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Nasopharyngeal carcinoma (NPC) is a very common head and neck cancer in southern china. Despite advances in surgical and chemotherapeutic approaches, its prognosis is still not promising. Hedgehog signaling pathway was reported to be involved in a number of cancers including head and neck. However, it remains unclear regarding the role of this pathway in NPC. By real-time PCR, we found Ptch1, Smo, and Gli-1 were expressed in all human nasopharyngeal epithelial tissues and cell lines. Compared with nasopharyngeal normal epithelial tissues, the mRNA expression level of Gli-1 was higher in carcinoma and nasopharyngitis (NPI) epithelial tissues. While compared with nasopharyngitis epithelia, the mRNA expression level of Ptch1 was lower in carcinoma epithelia and normal epithelia. The expressions of Smo mRNA were not significantly different among these epithelial tissues. Immunohistochemistry analysis revealed that the expression level of Gli-1 was higher in NPC than NPI. Thus, our data indicated that aberrant activation of hedgehog pathway in NPC. Furthermore, blocking the pathway with cyclopamine inhibited the proliferation of NPC epithelia cell lines. In addition, blockade of the pathway in three NPC cell lines with cyclopamine-induced tumor cell apoptosis. The transcription of hedgehog target genes also is inhibited by cyclopamine. These data suggested that hedgehog pathway may sustain nasopharyngeal tumor growth. Our data demonstrated that hedgehog signaling pathway was involved in NPC pathogenesis and might be a novel therapeutic target for NPC. [ABSTRACT FROM AUTHOR]

Abstract: Several antiangiogenic agents, including bevacizumab, sunitinib, and sorafenib, which mainly target the VEGF signaling system, have been approved for the treatment of human cancers. These drugs have been paired with conventional chemotherapeutic agents to treat different types of cancers, including colorectal and lung cancers; however, the patient response rate and resultant increase in overall survival time have been rather modest. The current antiangiogenic regimen is far from optimal. Improvements of therapeutic efficacy and minimization of adverse effects and drug resistance are urgent tasks that are most likely to be resolved by understanding the molecular mechanisms underlying tumor angiogenesis. The aim of this article is to discuss these clinically related issues, to highlight several recent examples of the complex interplays between tumor-produced angiogenic factors, and to propose a new paradigm for improvement of therapeutic intervention of tumor angiogenesis. [Copyright &y& Elsevier]

Abstract: Lymphatic endothelial cells (LECs) originally differentiated from venous endothelial cells express several specific makers that distinguish them from the blood vessels. Lymphangiogenesis, a complex process of sprouting of new lymphatic vessels, is regulated by multiple direct and indirect growth factors. Vascular endothelial growth factor-C (VEGF-C) is the most potent and selective lymphangiogenic factor that plays a crucial role in the establishment of the first lymphatic vessel during embryonic development and in mediating lymphatic metastasis. In addition to VEGF-C, recent studies show that a range of known tumor-produced angiogenic factors also stimulates lymphangiogenesis, suggesting complex and tight regulations of this process. These tumor-derived lymphangiogenic factors may either alone or jointly promote lymphatic metastasis. Understanding regulatory mechanisms of lymphangiogenesis is pivotal for development of lymphangiogenesis antagonists that might therapeutically be used for intervention of lymphatic metastasis. [Copyright &y& Elsevier]

Background: Advanced prostate cancer (PCa) will develop into castration-resistant prostate cancer (CRPC) and lead to poor prognosis. As the primary subtype of CRPC, CRPC-AR accounts for the major induction of PCa heterogeneity. CRPC-AR is mainly driven by 25 transcription factors (TFs), which we speculate may be the key factors driving PCa toward CRPC. Therefore, it is necessary to clarify the key regulator and its molecular mechanism mediating PCa progression. Methods: Firstly, we downloaded transcriptomic data and clinical information from TCGA-PRAD. The characteristic gene cluster was identified by PPI clustering, GO enrichment, co-expression correlation and clinical feature analyses for 25 TFs. Then, the effects of 25 TFs expression on prognosis of PCa patients was analyzed using univariate Cox regression, and the target gene was identified. The expression properties of the target gene in PCa tissues were verified using tissue microarray. Meanwhile, the related mechanistic pathway of the target gene was mined based on its function. Next, the target gene was silenced by small interfering RNAs (siRNAs) for cellular function and mechanistic pathway validation. Finally, CIBERSORT algorithm was used to analyze the infiltration levels of 22 immune cells in PCa patients with low and high expression of target gene, and validated by assaying the expression of related immunomodulatory factor. Results: We found that HOX family existed independently in 25 TFs, among which HOXC10, HOXC12 and HOXC13 had unique clinical features and the PCa patients with high HOXC13 expression had the worst prognosis. In addition, HOXC13 was highly expressed in tumor tissues and correlated with Gleason score and pathological grade. In vitro experiments demonstrated that silencing HOXC13 inhibited 22RV1 and DU145 cell function by inducing cellular DNA damage and activating cGAS/STING/IRF3 pathway. Immune infiltration analysis revealed that high HOXC13 expression suppressed infiltration of γδ T cells and plasma cells and recruited M2 macrophages. Consistent with these results, silencing HOXC13 up-regulated the transcriptional expression of IFN-β, CCL2, CCL5 and CXCL10. Conclusion: HOXC13 regulates PCa progression by mediating the DNA damage-induced cGAS/STING/IRF3 pathway and remodels TIME through regulation of the transcription of the immune factors IFN-β, CCL2, CCL5 and CXCL10. [ABSTRACT FROM AUTHOR]

Background. FGF signaling is critical to controlling various cancers. Nevertheless, the functions of FGF-related genes in PCa are still unknown. Objective. The objective of this study is to build a FGF-related signature that was capable of accurately predicting PCa survival and prognosis for BCR. Methods. The univariate and multivariate Cox regression, infiltrating immune cells, LASSO, and GSEA analyses were carried out to build a prognostic model. Results. A FGF-related signature that consists of PIK3CA and SOS1 was developed for the purpose of predicting PCa prognosis, and all patients were categorized into low- and high-risk groups. In comparison to the low-risk group, high-risk score patients had poorer BCR survival. This signature's predictive power has been investigated utilizing the AUC of the ROC curves. The risk score has been shown to be an independent prognostic factor by multivariate analysis. The four enriched pathways of the high-risk group were obtained by gene set enrichment analysis (GSEA) and found to be associated with the tumorigenesis and development of PCa, including focal adhesion, TGF-β signaling pathway, adherens junction, and ECM receptor interaction. The high-risk groups had considerably higher levels of immune status and tumor immune cell infiltration, suggesting a more favorable response to immune checkpoint inhibitors. IHC found that the expression of the two FGF-related genes in the predictive signature was extremely different in PCa tissues. Conclusion. To summarize, our FGF-related risk signature may effectively predict and diagnose PCa, indicating that in PCa patients, they are potential therapeutic targets and promising prognostic biomarkers. [ABSTRACT FROM AUTHOR]

Background: Recent meta-analyses have suggested a modest protective effect of high levels of physical activity on developing both prostate and bladder cancer, but significant heterogeneity between studies included in these meta-analyses existed. To our knowledge, few Chinese studies investigated the association between physical activity and prostate cancer and none between physical activity and bladder cancer. Given the inconsistencies between previous studies and because studies on the relation between physical activity and prostate and bladder cancer in China are scarce, it remains elusive whether there is a relationship between physical activity and prostate and bladder cancer within the Chinese population. Methods: We investigated the association between physical activity and risk of developing prostate and bladder cancer within a hospital-based case-control study in the East and South of China among 260 and 438 incident prostate and bladder cancer cases, respectively, and 427 controls. A questionnaire was administered to measure physical activity as metabolic equivalents (METs). Random effects logistic regression was used to calculate odds ratios (ORs) of prostate and bladder cancer for different levels of physical activity and for the specific activities of walking and cycling. Results: Increasing overall physical activity was associated with a significant reduction in prostate cancer risk (Ptrend = 0.04) with the highest activity tertile level showing a nearly 50% reduction in prostate cancer risk (OR = 0.53, 95%CI: 0.28–0.98). Overall physical activity was not significantly associated with risk of bladder cancer (Ptrend = 0.61), neither were vigorous (Ptrend = 0.60) or moderate levels of physical activity (Ptrend = 0.21). Walking and cycling were not significantly associated with either prostate (Ptrend> = 0.62) or bladder cancer risk (Ptrend> = 0.25). Conclusions: The findings of this largest ever case-control study in China investigating the relationship between physical activity and prostate and bladder cancer suggest that overall physical activity is associated with a decreased risk of prostate cancer, but not with bladder cancer. [ABSTRACT FROM AUTHOR]

• Stress response stated T cell (Tstr), a new identified T-cell subtype, is of significance in the progress of clear cell renal cell carcinoma (ccRCC). • The Tstr–related score (TCs) was shown to accurately predict the prognosis of ccRCC. • Compared with PD-L1, TCs was able to more accurately identify ccRCC patients who benefited from PD-1 blockade treatment. • Tstr cells may exert their pro-tumoral role in ccRCC, acting against mast cells, in the acute inflammatory tumor microenvironment. • TNFSF13B could serve as a potential biomarker to predict the effect of PD-1 blockade treatment in ccRCC patients. Establishment of a reliable prognostic model and identification of novel biomarkers are urgently needed to develop precise therapy strategies for clear cell renal cell carcinoma (ccRCC). Stress response stated T cells (Tstr) are a new T-cell subtype, which are related to poor disease stage and immunotherapy response in various cancers. 10 machine-learning algorithms and their combinations were applied in this work. A stable Tstr-related score (TCs) was constructed to predict the outcomes and PD-1 blockade treatment response in ccRCC patients. A nomogram based on TCs for personalized prediction of patient prognosis was constructed. Functional enrichment analysis and TimiGP algorithm were used to explore the underlying role of Tstr in ccRCC. The key TCs-related gene was identified by comprehensive analysis, and the bioinformatics results were verified by immunohistochemistry using a tissue microarray. A robust TCs was constructed and validated in four independent cohorts. TCs accurately predicted the prognosis and PD-1 blockade treatment response in ccRCC patients. The novel nomogram was able to precisely predict the outcomes of ccRCC patients. The underlying biological process of Tstr was related to acute inflammatory response and acute-phase response. Mast cells were identified to be involved in the role of Tstr as a protective factor in ccRCC. TNFS13B was shown to be the key TCs-related gene, which was an independent predictor of unfavorable prognosis. The protein expression analysis of TNFSF13B was consistent with the mRNA analysis results. High expression of TNFSF13B was associated with poor response to PD-1 blockade treatment. This study provides a Tstr cell–related score for predicting outcomes and PD-1 blockade therapy response in ccRCC. Tstr cells may exert their pro-tumoral role in ccRCC, acting against mast cells, in the acute inflammatory tumor microenvironment. TNFSF13B could serve as a key biomarker related to TCs. [ABSTRACT FROM AUTHOR]

This study was aimed at constructing a pyroptosis-related signature for prostate cancer (PCa) and elucidating the prognosis and immune landscape and the sensitivity of immune checkpoint blockade (ICB) therapy in signature-define subgroups of PCa. We identified 22 differentially expressed pyroptosis-related genes in PCa from The Cancer Genome Atlas (TCGA) database. The pyroptosis-related genes could divide PCa patients into two clusters with differences in survival. Seven genes were determined to construct a signature that was confirmed by qRT-PCR to be closely associated with the biological characteristics of malignant PCa. The signature could effectively and independently predict the biochemical recurrence (BCR) of PCa, which was validated in the GSE116918 and GSE21034. We found that patients in the high-risk group were more prone to BCR and closely associated with high-grade and advanced-stage disease progression. Outperforming clinical characteristics and nine published articles, our signature demonstrated excellent predictive performance. The patients in the low-risk group were strongly related to the high infiltration of various immune cells including CD8+ T cells and plasma B cells. Furthermore, the high-risk group with higher TMB levels and expression of immune checkpoints was more likely to benefit from immune checkpoint therapy such as PD-1 and CTLA-4 inhibitors. The sensitivity to chemotherapy, endocrine, and targeted therapy showed significant differences in the two risk groups. Our signature was a novel therapeutic strategy to distinguish the prognosis and guide treatment strategies. [ABSTRACT FROM AUTHOR]

Aim: To elucidates the mechanism that disulfiram/copper complex (DSF/Cu) treatment activates chloride channels and induces apoptosis in prostate cancer cells. Methods: Cellular membrane currents were measured by membrane clamp technique; western blot to detect protein expression; flow cytometry to detect apoptosis; immunofluorescence to detect target protein co‐localization, and further validated by a combination of protein‐protein interaction and mock protein molecular docking techniques. Results: DSF/Cu activated chloride channels and induced apoptosis in LNCaP (a type of androgen‐dependent prostate cancer cells) cells. The chloride currents activated by DSF/Cu were significantly reduced after knockdown of CLC3 with siRNA. In addition, DSF/Cu‐activated chloride currents were reduced to background current levels after perfusion with genistein, a highly specific tyrosine kinase inhibitor. Conversely, DSF/Cu failed to activate chloride currents in LNCaP cells after 30 minutes of pre‐incubation with genistein. When genistein was removed, and DSF/Cu was added, the activated currents were small and unstable, and gradually decreased. Immunofluorescence in LNCaP cells also showed co‐localization of the CLC3 protein with tyrosine kinase 2β (PTK2B). Conclusion: DSF/Cu can activate chloride channels and induce apoptosis in LNCaP cells with the involvement of tyrosine kinase. These results provide new insights into the target therapy of prostate cancer. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is a prevalent malignancy among men worldwide, and biochemical recurrence (BCR) after radical prostatectomy (RP) is a critical turning point commonly used to guide the development of treatment strategies for primary PCa. However, the clinical parameters currently in use are inadequate for precise risk stratification and informing treatment choice. To address this issue, we conducted a study that collected transcriptomic data and clinical information from 1662 primary PCa patients across 12 multicenter cohorts globally. We leveraged 101 algorithm combinations that consisted of 10 machine learning methods to develop and validate a 9-gene signature, named BCR SCR, for predicting the risk of BCR after RP. Our results demonstrated that BCR SCR generally outperformed 102 published prognostic signatures. We further established the clinical significance of these nine genes in PCa progression at the protein level through immunohistochemistry on Tissue Microarray (TMA). Moreover, our data showed that patients with higher BCR SCR tended to have higher rates of BCR and distant metastasis after radical radiotherapy. Through drug target prediction analysis, we identified nine potential therapeutic agents for patients with high BCR SCR. In conclusion, the newly developed BCR SCR has significant translational potential in accurately stratifying the risk of patients who undergo RP, monitoring treatment courses, and developing new therapies for the disease. • We have collected and curated global multicenter primary prostate cancer RNA sequencing data and follow-up data from 12 centers including Europe, America and Asia, and made them available for subsequent researchers to use. • A computational framework was included, consisting of 101 machine learning algorithm combinations, to identify a novel signature called BCR SCR for predicting the risk of biochemical recurrence after radical prostatectomy. • BCR SCR demonstrated superior performance compared to 102 previously established models for prostate cancer. • BCR SCR excels in forecasting post-surgery prostate biochemical recurrence, outdoing 102 models. [ABSTRACT FROM AUTHOR]

This study reports an effective and facile strategy for developing multifunctional nanoplatforms by the in situ doping of manganese metal into stellate mesoporous silica nanoparticles (Mn-SMSN). The resulting Mn-SMSN@DOX-IR-780 effectively integrated enhanced chemodynamic therapy (CDT) combined with tumor imaging in a single platform after additional loading of doxorubicin hydrochloride (DOX) and IR-780 iodide (IR-780) onto Mn-SMSN. Mn-SMSN@DOX-IR-780 demonstrated excellent in vitro efficacy in killing cancer cells and inhibiting cancer cell migration and invasion. Further mechanistic investigations demonstrated that Mn-SMSN@DOX-IR-780 effectively promoted the production of cytotoxic reactive oxygen species to kill tumor cells. Moreover, Mn-SMSN@DOX-IR-780 efficiently delivered DOX and IR-780 into cells, indicating potential for chemodynamic therapy and tumor imaging. In summary, the developed Mn-SMSN@DOX-IR-780 integrated CDT and image guidance, which can provide insights for future biomedical research applications concerning efficient prostate cancer treatment. [Display omitted] • Mn-SMSN@DOX-IR-780 is developed by in situ doping of manganese metal into Mn-SMSN. • Chemodynamic therapy (CDT) is integrated with tumor imaging by Mn-SMSN@DOX-IR-780. • This is achieved by loading of doxorubicin hydrochloride and IR-780 iodide onto Mn-SMSN. • Mn-SMSN@DOX-IR-780 promoted cytotoxic reactive oxygen species to kill tumor cells. • CDT and image guidance integration can provide insights for prostate cancer treatment. [ABSTRACT FROM AUTHOR]

The incidence of prostate cancer is gradually increasing. There are many methods for clinical treatment of prostate cancer, such as surgical treatment and endocrine treatment. In the case of advanced prostate cancer, we must not only extend patients' survival times but also enhance their quality of life. Endocrine medications are the most effective therapy for advanced prostate cancer. This research will investigate the therapeutic impact of a complete treatment model in prostate cancer in order to discover a trustworthy clinical treatment model. This research discovered that, as compared to endocrine treatment, radical resection of prostate cancer may diminish and reach lower serum PSA levels in a short amount of time, as well as sustain low PSA levels and delay progression to castration resistance. Moreover, the comprehensive treatment mode can effectively reduce the possibility of complications. The research results show that the comprehensive treatment model can play an important role in the treatment of prostate cancer. [ABSTRACT FROM AUTHOR]

Chemotherapy has been proven to be an efficient strategy for the treatment of prostate cancer (PC). However, the insufficient cellular uptake of drugs is the biggest challenge for PC therapy. Therefore, in order to address the above concern, we developed tumor-targeted hyaluronic acid-silver nanoparticles (HA-Ag NPs), in which hyaluronic acid can specially bind with its receptor CD44 overexpressed on LNCaP cells. HA-Ag NPs have been used to load paclitaxel (PTX) to prepare functionalized silver nanoparticles (HA-Ag-PTX). The average particle size of HA-Ag-PTX was about 70 nm and kept under 120 nm for eight days. androgen-sensitive prostate cancer cells (LNCaP) cells show good uptake of HA-Ag-PTX, and HA-Ag-PTX enters LNCaP cells in a clathrin-mediated energy-dependent manner. HA-Ag-PTX exhibits an excellent pH response release of PTX under the acidic condition, which is beneficial to enhance the distribution of PTX in the tumor microenvironment. HA-Ag-PTX effectively suppresses the migration and proliferation of LNCaP cells probably by arresting the cellular cycle at G 0/ G 1 phase and enhancing the production of the reactive oxygen species. It is worth mentioning that HA-Ag-PTX exhibits greater anticancer activity in comparison with free PTX in the LNCaP cell model, indicating that HA-Ag NPs can effectively enhance the anticancer efficacy of PTX. As a whole, these findings suggest that HA-Ag-PTX has promising potential for PC therapy. Hyaluronic acid-modified silver nanoparticle loaded with paclitaxel (HA-Ag-PTX) was prepared in this study. Hyaluronic acid was used as cancer cells-targeted moiety. HA-Ag-PTX exhibited great ability to suppress the migration and proliferation of androgen-sensitive prostate cancer cells (LNCaP). Furthermore, HA-Ag-PTX could also induce the apoptosis of LNCaP. These findings suggest that HA-Ag-PTX has promising potential for prostate cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Hypoxia signaling, especially the hypoxia inducible factor (HIF) pathway, is a major player in clear cell renal cell carcinoma (ccRCC), which is characterized by disorders in lipid and glycogen metabolism. However, the interaction between hypoxia and lipid metabolism in ccRCC progression is still poorly understood. Methods: We used bioinformatic analysis and discovered that glycerol-3-phosphate dehydrogenase 1 (GPD1) may play a key role in hypoxia and lipid metabolism pathways in ccRCC. Tissue microarray, IHC staining, and survival analysis were performed to evaluate clinical function. In vitro and in vivo assays showed the biological effects of GPD1 in ccRCC progression. Results: We found that the expression of GPD1 was downregulated in ccRCC tissues, and overexpression of GPD1 inhibited the progression of ccRCC both in vivo and in vitro. Furthermore, we demonstrated that hypoxia inducible factor-1α (HIF1α) directly regulates GPD1 at the transcriptional level, which leads to the inhibition of mitochondrial function and lipid metabolism. Additionally, GPD1 was shown to inhibit prolyl hydroxylase 3 (PHD3), which blocks prolyl-hydroxylation of HIF1α and subsequent proteasomal degradation, and thus reinforces the inhibition of mitochondrial function and phosphorylation of AMPK via suppressing glycerol-3-phosphate dehydrogenase 2 (GPD2). Conclusions: This study not only demonstrated that HIF1α-GPD1 forms a positive feedforward loop inhibiting mitochondrial function and lipid metabolism in ccRCC, but also discovered a new mechanism for the molecular basis of HIF1α to inhibit tumor activity, thus providing novel insights into hypoxia-lipid-mediated ccRCC therapy. [ABSTRACT FROM AUTHOR]

Background: ALDOA plays an essential role in cancer progression in different human cancers; however, its function has not been understood in prostate cancer (PCa). Methods: Associations of ALDOA expression with clinicopathological features and patient prognosis in PCa were evaluated based on data obtained from the Taylor database and our clinical tissue microarray. The potential roles of ALDOA in malignant progression were verified using a series of in vivo and in vitro experiments after stable ALDOA overexpression and knockdown in DU145 and PC3 cell lines. An aldolase A inhibitor was used to determine the effects of inhibition of ALDOA on PCa cell proliferation. Results: Higher expression of ALDOA was positively correlated with the incidence of postoperative metastasis and biochemical recurrence (BCR) and may predict poor prognosis in PCa patients. In vivo experiments demonstrated that overexpression of ALDOA could significantly promote cell proliferation, prolong the cell cycle, and significantly reduce the apoptosis rate of PCa cells. Knockdown of expression of ALDOA could inhibit the proliferation and shorten the cell cycle of PCa cells significantly, with no significant effects on cell apoptosis (P > 0.05). In vitro experiments showed that overexpression of ALDOA could significantly promote tumor growth (P < 0.05), while treatment with the Aldolase A inhibitor naphthol AS-E phosphate dose-dependently suppressed the growth of PCa cells (P < 0.01). The analysis of datasets from the Taylor database showed that there was negative regulatory relationship between the expression of ALDOA and MYPT1 (P < 0.001). Conclusion: Our study revealed that ALDOA played an important role in the progression of PCa. The MYPT1-ALDOA signaling axis may be a new target for the clinical treatment of PCa patients given its negative regulatory relationship. Our study suggests that Aldolase A inhibitors may represent a novel approach to inhibit the growth of PCa. [ABSTRACT FROM AUTHOR]

Prognostic tests using expression profiles of several dozen genes help provide treatment choices for prostate cancer (PCa). However, these tests require improvement to meet the clinical need for resolving overtreatment, which continues to be a pervasive problem in PCa management. Genomic selection (GS) methodology, which utilizes whole-genome markers to predict agronomic traits, was adopted in this study for PCa prognosis. We leveraged The Cancer Genome Atlas (TCGA) database to evaluate the prediction performance of six GS methods and seven omics data combinations, which showed that the Best Linear Unbiased Prediction (BLUP) model outperformed the other methods regarding predictability and computational efficiency. Leveraging the BLUP-HAT method, an accelerated version of BLUP, we demonstrated that using expression data of a large number of disease-relevant genes and with an integration of other omics data (i.e. miRNAs) significantly increased outcome predictability when compared with panels consisting of a small number of genes. Finally, we developed a novel stepwise forward selection BLUP-HAT method to facilitate searching multiomics data for predictor variables with prognostic potential. The new method was applied to the TCGA data to derive mRNA and miRNA expression signatures for predicting relapse-free survival of PCa, which were validated in six independent cohorts. This is a transdisciplinary adoption of the highly efficient BLUP-HAT method and its derived algorithms to analyze multiomics data for PCa prognosis. The results demonstrated the efficacy and robustness of the new methodology in developing prognostic models in PCa, suggesting a potential utility in managing other types of cancer. [ABSTRACT FROM AUTHOR]

Background: Solute Carrier Family 6 Member 1 (SLC6A1) has been identified as a cancer-promoting gene in various human cancers, such as clear cell renal cell carcinoma and ovarian cancer. However, its roles in prostate cancer (PCa) has not been fully elucidated. The aim of this study was to investigate the expression and clinical significance of SLC6A1 in PCa tissues and its effect on drug resistance to docetaxel in PCa.Methods: Expression patterns of SLC6A1 protein in PCa tissues were examined by immunohistochemistry based on Tissue microarray. Associations of SLC6A1 protein expression with various clinicopathological features and patients' prognosis of PCa were also statistically evaluated based on TCGA data. Roles of SLC6A1 deregulation in prostate carcinogenesis and drug resistance was further determined in vitro and in vivo experiments.Results: Based on TCGA Dataset, SLC6A1 expression was markedly higher in patients with high Gleason score, advanced clinical stage and positive biochemical recurrence than those with control features (all P < 0.05). Both unvariate and multivariate analyses demonstrated that SLC6A1 expression was significantly associated with biochemical recurrence-free survival in PCa patients. In addition, enforced expression of SLC6A1 effectively promoted cell proliferation, migration and invasion of PCa cells in vitro. Moreover, the inhibition of SLC6A1 suppressed the tumor growth in vivo. Additionally, immunohistochemical notches of PCNA and MMP-9 in the low-expression cluster were pointedly lower compared to those of NC group. Finally, the cell viability revealed that the overexpression of SLC6A1 obviously promoted the PCa cell resistant to docetaxel (DTX), and the transplanted tumor in the overexpression group had no significant reduction compared with the untreated group.Conclusions: Our data suggest that SLC6A1 overexpression may be associated with aggressive progression and short biochemical recurrence-free survival of PCa, and may be related to the resistance to docetaxel therapy. [ABSTRACT FROM AUTHOR]

Nonmutational epigenetic reprogramming is a crucial mechanism contributing to the pronounced heterogeneity of prostate cancer (PCa). Among these mechanisms, N6-methyladenosine (m6A)-modified long non-coding RNAs (lncRNAs) have emerged as key players. However, the precise roles of m6A-modified lncRNAs in PCa remain to be elucidated. In this study, methylated RNA immunoprecipitation sequencing (MeRIP-seq) was conducted on primary and metastatic PCa samples, leading to the identification of 21 lncRNAs exhibiting differential methylation and expression patterns. We further established a PCa prognostic signature, named m6A-modified lncRNA score (mLs), based on 9 differential methylated lncRNAs in 4 multicenter cohorts. The high mLs score cohort exhibited a tendency for earlier biochemical recurrence (BCR) compared to the low mLs score cohort. Remarkably, the predictive performance of the mLs score surpassed that of five previously reported lncRNA-based signatures. Functional enrichment analysis underscored a negative correlation between the mLs score and lipid metabolism. Additionally, through MeRIP-qPCR, we pinpointed a hub gene, MIR210HG, which was validated through in vitro and in vivo experiments. These findings collectively illuminate the landscape of m6A-methylated lncRNAs in PCa tissue via MeRIP-seq and harness this information to prognosticate PCa outcomes using the mLs score. Furthermore, our study validates, both experimentally and mechanistically, the facilitative role of MIR210HG in driving PCa progression. [ABSTRACT FROM AUTHOR]

Although dCTP pyrophosphatase 1 (DCTPP1) has been reported to be associated with poor clinical outcomes in various cancers, whether it plays an important role in prostate cancer (PCa) remains unclear. In this study, an immunohistochemical assay showed the protein expression level of DCTPP1 was significantly higher in PCa tissues than in non-cancerous tissues. Moreover, DCTPP1 was upregulated at both protein and mRNA levels in the PCa tissues from high Gleason score patients versus low Gleason score patients. The analysis of The Cancer Genome Atlas RNA-seq data suggested that upregulation of DCTPP1 was inversely correlated with biochemical recurrence free survival and overall survival. The roles of DCTPP1 in tumor progression and autophagy were further validated through cells invasion, migration, apoptosis and proliferation assays in vitro, as well as EMT and autophagy assays in vivo. Advanced bioinformatics analysis identified the evidence supporting the promotional role of DCTPP1 in tumor progression associated with autophagy. We conclude that DCTPP1 may play an important role in PCa progression associated with high autophagy. Overexpression of DCTPP1 may server as a biomarker for predicting poor BCR-free survival and overall survival for PCa patients. [ABSTRACT FROM AUTHOR]

Chloride intracellular channel 1 (CLIC1) is involved in the development of most aggressive human tumors, including gastric, colon, lung, liver, and glioblastoma cancers. It has become an attractive new therapeutic target for several types of cancer. In this work, we aim to identify natural products as potent CLIC1 inhibitors from Traditional Chinese Medicine (TCM) database using structure-based virtual screening and molecular dynamics (MD) simulation. First, structure-based docking was employed to screen the refined TCM database and the top 500 TCM compounds were obtained and reranked by X-Score. Then, 30 potent hits were achieved from the top 500 TCM compounds using cluster and ligand-protein interaction analysis. Finally, MD simulation was employed to validate the stability of interactions between each hit and CLIC1 protein from docking simulation, and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) analysis was used to refine the virtual hits. Six TCM compounds with top MM-GBSA scores and ideal-binding models were confirmed as the final hits. Our study provides information about the interaction between TCM compounds and CLIC1 protein, which may be helpful for further experimental investigations. In addition, the top 6 natural products structural scaffolds could serve as building blocks in designing drug-like molecules for CLIC1 inhibition. [ABSTRACT FROM AUTHOR]

BACKGROUND Autophagy has recently been found to play important roles in tumorigenesis and leucine-rich pentatricopeptide repeat motif-containing protein (LRPPRC) has been identified as an inhibitor that suppresses autophagy and mitophagy and maintains mitochondrial activity. The authors hypothesized that LRPPRC levels can be used as a biomarker for the diagnosis and prognosis of prostate cancer. METHODS Immunochemistry analysis was performed to evaluate the levels of LRPPRC in 112 samples collected from patients with prostate adenocarcinoma (PCa) and 38 samples from patients with benign prostatic hyperplasia (BPH) who were enrolled in hospitals in Guangzhou City, China and were followed for 10 years. RESULTS Significantly higher levels of LRPPRC were found in PCa samples compared with BPH samples. Greater than 75% of patients with PCa demonstrated high levels of LRPPRC whereas only 10% of patients with BPH were found to have similar levels of LRPPRC. The levels of LRPPRC were found to be positively correlated with tumor grade, metastasis, and serum prostate-specific antigen level, but were negatively correlated with hormone therapy sensitivity after 2 years of surgery and overall survival. The association between high levels of LRPPRC and late-stage PCa or hormone therapy insensitivity was confirmed in tissue samples collected from prostate-specific phosphatase and tensin homolog ( PTEN) -/- mice or hormone-dependent and hormone-independent PCa cell lines. CONCLUSIONS LRPPRC levels may be used as an independent biomarker for patients with PCa at a late stage with poor prognosis. Cancer 2014;120:1228-1236. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

The purpose of this study is to summarize the results of percutaneous nephrolithotomy (PCNL) for renal stones following failed extracorporeal shockwave lithotripsy (SWL), and to investigate the effect of previous SWL on the performances and morbidities of subsequent PCNL. Sixty-two patients with a history of failed SWL who underwent PCNL on the same kidney (group 1) were compared to 273 patients who had received PCNL as first treatment choice (group 2). Patient demographics, stone characteristics, operative findings, and complications were documented and compared. Groups 1 and 2 had similar patient demographics and stone characteristics. Mean time to establish access was comparable in both groups (10.5 ± 4.2 vs. 9.6 ± 4.5 min, p = 0.894). Time required to remove stones and total operative time were longer in group 1 (71.5 ± 10.3 vs. 62.3 ± 8.6 min, p = 0.011 and 95.8 ± 12.0 vs. 80.6 ± 13.2 min., p = 0.018, respectively). Group 1 had lower clearance rate compared to group 2 (83.9 vs. 93.4 %, p = 0.021), while postoperative complications were similar in both groups. Scattered stone fragments buried within the tissues made the procedure more difficult for stone fragmenting and extracting, which lead to longer operative time and inferior stone free rate. However, the PCNL procedure was safe and effective in patients with failed SWL. The risk of complications was similar and clearance rate was encouraging. [ABSTRACT FROM AUTHOR]

The role of placental growth factor (PlGF) in modulation of tumor angiogenesis and tumor growth remains an enigma. Furthermore, anti-PlGF therapy in tumor angiogenesis and tumor growth remains controversial in preclinical tumor models. Here we show that in both human and mouse tumors, PlGF induced the formation of dilated and normalized vascular networks that were hypersensitive to anti-VEGF and anti-VEGFR-2 therapy, leading to dormancy of a substantial number of avascular tumors. Loss-of-function using plgf shRNA in a human choriocarcinoma significantly accelerated tumor growth rates and acquired resistance to anti-VEGF drugs, whereas gain-of-function of PlGF in a mouse tumor increased anti-VEGF sensitivity. Further, we show that VEGFR-2 and VEGFR-1 blocking antibodies displayed opposing effects on tumor angiogenesis. VEGFR-1 blockade and genetic deletion of the tyrosine kinase domain of VEGFR-1 resulted in enhanced tumor angiogenesis. These findings demonstrate that tumor-derived PlGF negatively modulates tumor angiogenesis and tumor growth and may potentially serve as a predictive marker of anti-VEGF cancer therapy. [ABSTRACT FROM AUTHOR]

Abstract: Dendritic cells (DCs) have been widely used as cancer vaccines. However, their functional abilities have often been suppressed by tumor-secreted immunosuppressants such as transforming growth factor-beta (TGF-β). We developed a new strategy using a TGF-β insensitive DC as cancer vaccine. The effect of this vaccine was tested in a murine pulmonary metastases model of renal carcinoma (Renca). Tumor lysate-pulsed DCs (TP-DCs) were infected with retrovirus containing gene of dominant negative TGF-β type II receptor (TβRIIDN) and thus made TGF-β insensitive. Vaccination of the mice bearing Renca pulmonary metastases with the TβRIIDN TP-DC induced powerful tumor-specific cytotoxic T lymphocyte (CTL) responses, suppressed pulmonary metastases, and prolonged survival times. These results suggest TGF-β-insensitive TP-DC vaccine can be used to enhance the antitumor efficacy of DC vaccine. [Copyright &y& Elsevier]

The underlying mechanism by which anti-VEGF agents prolong cancer patient survival is poorly understood. We show that in a mouse tumor model, VEGF systemically impairs functions of multiple organs including those in the hematopoietic and endocrine systems, leading to early death. Anti-VEGF antibody, bevacizumab, and anti-VEGF receptor 2 (VEGFR-2), but not anti-VEGFR-1, reversed VEGF-induced cancer- associated systemic syndrome (CASS) and prevented death in tumor- bearing mice. Surprisingly, VEGFR2 blockage improved survival by rescuing mice from CASS without significantly compromising tumor growth, suggesting that "off-tumor" VEGF targets are more sensitive than the tumor vasculature to anti-VEGF drugs. Similarly, VEGF-induced CASS occurred in a spontaneous breast cancer mouse model overexpressing neu. Clinically, VEGF expression and CASS severity positively correlated in various human cancers. These findings define novel therapeutic targets of anti-VEGF agents and provide mechanistic insights into the action of this new class of clinically available anti-VEGF cancer drugs [ABSTRACT FROM AUTHOR]