Uniform block copolymer nanofibers for the delivery of paclitaxel in 2D and 3D glioblastoma tumor models.

Cancer treatment has transformed in recent years, with the introduction of immunotherapy providing substantial improvements in prognoses for certain cancers. However, traditional small molecule chemotherapeutics remain the major frontline of defence, and improving their delivery to solid tumors is of utmost importance for improving potency and reducing side effects. Here, length-controlled one-dimensional seed nanofibers (ca. 25 nm, DL = 1.05) were generated from poly(fluorenetrimethylenecarbonate)-block-poly(dimethylaminoethylmethacrylate) via living crystallization-driven self-assembly. Paclitaxel, with an encapsulation content ranging from 1 to 100 wt%, was loaded onto the preformed nanoparticles by solvent addition and evaporation. Drug loading was quantified by dynamic light scattering and transmission electron microscopy. Drug-loaded vectors were then incubated with U87 MG glioblastoma cells in a 2D cell assay for up to 72 h, and their anticancer properties were determined. It was observed that seed nanofibers loaded with 20 wt% paclitaxel were the most advantageous combination (IC50 = 0.48 µg mL-1), while pure seed nanofibers with no loaded drug displayed much lower cytotoxicity (IC50 = 11.52 µg mL-1). The IC50 of the loaded seed nanofibers rivaled that of the commercially approved Abraxane® (IC50 = 0.46 µg mL-1). 3D tumor spheroids were then cultured and subjected to the same stresses. Live/dead cell staining revealed that once more, seed nanofibers with 20 wt% paclitaxel, Abraxane®, and paclitaxel all exhibited similar levels of potency (55% viability), whereas control samples exhibited much higher cell viability (70%) after 3 days. These results demonstrate that nanofibers contain great potential as biocompatible drug delivery vehicles for cancer treatment as they exert a similar anticancer effect to the commercially available Abraxane®.

Correction: Hyporheic hydraulic geometry: Conceptualizing relationships among hyporheic exchange, storage, and water age.

[This corrects the article DOI: 10.1371/journal.pone.0262080.].

Genetic admixture drives climate adaptation in the bank vole.

Genetic admixture introduces new variants at relatively high frequencies, potentially aiding rapid responses to environmental changes. Here, we evaluate its role in adaptive variation related to climatic conditions in bank voles (Clethrionomys glareolus) in Britain, using whole-genome data. Our results reveal loci showing excess ancestry from one of the two postglacial colonist populations inconsistent with overall admixture patterns. Notably, loci associated with climate adaptation exhibit disproportionate amounts of excess ancestry, highlighting the impact of admixture between colonist populations on local adaptation. The results suggest strong and localized selection on climate-adaptive loci, as indicated by steep clines and/or shifted cline centres, during population replacement. A subset, including a haemoglobin gene, is associated with oxidative stress responses, underscoring a role of oxidative stress in local adaptation. Our study highlights the important contribution of admixture during secondary contact between populations from distinct climatic refugia enriching adaptive diversity. Understanding these dynamics is crucial for predicting future adaptive capacity to anthropogenic climate change.

ssVERDICT: Self-supervised VERDICT-MRI for enhanced prostate tumor characterization.

PURPOSE: Demonstrating and assessing self-supervised machine-learning fitting of the VERDICT (vascular, extracellular and restricted diffusion for cytometry in tumors) model for prostate cancer. METHODS: We derive a self-supervised neural network for fitting VERDICT (ssVERDICT) that estimates parameter maps without training data. We compare the performance of ssVERDICT to two established baseline methods for fitting diffusion MRI models: conventional nonlinear least squares and supervised deep learning. We do this quantitatively on simulated data by comparing the Pearson's correlation coefficient, mean-squared error, bias, and variance with respect to the simulated ground truth. We also calculate in vivo parameter maps on a cohort of 20 prostate cancer patients and compare the methods' performance in discriminating benign from cancerous tissue via Wilcoxon's signed-rank test. RESULTS: In simulations, ssVERDICT outperforms the baseline methods (nonlinear least squares and supervised deep learning) in estimating all the parameters from the VERDICT prostate model in terms of Pearson's correlation coefficient, bias, and mean-squared error. In vivo, ssVERDICT shows stronger lesion conspicuity across all parameter maps, and improves discrimination between benign and cancerous tissue over the baseline methods. CONCLUSION: ssVERDICT significantly outperforms state-of-the-art methods for VERDICT model fitting and shows, for the first time, fitting of a detailed multicompartment biophysical diffusion MRI model with machine learning without the requirement of explicit training labels.

Involvement of propranolol in suicides: cross-sectional study using coroner-reported data.

BACKGROUND: Propranolol is a beta-blocker medication indicated mostly for heart rhythm conditions and for physical symptoms of anxiety. Prescriptions for propranolol in the UK have increased since 2008. Recently, there have been concerns about the involvement of propranolol in intentional poisonings, but such deaths are not routinely reported. Therefore, use of coroner-reported and toxicology data enables unique investigation into the scale of involvement of propranolol in suicide. AIMS: To describe the extent to which propranolol is involved in suicides, including patterns over time and characteristics of people whose suicide involved propranolol compared with other suicides. METHOD: Data were derived from the National Programme on Substance Use Mortality (NPSUM). All suicides and deaths of undetermined intent between 2010 and 2021 in England, Wales and Northern Ireland were extracted, and a subset was identified where propranolol was involved in death. RESULTS: There were 4473 suicides of which 297 (6.6%) involved propranolol, with the proportion involving propranolol nearly quadrupling during the study period (3.4% v. 12.3%). Compared with all other suicides, a greater proportion of propranolol suicides were in women (56.6% v. 37.1%) and in people with diagnoses of depression (39.1% v. 27.1%) and anxiety (22.2% v. 8.6%). When suicide involved propranolol, an antidepressant was detected at post-mortem in 81.8% of deaths, most commonly a selective serotonin reuptake inhibitor (SSRIs) (51.5%), and most often citalopram (24.6%). CONCLUSIONS: A small number, but increasing proportion, of suicides reported to the NPSUM involve propranolol. Vigilance to the combined toxicity profile of medicines used alongside propranolol may be pertinent.

ACLY alternative splicing correlates with cancer phenotypes.

ATP-citrate lyase (ACLY) links carbohydrate and lipid metabolism and provides nucleocytosolic acetyl-CoA for protein acetylation. ACLY has two major splice isoforms: the full-length canonical "long" isoform and an uncharacterized "short" isoform in which exon 14 is spliced out. Exon 14 encodes 10 amino acids within an intrinsically disordered region and includes at least one dynamically phosphorylated residue. Both isoforms are expressed in healthy tissues to varying degrees. Analysis of human transcriptomic data revealed that the percent spliced in (PSI) of exon 14 is increased in several cancers and correlated with poorer overall survival in a pan-cancer analysis, though not in individual tumor types. This prompted us to explore potential biochemical and functional differences between ACLY isoforms. Here, we show that there are no discernible differences in enzymatic activity or stability between isoforms or phosphomutants of ACLY in vitro. Similarly, both isoforms and phosphomutants were able to rescue ACLY functions, including fatty acid synthesis and bulk histone acetylation, when re-expressed in Acly knockout cells. Deletion of Acly exon 14 in mice did not overtly impact development or metabolic physiology nor did it attenuate tumor burden in a genetic model of intestinal cancer. Notably, expression of epithelial splicing regulatory protein 1 (ESRP1) is highly correlated with ACLY PSI. We report that ACLY splicing is regulated by ESRP1. In turn, both ESRP1 expression and ACLY PSI are correlated with specific immune signatures in tumors. Despite these intriguing patterns of ACLY splicing in healthy and cancer tissues, functional differences between the isoforms remain elusive.

Extralimital terrestrials: A reassessment of range limits in Alaska's land mammals.

Understanding and mitigating the effects of anthropogenic climate change on species distributions requires the ability to track range shifts over time. This is particularly true for species occupying high-latitude regions, which are experiencing more extreme climate change than the rest of the world. In North America, the geographic ranges of many mammals reach their northernmost extent in Alaska, positioning this region at the leading edge of climate-induced distribution change. Over a decade has elapsed since the publication of the last spatial assessments of terrestrial mammals in the state. We compared public occurrence records against commonly referenced range maps to evaluate potential extralimital records and develop repeatable baseline range maps. We compared occurrence records from the Global Biodiversity Information Facility for 61 terrestrial mammal species native to mainland Alaska against a variety of range estimates (International Union for Conservation of Nature, Alaska Gap Analysis Project, and the published literature). We mapped extralimital records and calculated proportions of occurrences encompassed by range extents, measured mean direction and distance to prior range margins, evaluated predictive accuracy of published species models, and highlighted observations on federal lands in Alaska. Range comparisons identified 6,848 extralimital records for 39 of 61 (63.9%) terrestrial mainland Alaskan species. On average, 95.5% of Alaska Gap Analysis Project occurrence records and ranges were deemed accurate (i.e., > 90.0% correct) for 31 of 37 species, but overestimated extents for 13 species. The International Union for Conservation of Nature range maps encompassed 68.1% of occurrence records and were > 90% accurate for 17 of 39 species. Extralimital records represent either improved sampling and digitization or actual geographic range expansions. Here we provide new data-driven range maps, update standards for the archiving of museum-quality locational records and offer recommendations for mapping range changes for monitoring and conservation.

Psychological Responses During Latter Rehabilitation and Return to Sport After Anterior Cruciate Ligament Reconstruction Surgery.

CONTEXT: Despite positive physical outcomes of anterior cruciate ligament reconstruction (ACLR), many athletes do not return to sport afterward. OBJECTIVE: To determine if there were differences between athletes who returned to play and those who did not return to sport after ACLR in patterns of psychological responses to injury over the latter course of rehabilitation and return to sport. DESIGN: Case-control study. SETTING: Comprehensive orthopedic medical center referrals. PATIENTS OR OTHER PARTICIPANTS: Thirty-nine recreational and competitive athletes (13 to 58 years, 21 males) with a first ACL tear were observed over the course of the study. MAIN OUTCOME MEASURE(S): Return to sport. RESULTS: Fifty-two percent of participants returned to play by 9 months post-ACLR. Those who returned showed a linear decrease in reinjury anxiety from 4 to 9 months post-ACLR, whereas those who did not return showed a linear decrease from 4 to 6 months post-ACLR and then a leveling off from 6 to 9 months. Those who returned showed linear and quadratic effects on perceived limitations of ability with a decrease from 4 to 9 months post-ACLR that accelerated over time, whereas nonreturners showed a linear decrease over time. No significant differences were found between returners and nonreturners in knee self-efficacy, perceived percent recovery, and psychological distress. CONCLUSIONS: Our results suggest that reinjury anxiety and perceived limitations of ability are psychological constructs on which returners and nonreturners differ and therefore may be points of intervention to increase the likelihood of return to sport.

Mechanism of Action and Design of Potent Antibacterial Block Copolymer Nanoparticles.

Self-assembled polymer nanoparticles are promising antibacterials, with nonspherical morphologies of particular interest as recent work has demonstrated enhanced antibacterial activity relative to their spherical counterparts. However, the reasons for this enhancement are currently unclear. We have performed a multifaceted analysis of the antibacterial mechanism of action of 1D nanofibers relative to nanospheres by the use of flow cytometry, high-resolution microscopy, and evaluations of the antibacterial activity of pristine and tetracycline-loaded nanoparticles. Low-length dispersity, fluorescent diblock copolymer nanofibers with a crystalline poly(fluorenetrimethylenecarbonate) (PFTMC) core (length = 104 and 472 nm, height = 7 nm, width = 10-13 nm) and a partially protonated poly(dimethylaminoethyl methacrylate) (PDMAEMA) corona (length = 12 nm) were prepared via seeded growth living crystallization-driven self-assembly. Their behavior was compared to that of analogous nanospheres containing an amorphous PFTMC core (diameter of 12 nm). While all nanoparticles were uptaken into Escherichia coli W3110, crystalline-core nanofibers were observed to cause significant bacterial damage. Drug loading studies indicated that while all nanoparticle antibacterial activity was enhanced in combination with tetracycline, the enhancement was especially prominent when small nanoparticles (ca. 15-25 nm) were employed. Therefore, the identified differences in the mechanism of action and the demonstrated consequences for nanoparticle size and morphology control may be exploited for the future design of potent antibacterial agents for overcoming antibacterial resistance. This study also reinforces the requirement of morphological control over polymer nanoparticles for biomedical applications, as differences in activity are observed depending on their size, shape, and core-crystallinity.

Exploring Electrophilic Hydrophosphination via Metal Phosphenium Intermediates.

Two Mo(0) phosphenium complexes containing ancillary secondary phosphine ligands have been investigated with respect to their ability to participate in electrophilic addition at unsaturated substrates and subsequent P-H hydride transfer to "quench" the resulting carbocations. These studies provide stoichiometric "proof of concept" for a proposed new metal-catalyzed electrophilic hydrophosphination mechanism. The more strongly Lewis acidic phosphenium complex, [Mo(CO)4(PR2H)(PR2)]+ (R=Ph, Tolp), cleanly hydrophosphinates 1,1-diphenylethylene, benzophenone, and ethylene, while other substrates react rapidly to give products resulting from competing electrophilic processes. A less Lewis acidic complex, [Mo(CO)3(PR2H)2(PR2)]+, generally reacts more slowly but participates in clean hydrophosphination of a wider range of unsaturated substrates, including styrene, indene, 1-hexene, and cyclohexanone, in addition to 1,1-diphenylethylene, benzophenone, and ethylene. Mechanistic studies are described, including stoichiometric control reactions and computational and kinetic analyses, which probe whether the observed P-H addition actually does occur by the proposed electrophilic mechanism, and whether hydridic P-H transfer in this system is intra- or intermolecular. Preliminary reactivity studies indicate challenges that must be addressed to exploit these promising results in catalysis.

Does video e-learning improve pharmacy teams' attitudes and preparedness towards suicide prevention?

Background: Evidence on the role of pharmacy teams in suicide prevention is growing. To support pharmacy teams, a video e-learning was produced by the Centre for Pharmacy Postgraduate Education (CPPE) involving an 'on-the-sofa' style group interview with people with personal and professional experience of suicide and suicide research. Objective: The objective was to measure any change in attitudes and preparedness for suicide prevention, following a video e-learning produced for pharmacy staff. Methods: People working in any sector of pharmacy in England and who accessed the training video were invited to complete a pre- and post- training questionnaire, between September 2019 and March 2021. Question types included demographics, experiences, attitudes as measured by the Attitudes to Suicide Prevention (ASP) scale, and preparedness. Descriptive statistics were used to summarize demographics and experience and paired t-tests were used to compare pre- and post- questionnaire responses. Results: Both questionnaires were completed by 147 people. Most worked in community pharmacy (88%) and were pharmacists (64%) or pharmacy technicians (20%). Attitudes to suicide prevention improved significantly (pre:31.20 (SD 6.04); post:28.40 (SD 6.50), p < 0.0001) after watching the video, as did self-reported preparedness. Conclusions: Pharmacy teams' self-reported attitudes and preparedness for suicide prevention improved after watching this suicide awareness video compared to baseline. Suicide awareness training tailored to pharmacy teams may be valuable, but the longitudinal impact of any suicide prevention training requires further exploration.

Local adaptation and future climate vulnerability in a wild rodent.

As climate change continues, species pushed outside their physiological tolerance limits must adapt or face extinction. When change is rapid, adaptation will largely harness ancestral variation, making the availability and characteristics of that variation of critical importance. Here, we used whole-genome sequencing and genetic-environment association analyses to identify adaptive variation and its significance in the context of future climates in a small Palearctic mammal, the bank vole (Clethrionomys glareolus). We found that peripheral populations of bank vole in Britain are already at the extreme bounds of potential genetic adaptation and may require an influx of adaptive variation in order to respond. Analyses of adaptive loci suggest regional differences in climate variables select for variants that influence patterns of population adaptive resilience, including genes associated with antioxidant defense, and support a pattern of thermal/hypoxic cross-adaptation. Our findings indicate that understanding potential shifts in genomic composition in response to climate change may be key to predicting species' fate under future climates.

Exploring Executive Functioning of Adults With Probable Developmental Coordination Disorder Using the Jansari Assessment of Executive Functions.

Many individuals with Developmental Coordination Disorder (DCD) demonstrate executive functioning difficulties on standardized assessments, yet these difficulties have not been investigated using ecologically-valid measures. 26 adults with probable DCD (pDCD), and 26 typically developing (TD) adults completed selected background measures and the Jansari assessment of Executive Functions (JEF©). JEF© is an ecologically-valid measure that provides measures of Planning, Prioritization, Selective-Thinking, Creative-Thinking, Adaptive-Thinking, and Action-, Event- and Time-Based Prospective Memory. pDCD participants were impaired relative to TD participants, with difficulties in Planning, Action-, and Event-Based Prospective Memory. These findings are consistent with self-reported difficulty and provide avenues for research investigating intervention.

Net-spinning caddisflies create denitrifier-enriched niches in the stream microbiome.

Larval net-spinning caddisflies (Hydropsychidae) function as ecosystem engineers in streams where they construct protective retreats composed of organic and inorganic material affixed with silk filtration nets that alter streambed hydrology. We hypothesized that hydropsychid bio-structures (retreats, nets) are microhabitats for microbes with oxygen-sensitive metabolisms, and therefore increase the metabolic heterogeneity of streambed microbial assemblages. Metagenomic and 16 S rRNA gene amplicon analysis of samples from a montane stream (Cherry Creek, Montana, USA) revealed that microbiomes of caddisfly bio-structures are taxonomically and functionally distinct from those of the immediately adjacent rock biofilm (~2 cm distant) and enriched in microbial taxa with established roles in denitrification, nitrification, and methane production. Genes for denitrification, high oxygen affinity terminal oxidases, hydrogenases, oxidative dissimilatory sulfite reductases, and complete ammonia oxidation are significantly enriched in caddisfly bio-structures. The results suggest a novel ecosystem engineering effect of caddisflies through the creation of low-oxygen, denitrifier-enriched niches in the stream microbiome. Facilitation of metabolic diversity in streambeds may be a largely unrecognized mechanism by which caddisflies alter whole-stream biogeochemistry.

Prostate MR image quality of apparent diffusion coefficient maps versus fractional intracellular volume maps from VERDICT MRI using the PI-QUAL score and a dedicated Likert scale for artefacts.

PURPOSE: This study aimed to assess the image quality of apparent diffusion coefficient (ADC) maps derived from conventional diffusion-weighted MRI and fractional intracellular volume maps (FIC) from VERDICT MRI (Vascular, Extracellular, Restricted Diffusion for Cytometry in Tumours) in patients from the INNOVATE trial. The inter-reader agreement was also assessed. METHODS: Two readers analysed both ADC and FIC maps from 57 patients enrolled in the INNOVATE prospective trial. Image quality was assessed using the Prostate Imaging Quality (PI-QUAL) score and a subjective image quality Likert score (Likert-IQ). The image quality of FIC and ADC were compared using a Wilcoxon Signed Ranks test. The inter-reader agreement was assessed with Cohen's kappa. RESULTS: There was no statistically significant difference between the PI-QUAL score for FIC datasets compared to ADC datasets for either reader (p = 0.240 and p = 0.614). Using the Likert-IQ score, FIC image quality was higher compared to ADC (p = 0.021) as assessed by reader-1 but not for reader-2 (p = 0.663). The inter-reader agreement was 'fair' for PI-QUAL scoring of datasets with FIC maps at 0.27 (95% confidence interval; 0.08-0.46) and ADC datasets at 0.39 (95% confidence interval 0.22-0.57). For Likert scoring, the inter-reader agreement was also 'fair' for FIC maps at 0.38 (95% confidence interval; 0.10-0.65) and substantial for ADC maps at 0.62 (95% confidence interval; 0.39-0.86). CONCLUSION: Image quality was comparable for FIC and ADC. The inter-reader agreement was similar when using PIQUAL for both FIC and ADC datasets but higher for ADC maps compared to FIC maps using the image quality Likert score.

Use of artificial intelligence in the detection of primary prostate cancer in multiparametric MRI with its clinical outcomes: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Multiparametric MRI (mpMRI) has transformed the prostate cancer diagnostic pathway, allowing for improved risk stratification and more targeted subsequent management. However, concerns exist over the interobserver variability of images and the applicability of this model long term, especially considering the current shortage of radiologists and the growing ageing population. Artificial intelligence (AI) is being integrated into clinical practice to support diagnostic and therapeutic imaging analysis to overcome these concerns. The following report details a protocol for a systematic review and meta-analysis investigating the accuracy of AI in predicting primary prostate cancer on mpMRI. METHODS AND ANALYSIS: A systematic search will be performed using PubMed, MEDLINE, Embase and Cochrane databases. All relevant articles published between January 2016 and February 2023 will be eligible for inclusion. To be included, articles must use AI to study MRI prostate images to detect prostate cancer. All included articles will be in full-text, reporting original data and written in English. The protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 checklist. The QUADAS-2 score will assess the quality and risk of bias across selected studies. ETHICS AND DISSEMINATION: Ethical approval will not be required for this systematic review. Findings will be disseminated through peer-reviewed publications and presentations at both national and international conferences. PROSPERO REGISTRATION NUMBER: CRD42021293745.

Time- and glucose-dependent differentiation of 3T3-L1 adipocytes mimics dysfunctional adiposity.

The 3T3-L1 murine adipocyte cell line remains one of the most widely used models to study the mechanisms of obesity and related pathologies. Most studies investigate such mechanisms using mature adipocytes that have been chemically induced to differentiate for 7 days in media containing 25 mM glucose. However, the dysfunctional characteristics commonly observed in obesity including adipocyte hypertrophy, increased expression of inflammatory markers, enhanced production of reactive oxygen species (ROS), increased steroidogenic enzyme expression/activity and production of steroid hormones, are not necessarily mimicked in these cells. The aim of this study was to provide an inexpensive model which represents the well-known characteristics of obesity by manipulating the time of adipocyte differentiation and increasing the concentration of glucose in the cell media. Our results showed a glucose- and time-dependent increase in adipocyte hypertrophy, ROS production and gene expression of the pro-inflammatory cytokine interleukin-6 (IL-6), as well as a time-dependent increase in lipolysis and in the gene expression of the chemokine monocyte chemoattractant protein 1 (MCP1). We also showed that gene expression of the steroidogenic enzymes 11-beta-hydroxysteroid dehydrogenase type 1 (11ßHSD1), 17ßHSD type 7 and 12, as well as CYP19A1 (aromatase), were significantly higher in the hypertrophic model relative to the control adipocytes differentiated using the conventional method. The increase in 11ßHSD1 and 17ßHSD12 expression was consistent with the enhanced conversion of cortisone and androstenedione to cortisol and testosterone, respectively. As these characteristics reflect those commonly observed in obesity, hypertrophic 3T3-L1 adipocytes are an appropriate in vitro model to study mechanisms of adipocyte dysfunction in an era where the rise in obesity incidence is a global health concern, and where access to adipose tissue from obese patients are limited.

Integrating biogeography and behavioral ecology to rapidly address biodiversity loss.

Addressing climate change and biodiversity loss will be the defining ecological, political, and humanitarian challenge of our time. Alarmingly, policymakers face a narrowing window of opportunity to prevent the worst impacts, necessitating complex decisions about which land to set aside for biodiversity preservation. Yet, our ability to make these decisions is hindered by our limited capacity to predict how species will respond to synergistic drivers of extinction risk. We argue that a rapid integration of biogeography and behavioral ecology can meet these challenges because of the distinct, yet complementary levels of biological organization they address, scaling from individuals to populations, and from species and communities to continental biotas. This union of disciplines will advance efforts to predict biodiversity's responses to climate change and habitat loss through a deeper understanding of how biotic interactions and other behaviors modulate extinction risk, and how responses of individuals and populations impact the communities in which they are embedded. Fostering a rapid mobilization of expertise across behavioral ecology and biogeography is a critical step toward slowing biodiversity loss.

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. The Proclarix-MRI model combining prostate volume, Proclarix and mpMRI results was trained using the UCL cohort (n = 159) and validated in the Vall d'Hebron cohort (n = 562). Its diagnostic performance was established in correlation to biopsy outcome and compared to available clinical parameters and risk calculators. RESULTS: Clinical performance of the Proclarix-MRI model in the validation cohort did not significantly differ from the training cohort and resulted in a sensitivity for csPCa of 90%, 90% negative predictive value and 66% positive predictive value. The Proclarix-MRI score's specificity (68%) was significantly (P < 0.001) better than the MRI-European Randomized study of Screening for Prostate Cancer risk score (51%), Proclarix (27%) or mpMRI (28%) alone. In addition, Proclarix by itself was found to be useful in the MRI Prostate Imaging-Reporting and Data System (PI-RADS) score 3 subgroup by outperforming prostate-specific antigen density in terms of specificity (25% vs 13%, P = 0.004) at 100% sensitivity. CONCLUSION: When combined with mpMRI and prostate volume, Proclarix reliably predicted csPCa and ruled out men with no or indolent cancer. A large reduction of two thirds of unneeded biopsies was achieved. Proclarix can further be used with high confidence to reliably detect csPCa in men with an indeterminate PI-RADS score 3 mpMRI. Despite these encouraging results, further validation is needed.

Optimization of precision nanofiber micelleplexes for DNA delivery.

As nucleic acid (NA) technologies continue to revolutionize medicine, new delivery vehicles are needed to effectively transport NA cargoes into cells. Uniform and length-tunable nanofiber micelleplexes have recently shown promise as versatile polymeric delivery vehicles for plasmid DNA, however the effects of several key parameters on micelleplex transfection and stability remain unknown. In this work, we compare poly(fluorenetrimethylenecarbonate)-b-poly(2-(dimethylamino)ethyl methacrylate) (PFTMC-b-PDMAEMA) nanofiber micelleplexes to nanosphere micelleplexes and PDMAEMA polyplexes, examining the effects of complexation buffer, the temporal and serum stability of nanofiber micelleplexes, as well as the effects of cell density, cell type, and polymer DPn upon transfection efficiency and cell viability. These studies are vital for understanding the formation and biological activity of micelleplexes in more detail and should inform the future design of more advanced polymeric NA delivery systems.