The plasma proteome is linked with left ventricular and left atrial function parameters in patients with chronic heart failure.

AIMS: Examining the systemic biological processes in the heterogeneous syndrome of heart failure with reduced ejection fraction (HFrEF), as reflected by circulating proteins, in relation to echocardiographic characteristics, may provide insights into heart failure pathophysiology. We investigated the link of 4210 repeatedly measured circulating proteins with repeatedly measured echocardiographic parameters as well as with elevated left atrial pressure (LAP), in patients with HFrEF, to provide insights into underlying mechanisms. METHODS AND RESULTS: In 173 patients with HFrEF, we performed 6-monthly echocardiography and trimonthly blood sampling during a median follow-up of 2.7 (inter-quartile range: 2.5-2.8) years. We investigated circulating proteins in relation to echocardiographic parameters of left ventricular [left ventricular ejection fraction (LVEF), global longitudinal strain (GLS)] and left atrial function [left atrial reservoir strain (LASr)] and elevated LAP (E/e' ratio >15) and used gene enrichment analyses to identify underlying pathophysiological processes. We found 723, 249, 792, and 427 repeatedly measured proteins, with significant associations with LVEF, GLS, LASr, and E/e' ratio, respectively. Proteins associated with LASr reflected pathophysiological mechanisms mostly related to the extracellular matrix. Proteins associated with GLS reflected cardiovascular biological processes and diseases, whereas those associated with LVEF reflected processes involved in the sympathetic nervous system. Moreover, 49 proteins were associated with elevated LAP; after correction for LVEF, three proteins remained: cystatin-D, fibulin-5, and HSP40. CONCLUSION: Circulating proteins show varying associations with different echocardiographic parameters in patients with HFrEF. These findings suggest that pathways involved in atrial and ventricular dysfunction, as reflected by the plasma proteome, are distinct.

Palmitoylation-dependent regulation of cardiomyocyte Rac1 signaling activity and minor effects on cardiac hypertrophy.

S-palmitoylation is a reversible lipid modification catalyzed by 23 S-acyltransferases with a conserved zinc finger aspartate-histidine-histidine-cysteine (zDHHC) domain that facilitates targeting of proteins to specific intracellular membranes. Here we performed a gain-of-function screen in the mouse and identified the Golgi-localized enzymes zDHHC3 and zDHHC7 as regulators of cardiac hypertrophy. Cardiomyocyte-specific transgenic mice overexpressing zDHHC3 show cardiac disease, and S-acyl proteomics identified the small GTPase Rac1 as a novel substrate of zDHHC3. Notably, cardiomyopathy and congestive heart failure in zDHHC3 transgenic mice is preceded by enhanced Rac1 S-palmitoylation, membrane localization, activity, downstream hypertrophic signaling, and concomitant induction of all Rho family small GTPases whereas mice overexpressing an enzymatically dead zDHHC3 mutant show no discernible effect. However, loss of Rac1 or other identified zDHHC3 targets Gαq/11 or galectin-1 does not diminish zDHHC3-induced cardiomyopathy, suggesting multiple effectors and pathways promoting decompensation with sustained zDHHC3 activity. Genetic deletion of Zdhhc3 in combination with Zdhhc7 reduces cardiac hypertrophy during the early response to pressure overload stimulation but not over longer time periods. Indeed, cardiac hypertrophy in response to 2 weeks of angiotensin-II infusion is not diminished by Zdhhc3/7 deletion, again suggesting other S-acyltransferases or signaling mechanisms compensate to promote hypertrophic signaling. Taken together, these data indicate that the activity of zDHHC3 and zDHHC7 at the cardiomyocyte Golgi promote Rac1 signaling and maladaptive cardiac remodeling, but redundant signaling effectors compensate to maintain cardiac hypertrophy with sustained pathological stimulation in the absence of zDHHC3/7.

Multimodal Biomarkers That Predict the Presence of Gleason Pattern 4: Potential Impact for Active Surveillance.

PURPOSE: Latent grade group ≥2 prostate cancer can impact the performance of active surveillance protocols. To date, molecular biomarkers for active surveillance have relied solely on RNA or protein. We trained and independently validated multimodal (mRNA abundance, DNA methylation, and/or DNA copy number) biomarkers that more accurately separate grade group 1 from grade group ≥2 cancers. MATERIALS AND METHODS: Low- and intermediate-risk prostate cancer patients were assigned to training (n=333) and validation (n=202) cohorts. We profiled the abundance of 342 mRNAs, 100 DNA copy number alteration loci, and 14 hypermethylation sites at 2 locations per tumor. Using the training cohort with cross-validation, we evaluated methods for training classifiers of pathological grade group ≥2 in centrally reviewed radical prostatectomies. We trained 2 distinct classifiers, PRONTO-e and PRONTO-m, and validated them in an independent radical prostatectomy cohort. RESULTS: PRONTO-e comprises 353 mRNA and copy number alteration features. PRONTO-m includes 94 clinical, mRNAs, copy number alterations, and methylation features at 14 and 12 loci, respectively. In independent validation, PRONTO-e and PRONTO-m predicted grade group ≥2 with respective true-positive rates of 0.81 and 0.76, and false-positive rates of 0.43 and 0.26. Both classifiers were resistant to sampling error and identified more upgrading cases than a well-validated presurgical risk calculator, CAPRA (Cancer of the Prostate Risk Assessment; P < .001). CONCLUSIONS: Two grade group classifiers with superior accuracy were developed by incorporating RNA and DNA features and validated in an independent cohort. Upon further validation in biopsy samples, classifiers with these performance characteristics could refine selection of men for active surveillance, extending their treatment-free survival and intervals between surveillance.

Rpl3l gene deletion in mice reduces heart weight over time.

Introduction: The ribosomal protein L3-like (RPL3L) is a heart and skeletal muscle-specific ribosomal protein and paralogue of the more ubiquitously expressed RPL3 protein. Mutations in the human RPL3L gene are linked to childhood cardiomyopathy and age-related atrial fibrillation, yet the function of RPL3L in the mammalian heart remains unknown. Methods and Results: Here, we observed that mouse cardiac ventricles express RPL3 at birth, where it is gradually replaced by RPL3L in adulthood but re-expressed with induction of hypertrophy in adults. Rpl3l gene-deleted mice were generated to examine the role of this gene in the heart, although Rpl3l -/- mice showed no overt changes in cardiac structure or function at baseline or after pressure overload hypertrophy, likely because RPL3 expression was upregulated and maintained in adulthood. mRNA expression analysis and ribosome profiling failed to show differences between the hearts of Rpl3l null and wild type mice in adulthood. Moreover, ribosomes lacking RPL3L showed no differences in localization within cardiomyocytes compared to wild type controls, nor was there an alteration in cardiac tissue ultrastructure or mitochondrial function in adult Rpl3l -/- mice. Similarly, overexpression of either RPL3 or RPL3L with adeno-associated virus -9 in the hearts of mice did not cause discernable pathology. However, by 18 months of age Rpl3l -/- null mice had significantly smaller hearts compared to wild type littermates. Conclusion: Thus, deletion of Rpl3l forces maintenance of RPL3 expression within the heart that appears to fully compensate for the loss of RPL3L, although older Rpl3l -/- mice showed a mild but significant reduction in heart weight.

Frailty and polypharmacy in the community-dwelling elderly with multiple chronic diseases.

BACKGROUND: Both multi-morbidity (MM) and polypharmacy (PP) are common in the elderly and pose a challenge for health and social care systems. However, high-quality patient-centred care requires context-bound understanding of the patterns and use of medications in those with MM. Therefore, the aim of this study was to investigate the prevalence of PP in community-dwelling elderly, and the factors associated with MM, PP, excessive polypharmacy (EPP), and the types of drugs used. METHODS: We analysed data of 164 community-dwelling subjects aged ≥60 years from January to December 2020 at a general hospital in a rural area of Taiwan. MM was defined as >4 diagnoses of chronic health conditions. Non-polypharmacy (NP), PP, and EPP were defined as <5, 5-8, and >8 prescriptions, respectively. Other variables including basic activities of daily living (BADL), severity of frailty, depressive mood, screening for intellectual impairment, and nutritional status were also analysed. RESULTS: Of the 164 participants, 34.8% had >4 diagnoses, 66.5% had PP, and 26.2% had EPP. The patients with >4 diagnoses had worse performance in BADL, higher levels of frailty, and more prescriptions than those with fewer diagnoses. The EPP group had worse performance in BADL, a higher level of frailty, more comorbidities, and higher prevalences of diabetes mellitus and chronic kidney disease compared to the NP and PP groups. After adjusting for covariates, we further found a higher number of medications associated with having more comorbidities, and a higher level of frailty associated with having a greater number of medications. CONCLUSION: We found relationships between frailty and PP, and between PP and MM, but frailty did not associate with MM. Since frailty, PP, and MM may be viewed as an inevitable trinity of ageing, reducing PP could be a method to both prevent frailty and disentangle this trinity in the elderly.

Prosthetic Management of Severe Mandibular Deviation in a Hemi-Mandibulectomy Patient Following Osteoradionecrosis.

Rehabilitation of a patient after hemi-mandibulectomy without reconstruction represents a prosthodontic challenge. Indeed, mandibular deviation and decreased occlusal contacts are a common presentation post-surgery. This paper reports on a patient who presented with these challenges and where chronic osteoradionecrosis has resulted in significant mandibular deviation. A maxillary cobalt chrome mandibular deviation device, designed with palatal bite plane and constructed using 3D printing methods, resulted in a successful outcome. The authors aim to show how restorative management of similar patients can be successful using a modern approach.

Multiparametric Magnetic Resonance Imaging in the Diagnosis of Clinically Significant Prostate Cancer: an Updated Systematic Review.

There has been growing utilisation of multiparametric magnetic resonance imaging (MPMRI) as a non-invasive tool to diagnose and localise clinically significant prostate cancer (CSPCa). This updated systematic review examines the use of MPMRI in patients with an elevated risk of CSPCa who have had a prior negative transrectal ultrasound systematic biopsy (TRUS-SB) and who were biopsy naïve. MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews were searched for existing systematic reviews published up to September 2020. The literature search of the electronic databases combined disease-specific terms (prostate cancer, prostate carcinoma, etc.) and treatment-specific terms (magnetic resonance, etc.). Studies were included if they were randomised controlled trials (RCTs) comparing MPMRI to template transperineal mapping biopsy (TPMB) or to TRUS-SB. Thirty-six RCTs were eligible. For biopsy-naïve men, accuracy of diagnosis of CSPCa showed sensitivities from 87 to 96% and specificities ranging from 29 to 45%. Meta-analyses for CSPCa showed increased detection favouring MPMRI-targeted biopsy over TRUS-SB by 3% (95% confidence interval 0-7%, P = 0.03) and decreased detection of clinically insignificant prostate cancer (CISPCa) favouring MPMRI by 8% (95% confidence interval -11 to 5%, P < 0.00001). Accuracy of MPMRI for men with prior negative biopsy showed sensitivities of 78-100% and specificities of 30-100%. Meta-analyses comparing MPMRI to TRUS-SB showed increased detection of 5% (95% confidence interval 3-7%, P < 0.0001) with a reduction of CISPCa detection of 7% (95% confidence interval 4-9%, P < 0.00001). The growing acceptance of MPMRI utilisation internationally and the recent publication of several RCTs regarding MPMRI in reducing CISPCa detection rates, particularly in biopsy-naïve men, without loss of sensitivity for CSPCa necessitates the synthesis of updated evidence examining MPMRI in the diagnosis of CSPCa.

Norwich COVID-19 testing initiative pilot: evaluating the feasibility of asymptomatic testing on a university campus.

BACKGROUND: There is a high prevalence of COVID-19 in university-age students, who are returning to campuses. There is little evidence regarding the feasibility of universal, asymptomatic testing to help control outbreaks in this population. This study aimed to pilot mass COVID-19 testing on a university research park, to assess the feasibility and acceptability of scaling up testing to all staff and students. METHODS: This was a cross-sectional feasibility study on a university research park in the East of England. All staff and students (5625) were eligible to participate. All participants were offered four PCR swabs, which they self-administered over two weeks. Outcome measures included uptake, drop-out rate, positivity rates, participant acceptability measures, laboratory processing measures, data collection and management measures. RESULTS: 798 (76%) of 1053 who registered provided at least one swab; 687 (86%) provided all four; 792 (99%) of 798 who submitted at least one swab had all negative results and 6 participants had one inconclusive result. There were no positive results. 458 (57%) of 798 participants responded to a post-testing survey, demonstrating a mean acceptability score of 4.51/5, with five being the most positive. CONCLUSIONS: Repeated self-testing for COVID-19 using PCR is feasible and acceptable to a university population.

Aerobic exercise training attenuates detrimental effects of cigarette smoke exposure on peripheral muscle through stimulation of the Nrf2 pathway and cytokines: a time-course study in mice.

Cigarette smoke (CS) exposure reduces skeletal muscle function; however, the mechanisms involved have been poorly investigated. The current study evaluated the temporal effects of aerobic exercise training on oxidant and antioxidant systems as well as inflammatory markers in skeletal muscle of mice exposed to CS. Mice were randomly allocated to control, exercise, smoke, and smoke+exercise groups and 3 time points (4, 8, and 12 weeks; n = 12 per group). Exercise training and CS exposure were performed for 30 min/day, twice a day, 5 days/week for 4, 8, and 12 weeks. Aerobic exercise improved functional capacity and attenuated the increase in the cachexia index induced by CS exposure after 12 weeks. Concomitantly, exercise training downregulated tumor necrosis factor α concentration, glutathione oxidation, and messenger RNA (mRNA) expression of Keap1 (P < 0.01) and upregulated interleukin 10 concentration, total antioxidant capacity, and mRNA expression of Nrf2, Gsr, and Txn1 (P < 0.01) in muscle. Exercise increased mRNA expression of Hmox1 compared with the control after 12 weeks (P < 0.05). There were no significant differences between smoke groups for superoxide dismutase activity and Hmox1 mRNA expression. Exercise training improved the ability of skeletal muscle to adequately upregulate key antioxidant and anti-inflammatory defenses to detoxify electrophilic compounds induced by CS exposure, and these effects were more pronounced after 12 weeks. Novelty Exercise attenuates oxidative stress in skeletal muscle from animals exposed to CS via Nrf2 and glutathione pathways. Exercise is a helpful tool to control the inflammatory balance in skeletal muscle from animals exposed to CS. These beneficial effects were evident after 12 weeks.

Complex surgery and perioperative systemic therapy for genitourinary cancer of the retroperitoneum.

Objective: The purpose of the present guideline is to recommend surgical or systemic treatment for metastatic testicular cancer; T3b or T4, or node-positive, and metastatic renal cell cancer (rcc); and T3, T4, or node-positive upper tract urothelial (utuc) cancer. Methods: Draft recommendations were formulated based on evidence obtained through a systematic review of randomized controlled trials, comparative retrospective studies, and guideline endorsement. The draft recommendations underwent an internal review by clinical and methodology experts, and an external review by clinical practitioners. Results: The primary literature search yielded eight guidelines, five systematic reviews, and twenty-seven primary studies that met the eligibility criteria. Conclusions: Cytoreductive nephrectomy should no longer be considered the standard of care in patients with T3b or T4, or node-positive, and metastatic rcc. Eligible patients should be treated with systemic therapy and have their primary tumour removed only after review at a multidisciplinary case conference (mcc). Adjuvant sunitinib after surgery is not recommended. Patients with venous tumour thrombus should be considered for surgical intervention. Patients with T3, T4, or node-positive utuc should have their tumour removed without delay. Decisions concerning lymph node dissection should be done at a mcc and be based on stage, expertise, and imaging. Adjuvant systemic treatment is recommended for resected high-risk utuc. Patients with metastasis-positive testicular cancer with residual tumour after systemic treatment should be treated at specialized centres. For all complex retroperitoneal surgeries, the evidence shows that higher-volume centres are associated with lower rates of procedure-related mortality, and patients should be referred to higher-volume centres for surgical resection.

Twelve-month prostate volume reduction after MRI-guided transurethral ultrasound ablation of the prostate.

PURPOSE: To quantitatively assess 12-month prostate volume (PV) reduction based on T2-weighted MRI and immediate post-treatment contrast-enhanced MRI non-perfused volume (NPV), and to compare measurements with predictions of acute and delayed ablation volumes based on MR-thermometry (MR-t), in a central radiology review of the Phase I clinical trial of MRI-guided transurethral ultrasound ablation (TULSA) in patients with localized prostate cancer. MATERIALS AND METHODS: Treatment day MRI and 12-month follow-up MRI and biopsy were available for central radiology review in 29 of 30 patients from the published institutional review board-approved, prospective, multi-centre, single-arm Phase I clinical trial of TULSA. Viable PV at 12 months was measured as the remaining PV on T2-weighted MRI, less 12-month NPV, scaled by the fraction of fibrosis in 12-month biopsy cores. Reduction of viable PV was compared to predictions based on the fraction of the prostate covered by the MR-t derived acute thermal ablation volume (ATAV, 55°C isotherm), delayed thermal ablation volume (DTAV, 240 cumulative equivalent minutes at 43°C thermal dose isocontour) and treatment-day NPV. We also report linear and volumetric comparisons between metrics. RESULTS: After TULSA, the median 12-month reduction in viable PV was 88%. DTAV predicted a reduction of 90%. Treatment day NPV predicted only 53% volume reduction, and underestimated ATAV and DTAV by 36% and 51%. CONCLUSION: Quantitative volumetry of the TULSA phase I MR and biopsy data identifies DTAV (240 CEM43 thermal dose boundary) as a useful predictor of viable prostate tissue reduction at 12 months. Immediate post-treatment NPV underestimates tissue ablation. KEY POINTS: • MRI-guided transurethral ultrasound ablation (TULSA) achieved an 88% reduction of viable prostate tissue volume at 12 months, in excellent agreement with expectation from thermal dose calculations. • Non-perfused volume on immediate post-treatment contrast-enhanced MRI represents only 64% of the acute thermal ablation volume (ATAV), and reports only 60% (53% instead of 88% achieved) of the reduction in viable prostate tissue volume at 12 months. • MR-thermometry-based predictions of 12-month prostate volume reduction based on 240 cumulative equivalent minute thermal dose volume are in excellent agreement with reduction in viable prostate tissue volume measured on pre- and 12-month post-treatment T2w-MRI.

Nitrofurantoin safety and effectiveness in treating acute uncomplicated cystitis (AUC) in hospitalized adults with renal insufficiency: antibiotic stewardship implications.

Nitrofurantoin remains a key oral antibiotic stewardship program (ASP) option in the treatment of acute uncomplicated cystitis (AUC) due to multi-drug resistant (MDR) Gram negative bacilli (GNB). However, there have been concerns regarding decreased nitrofurantoin efficacy with renal insufficiency. In our experience over the past three decades, nitrofurantoin has been safe and effective in treating AUC in hospitalized adults with renal insufficiency. Accordingly, we retrospectively reviewed our recent experience treating AUC in hospitalized adults with decreased renal function (CrCl < 60 ml/min) with nitrofurantoin. Excluded were complicated urinary tract infections. Urinary isolated susceptibility testing was done by micro broth dilution (MBD). Treatment duration was 5-7 days. Cure was defined as eradication of the uropathogen and failure was defined as minimal/no decrease in urine colony counts. Of 26 evaluable patients with renal insufficiency (CrCl < 60 ml/min), nitrofurantoin eradicated the uropathogen in 18/26 (69%) of patients, and failed in 8/26 (31%). Of the eight failures, five were due to intrinsically resistant uropathogens, e.g., Proteus sp., and one failure was related to an alkaline urine. Of the treatment failures, only two were due to renal insufficiency, i.e., CrCl < 30 ml/min. Since there are few oral antibiotics available to treat AUC due to MDR GNB uropathogens, these results have important ASP implications. Currently, nitfurantoin is not recommended if CrCl < 60 ml/min. In our experience, used appropriately against susceptible uropathogens, nitrofurantoin was highly effective in nearly all patients with CrCl = 30-60 ml/min., and only failed in two patients due to renal insufficiency (CrCl < 30 ml/ml).

Nemo-Like Kinase (NLK) Is a Pathological Signaling Effector in the Mouse Heart.

Nemo-like kinase (NLK) is an evolutionary conserved serine/threonine protein kinase implicated in development, proliferation and apoptosis regulation. Here we identified NLK as a gene product induced in the hearts of mice subjected to pressure overload or myocardial infarction injury, suggesting a potential regulatory role with pathological stimulation to this organ. To examine the potential functional consequences of increased NLK levels, cardiac-specific transgenic mice with inducible expression of this gene product were generated, as well as cardiac-specific Nlk gene-deleted mice. NLK transgenic mice demonstrated baseline cardiac hypertrophy, dilation, interstitial fibrosis, apoptosis and progression towards heart failure in response to two surgery-induced cardiac disease models. In contrast, cardiac-specific deletion of Nlk from the heart, achieved by crossing a Nlk-loxP allele containing mouse with either a mouse containing a ß-myosin heavy chain promoter driven Cre transgene or a tamoxifen inducible α-myosin heavy chain promoter containing transgene driving a MerCreMer cDNA, protected the mice from cardiac dysfunction following pathological stimuli. Mechanistically, NLK interacted with multiple proteins including the transcription factor Stat1, which was significantly increased in the hearts of NLK transgenic mice. These results indicate that NLK is a pathological effector in the heart.

Cathepsin S Contributes to the Pathogenesis of Muscular Dystrophy in Mice.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin protein compromises the stability of the sarcolemma membrane surrounding each muscle cell fiber, leading to membrane ruptures and leakiness that induces myofiber necrosis, a subsequent inflammatory response, and progressive tissue fibrosis with loss of functional capacity. Cathepsin S (Ctss) is a cysteine protease that is actively secreted in areas of tissue injury and ongoing inflammation, where it participates in extracellular matrix remodeling and healing. Here we show significant induction of Ctss expression and proteolytic activity following acute muscle injury or in muscle from mdx mice, a model of DMD. To examine the functional ramifications associated with greater Ctss expression, the Ctss gene was deleted in the mdx genetic background, resulting in protection from muscular dystrophy pathogenesis that included reduced myofiber turnover and histopathology, reduced fibrosis, and improved running capacity. Mechanistically, deletion of the Ctss gene in the mdx background significantly increased myofiber sarcolemmal membrane stability with greater expression and membrane localization of utrophin, integrins, and ß-dystroglycan, which anchor the membrane to the basal lamina and underlying cytoskeletal proteins. Consistent with these results, skeletal muscle-specific transgenic mice overexpressing Ctss showed increased myofiber necrosis, muscle histopathology, and a functional deficit reminiscent of muscular dystrophy. Hence, Ctss induction during muscular dystrophy is a pathologic event that partially underlies disease pathogenesis, and its inhibition might serve as a new therapeutic strategy in DMD.

Targeted radiotherapy enhancement during electronic brachytherapy of accelerated partial breast irradiation (APBI) using controlled release of gold nanoparticles.

Several studies have demonstrated low rates of local recurrence with brachytherapy-based accelerated partial breast irradiation (APBI). However, long-term outcomes on toxicity (e.g. telangiectasia) and cosmesis remain a major concern. The purpose of this study is to investigate the dosimetric feasibility of using targeted non-toxic radiosensitizing gold nanoparticles (GNPs) for localized dose enhancement to the planning target volume (PTV) during electronic brachytherapy APBI while reducing normal tissue toxicity. We propose to incorporate GNPs into a micrometer-thick polymer film on the surface of routinely used lumpectomy balloon applicators and provide subsequent treatment using a 50 kVp Xoft device. An experimentally determined diffusion coefficient was used to determine space-time customizable distribution of GNPs for feasible in-vivo concentrations of 7 mg/g and 43 mg/g. An analytical approach from previously published work was employed to estimate the dose enhancement due to GNPs as a function of distance up to 1 cm from the lumpectomy cavity surface. Clinically significant dose enhancement values of at least 1.2, due to 2 nm GNPs, were found at 1 cm away from the lumpectomy cavity wall when using electronic brachytherapy APBI. Higher customizable dose enhancement was also achieved at other distances as a function of nanoparticle size. Our preliminary results suggest that significant dose enhancement can be achieved to residual tumor cells targeted with GNPs during APBI with electronic brachytherapy.

Extracellular vesicles such as prostate cancer cell fragments as a fluid biopsy for prostate cancer.

Extracellular vesicles (EVs) are cell-derived vesicles generated through a process of cell membrane shedding or storage vesicle release, as occurs during apoptosis, necrosis or exocytosis. Initially perceived as cellular by-products or 'dust' of insignificant biological importance, recent research has shed light on the role of EVs as mediators of intercellular communication, blood coagulation and disease progression. The prostate is a source of EVs and their abundance in complex biological fluids such as plasma, serum and urine make them compelling entities for a 'fluid biopsy'. As such, prostate cancer cell fragments (PCCF) are EVs generated by the tumor resident within the prostate and are also present in blood, expressing a portion of biomarkers representative of the primary tumor. High-throughput analytical techniques to determine biomarker expression on EVs is the last hurdle towards translating the full potential of prostate EVs for clinical use. We describe current state-of-the-art methods for the analysis of prostate-derived EVs in patient fluids such as plasma and the challenges that lie ahead in this emerging field of translational research.

Air exchange rates and migration of VOCs in basements and residences.

UNLABELLED: Basements can influence indoor air quality by affecting air exchange rates (AERs) and by the presence of emission sources of volatile organic compounds (VOCs) and other pollutants. We characterized VOC levels, AERs, and interzonal flows between basements and occupied spaces in 74 residences in Detroit, Michigan. Flows were measured using a steady-state multitracer system, and 7-day VOC measurements were collected using passive samplers in both living areas and basements. A walk-through survey/inspection was conducted in each residence. AERs in residences and basements averaged 0.51 and 1.52/h, respectively, and had strong and opposite seasonal trends, for example, AERs were highest in residences during the summer, and highest in basements during the winter. Airflows from basements to occupied spaces also varied seasonally. VOC concentration distributions were right-skewed, for example, 90th percentile benzene, toluene, naphthalene, and limonene concentrations were 4.0, 19.1, 20.3, and 51.0 µg/m(3), respectively; maximum concentrations were 54, 888, 1117, and 134 µg/m(3). Identified VOC sources in basements included solvents, household cleaners, air fresheners, smoking, and gasoline-powered equipment. The number and type of potential VOC sources found in basements are significant and problematic, and may warrant advisories regarding the storage and use of potentially strong VOCs sources in basements. PRACTICAL IMPLICATIONS: Few IAQ studies have examined basements. A sizable volume of air can flow between the basement and living area, and AERs in these two zones can differ considerably. In many residences, the basement contains significant emission sources and contributes a large fraction of VOC concentrations found in the living area. Exposures can be lowered by removing VOC sources from the basement; other exposure management options, such as local ventilation or isolation, are unlikely to be practical.

An open-label, phase 2 trial of bicalutamide dose escalation from 50 mg to 150 mg in men with CAB and castration resistance. A Canadian Urology Research Consortium Study.

BACKGROUND: Bicalutamide is a widely used, relatively non-toxic anti-androgen, particularly when used in combination with androgen deprivation. In men on combined androgen blockade (CAB), the typical dose is 50 mg per day. For men receiving monotherapy with bicalutamide anti-androgen, the dose is 150 mg per day. The objective was to determine the PSA response rate to increasing bicalutamide to 150 mg per day in men who develop castrate-resistant prostate cancer (CRPC) on CAB with goserelin acetate and bicalutamide 50 mg per day. METHODS: A national, multicentre, phase 2, open-label study in men on CAB with a rising PSA>2.0. The primary end point of the trial was PSA response at 12 months, defined as a decline by 50% or more compared with baseline value. Partial response was defined as a PSA decline of 10-49%. Secondary end points were duration of PSA response, change in slope of serum PSA, change in ratio of free PSA: total PSA at 3 months, 6 months and 12 months as compared with baseline; duration of the bicalutamide withdrawal response after discontinuation; the rate of cardiovascular events; and toxicity. The study was initially planned to accrue 100 patients, but was closed early due to diminishing accrual. RESULTS: Sixty-four patients were accrued; 61 patients received trial treatment and constituted the intention-to-treat (ITT) cohort. 70% were M0. Among 59 evaluable ITT patients, 13 (22%) patients had a >50% PSA decline, 5 (8%) had a decline between 10 and 50%, 4 (7%) had stabilization and 37 (63%) had PSA progression. The median duration was 3.7 months (95% confidence interval of 0.92-6.21 months). CONCLUSION: In patients with early biochemical failure on CAB with bicalutamide 50 mg, an increase in dose to 150 mg of bicalutamide resulted in a PSA response of ⩾ 50% in 22% of patients. Toxicity was mild. Bicalutamide dose intensification may benefit a subset of patients with CRPC. We believe this relatively inexpensive approach warrants further evaluation.

c-kit+ cells minimally contribute cardiomyocytes to the heart.

If and how the heart regenerates after an injury event is highly debated. c-kit-expressing cardiac progenitor cells have been reported as the primary source for generation of new myocardium after injury. Here we generated two genetic approaches in mice to examine whether endogenous c-kit(+) cells contribute differentiated cardiomyocytes to the heart during development, with ageing or after injury in adulthood. A complementary DNA encoding either Cre recombinase or a tamoxifen-inducible MerCreMer chimaeric protein was targeted to the Kit locus in mice and then bred with reporter lines to permanently mark cell lineage. Endogenous c-kit(+) cells did produce new cardiomyocytes within the heart, although at a percentage of approximately 0.03 or less, and if a preponderance towards cellular fusion is considered, the percentage falls to below approximately 0.008. By contrast, c-kit(+) cells amply generated cardiac endothelial cells. Thus, endogenous c-kit(+) cells can generate cardiomyocytes within the heart, although probably at a functionally insignificant level.