ACOX2 Serves as a Favorable Indicator Related to Lipid Metabolism and Oxidative Stress for Biochemical Recurrence in Prostate Cancer.

Given the heterogeneity of tumors, there is an urgent need for accurate prognostic parameters in prostate cancer (PCa) patients. Lipid metabolism (LM) reprogramming and oxidative stress (OS) play a vital role in the progression of PCa. In this work, we identified five LM-OS-related genes (including ACOX2, PPRAGC1A, PTGS1, PTGS2, and HAO1) associated with the biochemical recurrence (BCR) of PCa. Subsequently, a prognostic signature was established based on these five genes. Kaplan-Meier survival estimates, receiver operating characteristic curves, and relationship analysis between risk score and clinical characters were applied to measure the robustness of the signature in an external cohort. A nomogram of risk score combined with clinical characteristics was constructed for clinical application. Functional enrichment analysis suggested that the underlying mechanism related to the signature included the calcium signaling, lipid transport, and cell cycle signaling pathways. Furthermore, WEE1 inhibitor was identified as a potential agent related to the cell cycle for high-risk patients. The mRNA expression and the prognostic value of the five genes were determined, and ACOX2 was identified as the key gene related to the prognostic signature. The protein expression of ACOX2 was measured in a prostate tissue microarray through an immunohistochemistry assay, confirming the bioinformatics results. By constructing the ACOX2-overexpressing PCa cell lines PC-3 and 22Rv1, the biological function of PCa cells was investigated. The cell viability, colony formation, migration, and invasion ability of PCa cell lines overexpressing ACOX2 were hindered. Decreased cellular lipid content and elevated cellular ROS content were observed in ACOX2-overexpressing PCa cell lines with reduced G2/M phases. In conclusion, this work presents the first prognostic signature specifically focused on LM-OS for PCa. ACOX2 could serve as a favorable indicator for the BCR in PCa. Further experiments are required to identify the potential underlying mechanism.

A Unique Approach: Biomimetic Graphdiyne-Based Nanoplatform to Treat Prostate Cancer by Combining Cuproptosis and Enhanced Chemodynamic Therapy.

Purpose: Current treatment approaches for Prostate cancer (PCa) often come with debilitating side effects and limited therapeutic outcomes. There is urgent need for an alternative effective and safe treatment for PCa. Methods: We developed a nanoplatform to target prostate cancer cells based on graphdiyne (GDY) and a copper-based metal-organic framework (GDY-CuMOF), that carries the chemotherapy drug doxorubicin (DOX) for cancer treatment. Moreover, to provide GDY-CuMOF@DOX with homotypic targeting capability, we coated the PCa cell membrane (DU145 cell membrane, DCM) onto the surface of GDY-CuMOF@DOX, thus obtaining a biomimetic nanoplatform (DCM@GDY-CuMOF@DOX). The nanoplatform was characterized by using transmission electron microscope, atomic force microscope, X-ray diffraction, etc. Drug release behavior, antitumor effects in vivo and in vitro, and biosafety of the nanoplatform were evaluated. Results: We found that GDY-CuMOF exhibited a remarkable capability to load DOX mainly through π-conjugation and pore adsorption, and it responsively released DOX and generated Cu+ in the presence of glutathione (GSH). In vivo experiments demonstrated that this nanoplatform exhibits remarkable cell-killing efficiency by generating lethal reactive oxygen species (ROS) and mediating cuproptosis. In addition, DCM@GDY-CuMOF@DOX effectively suppresses tumor growth in vivo without causing any apparent side effects. Conclusion: The constructed DCM@GDY-CuMOF@DOX nanoplatform integrates tumor targeting, drug-responsive release and combination with cuproptosis and chemodynamic therapy, offering insights for further biomedical research on efficient PCa treatment.

Machine learning-based integration develops a stress response stated T cell (Tstr)-related score for predicting outcomes in clear cell renal cell carcinoma.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Atropisomeric Carboxylic Acids Synthesis via Nickel-Catalyzed Enantioconvergent Carboxylation of Aza-Biaryl Triflates with CO2.

Upgrading CO2 to value-added chiral molecules via catalytic asymmetric C-C bond formation is a highly important yet challenging task. Although great progress on the formation of centrally chiral carboxylic acids has been achieved, catalytic construction of axially chiral carboxylic acids with CO2 has never been reported to date. Herein, we report the first catalytic asymmetric synthesis of axially chiral carboxylic acids with CO2, which is enabled by nickel-catalyzed dynamic kinetic asymmetric reductive carboxylation of racemic aza-biaryl triflates. A variety of important axially chiral carboxylic acids, which are valuable but difficult to obtain via catalysis, are generated in an enantioconvergent version. This new methodology features good functional group tolerance, easy to scale-up, facile transformation and avoids cumbersome steps, handling organometallic reagents and using stoichiometric chiral materials. Mechanistic investigations indicate a dynamic kinetic asymmetric transformation process induced by chiral nickel catalysis.

Cu-Catalyzed Asymmetric Dicarboxylation of 1,3-Dienes with CO2.

Dicarboxylic acids and derivatives are important building blocks in organic synthesis, biochemistry, and the polymer industry. Although catalytic dicarboxylation with CO2 represents a straightforward and sustainable route to dicarboxylic acids, it is still highly challenging and limited to generation of achiral or racemic dicarboxylic acids. To date, catalytic asymmetric dicarboxylation with CO2 to give chiral dicarboxylic acids has not been reported. Herein, we report the first asymmetric dicarboxylation of 1,3-dienes with CO2 via Cu catalysis. This strategy provides an efficient and environmentally benign route to chiral dicarboxylic acids with high regio-, chemo-, and enantioselectivities. The copper self-relay catalysis, that is, Cu-catalyzed boracarboxylation of 1,3-dienes to give carboxylated allyl boronic ester intermediates and subsequent carboxylation of C-B bonds to give dicarboxylates, is key to the success of this dicarboxylation. Moreover, this protocol exhibits broad substrate scope, good functional group tolerance, easy product derivatizations, and facile synthesis of chiral liquid crystalline polyester and drug-like scaffolds.

FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to the HIF2α blockade by facilitating LDHA phosphorylation.

Renal cell carcinoma (RCC) is one of the three major malignant tumors of the urinary system and originates from proximal tubular epithelial cells. Clear cell renal cell carcinoma (ccRCC) accounts for approximately 80% of RCC cases and is recognized as a metabolic disease driven by genetic mutations and epigenetic alterations. Through bioinformatic analysis, we found that FK506 binding protein 10 (FKBP10) may play an essential role in hypoxia and glycolysis pathways in ccRCC progression. Functionally, FKBP10 promotes the proliferation and metastasis of ccRCC in vivo and in vitro depending on its peptidyl-prolyl cis-trans isomerase (PPIase) domains. Mechanistically, FKBP10 binds directly to lactate dehydrogenase A (LDHA) through its C-terminal region, the key regulator of glycolysis, and enhances the LDHA-Y10 phosphorylation, which results in a hyperactive Warburg effect and the accumulation of histone lactylation. Moreover, HIFα negatively regulates the expression of FKBP10, and inhibition of FKBP10 enhances the antitumor effect of the HIF2α inhibitor PT2385. Therefore, our study demonstrates that FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to HIF2α blockade by facilitating LDHA phosphorylation, which may be exploited for anticancer therapy.

Metformin escape in prostate cancer by activating the PTGR1 transcriptional program through a novel super-enhancer.

The therapeutic efficacy of metformin in prostate cancer (PCa) appears uncertain based on various clinical trials. Metformin treatment failure may be attributed to the high frequency of transcriptional dysregulation, which leads to drug resistance. However, the underlying mechanism is still unclear. In this study, we found evidences that metformin resistance in PCa cells may be linked to cell cycle reactivation. Super-enhancers (SEs), crucial regulatory elements, have been shown to be associated with drug resistance in various cancers. Our analysis of SEs in metformin-resistant (MetR) PCa cells revealed a correlation with Prostaglandin Reductase 1 (PTGR1) expression, which was identified as significantly increased in a cluster of cells with metformin resistance through single-cell transcriptome sequencing. Our functional experiments showed that PTGR1 overexpression accelerated cell cycle progression by promoting progression from the G0/G1 to the S and G2/M phases, resulting in reduced sensitivity to metformin. Additionally, we identified key transcription factors that significantly increase PTGR1 expression, such as SRF and RUNX3, providing potential new targets to address metformin resistance in PCa. In conclusion, our study sheds new light on the cellular mechanism underlying metformin resistance and the regulation of the SE-TFs-PTGR1 axis, offering potential avenues to enhance metformin's therapeutic efficacy in PCa.

A reactive oxygen species-related signature to predict prognosis and aid immunotherapy in clear cell renal cell carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is a malignant disease containing tumor-infiltrating lymphocytes. Reactive oxygen species (ROS) are present in the tumor microenvironment and are strongly associated with cancer development. Nevertheless, the role of ROS-related genes in ccRCC remains unclear. Methods: We describe the expression patterns of ROS-related genes in ccRCC from The Cancer Genome Atlas and their alterations in genetics and transcription. An ROS-related gene signature was constructed and verified in three datasets and immunohistochemical staining (IHC) analysis. The immune characteristics of the two risk groups divided by the signature were clarified. The sensitivity to immunotherapy and targeted therapy was investigated. Results: Our signature was constructed on the basis of glutamate-cysteine ligase modifier subunit (GCLM), interaction protein for cytohesin exchange factors 1 (ICEF1), methionine sulfoxide reductase A (MsrA), and strawberry notch homolog 2 (SBNO2) genes. More importantly, protein expression levels of GCLM, MsrA, and SBNO2 were detected by IHC in our own ccRCC samples. The high-risk group of patients with ccRCC suffered lower overall survival rates. As an independent predictor of prognosis, our signature exhibited a strong association with clinicopathological features. An accurate nomogram for improving the clinical applicability of our signature was constructed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that the signature was closely related to immune response, immune activation, and immune pathways. The comprehensive results revealed that the high-risk group was associated with high infiltration of regulatory T cells and CD8+ T cells and more benefited from targeted therapy. In addition, immunotherapy had better therapeutic effects in the high-risk group. Conclusion: Our signature paved the way for assessing prognosis and developing more effective strategies of immunotherapy and targeted therapy in ccRCC.

Arylcarboxylation of unactivated alkenes with CO2 via visible-light photoredox catalysis.

Photocatalytic carboxylation of alkenes with CO2 is a promising and sustainable strategy to synthesize high value-added carboxylic acids. However, it is challenging and rarely investigated for unactivated alkenes due to their low reactivities. Herein, we report a visible-light photoredox-catalyzed arylcarboxylation of unactivated alkenes with CO2, delivering a variety of tetrahydronaphthalen-1-ylacetic acids, indan-1-ylacetic acids, indolin-3-ylacetic acids, chroman-4-ylacetic acids and thiochroman-4-ylacetic acids in moderate-to-good yields. This reaction features high chemo- and regio-selectivities, mild reaction conditions (1 atm, room temperature), broad substrate scope, good functional group compatibility, easy scalability and facile derivatization of products. Mechanistic studies indicate that in situ generation of carbon dioxide radical anion and following radical addition to unactivated alkenes might be involved in the process.

Prognostic implication of heterogeneity and trajectory progression induced by enzalutamide in prostate cancer.

Background: Enzalutamide, as a second-generation endocrine therapy drug for prostate cancer (PCa), is prominent representative among the synthetic androgen receptor antagonists. Currently, there is lack of enzalutamide-induced signature (ENZ-sig) for predicting progression and relapse-free survival (RFS) in PCa. Methods: Enzalutamide-induced candidate markers were derived from single-cell RNA sequencing analysis integrating three enzalutamide-stimulated models (0-, 48-, and 168-h enzalutamide stimulation). ENZ-sig was constructed on the basis of candidate genes that were associated with RFS in The Cancer Genome Atlas leveraging least absolute shrinkage and selection operator method. The ENZ-sig was further validated in GSE70768, GSE94767, E-MTAB-6128, DFKZ, GSE21034, and GSE70769 datasets. Biological enrichment analysis was used to discover the underlying mechanism between high ENZ-sig and low ENZ-sig in single-cell RNA sequencing and bulk RNA sequencing. Results: We identified a heterogenous subgroup that induced by enzalutamide stimulation and found 53 enzalutamide-induced candidate markers that are related to trajectory progression and enzalutamide-stimulated. The candidate genes were further narrowed down into 10 genes that are related to RFS in PCa. A 10-gene prognostic model (ENZ-sig)-IFRD1, COL5A2, TUBA1A, CFAP69, TMEM388, ACPP, MANEA, FOSB, SH3BGRL, and ST7-was constructed for the prediction of RFS in PCa. The effective and robust predictability of ENZ-sig was verified in six independent datasets. Biological enrichment analysis revealed that differentially expressed genes in high ENZ-sig were more activated in cell cycle-related pathway. High-ENZ-sig patients were more sensitive to cell cycle-targeted drugs (MK-1775, AZD7762, and MK-8776) than low-ENZ-sig patients in PCa. Conclusions: Our results provided evidence and insight on the potential utility of ENZ-sig in PCa prognosis and combination therapy strategy of enzalutamide and cell cycle-targeted compounds in treating PCa.

Electroreductive Dicarboxylation of Unactivated Skipped Dienes with CO2.

Carboxylation of easily available alkenes with CO2 is highly important to afford value-added carboxylic acids. Although dicarboxylation of activated alkenes, especially 1,3-dienes, has been widely investigated, the challenging dicarboxylation of unactivated 1,n-dienes (n>3) with CO2 remains unexplored. Herein, we report the first dicarboxylation of unactivated skipped dienes with CO2 via electrochemistry, affording valuable dicarboxylic acids. Control experiments and DFT calculations support the single electron transfer (SET) reduction of CO2 to its radical anion, which is followed by sluggish radical addition to unactivated alkenes, SET reduction of unstabilized alkyl radicals to carbanions and nucleophilic attack on CO2 to give desired products. This reaction features mild reaction conditions, broad substrate scope, facile derivations of products and promising application in polymer chemistry.

Photocatalytic Carboxylation of C-N Bonds in Cyclic Amines with CO2 by Consecutive Visible-Light-Induced Electron Transfer.

Visible-light photocatalytic carboxylation with CO2 is highly important. However, it still remains challenging for reluctant substrates with low reduction potentials. Herein, we report a novel photocatalytic carboxylation of C-N bonds in cyclic amines with CO2 via consecutive photo-induced electron transfer (ConPET). It is also the first photocatalytic reductive ring-opening reaction of azetidines, pyrrolidines and piperidines. This strategy is practical to transform a variety of easily available cyclic amines to valuable ß-, γ-, δ- and ϵ-amino acids in moderate-to-excellent yields. Moreover, the method also features mild and transition-metal-free conditions, high selectivity, good functional-group tolerance, facile scalability and product derivations. Mechanistic studies indicate that the ConPET might be the key to generating highly reactive photocatalysts, which enable the reductive activation of cyclic amines to generate carbon radicals and carbanions as the key intermediates.

Identification and experimental validation of a tumor-infiltrating lymphocytes-related long noncoding RNA signature for prognosis of clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a common aggressive malignant tumor of the urinary system. Given the heterogeneity of the tumor microenvironment, immunotherapy may not fully exert its role in the treatment of advanced patients. Long noncoding RNA (lncRNA) has been reported to be critically associated with the differentiation and maturation of tumor-infiltrating lymphocytes (TILs), which work against tumor cells. In this study, we identified 10 TIL-related lncRNAs (AL590094.1, LINC02027, LINC00460, AC147651.1, AC026401.3, LINC00944, LINC01615, AP000439.2, AL162586.1, and AC084876.1) by Pearson correlation, univariate Cox regression, Lasso regression, and multivariate Cox regression based on The Cancer Genome Atlas (TCGA) database. A risk score model was established based on these lncRNAs. Next, a nomogram was constructed to predict the overall survival. By employing differentially expressed genes (DEGs) between groups with high and low risk scores, gene ontology (GO) enrichment analysis was performed to identify the major biological processes (BP) related to immune DEGs. We analyzed the mutation data of the groups and demonstrated that SETD2 and BAP1 had the highest mutation frequency in the high-risk group. The "CIBERSORT" R package was used to detect the abundance of TILs in the groups. The expression of lymphocyte markers was compared. We also determined the expression of two lncRNAs (AC084876.1 and AC026401.3) and their relationship with lymphocyte markers in the kidney tissue of ccRCC patients and showed that there was a positive correlation between AC084876.1 and FoxP3. Proliferation, migration, and invasion of AC084876.1-downregulated ccRCC cell lines were inhibited, and the expression of PD-L1 and TGF-ß secretion decreased. To our knowledge, this is the first bioinformatics study to establish a prognostic model for ccRCC using TIL-related lncRNAs. These lncRNAs were associated with T-cell activities and may serve as biomarkers of disease prognosis.

Integrated analysis reveals prognostic value and progression-related role of AMIGO2 in prostate cancer.

Background: Even though emerging studies supplied evidence that Adhesion Molecule with Ig Like Domain family 2 (AMIGO2) plays a critical role in numerous cancers, comprehensive analysis of the prognostic value and significant role of AMIGO2 in prostate cancer (PCa) have not been described. Methods: Differentially expressed analysis, survival analysis and univariate cox regression analysis were first performed to explore the diagnostic and prognostic role of AMIGO2 in various cancers, especially in PCa. Tissue microarray were used to examined the association between AMGIO2 and clinical features. Multivariate cox regression analysis, concordance index, nomogram construction, the receiver operator characteristic curve and calibration curves were further used to discover the effects of AMIGO2 on recurrence-free survival (RFS) and clinicopathological characteristics, including age, Gleason score (GS) and tumor stage. Genetic and Epigenetic Alterations analysis were further conducted to explore the potential effect of AMIGO2 in PCa and examined by biological function analysis and in vitro experiments. Results: AMIGO2 was associated with poor RFS (P<0.05) and differentially expressed (P<0.05) in multiple cancer type, especially in PCa. Besides, decreasing the expression of AMIGO2 inhibited PCa cell proliferation and colony formation in vitro. In addition, AMIGO2 was a reliable prognostic marker providing additional information (C-index: 0.7) that supplement the currently used prognosis evaluation system, e.g., T stage (C-index: 0.62) and GS (C-index: 0.65). A novel nomogram was established based on AMIGO2, tumor stage and GS with accuracies (areas under curve) of 0.70, 0.78 and 0.82 for predicting 3-, 5- and 7-year RFS, respectively. Bioinformatic analysis and in vitro examination also suggested that AMIGO2 might involve in the progression of PCa tumors inducing epithelial mesenchymal transition (EMT). Conclusions: We identified AMIGO2 as a pan-cancer gene that could not only be a prognostic biomarker in various cancers, especially in PCa, but may functionally promoting PCa progression via EMT and mediating docetaxel resistance, suggesting AMIGO2 as a potential target for future treatment of PCa.

Untargeted metabolomics reveals alterations in the metabolic reprogramming of prostate cancer cells by double-stranded DNA-modified gold nanoparticles.

Metabolic reprogramming plays an important role in the development of prostate cancer (PCa). However, there are few reports on the effects of nanomaterials as vectors on cancer metabolic reprogramming. Herein, a type of nanoparticle with good biocompatibility was synthesized by modifying the double-stranded of DNA containing a sulfhydryl group on the surface of gold nanoparticles (AuNPs-dsDNA) through salt-aging conjugation methods. The resultant AuNPs-dsDNA complexes possessed low toxicity to PC3 and DU145 cells in vitro. There was also no obvious hepatorenal toxicity after intravenous injection of AuNPs-dsDNA complexes in vivo, which indicated that these nanoparticles had good biological compatibilities. We investigated their biological functions using prostate cancer cells. Seahorse assay showed that AuNPs-dsDNA complexes could increase glycolysis and glycolysis capacity both in PC3 and DU145 cells. We further detected the expression of glycolysis-related genes by qPCR assay, and found that PKM2, PDHA, and LDHA were significantly upregulated. Furthermore, untargeted metabolomics revealed that PC (18:2(9Z,12Z)/18:2(9Z,12Z)) and PC (18:0/18:2 (9Z,12Z)) levels were decreased and inosinic acid level was increased in PC3 cells. Whereas (3S,6E,10E)-1,6,10,14-Phytatetraen-3-ol, Plasmenyl-PE 36:5 and Cer (d18:2/18:2) were decreased, PE 21:3 and 1-pyrrolidinecarboxaldehyde were increased in DU145 cells after co-culturing with AuNPs-dsDNA. In summary, we found that AuNPs and AuNPs-dsDNA complexes possibly regulate the metabolic reprogramming of cancer cells mainly through the lipid metabolic pathways, which could compensate for the previously mentioned phenomenon of enhanced glycolysis and glycolysis capacity. This will provide an important theoretical basis for our future research on the characteristic targeted design of nanomaterials for cancer metabolism.

Differential Expression of E2F Transcription Factors and Their Functional and Prognostic Roles in Human Prostate Cancer.

Given the tumor heterogeneity, most of the current prognostic indicators cannot accurately evaluate the prognosis of patients with prostate cancer, and thus, the best opportunity to intervene in the progression of this disease is missed. E2F transcription factors (E2Fs) have been reported to be involved in the growth of various cancers. Accumulating studies indicate that prostate cancer (PCa) carcinogenesis is attributed to aberrant E2F expression or E2F alteration. However, the expression patterns and prognostic value of the eight E2Fs in prostate cancer have yet to be explored. In this study, The Cancer Genome Atlas (TCGA), Kaplan-Meier Plotter, Metascape, the Kyoto Encyclopedia of Genes and Genomes (KEGG), CIBERSORT, and cBioPortal and bioinformatic analysis were used to investigate E2Fs in patients with PCa. Our results showed that the expression of E2F1-3, E2F5, and E2F6 was higher in prostate cancer tissues than in benign tissues. Furthermore, elevated E2F1-3 and E2F5 expression levels were associated with a higher Gleason score (GS), advanced tumor stage, and metastasis. Survival analysis suggested that high transcription levels of E2F1-3, E2F5, E2F6, and E2F8 were associated with a higher risk of biochemical recurrence. In addition, we developed a prognostic model combining E2F1, E2F6, Gleason score, and the clinical stage that may accurately predict a biochemical recurrence-free survival. Functional enrichment analysis revealed that the E2F family members and their neighboring genes were mainly enriched in cell cycle-related pathways. Somatic mutations in different subgroups were also investigated, and immune components were predicted. Further experiments are warranted to clarify the biological associations between Pca-related E2F family genes, which may influence prognosis via the cell cycle pathway.

Tumor Suppressor Role and Clinical Significance of the FEV Gene in Prostate Cancer.

Background: In our previous research, we developed a 32-gene risk index model that may be utilized as a robust prognostic method for predicting prostate cancer (PCa) recurrence after surgery. Among the 32 genes, the Fifth Ewing Variant (FEV) gene was one of the top downregulated genes in relapsed PCa. However, current understanding of the FEV gene and its involvement in PCa is limited. Methods: FEV mRNA expression was analyzed and correlated to clinical outcomes in PCa patients who underwent prostatectomy at the Massachusetts General Hospital. Specimens from tissue microarray (TMA) including 102 prostate cancer patients were analysis for the expression of FEV. Meanwhile, FEV expression profiles were also assessed in PCa cell lines and in BPH-1 prostate epithelial cells using western blotting and quantitative reverse transcription-PCR (qRT-PCR). Furthermore, we transfected LNCaP and PC-3 cells with either an empty vector or full-length FEV gene and performed in vitro cell functional assays. The part FEV plays in tumor xenograft growth was also assessed in vivo. Results: Of the 191 patients included in this study base on the DASL dataset, 77 (40.3%) and 24 (13.6%), respectively, developed prostate-specific antigen (PSA) relapse and metastasis postradical prostatectomy. Significant FEV downregulation was observed in PCa patients showing PSA failure and metastasis. The protein expression of FEV was significantly negatively correlated with the Gleason score and pathological stage in prostate cancer tissues. Similarly, FEV expression significantly decreased in all PCa cell lines relative to BPH-1 (all P < 0.05). Functional assays revealed that FEV expression markedly inhibited PCa cell growth, migration, and invasion, which in turn significantly repressed the growth of tumor xenografts in vivo. Conclusion: The results of this study suggest an association between downregulated FEV expression and PSA relapse in PCa patients. In addition, FEV may act as a tumor suppressor in PCa.

Photoredox-Catalyzed Defluorinative Functionalizations of Polyfluorinated Aliphatic Amides and Esters.

Selective C-F bond functionalization of perfluoalkyl units has huge potential towards accessing functionalized organofluorinated compounds, but remains challenging due to the high C-F bond strength and inherent selectivity challenges. We report a new catalytic approach to the selective functionalization of strong C-F bonds in polyfluorinated aliphatic esters and amides. This simple reaction proceeds in mild and operational fashion with divergent conversions, including hydrodefluorination, defluoroalkylation, and defluoroalkenylation, affording a diverse array of important partially fluorinated motifs. Straightforward downstream chemistry towards fluorinated alcohols, amines and drug derivatives highlights the potential of the protocol.