Histone acetylation is a dynamic modification regulated by the opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Deacetylation of histone tails results in ...chromatin tightening, and therefore, HDACs are generally regarded as transcriptional repressors. Counterintuitively, simultaneous deletion of
and
in embryonic stem cells (ESCs) reduces expression of the pluripotency-associated transcription factors
,
, and
(PSN). By shaping global histone acetylation patterns, HDACs indirectly regulate the activity of acetyl-lysine readers, such as the transcriptional activator BRD4. Here, we use inhibitors of HDACs and BRD4 (LBH589 and JQ1, respectively) in combination with precision nuclear run-on and sequencing (PRO-seq) to examine their roles in defining the ESC transcriptome. Both LBH589 and JQ1 cause a marked reduction in the pluripotent gene network. However, although JQ1 treatment induces widespread transcriptional pausing, HDAC inhibition causes a reduction in both paused and elongating polymerase, suggesting an overall reduction in polymerase recruitment. Using enhancer RNA (eRNA) expression to measure enhancer activity, we find that LBH589-sensitive eRNAs are preferentially associated with superenhancers and PSN binding sites. These findings suggest that HDAC activity is required to maintain pluripotency by regulating the PSN enhancer network via the recruitment of RNA polymerase II.
Transurethral resection of the prostate (TURP) is the standard operation for benign prostatic obstruction (BPO). Thulium laser transurethral vaporesection of the prostate (ThuVARP) vaporises and ...resects the prostate using a technique similar to TURP. The small amount of existing literature suggests that there may be potential advantages of ThuVARP over TURP.
To determine whether or not the outcomes from ThuVARP are equivalent to the outcomes from TURP in men with BPO treated in the NHS.
A multicentre, pragmatic, randomised controlled parallel-group trial, with an embedded qualitative study and economic evaluation.
Seven UK centres - four university teaching hospitals and three district general hospitals.
Men aged ≥ 18 years who were suitable to undergo TURP, presenting with bothersome lower urinary tract symptoms (LUTS) or urinary retention secondary to BPO.
Patients were randomised 1 : 1 to receive TURP or ThuVARP and remained blinded.
Two co-primary outcomes - patient-reported International Prostate Symptom Score (IPSS) and clinical measure of maximum urine flow rate (Qmax) at 12 months post surgery.
In total, 410 men were randomised, 205 to each arm. The two procedures were equivalent in terms of IPSS adjusted mean difference 0.28 points higher for ThuVARP (favouring TURP), 95% confidence interval (CI) -0.92 to 1.49 points. The two procedures were not equivalent in terms of Qmax (adjusted mean difference 3.12 ml/second in favour of TURP, 95% CI 0.45 to 5.79 ml/second), with TURP deemed superior. Surgical outcomes, such as complications and blood transfusion rates, and hospital stay were similar for both procedures. Patient-reported urinary and sexual symptoms were also similar between the arms. Qualitative interviews indicated similar patient experiences with both procedures. However, 25% of participants in the ThuVARP arm did not undergo their randomised allocation, compared with 2% of participants in the TURP arm. Prostate cancer was also detected less frequently from routine histology after ThuVARP (65% lower odds of detection) in an exploratory analysis. The adjusted mean differences between the arms were similar for secondary care NHS costs (£9 higher for ThuVARP, 95% CI -£359 to £376) and quality-adjusted life-years (0.01 favouring TURP, 95% CI -0.04 to 0.01).
Complications were recorded in prespecified categories; those not prespecified were excluded owing to variable reporting. Preoperative Qmax and IPSS data could not be collected for participants with indwelling catheters, making adjustment for baseline status difficult.
TURP was superior to ThuVARP in terms of Qmax, although both operations resulted in a Qmax considered clinically successful. ThuVARP also potentially resulted in lower detection rates of prostate cancer as a result of the smaller volume of tissue available for histology. Length of hospital stay after ThuVARP, anticipated to be a key benefit, was equal to that after TURP in this trial. Overall, both ThuVARP and TURP were effective procedures for BPO, with minor benefits in favour of TURP. Therefore, the results suggest that it may be appropriate that new treatment alternatives continue to be compared with TURP.
Longer-term follow-up to assess reoperation rates over time, and research into the comparative effectiveness of ThuVARP and TURP in large prostates.
Current Controlled Trials ISRCTN00788389.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 24, No. 41. See the NIHR Journals Library website for further project information.
Nocturia is a common urinary symptom of multiple sclerosis (MS) which can affect quality of life (QoL) adversely. Melatonin is a hormone known to regulate circadian rhythm and reduce smooth muscle ...activity such as in the bladder. There is limited evidence supporting use of melatonin to alleviate urinary frequency at night in the treatment of nocturia. The aim of this study was to evaluate the effect of melatonin on the mean number of nocturia episodes per night in patients with MS.
A randomized, double blind, placebo controlled crossover trial was conducted. 34 patients with nocturia secondary to multiple sclerosis underwent a 4-day pre-treatment monitoring phase. The patients were randomized to receive either 2 mg per night (taken at bedtime) of capsulated sustained-release melatonin (Circadin®) or 1 placebo capsule for 6 weeks followed by a crossover to the other regimen for an additional 6 weeks after a 1-month washout period.
From the 26 patients who completed the study, there was no significant difference observed in the signs or symptoms of nocturia when taking 2 mg melatonin compared to placebo. The primary outcome measure, mean number of nocturia episodes on bladder diaries, was 1.8/night at baseline, and 1.4/night on melatonin, compared with 1.6 for placebo (Medians 1.70, 1.50, and 1.30 respectively, p = 0.85). There was also no significant difference seen in LUTS, QoL and sleep quality when taking melatonin. No significant safety concerns arose.
This small study suggests that a low dose of melatonin taken at bedtime may be ineffective therapy for nocturia in MS.
(EudraCT reference) 2012-00418321 registered: 25/01/13. ISRCTN Registry: ISRCTN38687869 .
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Robotic radical prostatectomy (RARP) is a first-line curative treatment option for localized prostate cancer. Postoperative erectile dysfunction and urinary incontinence are common associated adverse ...side effects that can negatively impact patients' quality of life. Preserving the lateral neurovascular bundles (NS) during RARP improves functional outcomes. However, selecting men for NS may be difficult when there is concern about incurring in positive surgical margin (PSM) which in turn risks adverse oncological outcomes. The NeuroSAFE technique (intra-operative frozen section examination of the neurovascular structure adjacent prostate margin) can provide real-time pathological consult to promote optimal NS whilst avoiding PSM.
NeuroSAFE PROOF is a single-blinded, multi-centre, randomised controlled trial (RCT) in which men are randomly allocated 1:1 to either NeuroSAFE RARP or standard RARP. Men electing for RARP as primary treatment, who are continent and have good baseline erectile function (EF), defined by International Index of Erectile Function (IIEF-5) score > 21, are eligible. NS in the intervention arm is guided by the NeuroSAFE technique. NS in the standard arm is based on standard of care, i.e. a pre-operative image-based planning meeting, patient-specific clinical information, and digital rectal examination. The primary outcome is assessment of EF at 12 months. The primary endpoint is the proportion of men who achieve IIEF-5 score ≥ 21. A sample size of 404 was calculated to give a power of 90% to detect a difference of 14% between groups based on a feasibility study. Oncological outcomes are continuously monitored by an independent Data Monitoring Committee. Key secondary outcomes include urinary continence at 3 months assessed by the international consultation on incontinence questionnaire, rate of biochemical recurrence, EF recovery at 24 months, and difference in quality of life.
NeuroSAFE PROOF is the first RCT of intra-operative frozen section during radical prostatectomy in the world. It is properly powered to evaluate a difference in the recovery of EF for men undergoing RARP assessed by patient-reported outcome measures. It will provide evidence to guide the use of the NeuroSAFE technique around the world.
NCT03317990 (23 October 2017). Regional Ethics Committee; reference 17/LO/1978.
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•Experimentally naïve rats acquired lever pressing with delayed reinforcement when the immediate programmed consequence for lever pressing was the simultaneous retraction of two identical levers.•One ...lever initiated delayed reinforcement. A second lever initiated a time-out interval.•All rats emitted the majority of responding on the lever that initiated reinforcer delivery.•Responding decreased during extinction and recovered rapidly when reinforcement was reinstated.•Rats tracked contingencies when the functions of the two levers were switched.
Experimentally naïve rats acquired lever pressing with delayed reinforcement when the immediate programmed consequence for lever pressing was the simultaneous retraction of two identical levers. Presses on one lever also produced access to sweetened condensed milk after a delay of 10s following retraction. Presses on the second lever resulted in retraction only. Lever retraction prevented the possibility of adventitious reinforcement of contacting the operanda during the reinforcement delays. Several measures indicated that the delayed reinforcers strengthened behavior. The majority of responses for all rats were on the lever that initiated reinforcer delivery. Responding for seven out of eight rats decreased during a subsequent extinction phase in which retraction was the only consequence arranged for lever pressing. Responding recovered rapidly when food reinforcement was available again. Furthermore, when contingencies on the two levers were switched, rats allocated their behavior accordingly, showing control by the delayed reinforcers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Evidence from observational studies have shown that moderate intensity physical activity can reduce risk of progression and cancer-specific mortality in participants with prostate cancer. ...Epidemiological studies have also shown participants taking metformin to have a reduced risk of prostate cancer. However, data from randomised controlled trials supporting the use of these interventions are limited. The Prostate cancer-Exercise and Metformin Trial examines that feasibility of randomising participants diagnosed with localised or locally advanced prostate cancer to interventions that modify physical activity and blood glucose levels. The primary outcomes are randomisation rates and adherence to the interventions over 6 months. The secondary outcomes include intervention tolerability and retention rates, measures of insulin-like growth factor I, prostate-specific antigen, physical activity, symptom-reporting, and quality of life. Methods Participants are randomised in a 2 x 2 factorial design to both a physical activity (brisk walking or control) and a pharmacological (metformin or control) intervention. Participants perform the interventions for 6 months with final measures collected at 12 months follow-up. Discussion Our trial will determine whether participants diagnosed with localised or locally advanced prostate cancer, who are scheduled for radical treatments or being monitored for signs of cancer progression, can be randomised to a 6 months physical activity and metformin intervention. The findings from our trial will inform a larger trial powered to examine the clinical benefits of these interventions. Trial registration Prostate Cancer Exercise and Metformin Trial (Pre-EMpT) is registered on the ISRCTN registry, reference number ISRCTN13543667. Date of registration 2nd August 2018-retrospectively registered. First participant was recruited on 11th September 2018. Keywords: Prostate cancer, Metformin, Physical activity, Feasibility randomised controlled trial, Localised, Locally advanced, Radiotherapy, Prostatectomy, Active surveillance
Film is a form of engaging narrative being employed with greater frequency in undergraduate and graduate education. To optimize their pedagogical impact, it is important to carefully select films ...that address core course objectives. Additionally, viewing should be structured with written guidelines to direct the audience to consider the relevant dimensions associated with the instructional goals of the film. A course, "Medical Ethics and Film" is described to illustrate cinemeducation. In order to assess the impact of this recently developed course, students kept ongoing diaries in which they regularly wrote about their reactions to each film. Analysis of the diaries revealed that students routinely addressed the moral dilemmas portrayed and often applied specific ethical theories. While ethical theory is typically presented as a series of cognitive frameworks, students often expressed strong emotional reactions and frequently linked the dilemmas portrayed to their own life. Co-written with Alyssa Burnash, Molly Campbell, Megan Chmielewski, Morgan Edmonds, Heather Gregg, Lyndsey Ren Johnson, Ellie Lytle, Katelyn Mills, Natalie Nowak, Camdyn Odykirk, Kaycie Rachels, Mikayla Schrotenboer, Sierra Strutz, Teresa VanDyke, Sydney Zuke, and Michael Zurek.
Self-report measures used in PTSD research have the potential to limit the degree of symptom severity in military veterans, especially as there is often underreporting in this population (Kline, ...Falca-Dodson, Susner et al., 2010). Polyvagal Theory provides a framework assessing if physiological measures can tap into PTSD Symptomology (Porges, 1995). It is therefore hypothesized that lower scores on auditory processing tests will be positively correlated with higher scores on Stress and PTSD measures. Additionally, it is thought that lower scores on auditory processing tests as well as higher scores on PTSD and Stress Measures will be positively correlated with decreased Heart Rate Variability. After answering a series of survey questions, participants completed a hearing test as well as Auditory Processing tests while having their heart rate monitored; from that, heart rate variability was computed and several Hierarchical Linear Regressions were performed, controlling for Age, Sex, Branch of Service, and Active Duty Status. No statistically significant relationships were found between PTSD, heart rate variability, and auditory processing measures. Data collection was stopped early due to COVID19, which limited statistical power for analyses. The goal of this research is to determine a way to increase the accuracy of PTSD diagnosis.
Manufacturing processes for autologous cell therapy need to reproducibly generate in specification (quality and quantity) clinical product. However, patient variability prevents the level of control ...of cell input material that could be achieved in a cell line or allogeneic-based process. We have applied literature data on bone marrow–derived mesenchymal stromal cells variability to estimate probability distributions for stem cell yields given underlying truncated normal distributions in total nucleated cell concentration, stem cell percentage and plausible aspirate volumes. Monte Carlo simulation identified potential variability in harvested stem cell number in excess of an order of magnitude. The source material variability was used to identify the proportion of donor manufacturing runs that would achieve a target yield specification of 2E7 cells in a fixed time window with given proliferative rates and different aspirate volumes. A rapid, screening, development approach was undertaken to assess culture materials and process parameters (T-flask surface, medium, feed schedule) to specify a protocol with identified proliferative rate and a consequent model-based target aspirate volume. Finally, four engineering runs of the candidate process were conducted and a range of relevant quality parameters measured including expression of markers CD105, CD73, CD44, CD45, CD34, CD11b, CD19, HLA-DR, CD146 (melanoma cell adhesion molecule), CD106 (vascular cell adhesion molecule) and SSEA-4, specific metabolic activity and vascular endothelial growth factor secretion, and osteogenic differentiation potential. Our approach of using estimated distributions from publicly available information provides a route for data-poor earl- stage developers to plan manufacture with defined risk based on rational assumptions; furthermore, the models produced by such assumptions can be used to evaluate candidate processes, and can be incrementally improved with accumulating distribution understanding or subdivision by new process variables.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Transurethral resection of the prostate (TURP) is the standard operation for benign prostatic obstruction. Thulium laser transurethral vaporesection of the prostate (ThuVARP) is a technique with ...suggested advantages over TURP, including reduced complications and hospital stay. We aimed to investigate TURP versus ThuVARP in men with lower urinary tract symptoms or urinary retention secondary to benign prostatic obstruction.
In this randomised, blinded, parallel-group, pragmatic equivalence trial, men in seven UK hospitals with bothersome lower urinary tract symptoms or urinary retention secondary to benign prostatic obstruction were randomly assigned (1:1) at the point of surgery to receive ThuVARP or TURP. Patients were masked until follow-up completion. Centres used their usual TURP procedure (monopolar or bipolar). All trial surgeons underwent training on the ThuVARP technique. Co-primary outcomes were maximum urinary flow rate (Qmax) and International Prostate Symptom Score (IPSS) at 12-months post-surgery. Equivalence was defined as a difference of 2·5 points or less for IPSS and 4 mL per s or less for Qmax. Analysis was done according to the intention-to-treat principle. The trial is registered with the ISRCTN Registry, ISRCTN00788389.
Between July 23, 2014, and Dec 30, 2016, 410 men were randomly assigned to ThuVARP or TURP, 205 per study group. TURP was superior for Qmax (mean 23·2 mL per s for TURP and 20·2 mL per s for ThuVARP; adjusted difference in means −3·12, 95% CI −5·79 to −0·45). Equivalence was shown for IPSS (mean 6·3 for TURP and 6·4 for ThuVARP; adjusted difference in means 0·28, −0·92 to 1·49). Mean hospital stay was 48 h in both study groups. 91 (45%) of 204 patients in the TURP group and 96 (47%) of 203 patients in the ThuVARP group had at least one complication.
TURP and ThuVARP were equivalent for urinary symptom improvement (IPSS) 12-months post-surgery, and TURP was superior for Qmax. Anticipated laser benefits for ThuVARP of reduced hospital stay and complications were not observed.
UK National Institute for Health Research Health Technology Assessment Programme.
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