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Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa. [ABSTRACT FROM AUTHOR]

Whether TMPRSS2-ERG fusion and TP53 gene alteration coordinately promote prostate cancer (PCa) remains unclear. Here we demonstrate that TMPRSS2-ERG fusion and TP53 mutation / deletion co-occur in PCa patient specimens and this co-occurrence accelerates prostatic oncogenesis. p53 gain-of-function (GOF) mutants are now shown to bind to a unique DNA sequence in the CTNNB1 gene promoter and transactivate its expression. ERG and β-Catenin co-occupy sites at pyrimidine synthesis gene (PSG) loci and promote PSG expression, pyrimidine synthesis and PCa growth. β-Catenin inhibition by small molecule inhibitors or oligonucleotide-based PROTAC suppresses TMPRSS2-ERG- and p53 mutant-positive PCa cell growth in vitro and in mice. Our study identifies a gene transactivation function of GOF mutant p53 and reveals β-Catenin as a transcriptional target gene of p53 GOF mutants and a driver and therapeutic target of TMPRSS2-ERG- and p53 GOF mutant-positive PCa. TP53 alteration and TMPRSS2-ERG fusion are often found together in prostate cancer. Here, the authors show that gain-of-function mutant p53 collaborates with ERG proto-oncogene to drive prostate cancer tumourigenesis by activating beta-catenin expression and afterwards pyrimidine synthesis. [ABSTRACT FROM AUTHOR]

Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N7-methylguanosine (m7G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m7G tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5'tRNA fragments. 5'tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed m7G tRNA methylation in cancer cell translation control and tumour biology. [ABSTRACT FROM AUTHOR]

Background: ST6GALNAC family members function as sialyltransferases and have been implicated in cancer progression. However, their aberrant expression levels, prognostic values and specific roles in metastatic prostate cancer (PCa) remain largely unclear. Methods: Two independent public datasets (TCGA-PRAD and GSE21032), containing 648 PCa samples in total, were employed to comprehensively examine the mRNA expression changes of ST6GALNAC family members in PCa, as well as their associations with clinicopathological parameters and prognosis. The dysregulation of ST6GALNAC5 was further validated in a mouse PCa model and human PCa samples from our cohort (n = 64) by immunohistochemistry (IHC). Gene Set Enrichment Analysis, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and drug sensitivity analyses were performed to enrich the biological processes most related to ST6GALNAC5. Sulforhodamine B, transwell, luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to examine the PCa cell proliferation, invasion and transcriptional regulation, respectively. Results: Systematical investigation of six ST6GALNAC family members in public datasets revealed that ST6GALNAC5 was the only gene consistently and significantly upregulated in metastatic PCa, and ST6GALNAC5 overexpression was also positively associated with Gleason score and predicted poor prognosis in PCa patients. IHC results showed that (1) ST6GALNAC5 protein expression was increased in prostatic intraepithelial neoplasia and further elevated in PCa from a PbCre;PtenF/F mouse model; (2) overexpressed ST6GALNAC5 protein was confirmed in human PCa samples comparing with benign prostatic hyperplasia samples from our cohort (p < 0.001); (3) ST6GALNAC5 overexpression was significantly correlated with perineural invasion of PCa. Moreover, we first found transcription factor GATA2 positively and directly regulated ST6GALNAC5 expression at transcriptional level. ST6GALNAC5 overexpression could partially reverse GATA2-depletion-induced inhibition of PCa cell invasion. The GATA2-ST6GALNAC5 signature exhibited better prediction on the poor prognosis in PCa patients than GATA2 or ST6GALNAC5 alone. Conclusions: Our results indicated that GATA2-upregulated ST6GALNAC5 might serve as an adverse prognostic biomarker promoting prostate cancer cell invasion. [ABSTRACT FROM AUTHOR]

Since the theory of modern anatomical partitioning of the prostate was proposed, the differences in the incidence and pathological parameters of prostate cancer between the peripheral zone and transition zone have been gradually revealed. It suggests that there are differences in the pathogenic pathways and molecular biology of prostate cancer between different regions of origin. Over the past decade, advances in sequencing technologies have revealed more about molecules, genomes, and cell types specific to the peripheral and transitional zones. In recent years, the innovation of spatial imaging and multiple-parameter magnetic resonance imaging has provided new technical support for the zonal study of prostate cancer. In this work, we reviewed all the research results and the latest research progress in the study of prostate cancer in the past two decades. We summarized and proposed several vital issues and focused directions for understanding the differences between peripheral and transitional zones in prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose: Our study was to determine whether immediate androgen deprivation therapy (ADT) plus radiotherapy (RT) extends survival in men with node-positive prostate cancer (PCa) after radical prostatectomy (RP) compared with those who received ADT alone. Methods: A total of 99 consecutive patients with pathological positive lymph nodes (pN1) PCa were included in this study to receive immediate ADT plus RT (n = 70) or to receive immediate ADT alone (n = 29). The primary endpoint was castration-resistant prostate cancer (CRPC) free survival; the secondary endpoints were distant metastasis-free survival. Cox regression was used to assess the independent risk factors for CRPC. Results: The median follow-up time was 34.0 (24.8, 47.8) months and 34.25 (23.0, 49.0) months, respectively, in the ADT + RT group and ADT-alone group. The 5-year CRPC-free survival rate was 79.5% and 58.3%, respectively, in the ADT + RT group and ADT-alone group (p = 0.308). The 5-year distant metastasis-free survival rate was 71.4% and 38.8, respectively, in the ADT + RT group and ADT-alone group (p = 0.478). Compared with ADT-alone group, we saw a modest, but no significant improvement in CRPC-free survival and distant metastasis-free survival in ADT + RT group. The results of Cox regression showed that positive lymph nodes ≥ 4 was an independent risk factor for CRPC (p = 0.041). Conclusions: We found that immediate ADT plus RT compared to ADT alone did not improve CRPC-free and metastasis-free survival. Multivariate Cox regression analyses also indicated that patients with positive lymph nodes < 4 may benefits from ADT plus RT. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, and the development of castrate-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-related mortality. While CRPC typically develops through a gain in androgen receptor (AR) signaling, a subset of CRPC will lose reliance on the AR. This process involves genetic, epigenetic, and hormonal changes that promote cellular plasticity, leading to AR-indifferent disease, with neuroendocrine prostate cancer (NEPC) being the quintessential example. NEPC is enriched following treatment with second-generation antiandrogens and exhibits resistance to endocrine therapy. Loss of RB1, TP53, and PTEN expression and MYCN and AURKA amplification appear to be key drivers for NEPC differentiation. Epigenetic modifications also play an important role in the transition to a neuroendocrine phenotype. DNA methylation of specific gene promoters can regulate lineage commitment and differentiation. Histone methylation can suppress AR expression and promote neuroendocrinespecific gene expression. Emerging data suggest that EZH2 is a key regulator of this epigenetic rewiring. Several mechanisms drive AR-dependent castration resistance, notably AR splice variant expression, expression of the adrenalpermissive 3bHSD1 allele, and glucocorticoid receptor expression. Aberrant epigenetic regulation also promotes radioresistance by altering the expression of DNA repair- and cell cycle-related genes. Novel therapies are currently being developed to target these diverse genetic, epigenetic, and hormonal mechanisms promoting lineage plasticity-driven NEPC. [ABSTRACT FROM AUTHOR]

Background: Transgender and gender diverse (TGD) individuals experience an incongruence between their assigned birth sex and gender identity. They may have a higher prevalence of health conditions associated with cancer risk than cisgender people. Aim: To examine the prevalence of several cancer risk factors among TGD individuals compared with cisgender individuals. Design and setting: A cross-sectional analysis was conducted using data from the UK's Clinical Practice Research Datalink to identify TGD individuals between 1988–2020, matched to 20 cisgender men and 20 cisgender women on index date (date of diagnosis with gender incongruence), practice, and index age (age at index date). Assigned birth sex was determined from gender-affirming hormone use and procedures, and sex-specific diagnoses documented in the medical record. Method: The prevalence of each cancer risk factor was calculated and the prevalence ratio by gender identity was estimated using log binomial or Poisson regression models adjusted for age and year at study entry, and obesity where appropriate. Results: There were 3474 transfeminine (assigned male at birth) individuals, 3591 transmasculine (assigned female at birth) individuals, 131 747 cisgender men, and 131 827 cisgender women. Transmasculine people had the highest prevalence of obesity (27.5%) and 'ever smoking' (60.2%). Transfeminine people had the highest prevalence of dyslipidaemia (15.1%), diabetes (5.4%), hepatitis C infection (0.7%), hepatitis B infection (0.4%), and HIV infection (0.8%). These prevalence estimates remained elevated in the TGD populations compared with cisgender persons in the multivariable models. Conclusion: Multiple cancer risk factors are more prevalent among TGD individuals compared with cisgender individuals. Future research should examine how minority stress contributes to the increased prevalence of cancer risk factors in this population. [ABSTRACT FROM AUTHOR]

Background: Globally, despite prostate cancer (PCa) representing second most prevalent malignancy in male, the precise molecular mechanisms implicated in its pathogenesis remain unclear. Consequently, elucidating the key molecular regulators that govern disease progression could substantially contribute to the establishment of novel therapeutic strategies, ultimately advancing the management of PCa. Methods: A total of 49 PCa tissues and 43 adjacent normal tissues were collected from January 2017 to December 2021 at Zhongnan Hospital of Wuhan University. The advanced transcriptomic methodologies were employed to identify differentially expressed mRNAs in PCa. The expression of aspartoacylase (ASPA) in PCa was thoroughly evaluated using quantitative real-time PCR and Western blotting techniques. To elucidate the inhibitory role of ASPA in PCa cell proliferation and metastasis, a comprehensive set of in vitro and in vivo assays were conducted, including orthotopic and tumor-bearing mouse models (n = 8 for each group). A combination of experimental approaches, such as Western blotting, luciferase assays, immunoprecipitation assays, mass spectrometry, glutathione S-transferase pull-down experiments, and rescue studies, were employed to investigate the underlying molecular mechanisms of ASPA's action in PCa. The Student's t-test was employed to assess the statistical significance between two distinct groups, while one-way analysis of variance was utilized for comparisons involving more than two groups. A two-sided P value of less than 0.05 was deemed to indicate statistical significance. Results: ASPA was identified as a novel inhibitor of PCa progression. The expression of ASPA was found to be significantly down-regulated in PCa tissue samples, and its decreased expression was independently associated with patients' prognosis (HR = 0.60, 95% CI 0.40–0.92, P = 0.018). Our experiments demonstrated that modulation of ASPA activity, either through gain- or loss-of-function, led to the suppression or enhancement of PCa cell proliferation, migration, and invasion, respectively. The inhibitory role of ASPA in PCa was further confirmed using orthotopic and tumor-bearing mouse models. Mechanistically, ASPA was shown to directly interact with the LYN and inhibit the phosphorylation of LYN as well as its downstream targets, JNK1/2 and C-Jun, in both PCa cells and mouse models, in an enzyme-independent manner. Importantly, the inhibition of LYN activation by bafetinib abrogated the promoting effect of ASPA knockdown on PCa progression in both in vitro and in vivo models. Moreover, we observed an inverse relationship between ASPA expression and LYN activity in clinical PCa samples, suggesting a potential regulatory role of ASPA in modulating LYN signaling. Conclusion: Our findings provide novel insights into the tumor-suppressive function of ASPA in PCa and highlight its potential as a prognostic biomarker and therapeutic target for the management of this malignancy. [ABSTRACT FROM AUTHOR]

Background: Human malignancies are composed of heterogeneous subpopulations of cancer cells with phenotypic and functional diversity. Among them, a unique subset of cancer stem cells (CSCs) has both the capacity for self-renewal and the potential to differentiate and contribute to multiple tumor properties. As such, CSCs are promising cellular targets for effective cancer therapy. At the molecular level, hyper-activation of multiple stemness regulatory signaling pathways and downstream transcription factors play critical roles in controlling CSCs establishment and maintenance. To regulate CSC properties, these stemness pathways are controlled by post-translational modifications including, but not limited to phosphorylation, acetylation, methylation, and ubiquitination. Conclusion: In this review, we focus on E3 ubiquitin ligases and their roles and mechanisms in regulating essential hallmarks of CSCs, such as self-renewal, invasion and metastasis, metabolic reprogramming, immune evasion, and therapeutic resistance. Moreover, we discuss emerging therapeutic approaches to eliminate CSCs through targeting E3 ubiquitin ligases by chemical inhibitors and proteolysis-targeting chimera (PROTACs) which are currently under development at the discovery, preclinical, and clinical stages. Several outstanding issues such as roles for E3 ubiquitin ligases in heterogeneity and phenotypical/functional evolution of CSCs remain to be studied under pathologically and clinically relevant conditions. With the rapid application of functional genomic and proteomic approaches at single cell, spatiotemporal, and even single molecule levels, we anticipate that more specific and precise functions of E3 ubiquitin ligases will be delineated in dictating CSC properties. Rational design and proper translation of these mechanistic understandings may lead to novel therapeutic modalities for cancer procession medicine. [ABSTRACT FROM AUTHOR]

Purpose: Prostate cancer is the second most common cancer diagnosed worldwide and the third most common cancer among men in India. This study's objective was to characterise the mutational landscape of Indian prostate cancer using whole-exome sequencing to identify population-specific polymorphisms. Methods: Whole-exome sequencing was performed of 58 treatment-naive primary prostate tumors of Indian origin. Multiple computational and statistical analyses were used to profile the known common mutations, other deleterious mutations, driver genes, prognostic biomarkers, and gene signatures unique to each clinical parameter. Cox analysis was performed to validate survival-associated genes. McNemar test identified genes significant to recurrence and receiver-operating characteristic (ROC) analysis was conducted to determine its accuracy. OncodriveCLUSTL algorithm was used to deduce driver genes. The druggable target identified was modeled with its known inhibitor using Autodock. Results: TP53 was the most commonly mutated gene in our cohort. Three novel deleterious variants unique to the Indian prostate cancer subtype were identified: POLQ, FTHL17, and OR8G1. COX regression analysis identified ACSM5, a mitochondrial gene responsible for survival. CYLC1 gene, which encodes for sperm head cytoskeletal protein, was identified as an unfavorable prognostic biomarker indicative of recurrence. The novel POLQ mutant, also identified as a driver gene, was evaluated as the druggable target in this study. POLQ, a DNA repair enzyme implicated in various cancer types, is overexpressed and is associated with a poor prognosis. The mutant POLQ was subjected to structural analysis and modeled with its known inhibitor novobiocin resulting in decreased binding efficiency necessitating the development of a better drug. Conclusion: In this pilot study, the molecular profiling using multiple computational and statistical analyses revealed distinct polymorphisms in the Indian prostate cancer cohort. The mutational signatures identified provide a valuable resource for prognostic stratification and targeted treatment strategies for Indian prostate cancer patients. The DNA repair enzyme, POLQ, was identified as the druggable target in this study. [ABSTRACT FROM AUTHOR]

Androgen receptor (AR) signaling have been frequently targeted for treating prostate cancer (PCa). Even though primarily patients receive a good therapeutic outcome by targeting AR signaling axis, eventually it emerges resistance by altering the genetic makeup of prostate cells. However, to develop an effective therapeutic regime, it is essential to recognize key genetic alterations in PCa. The most common genetic alterations that give rise to distinct androgen different differentiation states are gene fusion of TMPRSS2 with ETS family genes, deletion, or mutation of tumor suppressor PTEN and TP53 gene, amplification or splicing of AR, altered DNA repair genes. In this review, we describe key genes and genetic changes that have been recognized to contribute to altered prostate environment. [ABSTRACT FROM AUTHOR]

Background: Metastasis is a crucial aspect of disease progression leading to death in patients with prostate cancer (PCa). However, its mechanism remains unclear. We aimed to explore the mechanism of lymph node metastasis (LNM) by analyzing the heterogeneity of tumor microenvironment (TME) in PCa using scRNA-seq. Methods: A total of 32,766 cells were obtained from four PCa tissue samples for scRNA-seq, annotated, and grouped. InferCNV, GSVA, DEG functional enrichment analysis, trajectory analysis, intercellular network evaluation, and transcription factor analysis were carried out for each cell subgroup. Furthermore, validation experiments targeting luminal cell subgroups and CXCR4 + fibroblast subgroup were performed. Results: The results showed that only EEF2 + and FOLH1 + luminal subgroups were present in LNM, and they appeared at the initial stage of luminal cell differentiation, which were comfirmed by verification experiments. The MYC pathway was enriched in the EEF2 + and FOLH1 + luminal subgroups, and MYC was associated with PCa LNM. Moreover, MYC did not only promote the progression of PCa, but also led to immunosuppression in TME by regulating PDL1 and CD47. The proportion of CD8 + T cells in TME and among NK cells and monocytes was lower in LNM than in the primary lesion, while the opposite was true for Th and Treg cells. Furthermore, these immune cells in TME underwent transcriptional reprogramming, including CD8 + T subgroups of CCR7 + and IL7R+, as well as M2-like monocyte subgroups expressing tumor-associated signature genes, like CCR7, SGKI, and RPL31. Furthermore, STEAP4+, ADGRF5 + and CXCR4+, and SRGNC + fibroblast subgroups were closely related to tumor progression, tumor metabolism, and immunosuppression, indicating their contributions in PCa metastasis. Meanwhile, The presence of CXCR4 + Fibroblasts in PCa was confirmed by polychromatic immunofluorescence. Conclusions: The significant heterogeneity of luminal, immune, and interstitial cells in PCa LNM may not only directly contribute to tumor progression, but also indirectly result in TME immunosuppression, which may be the cause of metastasis in PCa and in which MYC played an role. [ABSTRACT FROM AUTHOR]

Background: Castration-resistant prostate cancer (CRPC) is currently the main challenge for prostate cancer (PCa) treatment, and there is an urgent need to find novel therapeutic targets and drugs. Prohibitin (PHB1) is a multifunctional chaperone/scaffold protein that is upregulated in various cancers and plays a pro-cancer role. FL3 is a synthetic flavagline drug that inhibits cancer cell proliferation by targeting PHB1. However, the biological functions of PHB1 in CRPC and the effect of FL3 on CRPC cells remain to be explored. Methods: Several public datasets were used to analyze the association between the expression level of PHB1 and PCa progression as well as outcome in PCa patients. The expression of PHB1 in human PCa specimens and PCa cell lines was examined by immunohistochemistry (IHC), qRT-PCR, and Western blot. The biological roles of PHB1 in castration resistance and underlying mechanisms were investigated by gain/loss-of-function analyses. Next, in vitro and in vivo experiments were conducted to investigate the anti-cancer effects of FL3 on CRPC cells as well as the underlying mechanisms. Results: PHB1 expression was significantly upregulated in CRPC and was associated with poor prognosis. PHB1 promoted castration resistance of PCa cells under androgen deprivation condition. PHB1 is an androgen receptor (AR) suppressive gene, and androgen deprivation promoted the PHB1 expression and its nucleus-cytoplasmic translocation. FL3, alone or combined with the second-generation anti-androgen Enzalutamide (ENZ), suppressed CRPC cells especially ENZ-sensitive CRPC cells both in vitro and in vivo. Mechanically, we demonstrated that FL3 promoted trafficking of PHB1 from plasma membrane and mitochondria to nucleus, which in turn inhibited AR signaling as well as MAPK signaling, yet promoted apoptosis in CRPC cells. Conclusion: Our data indicated that PHB1 is aberrantly upregulated in CRPC and is involved in castration resistance, as well as providing a novel rational approach for treating ENZ-sensitive CRPC. [ABSTRACT FROM AUTHOR]

Despite decades of research and clinical trials, metastatic castration-resistant prostate cancer (mCRPC) remains incurable and typically fatal. Current treatments may provide modest increases in progression-free survival but can come with significant adverse effects and are disaggregated from the diagnostic imaging needed to fully assess the spread of metastatic disease. A theranostic approach, using radiolabeled ligands that target the cell surface protein PSMA, simplifies the visualization and disease treatment process by enabling both to use similar agents. Here, we describe an exemplary case wherein a gentleman in his 70s with mCRPC on diagnosis was treated with 177Lu-PSMA-617 and abiraterone, and remains disease-free to date, over five years later. [ABSTRACT FROM AUTHOR]

Background/Aim: The purpose of this article was to review the association between the ETS-related gene (ERG) and the phosphatase and tensin homolog (PTEN) genes with pathologic parameters of prostate cancer, emphasizing on Gleason score. Materials and Methods: We performed a PubMed-based search of the literature emphasizing on articles that use pathological techniques, and especially on those that report the use immunohistochemical staining and FISH to investigate the association between ERG and PTEN mutations with the histopathologic parameters of prostate cancer. Results: ERG expression is frequently marked in patients with prostate cancer, usually due to the occurrence of the TMPRSS2:ERG gene fusion. Although some studies reported a potential link between the expression of ERG and Gleason score, there is no strong evidence supporting this finding. On the contrary, there is more solid evidence correlating loss of PTEN expression with worse prognosis and higher Gleason scores. Few studies correlate the over-expression of ERG gene with the loss of PTEN expression. Finally, PTEN and ERG have been studied as potential therapeutic targets, and several promising results have been reported. Conclusion: Although, at some degree, ERG expression seems to be associated with the morphological features of prostate cancer, different studies reported controversial results. However, expression of PTEN is more clearly associated with the pathology and clinical course of the disease. More research is required to elucidate the role of these molecules in the molecular pathology of prostate cancer, as well as their potential use as therapeutic targets. [ABSTRACT FROM AUTHOR]

Although a variety of urinary cancer markers are available for in vitro diagnosis, inherent problems of urine environment—containing various inorganic/organic ions/molecules that vary in concentration over a 20‐fold range or more and significantly attenuate antibody avidity for markers—render conventional immunoassays unsuitable, remaining unresolved and a major challenge. Here we developed a 3D‐plus‐3D (3p3) immunoassay method, based on a single‐step urinary marker detection by 3D‐antibody probes, which are free of steric hindrance and capable of omnidirectional capture of markers in a 3D solution. The 3p3 immunoassay showed an excellent performance in the diagnosis of prostate cancer (PCa) through detecting PCa‐specific urinary engrailed‐2 protein, demonstrating 100% sensitivity and 100% specificity with the urine specimens of PCa‐related and other related disease patients and healthy individuals. This innovative approach holds a great potential in opening up a novel clinical route for precise in vitro cancer diagnosis and also pushing urine immunoassay closer to more widespread adoption. [ABSTRACT FROM AUTHOR]

The TMPRSS2-ERG fusion is the most common genomic rearrangement in human prostate cancer. However, in established adenocarcinoma, it is unknown how the ERG oncogene promotes a cancerous phenotype and maintains downstream androgen receptor (AR) signaling pathways. In this study, we utilized a murine prostate organoid system to explore the effects of ERG on tumorigenesis and determined the mechanism underlying prostate cancer dependence on ERG. Prostate organoids lacking PTEN and overexpressing ERG ( Pten -/- R26-ERG ) faithfully recapitulated distinct stages of prostate cancer disease progression. In this model, deletion of ERG significantly dampened AR-dependent gene expression. While ERG was able to reprogram the AR cistrome in the process of prostate carcinogenesis, ERG knockout in established prostate cancer organoids did not drastically alter AR binding, H3K27ac enhancer, or open chromatin profiles at these reprogrammed sites. Proteomic analysis of DNA-bound AR complexes demonstrated that ERG deletion causes a loss of recruitment of critical AR coregulators and basal transcriptional machinery, including NCOA3 and RNA polymerase II, but does not alter AR binding itself. Together, these data reveal a novel mechanism of ERG oncogene addiction in prostate cancer, whereby ERG facilitates AR signaling by maintaining coregulator complexes at AR bound sites across the genome. SIGNIFICANCE: These findings exploit murine organoid models to uncover the mechanism of ERG-mediated tumorigenesis and subsequent oncogenic dependencies in prostate cancer., (©2020 American Association for Cancer Research.)

Background: Prostate cancer (PCa) is the most common malignancy seen in men and the second leading cause of cancer-related death in males. The incidence and mortality associated with PCa has been rapidly increasing in China recently., Methods: Multiple diagnostic models of human PCa were developed based on Taylor database by combining the artificial neural networks (ANNs) to enhance the ability of PCa diagnosis. Genetic algorithm (GA) is used to select feature genes as numerical encoded parameters that reflect cancer, metastatic, or normal samples. Back propagation (BP) neural network and learning vector quantization (LVQ) neural network were used to build different Cancer/Normal, Primary/Metastatic, and Gleason Grade diagnostic models., Results: The performance of these modeling approaches was evaluated by predictive accuracy (ACC) and area under the receiver operating characteristic curve (AUC). By observing the statistically significant parameters of the three training sets, our Cancer/Normal, Primary/Metastatic, and Gleason Grade models' with ACC and AUC can be drawn (97.33%, 0.9832), (99.17%, 0.9952), and (90.48%, 0.8742), respectively., Conclusion: These results indicated that our diagnostic models of human PCa based on Taylor database combining the feature gene expression profiling data and artificial intelligence algorithms might act as a powerful tool for diagnosing PCa. Gleason Grade diagnostic models were used as novel prognostic diagnosis models for biochemical recurrence-free survival and overall survival, which might be helpful in the prognostic diagnosis of PCa in patients.

While screening and early detection have reduced mortality from prostate cancer, castration-resistant disease (CRPC) is still incurable. Here, we report that combined EZH2/HDAC inhibitors potently kill CRPCs and cause dramatic tumor regression in aggressive human and mouse CRPC models. Notably, EZH2 and HDAC both transmit transcriptional repressive signals: regulating histone H3 methylation and histone deacetylation, respectively. Accordingly, we show that suppression of both EZH2 and HDAC are required to derepress/induce a subset of EZH2 targets, by promoting the sequential demethylation and acetylation of histone H3. Moreover, we find that the induction of one of these targets, ATF3, which is a broad stress response gene, is critical for the therapeutic response. Importantly, in human tumors, low ATF3 levels are associated with decreased survival. Moreover, EZH2- and ATF3-mediated transcriptional programs inversely correlate and are most highly/lowly expressed in advanced disease. Together, these studies identify a promising therapeutic strategy for CRPC and suggest that these two major epigenetic regulators buffer prostate cancers from a lethal response to cellular stresses, thereby conferring a tractable therapeutic vulnerability. Epigenetic, transcriptional, and functional studies show that two major epigenetic regulators (EZH2 and HDAC) buffer advanced prostate cancer from lethal stress responses, revealing a promising combination therapy for castration-resistant disease. [ABSTRACT FROM AUTHOR]

Cholinergic receptor muscarinic 3 (CHRM3)‐mediated focal adhesion kinase/YES‐associated protein (YAP) signalling is essential for the growth of castration‐resistant prostate cancer (CRPC) cells. Here, we evaluated the molecular mechanisms through which CHRM3 overexpression facilitates castration‐resistant growth. Small RNA sequencing combined with in silico analyses revealed that CHRM3 was a putative target of miR‐15b‐5p. Notably, androgen deprivation suppressed miR‐15b‐5p expression and increased CHRM3 expression. Moreover, miR‐15b‐5p bound directly to CHRM3 and inhibited YAP activation induced by CHRM3 stimulation. Furthermore, miR‐15b‐5p abolished the growth of CRPC cells induced by CHRM3 stimulation. We conclude that the miR‐15b‐5p/CHRM3/YAP signalling axis promotes the castration‐resistant growth of prostate cancer. [ABSTRACT FROM AUTHOR]

Prostate cancer is the most common cancer in men. About 6% of those diagnosed will develop metastatic disease. Unfortunately, metastatic prostate cancer is fatal. Prostate cancer can be castration sensitive or castration resistant. Many treatments have been shown to improve progression free survival and overall survival in metastatic castration resistant prostate cancer (mCRPC). In recent years, studies have been exploring targeting mutations in the DNA Damage Repair (DDR) response that may amplify oncogenes. In this paper, we aim to discuss DDR, new approved targeted therapies, and the most recent clinical trials in the setting of metastatic CRPC. [ABSTRACT FROM AUTHOR]

In many real-world applications, such as those based on electronic health records, prognostic prediction of patient survival is based on heterogeneous sets of clinical laboratory measurements. To address the trade-off between the predictive accuracy of a prognostic model and the costs related to its clinical implementation, we propose an optimized L0-pseudonorm approach to learn sparse solutions in multivariable regression. The model sparsity is maintained by restricting the number of nonzero coefficients in the model with a cardinality constraint, which makes the optimization problem NP-hard. In addition, we generalize the cardinality constraint for grouped feature selection, which makes it possible to identify key sets of predictors that may be measured together in a kit in clinical practice. We demonstrate the operation of our cardinality constraint-based feature subset selection method, named OSCAR, in the context of prognostic prediction of prostate cancer patients, where it enables one to determine the key explanatory predictors at different levels of model sparsity. We further explore how the model sparsity affects the model accuracy and implementation cost. Lastly, we demonstrate generalization of the presented methodology to high-dimensional transcriptomics data. Author summary: Feature subset selection has become a crucial part of building biomedical models, due to the abundance of available predictors in many applications, yet there remains an uncertainty of their importance and generalization ability. Regularized regression methods have become popular approaches to tackle this challenge by balancing the model goodness-of-fit against the increasing complexity of the model in terms of coefficients that deviate from zero. Regularization norms are pivotal in formulating the model complexity, and currently L1-norm (LASSO), L2-norm (Ridge Regression) and their hybrid (Elastic Net) dominate the field. In this paper, we present a novel methodology that is based on the L0-pseudonorm, also known as the best subset selection, which has largely gone overlooked due to its challenging discrete nature. Our methodology makes use of a continuous transformation of the discrete optimization problem, and provides effective solvers implemented in a user friendly R software package. We exemplify the use of oscar-package in the context of prostate cancer prognostic prediction using both real-world hospital registry and clinical cohort data. By benchmarking the methodology against existing regularization methods, we illustrate the advantages of the L0-pseudonorm for better clinical applicability, selection of grouped features, and demonstrate its applicability in high-dimensional transcriptomics datasets. [ABSTRACT FROM AUTHOR]

Prostate cancer is the second most common cancer in men in the United States, and racial disparities are greatly observed in the disease. Specifically, African American (AA) patients have 60% higher incidence and mortality rates, in addition to higher grade and stage prostate tumors, than European American (EA) patients. In order to narrow the gap between clinical outcomes for these two populations, genetic and molecular signatures contributing to this disparity have been characterized. Over the past decade, profiles of prostate tumor samples from different ethnic groups have been developed using molecular and functional assays coupled with next generation sequencing or microarrays. Comparative genome-wide analyses of genomic, epigenomic, and transcriptomic profiles from prostate tumor samples have uncovered potential race-specific mutations, copy number alterations, DNA methylation, and gene expression patterns. In this study, we reviewed over 20 published studies that examined the aforementioned molecular contributions to racial disparities in AA and EA prostate cancer patients. The reviewed genomic studies revealed mutations, deletions, amplifications, duplications, or fusion genes differentially enriched in AA patients relative to EA patients. Commonly reported genomic alterations included mutations or copy number alterations of FOXA1, KMT2D, SPOP, MYC, PTEN, TP53, ZFHX3, and the TMPRSS2-ERG fusion. The reviewed epigenomic studies identified that CpG sites near the promoters of PMEPA1, RARB, SNRPN, and TIMP3 genes were differentially methylated between AA and EA patients. Lastly, the reviewed transcriptomic studies identified genes (e.g. CCL4, CHRM3, CRYBB2, CXCR4, GALR1, GSTM3, SPINK1) and signaling pathways dysregulated between AA and EA patients. The most frequently found dysregulated pathways were involved in immune and inflammatory responses and neuroactive ligand signaling. Overall, we observed that the genomic, epigenomic, and transcriptomic alterations evaluated between AA and EA prostate cancer patients varied between studies, highlighting the impact of using different methods and sample sizes. The reported genomic, epigenomic, and transcriptomic alterations do not only uncover molecular mechanisms of tumorigenesis but also provide researchers and clinicians valuable resources to identify novel biomarkers and treatment modalities to improve the disparity of clinical outcomes between AA and EA patients. [ABSTRACT FROM AUTHOR]

Oncogenic driver mutations have implications that extend beyond cancer cells themselves. Aberrant tumour cell signalling has various effects on the tumour microenvironment and anti-tumour immunity, with important consequences for therapy response and resistance. We provide an overview of how mutant RAS, one of the most prevalent oncogenic drivers in cancer, can instigate immune evasion programs at the tumour cell level and through remodelling interactions with the innate and adaptive immune cell compartments. Finally, we describe how immune evasion networks focused on RAS, and the immune checkpoint molecule PD-L1 can be disrupted through therapeutic intervention, and discuss potential strategies for combinatorial treatment. FNEpfXd-5bosXthPph8RiR Video abstract [ABSTRACT FROM AUTHOR]

Reprogramming of metabolism is a hallmark of tumors, which has been explored for therapeutic purposes. Prostate cancer (PCa), particularly advanced and therapy-resistant PCa, displays unique metabolic properties. Targeting metabolic vulnerabilities in PCa may benefit patients who have exhausted currently available treatment options and improve clinical outcomes. Among the many nutrients, glutamine has been shown to play a central role in the metabolic reprogramming of advanced PCa. In addition to amino acid metabolism, glutamine is also widely involved in the synthesis of other macromolecules and biomasses. Targeting glutamine metabolic network by maximally inhibiting glutamine utilization in tumor cells may significantly add to treatment options for many patients. This review summarizes the metabolic landscape of PCa, with a particular focus on recent studies of how glutamine metabolism alterations affect therapeutic resistance and disease progression of PCa, and suggests novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Castration-resistant prostate cancer often metastasizes to the bone, and such bone metastases eventually become resistant to available therapies, leading to the death of patients. Enriched in the bone, TGF-β plays a pivotal role in bone metastasis development. However, directly targeting TGF-β or its receptors has been challenging for the treatment of bone metastasis. We previously found that TGF-β induces and then depends on the acetylation of transcription factor KLF5 at K369 to regulate multiple biological processes, including the induction of EMT, cellular invasiveness, and bone metastasis. Acetylated KLF5 (Ac-KLF5) and its downstream effectors are thus potential therapeutic targets for treating TGF-β-induced bone metastasis in prostate cancer. Methods: A spheroid invasion assay was applied to prostate cancer cells expressing KLF5K369Q, which mimics Ac-KLF5, to screen 1987 FDA-approved drugs for invasion suppression. Luciferase- and KLF5K369Q-expressing cells were injected into nude mice via the tail artery to model bone metastasis. Bioluminescence imaging, micro-CT), and histological analyses were applied to monitor and evaluate bone metastases. RNA-sequencing, bioinformatic, and biochemical analyses were used to understand nitazoxanide (NTZ)-regulated genes, signaling pathways, and the underlying mechanisms. The binding of NTZ to KLF5 proteins was evaluated using fluorescence titration, high-performance liquid chromatography (HPLC), and circular dichroism (CD) analysis. Results: NTZ, an anthelmintic agent, was identified as a potent invasion inhibitor in the screening and validation assays. In KLF5K369Q-induced bone metastasis, NTZ exerted a potent inhibitory effect in preventive and therapeutic modes. NTZ also inhibited osteoclast differentiation, a cellular process responsible for bone metastasis induced by KLF5K369Q. NTZ attenuated the function of KLF5K369Q in 127 genes’ upregulation and 114 genes’ downregulation. Some genes’ expression changes were significantly associated with worse overall survival in patients with prostate cancer. One such change was the upregulation of MYBL2, which functionally promotes bone metastasis in prostate cancer. Additional analyses demonstrated that NTZ bound to the KLF5 protein, KLF5K369Q bound to the promoter of MYBL2 to activate its transcription, and NTZ attenuated the binding of KLF5K369Q to the MYBL2 promoter. Conclusions: NTZ is a potential therapeutic agent for bone metastasis induced by the TGF-β/Ac-KLF5 signaling axis in prostate cancer and likely other cancers. [ABSTRACT FROM AUTHOR]

Hippo signaling restricts tumor growth by inhibiting the oncogenic potential of YAP/TAZ‐TEAD transcriptional complex. Here, we uncover a context‐dependent tumor suppressor function of YAP in androgen receptor (AR) positive prostate cancer (PCa) and show that YAP impedes AR+ PCa growth by antagonizing TEAD‐mediated AR signaling. TEAD forms a complex with AR to enhance its promoter/enhancer occupancy and transcriptional activity. YAP and AR compete for TEAD binding and consequently, elevated YAP in the nucleus disrupts AR‐TEAD interaction and prevents TEAD from promoting AR signaling. Pharmacological inhibition of MST1/2 or LATS1/2, or transgenic activation of YAP suppressed the growth of PCa expressing therapy resistant AR splicing variants. Our study uncovers an unanticipated crosstalk between Hippo and AR signaling pathways, reveals an antagonistic relationship between YAP and TEAD in AR+ PCa, and suggests that targeting the Hippo signaling pathway may provide a therapeutical opportunity to treat PCa driven by therapy resistant AR variants. Synopsis: Deviating from its established oncogenic function, this study uncovers a context‐dependent tumor suppressor role of Hippo signalling pathway effector YAP in androgen receptor (AR)‐positive prostate cancer (PCa), and unexpected crosstalk between Hippo and AR signalling. TEAD forms a transcriptional complex with AR in PCa increasing its promoter and enhancer occupancy.Elevated nuclear YAP inhibits AR activity by competing for TEAD binding.Small molecule Hippo pathway inhibition or transgenic YAP activation decrease AR+ PCa growth. [ABSTRACT FROM AUTHOR]

Despite their contributions to the financial efficiency and environmental sustainability of industrial processes, robotic assembly and disassembly have been understudied in the existing literature. This is in contradiction to their importance in realizing the Fourth Industrial Revolution. More specifically, although most of the literature has extensively discussed how to optimally assemble or disassemble given products, the role of other factors has been overlooked. For example, and among other factors, the choices of the robots involved in implementing the sequence plans, which should ideally be taken into account throughout the whole chain consisting of design, assembly, disassembly, and reassembly, may greatly affect the underlying implications with a considerable impact on the viability and effectiveness of the measures aimed at substantiating, realizing, and strengthening the backbones of a circular economy. Isolating the foregoing operations from the rest of the components of the relevant ecosystems may lead to erroneous inferences toward both the necessity and efficiency of the underlying procedures. In this paper, we try to alleviate these shortcomings by comprehensively investigating the state of the art in robotic assembly and disassembly. We consider and review various aspects of manufacturing and remanufacturing frameworks while particularly focusing on their desirability for supporting a circular economy. [ABSTRACT FROM AUTHOR]

Purpose: Prostate cancer (PCa) lacks specific markers capable of distinguishing aggressive tumors from those with indolent behavior. Therefore, the aim of this study was to evaluate the immunostaining of candidate proteins (PTEN, AKT, TRPM8, and NKX3.1) through the immunohistochemistry technique (IHC) on patients with metastatic and non-metastatic PCa. Methods: Tissues from 60 patients were divided into three groups categorized according to prognostic parameters: better prognosis (n = 20), worse prognosis (n = 23), and metastatic (n = 17). Immunostaining was analyzed by a pathologist and staining classifications were considered according to signal intensity: (0) no staining, (+) weak, and (++ and +++) intermediate to strong. Results: AKT protein was associated (p = 0.012) and correlated (p = 0.014; Tau = − 0.288) with the prognostic groups. The immunostaining for TRPM8 (p = 0.010) and NKX3.1 (p = 0.003) proteins differed between malignant tumor and non-tumoral adjacent tissue as well as for proteins in cellular locations (nucleus and cytoplasm). TRPM8 was independently associated with the ISUP grade ≥ 4 (p = 0.024; OR = 8.373; 95% CI = 1.319–53.164). The NKX3.1 showed positive and predominantly strong immunostaining in all patients in both tumoral and non-tumoral adjacent tissues. All metastatic samples had positive immunostaining, with strong intensity for NKX3.1 (p = 0.021; Tau = − 0.302). In the non-metastatic group, this strong protein staining was not observed in any patients. Conclusion: This study confirmed that NKX3.1 is highly specific for prostate tissue and indicated that NKX3.1, AKT, and TRPM8 may be candidate markers for prostate cancer prognosis. [ABSTRACT FROM AUTHOR]

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Background: Histone demethylase RIOX2 was cloned as a c-Myc downstream gene involved in cell proliferation and has been implicated as an oncogenic factor in multiple tumor types. Its expression profiles and correlation with disease progression in prostate cancers are unknown. Methods: Transcriptomic profiles of Jumanji domain-containing protein genes were assessed using multiple public expression datasets generated from RNA-seq and cDNA microarray assays. RIOX2 protein expression was assessed using an immunohistochemistry approach on a tissue section array from benign and malignant prostate tissues. Gene expression profiles were analyzed using the bioinformatics software R package. Western blot assay examined androgen stimulation on RIOX2 protein expression in LNCaP cells. Results: Among 35 Jumanji domain-containing protein genes, 12 genes were significantly upregulated in prostate cancers compared to benign compartments. COX regression analysis identified that the ribosomal oxygenase 2 (RIOX2) gene was the only one significantly associated with disease-specific survival outcomes in prostate cancer patients. RIOX2 upregulation was confirmed at the protein levels using immunohistochemical assays on prostate cancer tissue sections. Meanwhile, RIOX2 upregulation was associated with clinicopathological features, including late-stage diseases, adverse Gleason scores, TP53 gene mutation, and disease-free status. In castration-resistant prostate cancers (CRPC), RIOX2 expression was positively correlated with AR signaling index but negatively correlated with the neuroendocrinal progression index. However, androgen treatment had no significant stimulatory effect on RIOX2 expression, indicating a parallel but not a causative effect of androgen signaling on RIOX2 gene expression. Further analysis discovered that RIOX2 expression was tightly correlated with its promoter hypomethylation and MYC gene expression, consistent with the notion that RIOX2 was a c-Myc target gene. Conclusion: The Jumanji domain-containing protein RIOX2 was significantly overexpressed in prostate cancer, possibly due to c-Myc upregulation. RIOX2 upregulation was identified as an independent prognostic factor for diseasespecific survival. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to develop and evaluate the deep learning-based classification model for recognizing the pathology of renal tumor from macroscopic cross-section image. Methods: A total of 467 pathology-confirmed patients who received radical nephrectomy or partial nephrectomy were retrospectively enrolled. The experiment of distinguishing malignant and benign renal tumor are conducted followed by performing the multi-subtypes classification models for recognizing four subtypes of benign tumor and four subtypes of malignant tumors, respectively. The classification models used the same backbone networks which are based on the convolutional neural network (CNN), including EfficientNet-B4, ResNet-18, and VGG-16. The performance of the classification models was evaluated by area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy. Besides, we performed the quantitative comparison among these CNN models. Results: For the model to differentiate the malignant tumor from the benign tumor, three CNN models all obtained relatively satisfactory performance and the highest AUC was achieved by the ResNet-18 model (AUC = 0.9226). There is not statistically significance between EfficientNet-B4 and ResNet-18 architectures and both of them are significantly statistically better than the VGG-16 model. The micro-averaged AUC, macro-averaged sensitivity, macro-averaged specificity, and micro-averaged accuracy for the VGG-16 model to distinguish the malignant tumor subtypes achieved 0.9398, 0.5774, 0.8660, and 0.7917, respectively. The performance of the EfficientNet-B4 is not better than that of VGG-16 in terms of micro-averaged AUC except for other metrics. For the models to recognize the benign tumor subtypes, the EfficientNet-B4 ranked the best performance, but had no significantly statistical difference with other two models with respect to micro-averaged AUC. Conclusions: The classification results were relatively satisfactory, which showed the potential for clinical application when analyzing the renal tumor macroscopic cross-section images. Automatically distinguishing the malignant tumor from benign tumor and identifying the subtypes pathology of renal tumor could make the patient-management process more efficient. [ABSTRACT FROM AUTHOR]

In this study, we established a novel immunologic gene prognostic index (IGPI) to predict metastasis and provided new insights into tumor immune microenvironment (TIME) for PCa patients receiving radical radiotherapy. GBP2 and IGF1 were independent factors associated with metastasis-free survival. IGPI score was calculated based on GBP2 and IGF1 and this score was an independent risk factor for PCa patients undergoing radical radiotherapy. Patients with higher IGPI score were at higher risk of metastasis and biochemical recurrence, which were externally validated in the TCGA database and other GEO datasets. IGPI score had demonstrated moderate diagnostic ability of radiation resistance (AUC: 0.889). This score increased with the augment of Gleason score and T stage, as well as biochemical recurrence. Using EPIC, ESTIMATE and immunophenoscore (IPS) algorithms, cancer associated fibroblasts (CAFs), macrophages, stromal score, and estimate score were significantly higher in patients with metastasis group compared to their counterpart. Besides, for CAFs, macrophages, stromal score, and estimate score, patients with higher scores were at higher risk of metastasis, and the HRs were 3.65, 4.01, 4.27, and 3.78, respectively. IGPI score was highly positively associated with stromal score (coefficient: 0.39), immune score (coefficient: 0.43), estimate score (coefficient: 0.45), CAFs (coefficient: 0.42) and macrophages (coefficient: 0.42), while showing the opposite relationship with tumor purity (coefficient: − 0.45). In conclusion, we found that IGPI based on GBP2 and IGF1 might serve as a biomarker predicting metastasis for PCa patients. Besides, the current data further highlight the importance of CAFs in the metastatic process of PCa. [ABSTRACT FROM AUTHOR]

Background: A huge focus is being placed on the development of novel signatures in the form of new combinatorial regimens to distinguish the neuroendocrine (NE) characteristics from castration resistant prostate cancer (CRPC) timely and accurately, as well as predict the disease-free survival (DFS) and progression-free survival (PFS) of prostate cancer (PCa) patients. Methods: Single cell data of 4 normal samples, 3 CRPC samples and 3 CRPCNE samples were obtained from GEO database, and CellChatDB was used for potential intercellular communication, Secondly, using the "limma" package (v3.52.0), we obtained the differential expressed genes between CRPC and CRPC-NE both in single-cell RNA seq and bulk RNA seq samples, and discovered 12 differential genes characterized by CRPC-NE. Then, on the one hand, the diagnosis model of CRPC-NE is developed by random forest algorithm and artificial neural network (ANN) through Cbioportal database; On the other hand, using the data in Cbioportal and GEO database, the DFS and PFS prognostic model of PCa was established and verified through univariate Cox analysis, least absolute shrinkage and selection operator (Lasso) regression and multivariate Cox regression in R software. Finally, somatic mutation and immune infiltration were also discussed. Results: Our research shows that there exists specific intercellular communication in classified clusters. Secondly, a CRPC-NE diagnostic model of six genes (HMGN2, MLLT11, SOX4, PCSK1N, RGS16 and PTMA) has been established and verified, the area under the ROC curve (AUC) is as high as 0.952 (95% CI: 0.882-0.994). The mutation landscape shows that these six genes are rarely mutated in the CRPC and NEPC samples. In addition, NE-DFS signature (STMN1 and PCSK1N) and NE-PFS signature (STMN1, UBE2S and HMGN2) are good predictors of DFS and PFS in PCa patients and better than other clinical features. Lastly, the infiltration levels of plasma cells, T cells CD4 naive, Eosinophils and Monocytes were significantly different between the CRPC and NEPC groups. Conclusions: This study revealed the heterogeneity between CRPC and CRPCNE from different perspectives, and developed a reliable diagnostic model of CRPC-NE and robust prognostic models for PCa. [ABSTRACT FROM AUTHOR]

Background/aim: To investigate the effect of antibiotic treatment on PSA when deciding on prostate biopsy. Materials and methods: A total of 206 patients with an elevated PSA level (2.5–30) were included. Mp-MRI could be done on 129 patients. Patients were given ciprofloxacin (500 mg, b.i.d. p.o.) for 4 weeks and PSA measurements were repeated. Systematic prostate biopsy was performed regardless of PSA changes on all patients. Additionally, cognitive biopsies were performed from PI-RADs III, IV, and V lesions. Results: Prostate cancer was detected in 36.4% of patients. 53.3% had Gleason score of 3+3, 46.7% had Gleason score ≥ 3+4. PSA values decreased in 56.3% and in 43.7% and remained the same or increased but cancer detection rates were not different: 34.5% vs. 38.9%, respectively (p = 0.514). PSA change in whole group was significant (6.38 ng/mL vs. 5.95 ng/mL, respectively (p = 0.01). No significant PSA decrease was observed in cancer patients (7.1 ng/mL vs. 7.05 ng/mL, p = 0.09), whereas PSA decrease was significant in patients with benign pathology (6.1 ng/mL vs. 5.5 ng/mL, p = 0.01). In patients with PI-RADs IV-V lesions, adenocarcinoma was present in 33.9% and 30.4% with or without PSA decrease, respectively (p = 0.209). Clinically significant cancer was higher in patients with after antibiotherapy PSA values >4 ng/mL regardless of PI-RADs grouping (p = 0.08). Addition of any PSA value to PI-RADs grouping did not have any significant effect on the detection of cancer. Conclusion: PSA change after antibiotic treatment has no effect in detecting cancer and should not delay performing a biopsy. [ABSTRACT FROM AUTHOR]

Introduction: Seminoma comprises approximately 50% of testicular germ cell tumors. Retroperitoneal lymph nodes are the most common initial metastatic sites but renal metastases are infrequent and the majority of renal tumors represent primary neoplasm. Case Presentation: In this study, we present a 48-year-old male with metastases of seminoma to the cervical lymph nodes and kidney after a 25-year interval. Conclusion: This presentation emphasizes the necessity of advising all patients who are discharged from follow-up that there is a chance of late remote relapse and that if they acquire any illness after discharge, they must inform their doctor about their previous seminoma. [ABSTRACT FROM AUTHOR]

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of prostate cancer, and the molecular mechanism driving mCRPC progression has not yet been fully elucidated. Immunotherapies such as chimeric antigen receptor, T-cell therapy and immune checkpoint blockade have exerted promising antitumor effects in hematological and solid tumor malignancies; however, no encouraging responses have been observed against mCRPC. The deubiquitinase USP13 functions as a tumor suppressor in many human cancers, as it sustains the protein stability of PTEN and TP53; however, its role in prostate cancer (PCa) and involvement in DNA damage and AR signaling remain unclear. In the current study, we explored the prognostic value of USP13 in PCa based on the TCGA database, and we analyzed the expression of USP13 in PCa tissues and adjacent normal tissues based on TCGA and our cohort. The results suggested that USP13 is overexpressed in PCa tumors and has the potential to be an independent biomarker for the overall survival of PCa patients. Additionally, enrichment analysis indicated that USP13 may participate in the AR pathway and PI3k/Wnt signaling, which are closely related to PCa progression. We also observed a significant correlation between the expression of USP13 and AR-related genes, DDR genes and mismatch repair genes based on the TCGA_PRAD dataset, which further supported the critical role of USP13 in AR activation and the DNA damage response of PCa. USP13 was also found to be enriched in protein neddylation, and expression of USP13 was significantly associated with infiltration of immune cells and expression of immunomodulators. Taken together, our study revealed a key role of USP13 in contributing to PCa progression by participating in multiple oncogenic signaling pathways, the DNA damage response and the immunosuppressive tumor microenvironment. Targeting USP13 may inhibit tumor growth and provide additional benefits in cooperation with DDR inhibitors and immunotherapy. [ABSTRACT FROM AUTHOR]

Aim: The role of surgical castration and rosuvastatin treatment on lipid profile and lipid metabolism related markers was evaluated for their prognostic significance in metastatic prostate cancer (mPC) patients. Methods: A total of 84 newly diagnosed castrated mPC patients treated with castration were recruited and divided into two groups: Group I served as control (statin non-users) while group II treated with Rosuvastatin (20 mg/day) for 6 months and served as statin users. Prostate specific antigen (PSA), epidermal growth factor receptor (EGFR), Caveolin-1 (CAV1), lipid profile (LDL, HDL, triglycerides (TG) and total cholesterol (TC)) and lipid metabolism related markers (aldoketoreductase (AKR1C4), HMG-CoA reductase (HMGCR), ATP-binding cassette transporter A1 (ABCA1), and soluble low density lipoprotein receptor related protein 1 (SLDLRP1)) were measured at baseline, after 3 and 6 months. Overall survival (OS) was analyzed by Kaplan-Meier and COX regression for prognostic significance. Results: Before castration, HMG-CoA reductase was elevated in patients <65 years (P = 0.009). Bone metastasis was associated with high PSA level (P = 0.013), but low HMGCR (P = 0.004). Patients with positive family history for prostate cancer showed high levels of EGFR, TG, TC, LDL, alkaline phosphatase (ALP), but low AKR1C4, SLDLRP1, CAV1 and ABCA-1 levels. Smokers had high CAV1 level (P = 0.017). After 6 months of castration and rosuvastatin administration, PSA, TG, LDL and TC were significantly reduced, while AKR1C4, HMGCR, SLDLRP1, CAV1 and ABCA-1 were significantly increased. Overall survival was reduced in patients with high baseline of SLDLRP1 (>3385 pg/ml, P = 0.001), PSA (>40 ng/ml, P = 0.003) and CAV1 (>4955 pg/ml, P = 0.021). Conclusion: Results of the current study suggest that the peripheral lipidogenic effects of rosuvastatin may have an impact on the treatment outcome and survival of castrated mPC patients. Trail registration: This trial was registered at the Pan African Clinical Trial Registry with identification number PACTR202102664354163 and at ClinicalTrials.gov with identification number NCT04776889. [ABSTRACT FROM AUTHOR]

Background: The mTOR signaling pathway plays an important role in cancer. As a master regulator, the status of MTOR affects pathway activity and the efficacy of mTOR inhibitor therapy. However, little research has been performed to explore MTOR in colorectal cancer (CRC).Methods: In this study, gene expression and clinical data were analyzed using The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Signaling pathways related to MTOR in CRC were identified by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). Somatic mutation data were downloaded from TCGA and analyzed using the maftools R package. Tumor Immune Estimation Resource (TIMER) and CIBERSORT were used to analyze correlations between MTOR and tumor-infiltrating immune cells (TIICs). Finally, we detected MTOR mutations in a CRC cohort from our database using whole-exome sequencing.Results: We found that MTOR was overexpressed in Asian CRC patients and associated with a poor prognosis. Enrichment analysis showed that MTOR was involved in metabolism, cell adhesion, and translation pathways in CRC. High MTOR expression was correlated with high tumor mutation burden (TMB) and several TIICs. Finally, we found that the mTOR signaling pathway was activated in CRC lines characterized by microsatellite instability (MSI), and the frequency of MTOR mutations was higher in MSI-high (MSI-H) patients than in microsatellite stable (MSS) patients.Conclusions: MTOR may represent a comprehensive indicator of prognosis and immunological status in CRC. The genomic signatures of MTOR may provide guidance for exploring the role of mTOR inhibitors in CRC. [ABSTRACT FROM AUTHOR]