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At least 19 recordsLinked to original sources

PubMed2026

Impact of homologous recombination repair gene mutations on survival in metastatic prostate cancer: A real-world analysis from an observational database.

The prognostic significance of homologous recombination repair gene (HRRg) mutations across the different metastatic prostate cancer stages remains unclear. This retrospective real-world study analyzed 162 metastatic castration-sensitive (mCSPC) and 126 castration-resistant (mCRPC) patients from the ProGène database, stratified by HRRg mutational status. Mutation prevalence was similar in both groups (16.0% in mCSPC vs. 13.5% in mCRPC). HRR-positive mCSPC patients had significantly shorter median overall survival (OS) (24.0months; 95% confidence interval [CI]: 16.0-41.0) compared to HRR-negative patients (45.0months; 95% CI: 34.0-69.0; P=0.04). Notably, BRCA2-mutated patients exhibited a reduced median OS of 24.0months (95% CI: 9.0-40.0; P=0.036) and a faster progression-free survival compared to HRR-negative patients (median PFS=8.0months; 95% CI: 0.0-14.0 vs. 17.0months; 95% CI: 12.0-20.0; P=0.006). These findings suggest that HRRg mutations - especially BRCA2 - are associated with worse prognosis in mCSPC, supporting the value of early genomic screening to guide personalized treatment strategies.

Humans↗

PubMed2026

Non-Cancer Causes of Death in Patients With Metastatic Hormone-Sensitive Prostate Cancer: A Real-World Analysis.

BACKGROUND: As overall survival improves in metastatic hormone-sensitive prostate cancer (mHSPC), non-cancer causes of death are increasingly relevant. METHODS: We conducted a real-world multicenter study of patients diagnosed with mHSPC treated with ADT alone or in combination. Causes of death before progression to castration-resistant prostate cancer (CRPC) were classified as cancer- or non-cancer-related. Deaths were classified as non-cancer-related if they occurred in the absence of cancer progression. RESULTS: Among 565 patients, 35 (6.2%) died from non-cancer-related causes without disease progression, mainly infections (34%) and cardiovascular events (20%). CONCLUSIONS: Non-cancer mortality represents a meaningful proportion of deaths in mHSPC, supporting systematic cardiovascular risk evaluation and infection-prevention strategies.

Humans↗

PubMed2025

KDM3B Regulates Postradiation Fibrotic Responses in Prostate Stroma via N6-methyladenosine Modification of LOX.

PURPOSE: Genome-wide association studies have uncovered single-nucleotide polymorphisms (SNPs) linked to radiation therapy (RT)-induced toxicities in patients with prostate cancer. SNP rs17599026, located in intron 21 of the KDM3B gene, has been associated with late-onset urinary toxicity, with an increased frequency of urination observed 2 years post-RT compared with pretreatment conditions. This study aimed to explore the underlying mechanisms driving this association. METHODS AND MATERIALS: A clustered regularly interspaced short palindromic repeats-dead Cas9 prime editing system was used to mimic KDM3B genetic variants in prostate stromal cell lines. Murine models with wild-type and heterozygous Kdm3b genotypes were used to assess fibrosis following radiation. RNA immunoprecipitation, transcript stability assays, and protein analysis elucidated the role of N6-methyladenosine (m6A) modification in regulating lysyl oxidase (LOX) expression. α-ketoglutarate (α-KG) supplementation was tested for its effects on KDM3B protein stability, LOX expression, and fibrosis mitigation. RESULTS: The rs17599026 SNP reduced KDM3B protein expression via circular RNA and microRNA-mediated mechanisms, leading to decreased m6A modification and increased stability of LOX messenger RNA. Elevated LOX expression promoted collagen cross-linking and fibrosis in prostate stroma. α-KG supplementation restored KDM3B protein levels, reduced LOX expression, and mitigated fibrosis in vitro and in vivo. CONCLUSIONS: KDM3B genetic variations influence radiation-induced fibrosis through posttranscriptional regulation of LOX. Dietary α-KG supplementation may serve as a mechanism-based strategy to alleviate radiation toxicity in patients with prostate cancer, offering a potential therapeutic pathway to improve treatment outcomes.

Male↗

PubMed2026

Prognostic value of circulating tumor DNA and copy-number alterations in patients receiving tandem [225Ac]Ac-/[177Lu]Lu-PSMA-617 therapy for metastatic castration-resistant prostate cancer: a prospective observational study.

BACKGROUND: Prostate-specific membrane antigen-targeted radioligand therapy (PSMA-RLT) demonstrates clinical efficacy in metastatic castration-resistant prostate cancer (mCRPC), yet robust biomarkers for dynamic treatment monitoring and resistance remain lacking. We investigated circulating tumor DNA (ctDNA)-derived tumor fraction (TFx) and genome-wide copy-number alterations (CNAs) as non-invasive biomarkers of treatment response and resistance biology. METHODS: Seventy-eight patients with advanced mCRPC receiving tandem [225Ac]Ac-/[177Lu]Lu-PSMA-617 were prospectively enrolled. Plasma samples collected longitudinally (n = 172) underwent ultra-low-pass whole-genome sequencing. TFx was estimated using ichorCNA, and recurrent CNAs were identified using GISTIC2.0. Associations with progression and overall survival (OS) were assessed using Cox proportional hazards models, including time-dependent analyses. RESULTS: Baseline TFx differed across metastatic disease stages (p = 0.027) and dynamic TFx changes paralleled PSA kinetics during early treatment. Modelled as a time-dependent variable, TFx was associated with a significantly increased risk of progression (HR 4.9, 95% CI 1.2-20.1, p = 0.026). Unsupervised clustering identified distinct high- and low-CNA burden groups strongly correlated with TFx (p = 8.09 × 10⁻8). High CNA burden was associated with shorter median OS (8.3 vs 13.8 months). Multivariable analysis identified baseline logPSA and logALP as independent predictors of OS. Recurrent CNAs affected key tumor suppressors (PTEN, RB1, BRCA2, ATM) and were enriched in pathways related to TP53 signalling, homologous recombination repair, and oncogenic signaling. Longitudinal analyses demonstrated persistence and expansion of specific amplifications at progression. CONCLUSIONS: ctDNA-derived TFx represents a dynamic biomarker of treatment response and progression risk, while CNA profiling provides insight into resistance mechanisms in mCRPC treated with PSMA-RLT. These findings support the integration of ctDNA-based biomarkers into clinical stratification and real-time monitoring strategies.

Humans↗

PubMed2026

Ablative radiotherapy in castration-resistant prostate cancer.

OBJECTIVE: To prove the oncological benefit of ablative radiotherapy in patients with up to five metastases from castration-resistant prostate cancer (CRPC) a single-centre randomised trial was initiated. PATIENTS AND METHODS: This monocentric, randomised, phase II clinical trial enrolled patients with up to five prostate-specific membrane antigen-positive bone or lymph node metastases developing prostate-specific antigen (PSA) progression during androgen deprivation (ADT) or ADT and androgen-receptor targeted therapy. Participants were randomised (2:1) to receive metastasis-directed therapy (MDT) or observation (OBS) without changing systemic therapy. The primary endpoint was the proportion of patients having PSA progression within 1 year, with statistical analyses conducted using intention-to-treat principles. Here, results of a planned interim analysis of the primary endpoint are reported. RESULTS: A total of 30 patients (12 in the observation arm and 18 in the MDT arm) were enrolled, PSA progression within 1 year occurred in 44% of the MDT group vs 75% in the OBS group (P = 0.14, not significant). The median time to PSA progression was significantly longer in the MDT arm (12.4 months) compared to the OBS arm (2.9 months, P = 0.03). The pre-defined criteria to discontinue the study were not met. Limitations include the single-centre design and small sample size at interim analysis. CONCLUSION: This pre-planned interim analysis of the primary endpoint did not meet the discontinuation criteria of the study protocol, suggesting that MDT in oligometastatic CRPC may extend the time to PSA progression without immediate change of systemic therapy. The continuation of the study in a multicentre setting is planned (Institutional funding by the TU Dresden, ClinicalTrials.gov identifier: NCT04141709).

Humans↗

PubMed2026

Optimizing prostate biopsy decision making - (MUSIC-screen): A 1:1 randomized controlled trial comparing micro-ultrasound versus multiparametric magnetic resonance imaging for prostate cancer diagnosis.

BACKGROUND: Micro-ultrasound (microUS) represents a potential alternative to multiparametric magnetic resonance (mpMRI) in guiding prostate biopsy, with level 1 evidence demonstrating non-inferiority to detect Grade Group ≥2 (GG ≥ 2) prostate cancer in biopsy-naïve men. However, a critical gap remains in the screening pathway, in which imaging is needed to identify men at risk and determine whether biopsy is warranted. METHODS: MUSIC-Screen is a phase 3, open-label, noninferiority 1:1 randomized controlled trial evaluating microUS as an alternative imaging compared to mpMRI for determining the need for prostate biopsy in biopsy- and imaging- naïve men at risk for GG ≥ 2. A total of 1284 men will be randomized to undergo either microUS or mpMRI. Men with PRI-MUS 3-5 or PI-RADS 3-5 lesion will undergo targeted and systematic biopsy. Men with negative imaging and PSA density ≥ 0.15 will undergo systematic biopsy, while those with PSA density < 0.15 will defer biopsy. RESULTS: The primary outcome is GG ≥ 2 detection in each study arm. The primary hypothesis is that microUS is non-inferior to mpMRI for screening and detection of GG ≥ 2. Secondary objectives include comparison of GG ≥ 2 detection rates in targeted cores among patients with PRI-MUS or PI-RADS scores of 3-5, proportion of men who defer biopsy but are diagnosed with GG ≥ 2 within 8 years, assessment of the negative predictive value of each imaging modality, and health economic analyses. CONCLUSION: MUSIC-Screen will determine whether microUS can be used as an imaging modality to inform biopsy decision making that is non-inferior to mpMRI for GG ≥ 2 prostate cancer detection. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06626022.

Humans↗

PubMed2026

Reduced Length of ADT and ARTA With XRT in High-Risk Prostate Cancer (RELAX): A Randomised Controlled Trial.

AIM: To assess the efficacy of a short, intensified regimen of androgen deprivation therapy (ADT) and androgen receptor-targeted agent (ARTA) with curative-intent external beam radiotherapy (XRT) for high-risk prostate cancer (HRPCa) staged with prostate specific membrane antigen (PSMA) imaging. MATERIALS AND METHODS: The RELAX (Reduced Length of ADT and ARTA with XRT in high-risk prostate cancer) trial is a multicentre, phase II randomised non-inferiority trial comparing 9 months of ADT and 6 months of ARTA against the standard 24-month ADT, with definitive dose-escalated hypofractionated pelvic radiotherapy for PSMA-staged non-metastatic HRPCa. The primary endpoint is 5-year disease-free survival (DFS), defined from randomisation to first biochemical or clinico-radiological recurrence or any-cause death. Secondary endpoints include biochemical failure-free survival, metastasis-free survival, overall survival, testosterone recovery, treatment-related adverse effects, and patient-reported outcomes. Participants are monitored with serial serum PSA and testosterone levels, CTCAE and PRO-CTCAE assessments, and PSMA-PETCT at recurrence. The non-inferiority margin is set at 10% absolute difference from an expected 5-year DFS of 85% in the standard arm, with intention-to-treat analysis. The trial is ethics board approved and funded by institutional intramural grant, and registered on clinicaltrials.gov (NCT06818682). RESULTS: The planned accrual of 206 participants commenced in February 2025, with nearly a third of enrolment completed till date. CONCLUSION: The RELAX trial incorporates contemporary standards of PSMA-based staging, dose-escalated hypofractionated radiotherapy, and ARTA for HRPCa. The results are expected to inform the efficacy of a shorter, intensified androgen suppression strategy against the prevailing standard of long-term ADT for these patients.

Humans↗

PubMed2024

Exploring the clinical and biological significance of the cell cycle-related gene CHMP4C in prostate cancer.

BACKGROUND: Prostate cancer (PCa) stands as the second most prevalent malignancy impacting male health, and the disease's evolutionary course presents formidable challenges in the context of patient treatment and prognostic management. Charged multivesicular body protein 4 C (CHMP4C) participates in the development of several cancers by regulating cell cycle functions. However, the role of CHMP4C in prostate cancer remains unclear. METHODS: In terms of bioinformatics, multiple PCa datasets were employed to scrutinize the expression of CHMP4C. Survival analysis coupled with a nomogram approach was employed to probe into the prognostic significance of CHMP4C. Gene set enrichment analysis (GSEA) was conducted to interrogate the functional implications of CHMP4C. In terms of cellular experimentation, the verification of RNA and protein expression levels was executed through the utilization of qRT-PCR and Western blotting. Upon the establishment of a cell line featuring stable CHMP4C knockdown, a battery of assays, including Cell Counting Kit-8 (CCK-8), wound healing, Transwell, and flow cytometry, were employed to discern the impact of CHMP4C on the proliferation, migration, invasion, and cell cycle function of PCa cells. RESULTS: The expression of CHMP4C exhibited upregulation in both PCa cells and tissues, and patients demonstrating elevated CHMP4C expression levels experienced a notably inferior prognosis. The nomogram, constructed using CHMP4C along with clinicopathological features, demonstrated a commendable capacity for prognostic prediction. CHMP4C knockdown significantly inhibited the proliferation, migration, and invasion of PCa cells (LNcaP and PC3). CHMP4C could impact the advancement of the PCa cell cycle, and its expression might be regulated by berberine. Divergent CHMP4C expression among PCa patients could induce alterations in immune cell infiltration and gene mutation frequency. CONCLUSIONS: Our findings suggest that CHMP4C might be a prognostic biomarker in PCa, potentially offering novel perspectives for the advancement of precision therapy for PCa.

Humans↗

PubMed2026

The 'Prostate Cancer Screening for People at Genetic Risk of Aggressive Disease' (PATROL) study.

BACKGROUND: Inherited (germline) pathogenic and likely pathogenic variants (gPVs) in key genes associated with increased risk of prostate cancer (PCa) now warrant more attentive PCa screening per National Comprehensive Cancer Network (NCCN) guidelines-e.g., BRCA2, HOXB13, ATM, BRCA1, MSH2, MSH6, CHEK2 and TP53. However, the optimal early detection strategy for gPV carriers, including use of age-adjusted PSA thresholds and prostate imaging may be refined. and as a means to investigate novel biomarkers. STUDY DESIGN: 'Prostate Cancer Screening for People at Genetic Risk of Aggressive Disease' (PATROL) is a multicentre, prospective early detection study for individuals at increased risk for PCa due to carrying a gPV in a PCa risk gene. ENDPOINTS: The primary endpoint is to determine the positive predictive value of pre-defined age-directed prostate-specific antigen (PSA) level thresholds and prostate-specific imaging, e.g., multiparametric magnetic resonance imaging (MRI) for clinically significant PCa on biopsy for individuals at risk of PCa due to a gPV. Exploratory endpoints include characterising clinicopathological characteristics of PCa and patient-reported outcomes. Biospecimens will be collected to evaluate emerging clinical and research biomarkers. PATIENTS AND METHODS: Key eligibility includes: individuals aged ≥40 years who carry a gPV in an eligible gene, who have no prior diagnosis of PCa, do not have another active malignancy, and provide informed consent. Study procedures include annual physical examination and PSA. Imaging with MRI is optional at baseline and recommended if the PSA level is above the protocol-recommended PSA level threshold. Participants will be offered prostate biopsy for any clinical concern, PSA level >1.0 ng/mL if aged <50 years; PSA level >1.5 ng/mL if aged 50-59 years; PSA level >2.0 ng/mL if aged ≥60 years. If PCa is diagnosed, clinical care is determined by the participant and treating physician. If opting for active surveillance, study procedures will be collected annually for 10 years or until definitive treatment. If definitive treatment, study procedures will be collected for an additional 1 year. Long-term clinical outcomes will be collected annually until the study closes.

Humans↗

PubMed2026

Development and pilot testing of a prostate cancer polygenic risk report.

BACKGROUND: Polygenic risk scores (PRS) are increasingly being incorporated into clinical care, yet optimal strategies for communicating PRS results to patients and clinicians remain undefined. Effective report design is critical to ensure comprehension and appropriate use, particularly for complex conditions such as prostate cancer where screening decisions are nuanced. We developed and pilot tested patient-facing materials to communicate integrated polygenic and monogenic risk for prostate cancer in the context of a randomized clinical trial. METHODS: We designed a summary report and accompanying Frequently Asked Questions (FAQ) page to communicate prostate cancer genetic risk within the Prostate Cancer, Genetic Risk, and Equitable Screening Study (ProGRESS). Materials were developed through an iterative, multidisciplinary process informed by existing literature on genomic risk communication. We conducted semi-structured interviews with a national sample of eight men eligible for prostate cancer screening to evaluate comprehension, interpretation of visual elements, perceived usefulness, and preferences for improvement. Interviews were transcribed and analyzed using reflexive thematic analysis. RESULTS: Participants generally found the summary report and FAQ page understandable and visually engaging. Graphical displays of absolute risk, particularly pictograph arrays, facilitated comprehension and helped contextualize risk. Visual cues such as color and bold formatting effectively directed attention to key information, with red coloring perceived as particularly salient for high-risk results. In contrast, more complex visualizations, including bell curves and incidence curves, were frequently misunderstood or not interpreted as intended. Participants expressed a desire for clearer guidance regarding next steps and additional accessible information, suggesting supplementary resources such as hyperlinks or QR codes. Concerns about readability included small font size and high text density. CONCLUSIONS: In this qualitative pilot study, patient-facing materials for communicating prostate cancer PRS were generally well received, with specific design features such as simple visualizations and clear formatting enhancing understanding. Findings highlight the importance of intuitive risk displays and actionable guidance in PRS reporting. These results provide practical insights to inform the design of genomic risk reports as PRS-based prostate cancer screening approaches move toward clinical implementation. TRIAL REGISTRATION: ClinicalTrials.gov NCT05926102; date of registry: July 3, 2023.

Aged↗

PubMed2026

Uncovering the diagnostic potential of seminal fluid beyond fertility: cfDNA methylation analysis for the detection of clinically significant prostate cancer.

Research on the potential use of seminal fluid as a liquid biopsy for prostate cancer detection has been limited due to challenges associated with acquisition of this bodily fluid in clinical studies. Here we sought to expand on our previous analysis, which demonstrated high levels of prostate-derived cell free DNA (cfDNA) in seminal fluid in presumed healthy individuals, to a much larger cohort that included participants with prostate cancer. A total of 279 men scheduled for prostate biopsy were enrolled over 4 months across 12 sites. Prior to their biopsy, participants mailed a seminal fluid sample collected at home to the laboratory, from which cfDNA was extracted and underwent methylation analysis. Consistent with our earlier study in healthy individuals, we observed an abundance of high molecular weight (HMW) cfDNA in all samples. Tissue-of-origin deconvolution revealed that granulocytes and sperm were the principal contributors to seminal fluid cfDNA, while prostate-derived cfDNA was present at abundances readily detectable with current technologies. The nucleosomal fraction was very pronounced in some but not all samples and was determined to be correlated with the relative sperm signal. The sperm signal was also observed to be associated with an increase in small insert sizes (< 125 bp) in the sequenced libraries. Unsupervised clustering revealed two distinct populations driven by the abundance of sperm and granulocytes. Since summarizing at the genomic region level confounded tissues of different origins, fragment-level DNA methylation features were used to characterize and quantify the prostate cancer related signal, and features associated with clinically significant prostate cancer were identified. This study expands on our previous work to further characterize seminal fluid and highlights its potential as a promising liquid biopsy medium for the detection and monitoring of clinically significant prostate cancer.

Humans↗

PubMed2026

Potential impact of NUCB2 genetic variants with the clinicopathological characteristics of prostate cancer.

The most prevalent illness in men is prostate cancer, which risk increases with age and obesity. The precursor NUCB2 gene produces the adipokine nesfatin-1, which was first found in hypothalamic neurons. It is currently unclear how NUCB2 polymorphisms, cancer-promoting lifestyle factors, and prostate cancer are related. We investigated the relationship between clinicopathological features and 4 NUCB2 gene polymorphisms in prostate cancer when compared to healthy individuals. Compared with the wild-type T/T genotype, carriage of at least one G allele (T/G or G/G genotypes) at the NUCB2 SNP rs10766383 was linked with a declined risk of clinical T3+T4 stage, pathologic T3+T4 stage, and perineural invasion. In addition, the TG/GG genotypes at rs10766383 were also associated to a lower risk of clinical T3+T4 stage and perineural invasion in patients with biochemical recurrence. Importantly, GTEx data indicated that the wild-type TT homozygous genotype was linked with markedly higher NUCB2 levels compared to the GG allele of variant rs10766383 variant in mucosa and whole blood tissues. Thus, the NUCB2 SNP rs10766383 may play a protective function against prostate cancer progression.

Humans↗

PubMed2025

Systems biology successes and areas for opportunity in prostate cancer.

Systems biology approaches have been applied to prostate cancer to model how individual cellular and molecular components interact to influence cancer development, progression, and treatment responses. The integration of multi-omic experimental data with computational models has provided insights into the molecular characteristics of prostate cancer and emerging treatment strategies that have the potential to improve patient outcomes. Here, we highlight recent advancements that have emerged from systems modeling in prostate cancer. These include descriptions of the molecular landscape of prostate cancer and how genomic alterations inform computational models of disease progression, how evolutionary processes give rise to mechanisms of therapeutic resistance, and the development of innovative treatment strategies such as adaptive therapy. We also highlight current challenges in prostate cancer that can be addressed through systems biology approaches. These include tumor heterogeneity, poor immunotherapy response, a paucity of experimental model systems, and the ongoing translation of computational models for clinical decision making. Leveraging systems biology approaches has the potential to lead to a better understanding of the disease and better patient outcomes in the treatment of prostate cancer.

Humans↗

PubMed2026

Bifunctional covalent organic framework for rapid isolation of extracellular vesicles and proteomics-based biomarker discovery.

Extracellular vesicles (EVs), serving as crucial carriers of biomarkers for tumor diagnosis and prognostic evaluation, as well as drug delivery vehicles and therapeutic targets, making it a research hotspot. The isolation methods represent a key aspect of EV-associated research. In this work, an alkynyl-functionalized covalent organic framework (COF) was synthesized under acidic conditions at room temperature and further modified by photo-initiated thiol-yne click reaction, yielding a bifunctionalized COF material decorated with distearoyl phosphatidylethanolamine (DSPE) and Ti4+. This bifunctional COF material (COF-DSPE-Ti) can leverage the bifunctional synergistic effect between DSPE and Ti4+ sites, thereby facilitating the efficient isolation of EVs. This synergistic effect enables the efficient isolation of EVs within 3 min. Proteomic analysis reveals that this isolation method significantly outperforms ultracentrifugation, and an effective EV isolation and analysis can be completed using only 10 μL of plasma sample. For clinical liquid biopsy, the integration of the COF-DSPE-Ti method with proteomics lead to the identification of 64 upregulated proteins in plasma samples from colorectal cancer (CRC) patients, among which S100A9 emerged as a potential EV biomarker. In addition, KLK2, KLK3, and FOLH1, which have been established as diagnostic markers for prostate cancer (PCa), are successfully identified in EVs isolated from the urine of PCa patients. These findings demonstrate the reliability of this approach for screening EV-associated biomarkers and provide a novel strategy for the early diagnosis and prognostic assessment of CRC and PCa.

Proteomics↗

PubMed2026

Pelvic lymph node dissection in prostate cancer: current evidence, controversies, and future directions.

BACKGROUND: Pelvic lymph node dissection (PLND) remains controversial in the management of prostate cancer. Although it provides the most accurate pathological staging, its therapeutic value beyond staging has long been debated due to conflicting evidence and concerns regarding procedure-related morbidity. OBJECTIVE: To critically evaluate the contemporary role of PLND, particularly extended pelvic lymph node dissection (ePLND), in prostate cancer management in the context of modern imaging, risk stratification tools, and evolving oncologic endpoints. EVIDENCE ACQUISITION: A narrative review of recent literature was conducted, focusing on high-level evidence including randomized trials, observational studies, and contemporary guideline recommendations addressing the indications, extent, oncologic outcomes, and complications of PLND. EVIDENCE SYNTHESIS: Recent randomized and observational studies suggest that ePLND improves nodal staging accuracy and may be associated with modest improvements in metastasis-free survival (MFS) in selected patients with intermediate- and high-risk prostate cancer, although the absolute benefit remains limited and causality is not definitively established. Advances in molecular imaging, particularly prostate-specific membrane antigen (PSMA) PET/CT, together with multiparametric MRI, validated nomograms, and emerging genomic classifiers, now allow more precise identification of patients most likely to benefit from ePLND. The integration of these tools supports a more individualized surgical strategy, including image-guided and sentinel lymph node approaches designed to maximize staging accuracy while minimizing unnecessary dissection. CONCLUSIONS: In the contemporary PSMA imaging era, ePLND continues to play an important role in nodal staging and may contribute to improved oncologic outcomes in carefully selected patients.

Humans↗

PubMed2026

The establishment of prostate-specific, SKP2 humanized mice by CRISPR knock-in method reveals neoplastic initiation and microenvironmental reprogramming.

Genetic inactivation of SKP2 has been shown to effectively prevent cancer initiation and block tumorigenesis. However, direct in vivo evidence for SKP2 on cancer initiation and prostatic microenvironment is still lacking and a SKP2 humanized mouse model is critical for developing prostate cancer immunoprevention approaches through targeting SKP2. We therefore have established a prostate-specific human SKP2 knock-in mouse model driven by an endogenous mouse probasin promoter. Overexpression of hSKP2 induces PIN and low-grade carcinoma. RNA-sequencing analysis revealed significant gene expression alterations in EMT, extracellular matrix, and interferon signaling. Single-cell deconvolution showed an increase of fibroblast population and a decrease of CD8+ T cell and B cell populations. Consistent with these results from the SKP2 humanized mouse, SKP2 protein is overexpressed in human prostatic hyperplasia, PIN and prostate adenocarcinoma compared to normal prostate tissues. Overexpression of SKP2 markedly increased cell migration and invasion and induced the gene expression of EMT and interferon pathways. Inhibition of SKP2 signaling by Flavokawain A and C1 reverses EMT and affects EMT and interferon-related gene expression. In addition, paired prostate organoids were derived from SKP2 humanized and wild-type mice for drug screening and validated by known SKP2 inhibitors, Flavokawain A and C1. Both of which selectively decreased viability and altered the morphologies of organoids of hSKP2 knock-in rather than wild-type mice. Our studies provide a well-characterized prostate-specific hSKP2 knock-in mouse model and offer new mechanistic insights for understanding the oncogenic role of SKP2 in shaping the prostatic microenvironment during early carcinogenesis.

Animals↗

PubMed2026

Inactivation of CDK12 Enhances Mitochondrial Efficiency to Suppress DNA Damage.

Inactivation of cyclin-dependent kinase 12 (CDK12) characterizes a subset of prostate cancers but it is not understood how cells adapt to declining activity of this major transcription elongation kinase. To probe this response, we developed a cell line resistant to an inhibitor targeting CDK12 and its paralog, CDK13. CDK13 can compensate for the loss of CDK12, which is why we used the dual inhibitor THZ531. Targeted drug screening of the parental and resistant cell lines revealed cross-resistance to other transcriptional kinases but no clear acquired point of vulnerability. Using genome-wide mapping of mRNA-stabilization based on metabolic labelling of RNA, we report selective mRNA stabilization of factors promoting oxidative phosphorylation in the resistant cells. We go on to show that loss of CDK12 activity enhances ATP production both in cell line models and in patient tumours. Finally, we show that dual inhibition of CDK12/13 results in excessive phosphorylation of the DNA damage H2AX in prostate cancer cells but not in our CDK12/13 inhibitor-resistant model system. In brief, we propose that inactivation of CDK12 rewires cellular energy metabolism to suppress DNA damage.

Humans↗

PubMed2026

Enrichment Performance Assessment of Extracellular Vesicles Using Different Functionalized Magnetic Materials and Application in Urinary Proteomics of Prostate Cancer.

Extracellular vesicles (EVs) are lipid bilayer nanovesicles that mediate intercellular communication and hold significant potential for clinical applications. Although material-based isolation strategies offer promising alternatives to conventional methods, their relative performances have not been systematically evaluated. In this study, we conducted a comparative assessment of magnetic nanomaterials with distinct surface functionalities, including metal oxides (TiO2), metal-organic frameworks (UiO-66), biopolymeric materials (chitosan), and lipid probes (DSPE-PEG, DOPE-PEG, and CLS-PEG). A comprehensive evaluation across multiple dimensions including capture capacity, capture rate, sample volume, and product purity reveals that the bifunctional magnetic nanomaterial Fe3O4@UiO-66@DSPE material exhibits superior EV capture performance. This material enables the efficient and stable enrichment of high-purity EVs by synergizing Zr4+-phosphate coordination with lipid bilayer anchoring, and preserves EV biological integrity and activity. Meanwhile, this method could be highly compatible with proteomics, and over 1000 proteins are identified by proteomic analysis of urinary EVs, while 34 proteins are upregulated and 25 proteins are downregulated in prostate cancer patients relative to healthy donors. Notably, the differentially expressed proteins, such as AGT, ITIH4, and PGLYRP2, are associated with disease progression. Overall, this work highlights the superior performance of the Fe3O4@UiO-66@DSPE material for efficient and selective EV isolation. It provides a powerful tool for clinical liquid biopsy and proteomic biomarker discovery, enabling early diagnosis, prognostic evaluation, and precision therapy.

Humans↗