Targeting exosome biogenesis and release may have potential clinical implications for cancer therapy. Herein, we have optimized a quantitative high throughput screen (qHTS) assay to identify ...compounds that modulate exosome biogenesis and/or release by aggressive prostate cancer (PCa) CD63-GFP-expressing C4-2B cells. A total of 4,580 compounds were screened from the LOPAC library (a collection of 1,280 pharmacologically active compounds) and the NPC library (NCGC collection of 3,300 compounds approved for clinical use). Twenty-two compounds were found to be either potent activators or inhibitors of intracellular GFP signal in the CD63-GFP-expressing C4-2B cells. The activity of lead compounds in modulating the secretion of exosomes was validated by a tunable resistive pulse sensing (TRPS) system (qNano-IZON) and flow cytometry. The mechanism of action of the lead compounds in modulating exosome biogenesis and/or secretion were delineated by immunoblot analysis of protein markers of the endosomal sorting complex required for transport (ESCRT)-dependent and ESCRT-independent pathways. The lead compounds tipifarnib, neticonazole, climbazole, ketoconazole, and triademenol were validated as potent inhibitors and sitafloxacin, forskolin, SB218795, fenoterol, nitrefazole and pentetrazol as activators of exosome biogenesis and/or secretion in PC cells. Our findings implicate the potential utility of drug-repurposing as novel adjunct therapeutic strategies in advanced cancer.
Systematic characterization of the cancer microbiome provides the opportunity to develop techniques that exploit non-human, microorganism-derived molecules in the diagnosis of a major human disease. ...Following recent demonstrations that some types of cancer show substantial microbial contributions
, we re-examined whole-genome and whole-transcriptome sequencing studies in The Cancer Genome Atlas
(TCGA) of 33 types of cancer from treatment-naive patients (a total of 18,116 samples) for microbial reads, and found unique microbial signatures in tissue and blood within and between most major types of cancer. These TCGA blood signatures remained predictive when applied to patients with stage Ia-IIc cancer and cancers lacking any genomic alterations currently measured on two commercial-grade cell-free tumour DNA platforms, despite the use of very stringent decontamination analyses that discarded up to 92.3% of total sequence data. In addition, we could discriminate among samples from healthy, cancer-free individuals (n = 69) and those from patients with multiple types of cancer (prostate, lung, and melanoma; 100 samples in total) solely using plasma-derived, cell-free microbial nucleic acids. This potential microbiome-based oncology diagnostic tool warrants further exploration.
The renal excretion of PSMA radiotracer may render PSMA PET/CT imaging interpretation difficult to identify local recurrence and lymph node metastases in prostate cancer patients.
To evaluate the ...best acquisition method to increase the detection rate of local recurrence and pelvic metastases on PSMA PET/CT by performing dual time-point imaging (delayed imaging) after hyperhydration, diuretics, and contrast enhancement.
Patients with prior history of prostate adenocarcinoma underwent PSMA PET/CT for primary staging or due to biochemical recurrence. PSMA PET/CT acquisition consisted of delayed pelvic imaging after hyperhydration, diuretics, and excretory-phase contrast. SUV values obtained in local recurrence lesions, locoregional lymph node metastases, and bone metastases in the early and delayed PSMA PET/CT images were compared.
A total of 182 patients (medians: age = 66.5; Gleason score = 7.0; total PSA = 1.5) underwent PSMA PET/CT. Twenty-one patients (12%) were scanned due to primary staging, and 161 patients due to biochemical recurrence (88%). Delayed images (with only hyperhydration, without contrast or diuretics) increased diagnostic certainty in identifying local recurrence in 26.6% of patients and locoregional lymph nodes in 25%. There was a significant increase in SUV values in the delayed images compared to early images in the local recurrence (p < 0.0001), locoregional lymph node metastases (p < 0.0001), and bone metastases (p < 0.0199). Adding excretory-phase contrast to the delayed images increased diagnostic certainty in identifying local recurrence in 9.4% of patients and locoregional lymph nodes in 8.3%. The use of diuretics only in delayed images (without excretory-phase contrast) increased diagnostic certainty in identifying local recurrence in 14% of patients; while for identifying pelvic lymph nodes increase was only mild (2.8%). The association of diuretics with excretory-phase contrast increased the diagnostic certainty in identifying local recurrence in 15.6% of patients and locoregional lymph nodes in 5.6%.
Delayed PSMA PET/CT images increase the diagnostic certainty of identifying local recurrence and locoregional metastases in prostate cancer patients. The addition of diuretics increases diagnostic certainty and may be useful in selected cases. However, the addition of excretory-phase contrast (regardless of the use of diuretics) only mildly impacted diagnostic certainty and may be omitted.
Herein, a novel electrochemical ultrasensitive immunosensor was designed for detecting prostate-specific antigen (PSA) with three-dimensional (3D) PtCu hollow nanoframes (PtCu HNFs) as signal ...amplification. The highly opened PtCu HNFs were synthesized by a one-pot solvothermal method with cetyltrimethylammonium chloride (CTAC) and trishydroxymethyl aminomethane (Tris) as co-structuring directors. The architectures enlarged the loading of prostate specific antibodies (Ab) and efficiently catalyzed hydrogen peroxide (H2O2) reaction, ultimately amplifying the signals. And polylysine was used to disperse PtCu HNFs, improve the biocompatibility and bind the Ab on the electrode surface. The fabricated immunosensor exhibited lower detection limit (0.003 ng mL–1, S/N = 3), and wider linear range (0.01–100.0 ng mL–1), along with the improved reproducibility, selectivity and stability for the assay of PSA. Thus, it is a desirable platform for PSA detection in clinical diagnosis and practical applications.
•Uniform PtCu HNFs were synthesized by a simple solvothermal method.•Tris and CTAC acted as the co-structure-directing agents.•Polylysine can well disperse PtCu HNFs with increased biocompatibility.•PtCu HNFs was constructed for PSA immunosensor with excellent analytic performance.
For the last decade PET and PET/CT with (11)C-choline have been proposed for the evaluation of prostate cancer (PC), but the diagnostic performance of (11)C-choline PET/CT is still a matter of ...debate. We performed a comprehensive review of the most important clinical application of (11)C-choline PET, restaging of patients with biochemical relapse, following a rigorous methodological approach and including assessment of the risk of bias. We conducted a systematic review and meta-analysis of the literature assessing (11)C-choline PET/CT for its accuracy in the diagnosis and ability to detect the site of recurrence of PC in the restaging of patients with biochemical recurrence after initial treatment with curative intent.
We performed a comprehensive literature search of PubMed and the Cochrane Library to determine the accuracy for the detection of the site of recurrence (prostate bed recurrences, metastatic spread to locoregional pelvic lymph nodes or distant metastases). Only studies with a reference standard (for prostatic bed histopathology, for histopathology or biopsy of distant metastases or a composite reference standard with clinical follow-up of at least 12 months, correlative imaging and clinical data) were included.
Overall 425 studies were retrieved, of which 43 were judged as potentially relevant and 29 with 2,686 participants were finally included. Of these 29 studies, 18 reported results for any relapse, All 18 studies, with a total of 2,126 participants, reported detection rates. The pooled rate was 62 % (95 % CI 53 - 71 %). Of the 18 studies, 12 with 1,270 participants reported useful data to derive sensitivity and specificity. The pooled sensitivity was 89 % (95 % CI 83 - 93 %) and the pooled specificity was 89 % (95 % CI 73 - 96 %). Of 11 studies reporting results for local relapse, 9 with 993 participants reported detection rates. The pooled rate was 27 % (95 % CI 16 - 38 %). Six studies with 491 participants reported sensitivity and specificity. The pooled sensitivity was 61 % (95 % CI 40 - 80 %) and the pooled specificity was 97 % (95 % CI 87 - 99 %). Ten studies reported results for lymph nodes and distant metastases. For nodal disease, 7 studies with 752 participants reported detection rates. The pooled rate was 36 % (95 % CI 22 - 50 %). For bone metastases, 8 studies with 775 participants reported detection rates. The pooled rate was 25 % (95 % CI 16 - 34 %).
There is a significant amount of (11)C-choline PET data published showing a high degree of consistency in inclusion criteria, acquisition protocols and scan interpretation criteria. Furthermore, the quality of the data derived limited to the same standard of reference was acceptable. Despite a high variability in the observed prevalence of any relapse, the diagnostic performance of (11)C-choline PET was in line with previous meta-analyses. Our data confirm the very good accuracy of (11)C-choline PET for detection of lymph node metastases and/or distant lesions in a single examination in patients with biochemical relapse.
Organic building blocks are the centerpieces of “one‐for‐all” nanoparticle development. Herein, we report the synthesis of a novel aza‐BODIPY‐lipid building block and its self‐assembly into a ...liposomal nanoparticle (BODIPYsome). We observed optically stable NIR J‐aggregation within the BODIPYsome that is likely attributed to J‐dimerization. BODIPYsomes with cholesterol showed enhanced colloidal stability while maintaining a high extinction coefficient (128 mm−1 cm−1) and high fluorescence quenching (99.70±0.09 %), which enables photoacoustic (PA) properties from its intact structure and recovered NIR fluorescence properties when it is disrupted in cancer cells. Finally, its capabilities for optical imaging (PA/fluorescence) were observed in an orthotopic prostate tumor mouse model 24 h after intravenous administration. Overall, the BODIPYsome opens the door for engineering new building blocks in the design of optically stable biophotonic imaging agents.
BODIPYsome: The synthesis of a novel aza‐BODIPY‐lipid building block and its self‐assembly into BODIPYsome, which has optically stable NIR J‐aggregation that is attributed to J‐dimerization, is presented. BODIPYsomes exhibit a high extinction coefficient and high fluorescence quenching, enabling photoacoustic imaging when intact and recovered NIR fluorescence upon disruption.
Exosomes are small (30–100 nm) membrane vesicles that serve as regulatory agents for intercellular communication in cancers. Currently, exosomes are detected by immuno‐based assays with appropriate ...pretreatments like ultracentrifugation and are time consuming (>12 h). We present a novel pretreatment‐free fluorescence‐based sensing platform for intact exosomes, wherein exchangeable antibodies and fluorescent reporter molecules were aligned inside exosome‐binding cavities. Such antibody‐containing fluorescent reporter‐grafted nanocavities were prepared on a substrate by well‐designed molecular imprinting and post‐imprinting modifications to introduce antibodies and fluorescent reporter molecules only inside the binding nanocavities, enabling sufficiently high sensitivity to detect intact exosomes without pretreatment. The effectiveness of the system was demonstrated by using it to discriminate between normal exosomes and those originating from prostate cancer and analyze exosomes in tear drops.
Making a good impression: A novel pretreatment‐free fluorescence‐based sensing platform for intact exosomes was prepared by using molecular imprinting and post‐imprinting modifications, in which exchangeable antibodies and fluorescent reporter molecules were aligned only inside exosome‐binding cavities. The resulting high sensitivity enabled exosome detection without sample pretreatment. The system was used to distinguish cancer‐secreted exosomes from normal ones.
Objectives
This study aims to define consensus-based criteria for acquiring and reporting prostate MRI and establishing prerequisites for image quality.
Methods
A total of 44 leading urologists and ...urogenital radiologists who are experts in prostate cancer imaging from the European Society of Urogenital Radiology (ESUR) and EAU Section of Urologic Imaging (ESUI) participated in a Delphi consensus process. Panellists completed two rounds of questionnaires with 55 items under three headings: image quality assessment, interpretation and reporting, and radiologists’ experience plus training centres. Of 55 questions, 31 were rated for agreement on a 9-point scale, and 24 were multiple-choice or open. For agreement items, there was consensus agreement with an agreement ≥ 70% (score 7–9) and disagreement of ≤ 15% of the panellists. For the other questions, a consensus was considered with ≥ 50% of votes.
Results
Twenty-four out of 31 of agreement items and 11/16 of other questions reached consensus. Agreement statements were (1) reporting of image quality should be performed and implemented into clinical practice; (2) for interpretation performance, radiologists should use self-performance tests with histopathology feedback, compare their interpretation with expert-reading and use external performance assessments; and (3) radiologists must attend theoretical and hands-on courses before interpreting prostate MRI. Limitations are that the results are expert opinions and not based on systematic reviews or meta-analyses. There was no consensus on outcomes statements of prostate MRI assessment as quality marker.
Conclusions
An ESUR and ESUI expert panel showed high agreement (74%) on issues improving prostate MRI quality. Checking and reporting of image quality are mandatory. Prostate radiologists should attend theoretical and hands-on courses, followed by supervised education, and must perform regular performance assessments.
Key Points
• Multi-parametric MRI in the diagnostic pathway of prostate cancer has a well-established upfront role in the recently updated European Association of Urology guideline and American Urological Association recommendations
.
• Suboptimal image acquisition and reporting at an individual level will result in clinicians losing confidence in the technique and returning to the (non-MRI) systematic biopsy pathway. Therefore, it is crucial to establish quality criteria for the acquisition and reporting of mpMRI
.
• To ensure high-quality prostate MRI, experts consider checking and reporting of image quality mandatory. Prostate radiologists must attend theoretical and hands-on courses, followed by supervised education, and must perform regular self- and external performance assessments
.
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