Circulating tumor extracellular vesicles to monitor metastatic prostate cancer genomics and transcriptomic evolution.

Extracellular vesicles (EVs) secreted by tumors are abundant in plasma, but their potential for interrogating the molecular features of tumors through multi-omic profiling remains widely unexplored. Genomic and transcriptomic profiling of circulating EV-DNA and EV-RNA isolated from in vitro and in vivo models of metastatic prostate cancer (mPC) reveal a high contribution of tumor material to EV-loaded DNA/RNA, validating the findings in two cohorts of longitudinal plasma samples collected from patients during androgen receptor signaling inhibitor (ARSI) or taxane-based therapy. EV-DNA genomic features recapitulate matched-patient biopsies and circulating tumor DNA (ctDNA) and associate with clinical progression.

Minimizing higher-order aggregation maximizes iron mobilization by small molecules.

The natural product hinokitiol mobilizes iron across lipid bilayers at low concentrations and restores hemoglobinization in iron transporter protein-deficient systems. But hinokitiol fails to similarly mobilize iron at higher concentrations, limiting its uses in chemical biology and medicine. Here we show that at higher concentrations, hinokitiol:Fe(III) complexes form large, higher-order aggregates, leading to loss of transmembrane iron mobilization.

Accurate diagnosis of prostate cancer by combining Proclarix with magnetic resonance imaging.

Objectives: To assess of the clinical performance of Proclarix (a novel Conformité Européenne [CE]-marked biomarker test aiding in the identification of clinically significant prostate cancer [csPCa]) alone or in combination with multiparametric magnetic resonance imaging (mpMRI) to predict csPCa (International Society of Urological Pathology Grade Group ≥2).

Patients And Methods: The study included blood samples from 721 men undergoing mpMRI followed by biopsy at University College London, London, and Vall d'Hebron University Hospital, Barcelona. Samples were tested blindly.

A combination of molecular and clinical parameters provides a new strategy for high-grade serous ovarian cancer patient management.

Background: High-grade serous carcinoma (HGSC) is the most common and deadly subtype of ovarian cancer. Although most patients will initially respond to first-line treatment with a combination of surgery and platinum-based chemotherapy, up to a quarter will be resistant to treatment. We aimed to identify a new strategy to improve HGSC patient management at the time of cancer diagnosis (HGSC-1LTR).

Comparison of Proclarix, PSA Density and MRI-ERSPC Risk Calculator to Select Patients for Prostate Biopsy after mpMRI.

Tools to properly select candidates for prostate biopsy after magnetic resonance imaging (MRI) have usually been analyzed in overall populations with suspected prostate cancer (PCa). However, the performance of these tools can change regarding the Prostate Imaging-Reporting and Data System (PI-RADS) categories due to the different incidence of clinically significant PCa (csPCa). The objective of the study was to analyze PSA density (PSAD), MRI-ERSPC risk calculator (RC), and Proclarix to properly select candidates for prostate biopsy regarding PI-RADS categories.

Comparative Analysis of PSA Density and an MRI-Based Predictive Model to Improve the Selection of Candidates for Prostate Biopsy.

This study is a head-to-head comparison between mPSAD and MRI-PMbdex. The MRI-PMbdex was created from 2432 men with suspected PCa; this cohort comprised the development and external validation cohorts of the Barcelona MRI predictive model. Pre-biopsy 3-Tesla multiparametric MRI (mpMRI) and 2 to 4-core transrectal ultrasound (TRUS)-guided biopsies for suspicious lesions and/or 12-core TRUS systematic biopsies were scheduled.

Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor.

Targeting the kinases MNK1 and MNK2 has emerged as a valuable strategy in oncology. However, most of the advanced inhibitors are acting in an adenosine triphosphate (ATP)-competitive mode, precluding the evaluation of different binding modes in preclinical settings. Using rational design, we identified and validated the 4,6-diaryl-pyrazolo[3,4-]pyridin-3-amine scaffold as the core for MNK inhibitors.

Multiparametric Magnetic Resonance Imaging Grades the Aggressiveness of Prostate Cancer.

We sought to find further evidence showing the increase in PCa aggressiveness as PI-RADS score increases from four surrogates of PCa aggressiveness: i. prostate biopsy GG (≤3 vs. >3), ii.

The Barcelona Predictive Model of Clinically Significant Prostate Cancer.

A new and externally validated MRI-PM for csPCa was developed in the metropolitan area of Barcelona, and a web-RC designed with the new option of selecting the csPCa probability threshold. The development cohort comprised 1486 men scheduled to undergo a 3-tesla multiparametric MRI (mpMRI) and guided and/or systematic biopsies in one academic institution of Barcelona. The external validation cohort comprised 946 men in whom the same diagnostic approach was carried out as in the development cohort, in two other academic institutions of the same metropolitan area.

BRCA1 mutations in high-grade serous ovarian cancer are associated with proteomic changes in DNA repair, splicing, transcription regulation and signaling.

Despite recent advances in the management of BRCA1 mutated high-grade serous ovarian cancer (HGSC), the physiology of these tumors remains poorly understood. Here we provide a comprehensive molecular understanding of the signaling processes that drive HGSC pathogenesis with the addition of valuable ubiquitination profiling, and their dependency on BRCA1 mutation-state directly in patient-derived tissues. Using a multilayered proteomic approach, we show the tight coordination between the ubiquitination and phosphorylation regulatory layers and their role in key cellular processes related to BRCA1-dependent HGSC pathogenesis.

Improving the Early Detection of Clinically Significant Prostate Cancer in Men in the Challenging Prostate Imaging-Reporting and Data System 3 Category.

Background: Prostate Imaging-Reporting and Data System (PI-RADS) category 3 is a challenging scenario for detection of clinically significant prostate cancer (csPCa) and some tools can improve the selection of appropriate candidates for prostate biopsy.

Objective: To assess the performance of the European Randomized Study of Screening for Prostate Cancer (ERSPC) magnetic resonance imaging (MRI) model, the new Proclarix test, and prostate-specific antigen density (PSAD) in selecting candidates for prostate biopsy among men in the PI-RADS 3 category.

Design Setting And Participants: We conducted a head-to-head prospective analysis of 567 men suspected of having PCa for whom guided and systematic biopsies were scheduled between January 2018 and March 2020 in a single academic institution.

Who with suspected prostate cancer can benefit from Proclarix after multiparametric magnetic resonance imaging?

Proclarix is a new blood-based test to assess the likelihood of clinically significant prostate cancer (csPCa) defined as 2 grade group. In this study, we analyzed whether Proclarix and PSA density (PSAD) could improve the selection of candidates for prostate biopsy after multiparametric magnetic resonance imaging (mpMRI). Proclarix and PSAD were assessed in 567 consecutive men with suspected PCa in whom pre-biopsy 3 Tesla mpMRI, scoring with Prostate Imaging-Report and Data System (PI-RADS) v.

The Efficacy of Proclarix to Select Appropriate Candidates for Magnetic Resonance Imaging and Derived Prostate Biopsies in Men with Suspected Prostate Cancer.

Purpose: To analyze how Proclarix is valuable to appropriately select candidates for multiparametric magnetic resonance imaging (mpMRI) and derived biopsies, among men with suspected prostate cancer (PCa). Proclarix is a new marker computing the clinically significant PCa (csPCa) risk, based on serum thosmbospondin-1, cathepsin D, prostate-specific antigen (PSA) and percent free PSA, in addition to age, that has been developed in men with serum PSA 2 to 10 ng/mL, prostate volume ≥35 mL, and normal digital rectal examination (DRE).

Materials And Methods: Proclarix score (0%-100%) is analyzed in a prospective frozen serum collection of 517 correlative men scheduled for guided and/or systematic biopsies after mpMRI.

Loss of microRNA-135b Enhances Bone Metastasis in Prostate Cancer and Predicts Aggressiveness in Human Prostate Samples.

About 70% of advanced-stage prostate cancer (PCa) patients will experience bone metastasis, which severely affects patients' quality of life and progresses to lethal PCa in most cases. Hence, understanding the molecular heterogeneity of PCa cell populations and the signaling pathways associated with bone tropism is crucial. For this purpose, we generated an animal model with high penetrance to metastasize to bone using an intracardiac percutaneous injection of PC3 cells to identify PCa metastasis-promoting factors.

Mechanisms of cellular iron sensing, regulation of erythropoiesis and mitochondrial iron utilization.

To maintain an adequate iron supply for hemoglobin synthesis and essential metabolic functions while counteracting iron toxicity, humans and other vertebrates have evolved effective mechanisms to conserve and finely regulate iron concentration, storage, and distribution to tissues. At the systemic level, the iron-regulatory hormone hepcidin is secreted by the liver in response to serum iron levels and inflammation. Hepcidin regulates the expression of the sole known mammalian iron exporter, ferroportin, to control dietary absorption, storage and tissue distribution of iron.

The current recommendation for the management of isolated high-grade prostatic intraepithelial neoplasia.

Objective: To analyse the current predictive value of isolated high-grade prostatic intraepithelial neoplasia (HGPIN) for clinically significant prostate cancer (csPCa) detection in repeat biopsies.

Patients And Methods: A cohort of 293 men with isolated HGPIN detected in previous biopsies performed without multiparametric magnetic resonance imaging (mpMRI), and who underwent repeat biopsy within 1 to 3 years, was analysed. Pre-repeat biopsy mpMRI and guided biopsies to suspicious lesions (Prostate Imaging - Reporting and Data System [PI-RADS] ≥3) and/or and systematic biopsies were performed.

The Novel KIF1A Missense Variant (R169T) Strongly Reduces Microtubule Stimulated ATPase Activity and Is Associated With NESCAV Syndrome.

KIF1A is a microtubule-dependent motor protein responsible for fast anterograde transport of synaptic vesicle precursors in neurons. Pathogenic variants in have been associated with a wide spectrum of neurological disorders. Here, we report a patient presenting a severe neurodevelopmental disorder carrying a novel missense variant p.

Proteomic Studies on the Management of High-Grade Serous Ovarian Cancer Patients: A Mini-Review.

High-grade serous ovarian cancer (HGSC) remains the most common and deadly subtype of ovarian cancer. It is characterized by its late diagnosis and frequent relapse despite standardized treatment with cytoreductive surgery and platinum-based chemotherapy. The past decade has seen significant advances in the clinical management and molecular understanding of HGSC following the publication of the Cancer Genome Atlas (TCGA) researchers and the introduction of targeted therapies with anti-angiogenic drugs and poly(ADP-ribose) polymerase inhibitors in specific subgroups of patients.

A Randomised Controlled Trial to Assess the Benefit of Posterior Rhabdosphincter Reconstruction in Early Urinary Continence Recovery after Robot-assisted Radical Prostatectomy.

Posterior rhabdosphincter reconstruction (PRR) has been proposed to improve early urinary continence (UC) recovery after radical prostatectomy (RP). In order to generate level 1b evidence, we designed a double-blind randomised controlled trial powered to detect a 20% increase in early UC recovery after robot-assisted RP (RARP). A group of 153 patients with cT1c-3a N0M0 prostate cancer were randomised (73 to control arm and 80 to PRR arm) and 152 completed 12-mo follow-up.

Prediction of clinically significant prostate cancer after negative prostate biopsy: The current value of microscopic findings.

Objective: To assess the current ability of atypical small acinar proliferation (ASAP), multifocal high-grade prostatic intraepithelial neoplasia (mHGPIN), HGPIN with atypia (PINATYP) and other non-malignant lesions to predict clinically significant prostate cancer (csPCa) in repeat prostate biopsies.

Methods: This retrospective study analyzed 377 repeat prostate biopsies, carried out between 2.014 and 2.

(Bora), Which Promotes Plk1 Activation by Aurora A, Has an Oncogenic Role in Ovarian Cancer.

Identifying novel actionable factors that critically contribute to tumorigenesis is essential in ovarian cancer, an aggressive and disseminative tumor, with limited therapeutic options available. Here we show that (BORA), a mitotic protein that plays a key role in activating the master mitotic kinase polo-like kinase 1 (PLK1), has an oncogenic role in ovarian cancer. Gain and loss of function assays on mouse models and ex vivo patient-derived ascites cultures revealed an oncogenic role of BORA in tumor development and a transcriptome-analysis in clinically representative models depicted BORA's role in survival, dissemination and inflammatory cancer related-pathways.