^11C-choline PET/MRI for Characterization of Primary High-Risk Prostate Cancer： Correlations between Positron Emission Tomography Imaging Parameters and Clinical Features

Purpose： The aim of this study was to determine whether PET （positron emission tomography） imaging parameters from simultaneous ^11C-choline PET/MRI （magnetic resonance imaging） could be used to characterize primary prostate cancer. Methods： Forty-six patients with biopsy-proven high-risk prostate cancer （clinical T stage ≥ cT2c, a Gleason score 〉 8, or PSA （prostate-specific antigen） level 〉 20 ng/mL） were prospectively enrolled. A SUV （standardized uptake value） histogram analysis including maximum SUV, mean SUV, SUV variance, SUV entropy, MTV （metabolic tumor volume）, and UVP （uptake volume product） was applied for the calculation of PET imaging parameters. Correlations between the PSA level and Gleason score were then evaluated. Results： Maximum SUV, mean SUV, MTV, UVP, and SUV variance were significantly correlated with PSA level, whereas SUV variance was the only parameter negatively correlated with the Gleason score. Multivariate logistic regression analysis demonstrated that MTV and PSA level at diagnosis were independent predictors of positive distant metastasis status. Conclusions： PET imaging parameters from simultaneous ^11C-choline PET/MRI were correlated with PSA level. However, ^11C-choline metabolic tumor heterogeneity was not associated with biospecimen-derived Gleason scores in prostate cancer. To apply PET texture quantification analysis to prostate cancer, a more specific PET radiotracer is required.

Targeted-cryosurgical ablation of the prostate with androgen deprivation therapy:quality of life in high-risk prostate cancer patients

Aim： To present preliminary results on health-related quality of life （QoL）, prostate-associated symptoms and therapeutic effects of targeted-cryosurgical ablation of the prostate （TCSAP） with androgen deprivation therapy （ADT） in high-risk prostate cancer （PCa） patients. Methods： Thirty-four men with high-risk PCa features underwent TCSAP, and ADT was added to improve the treatment outcomes. High-risk parameters were defined as either prostate-specific antigen （PSA） ≥ 10ng/mL, or Gleason score 〉 8, or both. The Genito-Urinary Group of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 （EORTC QLQ-C30） with prostate-cancer-specific module （QLQ-PR25） was used for evaluating morbidities and PSA levels were recorded every 3 months. PSA failure was defined as the inability to reach a nadir of 0.4 ng/mL or less. Results： Although it was not statistically significant, the global health status scores increased after TCSAP with ADT. The scores for five functional scales also became higher after treatment. The most prominent symptom after treatment was sexual dysfunction, followed by treatment-related and irritative voiding symptoms. Conclusion： TCSAP with ADT appears to be minimally invasive with high QoL except for sexual dysfunction. Long-term follow-up of PSA data and survival is necessary before any conclusions can be made on the efficacy of this promising new therapeutic modality in the treatment of PCa.

Concurrent chemoradiation for high-risk prostate cancer

There are estimated to be 220800 cases of prostate cancer diagnosed in 2015, making up 26% of all cancer diagnoses. Fortunately, adenocarcinoma of the prostate is often a highly treatable malignancy. Even though the majority of prostate cancer patients present with localized disease, prostate cancer still accounts for over 27000 deaths a year. There is a subset of patients thatare likely to recur after locoregional treatment that is thought of as a "high-risk" population. This more aggressive subset includes patients with clinical stage greater than T2 b, Gleason score greater than 7, and prostate specific antigen greater than 20 ng/d L. The rate of biochemical relapse in this high risk group is 32%-70% within five years of definitive focal therapy. Given these discouraging outcomes, attempts have been made to improve cure rates by radiation dose escalation, addition of androgen depravation therapy, and addition of chemotherapy either sequentially or concurrently with radiation. One method that has been shown to improve clinical outcomes is the addition of chemotherapy to radiotherapy for definitive treatment. Concurrent chemoradiation with 5-fluorouracil, estramustine phosphate, vincristine, docetaxel, and paclitaxel has been studied in the phase I and/or II setting. These trials have identified the maximum tolerated dose of chemotherapy and radiation that can be safely delivered concurrently and established the safety and feasibility of this technique. This review will focus on the addition of concurrent chemotherapy to radiotherapy in the definitive management of high-risk prostate cancer.

RARP in high-risk prostate cancer： use of multi-parametric MRI and nerve sparing techniques

To examine the outcomes of patients with high-risk prostate cancer （PCa） treated by robot-assisted radical prostatectomy （RARP） and evaluate the value of multi-parametric magnetic resonance imaging （MRI） in estimating tumor stage, extracapsular extension, and grade, and the application of nerve sparing （NS） techniques. Patient demographics, preoperative imaging, surgical parameters, pathological features, functional and recurrence outcomes were collected retrospectively in patients with high-risk PCa who underwent RARP between December 2009 and October 2013. Pathological whole mount slides to assess NS were compared with potency, recovery of continence, and surgical margins （SM）. Forty-four cases of high-risk PCa were identified with a median followup of 24 months and positive surgical margins （PSM） rate of 14%. Continence returned in 86%, with potency rate of 58%. Of the 25 cases with a preoperative multi-parametric MRI, MRI improved clinical staging from 28% to 88%, respectively. Following risk stratification of NS by microscopic analysis of whole mount pathology, patients with Group A （bilateral NS）, Group B （unilateral NS）, Group C （partial NS）, and Group D （non-NS） had 100%, 92%, 91%, and 50% continence rates, and 100%, 80%, 45%, and 0% potency rates, respectively, with an inverse correlation to PSM. RARP in men with high-risk PCa can achieve favorable oncologic and functional outcomes. Preoperative MRI may localize high-grade tumors and improve clinical staging. Extent of NS is influenced by clinical staging and may balance potency and continence with PSMs.

Evaluation of the prognostic nutritional index for the prognosis of Chinese patients with high/extremely high-risk prostate cancer after radical prostatectomy

BACKGROUND The incidence of prostate cancer(PCa)is on the rise in China.The risk level of patients with PCa is associated with disease-free survival rate at 10 years after radical prostatectomy.Predicting prognosis in advance according to the degree of risk can provide a reference for patients,especially treatment options and postoperative adjuvant treatment measures for high-risk/extremely high-risk patients.AIM To explore the predictive value of the prognostic nutritional index(PNI)for biological recurrence in Chinese patients with high/extremely high-risk PCa after radical prostatectomy.METHODS The biochemical test results and clinical data of 193 patients who underwent radical prostatectomy for the first time from January 2015 to December 2020 were retrospectively collected.The PNI value of peripheral blood within 1 wk before surgery was calculated,and during the follow-up period,prostate-specific antigen≥0.2 ng/mL was considered to have biological recurrence.The receiver operating characteristic(ROC)curve was used to calculate the optimal critical value and area under the curve(AUC)of the patients.According to the critical value,the progression-free survival of the high PNI group and low PNI group was compared.The independent influencing factors of the patients’prognosis were obtained by the Cox proportional hazards regression model.RESULTS The non-biological recurrence rates at 1,3,and 5 years were 92.02%,84.05%,and 74.85%,respectively.The optimal critical value for PNI to predict biological recurrence was 46.23,and the AUC was 0.789(95%confidence interval:0.651-0.860;P<0.001).The sensitivity and specificity were 82.93%and 62.30%,respectively.In accordance with the optimal critical value of the ROC curve(46.23),193 patients were further divided into a high PNI group(PNI≤46.23,n=108)and low PNI group(PNI>46.23,n=85).The incidence of postoperative complications in the high PNI group was lower than that in the low PNI group(21.18%vs 38.96%).Kaplan-Meier survival analysis showed that the overall survival rate at 5 years in the low PNI group was 87.96%(13/108),which was lower than that in the high PNI group(61.18%,33/85;P<0.05).Low PNI[hazard ratio(HR)=1.74;P=0.003]and positive incisal margin status(HR=2.14;P=0.001)were independent predictors of biological recurrence in patients with high/extremely high-risk PCa.CONCLUSION The PNI has predictive value for the prognosis of patients with high/extremely high-risk PCa,and is an independent prognostic factor.Patients with low PNI value have a shorter time of nonbiological recurrence after prostatectomy.It is expected that the combined prediction of other clinicopathological data will further improve the accuracy and guide postoperative adjuvant therapy to improve the quality of prognosis.

Dose escalation of external beam radiotherapy for high-risk prostate cancerdImpact of multiple high-risk factor

Objective:To retrospectively investigate the treatment outcomes of external beam radiotherapy with androgen deprivation therapy(ADT)in high-risk prostate cancer in three radiotherapy dose groups.Methods:Between 1998 and 2013,patients with high-risk prostate cancer underwent threedimensional conformal radiotherapy or intensity-modulated radiotherapy of 66 Gy,72 Gy,or 78 Gy with ADT.Prostate-specific antigen(PSA)relapse was defined using the Phoenix definition.PSA relapse-free survival(PRFS)was evaluated in each radiotherapy dose group.Moreover,high-risk patients were divided into H-1(patients with multiple high-risk factors)and H-2(patients with a single high-risk factor)as risk subgroups.Results:Two hundred and eighty-nine patients with a median follow-up period of 77.3 months were analyzed in this study.The median duration of ADT was 10.1 months.Age,Gleason score,T stage,and radiotherapy dose influenced PRFS with statistical significance both in univariate and multivariate analyses.The 4-year PRFS rates in Group-66 Gy,Group-72 Gy and Group-78 Gy were 72.7%,81.6%and 90.3%,respectively.PRFS rates in the H-1 subgroup differed with statistical significance with an increasing radiotherapy dose having a more favorable PRFS,while PRFS rates in H-2 subgroup did not differ with increase in radiotherapy dose.Conclusion:Dose escalation for high-risk prostate cancer in combination with ADT improved PRFS.PRFS for patients in the H-1 subgroup was poor,but dose escalation in those patients was beneficial,while dose escalation in the H-2 subgroup was not proven to be effective for improving PRFS.

Proficiency score as a predictor of early trifecta achievement during the learning curve of robot-assisted radical prostatectomy for high-risk prostate cancer:Results of a multicentric series

Background:Recently,an innovative tool called“proficiency score”was introduced to assess the learning curve for robot-assisted radical prostatectomy(RARP).However,the initial study only focused on patients with low-risk prostate cancer forwhompelvic lymph node dissection(PLND)was not required.To address this issue,we aimed to validate proficiency scores of a contemporarymulticenter cohort of patients with high-risk prostate cancer treated with RARP plus extended PLND by trainee surgeons.Material andmethods:Between 2010 and 2020,4 Italian institutional prostate-cancer datasets weremerged and queried for“RARP”and“high-risk prostate cancer.”High-risk prostate cancer was defined according to the most recent European Association of Urology guidelines as follows:prostate-specific antigen>20 ng/mL,International Society ofUrological Pathology≥4,and/or clinical stage(cT)≥2c on preoperative imaging.The selected cohort(n=144)included clinical cases performed by trainee surgeons(n=4)after completing their RARP learning curve(50 procedures for low-risk prostate cancer).The outcome of interest,the proficiency score,was defined as the coexistence of all the following criteria:a comparable operation time to the interquartile range of the mentor surgeon at each center,absence of any significant perioperative complications Clavien-Dindo Grade 3–5,no perioperative blood transfusions,and negative surgical margins.A logistic binary regression model was built to identify the predictors of 1-year trifecta achievement in the trainee cohort.For all statistical analyses,a 2-sided p<0.05 was considered significant.Results:A proficiency score was achieved in 42.3%patients.At univariable level,proficiency score was associated with 1-year trifecta achievement(odds ratio,8.77;95%confidence interval,2.42–31.7;p=0.001).After multivariable adjustments for age,nerve-sparing,and surgical technique,the proficiency score independently predicted 1-year trifecta achievement(odds ratio,9.58;95%confidence interval,1.83–50.1;p=0.007).Conclusions:Our findings support the use of proficiency scores in patients and require extended PLND in addition to RARP.

Adaptive ultra-hypofractionated whole-pelvic radiotherapy in high-risk and very high-risk prostate cancer on 1.5-Tesla MR-Linac:Estimated delivered dose and early toxicity results

Background: Magnetic resonance(MR)-guided ultra-hypofractionated radiotherapy with whole-pelvic irradiation(UHF-WPRT)is a novel approach to radiotherapy for patients with high-risk(HR)and very high-risk(VHR)prostate cancer(PCa).However,the inherent complexity of adaptive UHF-WPRT might inevitably result in longer on-couch time.We aimed to estimate the delivered dose,study the feasibility and safety of adaptive UHF-WPRT on a 1.5-Tesla MR-Linac.Methods: Ten patients with clinical stage T3a-4N0-1M0-1c PCa,who consecutively received UHF-WPRT,were enrolled prospectively.The contours of the target and organ-at-risks on the position verification-MR(PV-MR),beam-on 3D-MR(Bn-MR),and post-MR(after radiotherapy delivery)were derived from the pre-MR data by deformable image registration.The physician then manually adjusted them,and dose recalculation was performed accordingly.GraphPad Prism 9(GraphPad Prism Software Inc.)was utilized for conducting statistical analyses.Results: In total,we collected 188 MR scans(50 pre-MR,50 PV-MR,44 Bn-MR,and 44 post-MR scans).With median 59 min,the mean prostate clinical target volume(CTV)-V_(100%)was 98.59%±2.74%,and the mean pelvic CTVp-V_(100%)relative percentages of all scans was 99.60%±1.18%.The median V29 Gy change in the rectal wall was−2%(−18%to 20%).With a median follow-up of 9 months,no patient had acute Common Terminology Criteria for Adverse Events(CTCAE)grade 2 or more severe genitourinary(GU)or gastrointestinal(GI)toxicities(0%).Conclusion: UHF-RT to the prostate and the whole pelvis with concomitant boost to positive nodes using an Adapt-To-Shape(ATS)workflow was technically feasible for patients with HR and VHR PCa,presenting only mild GU and GI toxicities.The estimated target dose during the beam-on phase was clinically acceptable based on the 3D-MR-based dosimetry analysis.Clinical trial registration Chinese Clinical Trial Registry ChiCTR2000033382.

Marker Ki-67 is a potential biomarker for the diagnosis and prognosis of prostate cancer based on two cohorts

BACKGROUND Prostate cancer(PCa)is a widespread malignancy,predominantly affecting elderly males,and current methods for diagnosis and treatment of this disease continue to fall short.The marker Ki-67(MKI67)has been previously demonstrated to correlate with the proliferation and metastasis of various cancer cells,including those of PCa.Hence,verifying the association between MKI67 and the diagnosis and prognosis of PCa,using bioinformatics databases and clinical data analysis,carries significant clinical implications.AIM To explore the diagnostic and prognostic efficacy of antigens identified by MKI67 expression in PCa.METHODS For cohort 1,the efficacy of MKI67 diagnosis was evaluated using data from The Cancer Genome Atlas(TCGA)and Genotype-Tissue Expression(GTEx)databases.For cohort 2,the diagnostic and prognostic power of MKI67 expression was further validated using data from 271 patients with clinical PCa.RESULTS In cohort 1,MKI67 expression was correlated with prostate-specific antigen(PSA),Gleason Score,T stage,and N stage.The receiver operating characteristic(ROC)curve showed a strong diagnostic ability,and the Kaplan-Meier method demonstrated that MKI67 expression was negatively associated with the progression-free interval(PFI).The time-ROC curve displayed a weak prognostic capability for MKI67 expression in PCa.In cohort 2,MKI67 expression was significantly related to the Gleason Score,T stage,and N stage;however,it was negatively associated with the PFI.The time-ROC curve revealed the stronger prognostic capability of MKI67 in patients with PCa.Multivariate COX regression analysis was performed to select risk factors,including PSA level,N stage,and MKI67 expression.A nomogram was established to predict the 3-year PFI.CONCLUSION MKI67 expression was positively associated with the Gleason Score,T stage,and N stage and showed a strong diagnostic and prognostic ability in PCa.

CircTHSD4 promotes the malignancy and docetaxel (DTX) resistance in prostate cancer by regulating miR-203/HMGA2 axis

Objective:Circular ribose nudeic acids(circRNAs)are implicated in tumor progression and drug resistance of prostate cancer(PCa).The current work explored the function of circ_0005203(aircTHSD4)in the malignancy and docetaxel(DTX)resistance of PCa.Methods:circTHSD4 expression within PCa as well as matched non-carcinoma samples was measured through real time reverse transcription quantitative polymerase chain reaction(RT-qPCR).In addition,a subcellular fraction assay was conducted to determine circTHSD4 subcellular localization within PCa cells.In addition,we performed a Western blot(WB)assay to detect high mobility.group A2 protein(HMGA2)levels.Besides,functional associations of two molecules were investigated through dual luciferase reporter assay.Cell Counting Kit(CCK)-8,colony formation together with Transwell assay was conducted to assess malignant phenotypes of PCa cells,whereas flow cytometry was performed to determine cell apoptosis.Furthermore,a xenograft mouse model was constructed to verify the effect of circTHSD4 on the carcinogenesis of PCa cells.Results:According to RT-qPCR results,circTHSD4 was up-regulated within PCa tissues and cells,which predicted the dismal prognostic outcome of PCa cases.circTHSD4 silencing within PCa cells markedly suppressed cell growth,migration,and colony fomation.circTHSD4 silencing remarkably elevated PCa cell apoptosis and carcinogenesis within the xenograft model.Further,circTHSD4 silencing enhanced docetaxel(DTX)sensitivity in PCa cells.Furthermore,we demonstrated that circTHSD4 modulated the malignancy of PCa cells by regulating HMGA2 expression through sponging miR 203.Conclusion:Together,our findings suggest that cirCTHSD4 overexpression could promote the malignant phenotype and DTX resistance in PCa through the regulation of the miR 203/HMGA2 axis.

Genetic variation of circHIBADH enhances prostate cancer risk through regulating HNRNPA1-related RNA splicing

The current study aimed to investigate associations of circRNAs and related genetic variants with the risk of prostate cancer(PCa)as well as to elucidate biological mechanisms underlying the associations.We first compared expression levels of circRNAs between 25 paired PCa and adjacent normal tissues to identify riskassociated circRNAs by using the MiOncoCirc database.We then used logistic regression models to evaluate associations between genetic variants in candidate circRNAs and PCa risk among 4662 prostate cancer patients and 3114 healthy controls,and identified circHIBADH rs11973492 T>C as a significant risk-associated variant(odds ratio=1.20,95%confidence interval:1.08-1.34,P=7.06×10^(-4))in a dominant genetic model,which altered the secondary structure of the corresponding RNA chain.In the in silico analysis,we found that circHIBADH sponged and silenced 21 RNA-binding proteins(RBPs)enriched in the RNA splicing pathway,among which HNRNPA1 was identified and validated as a hub RBP using an external RNA-sequencing data as well as the in-house(four tissue samples)and publicly available single-cell transcriptomes.Additionally,we demonstrated that HNRNPA1 influenced hallmarks including MYC target,DNA repair,and E2F target signaling pathways,thereby promoting carcinogenesis.In conclusion,genetic variants in circHIBADH may act as sponges and inhibitors of RNA splicing-associated RBPs including HNRNPA1,playing an oncogenic role in PCa.

Unlocking the potential-vitamin D in prostate cancer prevention

Prostate cancer poses a significant health challenge globally,demanding proactive prevention strategies.This editorial explores the emerging role of vitamin D in prostate cancer prevention.While traditionally associated with bone health,vitamin D is increasingly recognized for its broader impact on immune function,cellular signaling,and cancer prevention.Epidemiological studies suggest an intriguing link between vitamin D deficiency and elevated prostate cancer risk,particularly in regions with limited sunlight exposure.Mechanistically,vitamin D regulates cellular processes,inhibiting unchecked cancer cell growth and bols-tering immune surveillance.Personalized prevention strategies,considering individual factors,are deemed essential for harnessing the full potential of vitamin D.To unlock this potential,the future calls for robust research,public awareness campaigns,dietary improvements,and vigilant medical guidance.Collaborative efforts are poised to pave the way toward a future where vitamin D stands as a sentinel in prostate cancer prevention,ushering in hope and improved health for men worldwide.

Analysis of risk factors leading to anxiety and depression in patients with prostate cancer after castration and the construction of a risk prediction model

BACKGROUND Cancer patients often suffer from severe stress reactions psychologically,such as anxiety and depression.Prostate cancer(PC)is one of the common cancer types,with most patients diagnosed at advanced stages that cannot be treated by radical surgery and which are accompanied by complications such as bodily pain and bone metastasis.Therefore,attention should be given to the mental health status of PC patients as well as physical adverse events in the course of clinical treatment.AIM To analyze the risk factors leading to anxiety and depression in PC patients after castration and build a risk prediction model.METHODS A retrospective analysis was performed on the data of 120 PC cases treated in Xi'an People's Hospital between January 2019 and January 2022.The patient cohort was divided into a training group(n=84)and a validation group(n=36)at a ratio of 7:3.The patients’anxiety symptoms and depression levels were assessed 2 wk after surgery with the Self-Rating Anxiety Scale(SAS)and the Selfrating Depression Scale(SDS),respectively.Logistic regression was used to analyze the risk factors affecting negative mood,and a risk prediction model was constructed.RESULTS In the training group,35 patients and 37 patients had an SAS score and an SDS score greater than or equal to 50,respectively.Based on the scores,we further subclassified patients into two groups:a bad mood group(n=35)and an emotional stability group(n=49).Multivariate logistic regression analysis showed that marital status,castration scheme,and postoperative Visual Analogue Scale(VAS)score were independent risk factors affecting a patient's bad mood(P<0.05).In the training and validation groups,patients with adverse emotions exhibited significantly higher risk scores than emotionally stable patients(P<0.0001).The area under the curve(AUC)of the risk prediction model for predicting bad mood in the training group was 0.743,the specificity was 70.96%,and the sensitivity was 66.03%,while in the validation group,the AUC,specificity,and sensitivity were 0.755,66.67%,and 76.19%,respectively.The Hosmer-Lemeshow test showed aχ^(2) of 4.2856,a P value of 0.830,and a C-index of 0.773(0.692-0.854).The calibration curve revealed that the predicted curve was basically consistent with the actual curve,and the calibration curve showed that the prediction model had good discrimination and accuracy.Decision curve analysis showed that the model had a high net profit.CONCLUSION In PC patients,marital status,castration scheme,and postoperative pain(VAS)score are important factors affecting postoperative anxiety and depression.The logistic regression model can be used to successfully predict the risk of adverse psychological emotions.

Inflammatory response in gastrointestinal cancers:Overview of six transmembrane epithelial antigens of the prostate in pathophysiology and clinical implications

Chronic inflammation is known to increase the risk of gastrointestinal cancers(GICs),the common solid tumors worldwide.Precancerous lesions,such as chronic atrophic inflammation and ulcers,are related to inflammatory responses in vivo and likely to occur in hyperplasia and tumorigenesis.Unfortunately,due to the lack of effective therapeutic targets,the prognosis of patients with GICs is still unsatisfactory.Interestingly,it is found that six transmembrane epithelial antigens of the prostate(STEAPs),a group of metal reductases,are significantly associated with the progression of malignancies,playing a crucial role in systemic metabolic homeostasis and inflammatory responses.The structure and functions of STEAPs suggest that they are closely related to intracellular oxidative stress,responding to inflammatory reactions.Under the imbalance status of abnormal oxidative stress,STEAP members are involved in cell transformation and the development of GICs by inhibiting or activating inflammatory process.This review focuses on STEAPs in GICs along with exploring their potential molecular regulatory mechanisms,with an aim to provide a theoretical basis for diagnosis and treatment strategies for patients suffering from these types of cancers.

Aspartoacylase suppresses prostate cancer progression by blocking LYN activation

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 pulldown 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<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.Conclusions: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.

Treatment-induced neuroendocrine prostate cancer and de novo neuroendocrine prostate cancer:Identification,prognosis and survival,genetic and epigenetic factors

Neuroendocrine prostate cancer(NEPC)shows an aggressive behavior compared to prostate cancer(PCa),also known as prostate adenocarcinoma.Scanty foci in PCa can harbor genetic alternation that can arise in a heterogeneity of prostate cancer.NEPC may arise de novo or develop following androgen deprivation therapy(ADT).NEPC that arise following ADT has the nomenclature“treatmentemerging/induced NEPC(t-NEPC)”.t-NEPC would be anticipated in castration resistant prostate cancer(CRPC)and metastatic PCa.t-NEPC is characterized by low or absent androgen receptor(AR)expression,independence of AR signaling,and gain of neuroendocrine phenotype.t-NEPC is an aggressive metastatic tumor,develops from PCa in response to drug induced ADT,and shows very short response to conventional therapy.t-NEPC occurs in 10%-17%of patients with CRPC.De novo NEPC is rare and is accounting for less than 2%of all PCa.The molecular mechanisms underlying the trans-differentiation from CRPC to t-NEPC are not fully elucidated.Sphingosine kinase 1 plays a significant role in t-NEPC development.Although neuroendocrine markers:Synaptophysin,chromogranin A,and insulinoma associated protein 1(INSM1)are expressed in t-NEPC,they are non-specific for diagnosis,prognosis,and follow-up of therapy.t-NEPC shows enriched genomic alteration in tumor protein P53(TP53)and retinoblastoma 1(RB1).There are evidences suggest that t-NEPC might develop through epigenetic evolution.There are genomic,epigenetic,and transcriptional alterations that are reported to be involved in development of t-NEPC.Knock-outs of TP53 and RB1 were found to contribute in development of t-NEPC.PCa is resistant to immunotherapy,and at present there are running trials to approach immunotherapy for PCa,CRPC,and t-NEPC.

Icariin plus curcumol enhances autophagy through the mTOR pathway and promotes cathepsin B-mediated pyroptosis of prostate cancer cells

Objective:To examine the effect of icariin plus curcumol on prostate cancer cells PC3 and elucidate the underlying mechanisms.Methods:We employed the Cell Counting Kit 8 assay and colony formation assay to assess cell viability and proliferation.Autophagy expression was analyzed using monodansylcadaverine staining.Immunofluorescence and Western blot analyses were used to evaluate protein expressions related to autophagy,pyroptosis,and the mTOR pathway.Cellular damage was examined using the lactate dehydrogenase assay.Moreover,cathepsin B and NLRP3 were detected by co-immunoprecipitation.Results:Icariin plus curcumol led to a decrease in PC3 cell proliferation and an enhancement of autophagy.The levels of LC3-Ⅱ/LC3-Ⅰand beclin-1 were increased,while the levels of p62 and mTOR were decreased after treatment with icariin plus curcumol.These changes were reversed upon overexpression of mTOR.Furthermore,3-methyladenine resulted in a decrease in inflammatory cytokines,pyroptosis-related protein levels,and lactate dehydrogenase concentration,compared to the icariin plus curcumol group.Inhibiting cathepsin B reversed the regulatory effects of icariin plus curcumol.Conclusions:Icariin plus curcumol demonstrates great potential as a therapeutic agent for castration-resistant prostate cancer by enhancing autophagy via the mTOR pathway and promoting pyroptosis mediated by cathepsin B.These findings provide valuable insights into the molecular mechanisms underlying the therapeutic potential of icariin and curcumol for prostate cancer treatment.

Genetic variant in a BaP-activated super-enhancer increases prostate cancer risk by promoting AhR-mediated FAM227A expression

Genetic variants in super-enhancers(SEs)are increasingly implicated as a disease risk-driving mechanism.Previous studies have reported an associations between benzo[a]pyrene(BaP)exposure and some malignant tumor risk.Currently,it is unclear whether BaP is involved in the effect of genetic variants in SEs on prostate cancer risk,nor the associated intrinsic molecular mechanisms.In the current study,by using logistic regression analysis,we found that rs5750581T>C in 22q-SE was significantly associated with prostate cancer risk(odds ratio=1.26,P=7.61×10^(-5)).We also have found that the rs6001092T>G,in a high linkage disequilibrium with rs5750581T>C(r^(2)=0.98),is located in a regulatory aryl hydrocarbon receptor(AhR)motif and may interact with the FAM227A promoter in further bioinformatics analysis.We then performed a series of functional and BaP acute exposure experiments to assess biological function of the genetic variant and the target gene.Biologically,the rs6001092-G allele strengthened the transcription factor binding affinity to AhR,thereby upregulating FAM227A,especially upon exposure to BaP,which induced the malignant phenotypes of prostate cancer.The current study highlights that AhR acts as an environmental sensor of BaP and is involved in the SE-mediated prostate cancer risk,which may provide new insights into the etiology of prostate cancer associated with the inherited SE variants under environmental carcinogen stressors.

MAPK9 as a therapeutic target:unveiling ferroptosis in localized prostate cancer progression

Background:Ferroptosis,a lipid peroxidation-mediated programmed cell death,is closely linked to tumor development,including prostate cancer(PCa).Despite established connections between ferroptosis and PCa,a comprehensive investigation is essential for understanding its impact on patient prognosis.Methods:A risk model incorporating four ferroptosis-related genes was developed and validated.Elevated risk scores correlated with an increased likelihood of biochemical recurrence(BCR),diminished immune infiltration,and adverse clinicopathological characteristics.To corroborate these results,we performed validation analyses utilizing datasets from both the Cancer Genome Atlas Cohort(TCGA)and the Gene Expression Synthesis Cohort(GEO).Moreover,we conducted further investigations into the pivotal gene identified in our model to explore its impact on tumor characteristics through cell proliferation and invasion assays,as well as animal studies conducted in vivo.Additionally,we conducted further experiments involving ferroptosis-related analysis to validate its association with ferroptosis.Results:The risk model demonstrated exceptional predictive capabilities for prognosis and therapeutic outcomes in PCa patients.Mitogen-activated protein kinase 9(MAPK9)emerged as a crucial gene within the model.In vivo and in vitro experiments explored MAPK9’s role in ferroptosis and its influence on tumor migration and proliferation.Conclusion:The findings provide a novel perspective for advancing ferroptosis exploration in PCa,bridging basic research and clinical applications.

Aminated Cyclopropylmethylphosphonates as Potent Prostate Cancer Inhibitors

Inspired by the anti-pancreatic promising results of our novel aminated cyclopropylmethylphosphonate compounds, an in vitro anti-prostate cancer activity exploration of these compounds was carried out on human prostate cancer cell line PC-3, and showed potent inhibiting activity at low micromolar concentrations (with an IC50 of approximately 45 μM).