplay between AKT, NF-κB and AR signaling in CRPC, and the preclinical studies suggest that a novel role for PCAT1 as a therapeutic target.

Long non-coding RNA NEAT1 promotes bone metastasis of prostate cancer through N6-methyladenosine.

BACKGROUND: N6-methyladenosine (m6A) is the most prevalent messenger RNA modification in mammalian cells. However, the disease relevant function of m6A on specific oncogenic long non-coding RNAs (ncRNAs) is not well understood. METHODS: We analyzed the m6A status using patients samples and bone metastatic PDXs. Through m6A high-throughput sequencing, we identified the m6A sites on NEAT1-1 in prostate bone metastatic PDXs. Mass spec assay showed interaction among NEAT1-1, CYCLINL1 and CDK19. RNA EMSA, RNA pull-down, mutagenesis, CLIP, western blot, ChIP and ChIRP assays were used to investigate the molecular mechanisms underlying the functions of m6A on NEAT1-1. Loss-of function and rescued experiments were executed to detect the biological roles of m6A on NEAT1-1 in the PDX cell phenotypes in vivo. RESULTS: In this study, we identified 4 credible m6A sites on long ncRNA NEAT1-1. High m6A level of NEAT1-1 was related to bone metastasis of prostate cancer and m6A level of NEAT1-1 was a powerful predictor of eventual death. Transcribed NEAT1-1 served as a bridge to facility the binding between CYCLINL1 and CDK19 and promoted the Pol II ser2 phosphorylation. Importantly, depletion of NEAT1-1or decreased m6A of NEAT1-1 impaired Pol II Ser-2p level in the promoter of RUNX2. Overexpression of NEAT1-1 induced cancer cell metastasis to lung and bone; xenograft growth and shortened the survival of mice, but NEAT1-1 with m6A site mutation failed to do these. CONCLUSION: Collectively, the findings indicate that m6A on ncRNA NEAT1-1 takes critical role in regulating Pol II ser2 phosphorylation and may be novel specific target for bone metastasis cancer therapy and diagnosis. New complex CYCLINL1/CDK19/NEAT1-1 might provide new insight into the potential mechanism of the pathogenesis and development of bone metastatic prostate cancer.

Correction to: Targeting TR4 nuclear receptor suppresses prostate cancer invasion via reduction of infiltrating acrophages with alteration of the TIMP-1/MMP2/MMP9 signals.

An amendment to this paper has been published and can be accessed via the original article.

Comparison of Two Numerical Parameters to Assess Detrusor Contractility in Prognosing Short-Term Outcome after Transurethral Resection of the Prostate.

OBJECTIVE: To investigate and compare the influence of two numerical detrusor contractility parameters, the bladder contractility index (BCI) and the maximum Watts factor (WFmax), on transurethral resection of the prostate (TURP) outcome. METHODS: A retrospective study was conducted on 236 patients who had undergone urodynamic assessment preoperatively and TURP for benign prostatic obstruction. They were evaluated by International Prostate Symptom Score (IPSS) and uroflowmetry preoperatively and 3 months postoperatively. Related criteria were established to determine the overall efficacy of TURP. Logistic regression analysis and receiver operating characteristic curves were made to investigate the influence of the BCI and WFmax on TURP efficacy. RESULTS: Among the 236 patients, 195 treatments were effective and 41 ineffective. Multivariate analysis showed that both the BCI (OR 1.038) and the WFmax (OR 1.291) could influence TURP efficacy. For predicting TURP efficacy, the optimal cut-off values of the BCI and WFmax were 98.7 and 10.27 W/m2, respectively. The AUC, sensitivity and specificity of the BCI were 0.722, 78.5% and 61.0%; those of the WFmax were 0.761, 73.9% and 73.2%, with no significant difference (p > 0.05). CONCLUSIONS: To some extent, the BCI and the WFmax can predict TURP efficacy equally well. A discrimination level of 10.27 W/m2 may be a threshold value for detrusor underactivity (DU); as regards the BCI, the current threshold value is appropriate to diagnose DU.

Androgen deprivation therapy with chemotherapy or abiraterone for patients with metastatic hormone-naive prostate cancer: a systematic review and meta-analysis.

Patients with metastasis prostate cancer underwent androgen deprivation therapy (ADT) in the considering of the leading role of androgen receptor pathway. However, the resistance occurred within 1 year or more. The combination of cytotoxic chemotherapy and abiraterone for ADT therapy was performed in recent randomized controlled trials. The meta-analysis was focused on the treatment comparisons between additional treatment with ADT and ADT alone. A significant difference was observed that the overall survival benefit of early and active additional treatment with ADT in patients with hormone-sensitive metastatic prostate cancer. However, a great proportion of patients with metastatic disease have metastases after receiving ADT. It will be important to further improve the treatment options.

The role of C1QBP in CSF-1-dependent PKCζ activation and macrophage migration.

Macrophages view as double agents in tumor progression. Trafficking of macrophages to the proximity of tumors is mediated by colony-stimulating factor-1 (CSF-1), a growth factor. In this study, we investigated the role of complement1q-binding protein (C1QBP)/ atypical protein kinase C ζ (PKCζ) in CSF-1-induced macrophage migration. Disruption of C1QBP expression impaired chemotaxis and adhesion of macrophage. Phosphorylation of PKCζ is an essential component in macrophage chemotaxis signaling pathway. C1QBP could interact with PKCζ in macrophage. C1QBP knockdown inhibited CSF-1 induced phosphorylation of PKCζ and integrin-ß1. However, C1QBP knockdown didn't affect the phosphorylation of PKCζ induced by MCP-1. Furthermore, CSF-1 from RCC cell condition medium promoted macrophage chemotaxis and adhesion. Taken together, our results demonstrated that C1QBP plays an essential role in CSF-1 induced migration of macrophages.

CD4 + T cells promote renal cell carcinoma proliferation via modulating YBX1.

Renal cell carcinoma (RCC) is a common urologic tumor and the third leading cause of death among urological tumors. Recent studies demonstrate that RCC tumors are more heavily infiltrated by lymphocytes than other cancers. However, the exact roles played by CD4 + T cells in RCC proliferation remain unknown. In this study, we cocultured RCC cells with CD4 + T cells. Stable knockdown of YBX1 in RCC cells was constructed. The effects of CD4 + T cells, TGFß1 and YBX1 on RCC cells were investigated using cell viability assays. In situ RCC nude mouse model was used to observe the tumor growth. The potential mechanisms of CD4 + T cells and YBX1 in RCC cells proliferation were explored by qRT-PCR and western blot. Expression of CD4, Foxp3 and TGFß1 in RCC were quantified by immunohistochemical staining. The results indicated that CD4, Foxp3 and TGFß1 were significantly up-regulated in RCC tissues. Human clinical sample and in vitro cell lines studies showed that RCC cells had better capacity than its surrounding normal kidney epithelial cells to recruit the CD4 + T cells. In vivo mouse model studies were consistent with the results by in vitro cell lines studies showing infiltrating T cells enhanced RCC cell proliferation. qRT-PCR and western blot exhibited that CD4 + T cells could enhance RCC cell proliferation via activating YBX1/HIF2α signaling pathway. Furthermore, CD4 + T cells functioned through inducing TGFß1 expression. In a word, infiltrating CD4 + T cells promoted TGFß1 expression in both RCC and T cells and regulated RCC cells proliferation via modulating TGFß1/YBX1/ HIF2α signals.

Ultrasmall bimodal nanomolecules enhanced tumor angiogenesis contrast with endothelial cell targeting and molecular pharmacokinetics.

Nonintrusive and precise imaging for tumor angiogenesis is critical in accurate assessment of cancer diagnosis and prognosis. However, reticulo-endothelial system (RES) capture and inadequate accumulation remain major bottlenecks for current nanoparticle to retain at tumor angiogenesis site. Herein, we report the ultrasmall contrast agent (cNGR-Au:Gd@GSH NMs) could accumulate at tumor vasculature site and enhance the tumor angiogenesis-contrast. It is demonstrated that by loading Au and Gd atom into the naturally-occurring glutathione (GSH) shell with cNGR peptide modification, cNGR-Au:Gd@GSH NMs exhibit the high X-ray photon absorption, longer rotational correlation time and efficient tumor vascular endothelia cell targeting. In vivo studies further indicate the cNGR-Au:Gd@GSH NMs prominently enhance tumor angiogenesis-contrast both on the computed tomography (CT) and magnetic resonance imaging (MRI) modalities by escaping the RES capture and target delivering. Our data imply that the cNGR-Au:Gd@GSH NMs may serve as the high-efficiency contrast agent to assess tumor angiogenesis in a nonintrusive technique.