International study into the use of intermittent hormone therapy in the treatment of carcinoma of the prostate : A meta-analysis of 1446 patients

OBJECTIVE: To review pooled phase II data to identify features of different regimens of intermittent hormone therapy (IHT), developed to reduce the morbidity of treating metastatic prostate cancer, and which carries a theoretical advantage of delaying the onset of androgen-independent prostate cancer, (AIPC) that are associated with success, highlighting features which require exploration with prospective trials to establish the best strategies for using this treatment. METHODS: Individual data were collated on 1446 patients with adequate information, from 10 phase II studies with >50 cases, identified through Pubmed. RESULTS: Univariate and multivariate Cox proportional hazard models were developed to predict treatment success with a high degree of statistical success. The prostate-specific antigen (PSA) nadir, the PSA threshold to restart treatment, and medication type and duration, were important predictors of outcome. CONCLUSIONS: The duration of biochemical remission after a period of HT is a durable early indicator of how rapidly AIPC and death will occur, and will make a useful endpoint in future trials to investigate the best ways to use IHT based on the important treatment cycling variables described above. Patients spent a mean of 39% of the time off treatment. The initial PSA level and PSA nadir allow the identification of patients with prostate cancer in whom it might be possible to avoid radical therapy.Peer reviewe

Hedgehog Signalling in Androgen Independent Prostate Cancer

Objectives: Androgen-deprivation therapy effectively shrinks hormone-naïve prostate cancer, both in the prostate and at sites of distant metastasis. However prolonged androgen deprivation generally results in relapse and androgen-independent tumour growth, which is inevitably fatal. The molecular events that enable prostate cancer cells to proliferate in reduced androgen conditions are poorly understood. Here we investigate the role of Hedgehog signalling in androgen-independent prostate cancer (AIPC). Methods: Activity of the Hedgehog signalling pathway was analysed in cultured prostate cancer cells, and circulating prostate tumour cells were isolated from blood samples of patients with AIPC. Results: AIPC cells were derived through prolonged culture in reduced androgen conditions, modelling hormone therapy in patients, and expressed increased levels of Hedgehog signalling proteins. Exposure of cultured AIPC cells to cyclopamine, which inhibits Hedgehog signalling, resulted in inhibition of cancer cell growth. The expression of the Hedgehog receptor PTCH and the highly prostate cancer-specific gene DD3PCA3 was significantly higher in circulating prostate cancer cells isolated from patients with AIPC compared with samples prepared from normal individuals. There was an association between PTCH and DD3PCA3 expression and the length of androgen-ablation therapy. Conclusions: Our data are consistent with reports implicating overactivity of Hedgehog signalling in prostate cancer and suggest that Hedgehog signalling contributes to the androgen-independent growth of prostate cancer cells. As systemic anti-Hedgehog medicines are developed, the Hedgehog pathway will become a potential new therapeutic target in advanced prostate cancer.Peer reviewedFinal Accepted Versio

Simplified speciation and atmospheric volatile organic compound emission rates from non-aerosol personal care products

Volatile organic compounds (VOCs) emitted from personal care products (PCPs) can affect indoor air quality and outdoor air quality when ventilated. In this paper, we determine a set of simplified VOC species profiles and emission rates for a range of non-aerosol PCPs. These have been constructed from individual vapor analysis from 36 products available in the UK, using equilibrium headspace analysis with selected-ion flow-tube mass spectrometry (SIFT-MS). A simplified speciation profile is created based on the observations, comprising four alcohols, two cyclic volatile siloxanes, and monoterpenes (grouped as limonene). Estimates are made for individual unit-of-activity VOC emissions for dose-usage of shampoos, shower gel, conditioner, liquid foundation, and moisturizer. We use these values as inputs to the INdoor air Detailed Chemical Model (INDCM) and compare results against real-world case-study experimental data. Activity-based emissions are then scaled based on plausible usage patterns to estimate the potential scale of annual per-person emissions for each product type (eg, 2 g limonene person−1 yr−1 from shower gels). Annual emissions from non-aerosol PCPs for the UK are then calculated (decamethylcyclopentasiloxane 0.25 ktonne yr−1 and limonene 0.15 ktonne yr−1) and these compared with the UK National Atmospheric Emissions Inventory estimates for non-aerosol cosmetics and toiletries

Detection of TMPRSS2 : ERG fusion gene in circulating prostate cancer cells

Creative Commons Attribution-NonCommercial-Share Alike 3.0 license (CC BY-NC SA)Aim: To investigate the existence of TMPRSS2:ERG fusion gene in circulating tumor cells (CTC) from prostate cancer patients and its potential in monitoring tumor metastasis. Methods: We analyzed the frequency of TMPRSS2: ERG and TMPRSS2:ETV1 transcripts in 27 prostate cancer biopsies from prostatectomies, and TMPRSS2:ERG transcripts in CTC isolated from 15 patients with advanced androgen independent disease using reverse transcription polymerase chain reaction (RT-PCR). Fluorescence in situ hybridization (FISH) was applied to analyze the genomic truncation of ERG, which is the result of TMPRSS2:ERG fusion in 10 of the 15 CTC samples. Results: TMPRSS2: ERG transcripts were found in 44% of our samples, but we did not detect expression of TMPRSS2:ETV1. Using FISH analysis we detected chromosomal rearrangements affecting the ERG gene in 6 of 10 CTC samples, including 1 case with associated TMPRSS2:ERG fusion at the primary site. However, TMPRSS2:ERG transcripts were not detected in any of the 15 CTC samples, including the 10 cases analyzed by FISH. Conclusion: Although further study is required to address the association between TMPRSS2:ERG fusion and prostate cancer metastasis, detection of genomic truncation of the ERG gene by FISH analysis could be useful for monitoring the appearance of CTC and the potential for prostate cancer metastasis.Peer reviewedFinal Published versio

HST Optical-NIR Colors of Nearby R1/4R^{1/4} and Exponential Bulges

We have analysed $V$, $H$ and $J$ HST images for a sample of early- to late-type spiral galaxies, and reported elsewhere the statistical frequency of $R^{1/4}$-law and exponential bulges in our sample as a function of Hubble type, and the frequency of occurrence and structural properties of the resolved central nuclei hosted by intermediate- to late-type bulges and disks (see references in the text). Here we use these data to show that: {\it (i)} The $V-H$ color distribution of the $R^{1/4}$ bulges peaks around $\sim 1.3$, with a sigma $\Delta (V-H) \sim 0.1$ magnitudes. Assuming a solar metallicity, these values correspond to stellar ages of $\approx 6 \pm 3$ Gyrs. In contrast, the $V-H$ color distribution of the exponential bulges peaks at $\sim 0.9$ and has a sigma $\Delta (V-H) \sim 0.4$ mags. This likely implies significantly smaller ages and/or lower metallicities for (a significant fraction of the stars in) the exponential bulges compared to the $R^{1/4}$-law spheroids. {\it (ii)} Most of the central nuclei hosted by the exponential bulges have $V-H$ and $J-H$ colors which are compatible with relatively unobscured stellar populations. Assuming no or little dust effects, ages \gta 1 Gyrs are suggested for these nuclei, which in turn imply masses of about a few 10$^6$ to a few 10$^7$ M$_\odot$, i.e., sufficient to dissolve progenitor bars with masses consistent with those inferred for the exponential bulges by their luminosities. {\it (iii)} While different bulge-nucleus pairs cover a large range of $V-H$ colors, each bulge-nucleus pair has quite similar $V-H$ colors, and thus possibly similar stellar populations. (abridged)Comment: ApJ, accepted, Dec 10, 2000 Issu

The impact of sequencing depth on the inferred taxonomic composition and AMR gene content of metagenomic samples

Shotgun metagenomics is increasingly used to characterise microbial communities, particularly for the investigation of antimicrobial resistance (AMR) in different animal and environmental contexts. There are many different approaches for inferring the taxonomic composition and AMR gene content of complex community samples from shotgun metagenomic data, but there has been little work establishing the optimum sequencing depth, data processing and analysis methods for these samples. In this study we used shotgun metagenomics and sequencing of cultured isolates from the same samples to address these issues. We sampled three potential environmental AMR gene reservoirs (pig caeca, river sediment, effluent) and sequenced samples with shotgun metagenomics at high depth (~ 200 million reads per sample). Alongside this, we cultured single-colony isolates of Enterobacteriaceae from the same samples and used hybrid sequencing (short- and long-reads) to create high- quality assemblies for comparison to the metagenomic data. To automate data processing, we developed an open- source software pipeline, ‘ResPipe’

A low exhaled nitric oxide level excludes a short-term benefit from inhaled corticosteroids in suspected asthma: A randomized placebo-controlled trial

Background and objective: Fractional exhaled nitric oxide (FeNO) is a non-invasive biomarker that reflects IL-4/IL-13 production and therefore represents T2 allergic inflammation. FeNO has previously been used to guide inhaled corticosteroid (ICS) treatment in asthma. The purpose of this study was to determine if a low FeNO (≤27 ppb) could be used to reliably identify patients with symptoms suggestive of asthma who would not benefit from initiating treatment with an ICS. Methods: A total of 180 steroid-naïve adults with healthcare professional suspected asthma and an FeNO of ≤27 ppb were randomized to receive either 400 mcg of budesonide or placebo daily for 3 months. The primary outcome was the difference in the Asthma Control Questionnaire 7 (ACQ7) between treatment groups and the study was powered to determine equivalence. Secondary outcomes were the difference in FEV , Medical Research Council and Leicester Cough Questionnaire scores. Results: One hundred and thirty-four patients (68 budesonide and 66 placebo) completed the study and were included in the analysis. The between-group mean difference in ACQ7 from baseline to the end of the study was −0.25 and the 95% CI around this difference was −0.004 to 0.495 confirming equivalence (p < 0.05). Differences in forced expiratory volume over 1 s and other secondary outcomes were also small and clinically unimportant. Conclusion: The results of this study suggest that steroid-naïve patients with symptoms suggestive of asthma and an FeNO ≤ 27 ppb are unlikely to benefit from initiating treatment with an ICS over 3 months. However, further research is recommended to confirm these findings before withholding ICS treatment.

Artists on the edge of the world : an integrated approach to the study of Magdalenian engraved stone plaquettes from Jersey (Channel Islands)

Excavations at Les Varines were funded by Jersey Heritage through the States of Jersey Tourism Development Fund (https://www.gov.je/Leisure/Events/TourismDevelopmentFundTDF/pages/abouttdf.aspx) in 2013-15 and in 2017 (BS received the funding), by the British Museum research fund in 2016-18 (https://www.britishmuseum.org/research) (Grant nos EC164/EC208) (BS received the funding), in 2016 by British Academy (https://www.thebritishacademy.ac.uk) small grant SG152868 (CC received the funding) and Society of Antiquaries (https://www.sal.org.uk/) Research Grants R121086 in 2017 and BH181355 in 2018 (CC received the funding). Funding from the Universities of Manchester, Southampton and UCL supported student training at the excavation. Silvia Bello’s work was part of the ‘Human Behaviour in 3D’ Project funded by the Calleva Foundation. Beccy Scott’s work was also supported by the Calleva foundation (Pathways to Ancient Britain project).The Upper Palaeolithic is characterised by the appearance of iconographic expressions most often depicting animals, including anthropomorphic forms, and geometric signs. The Late Upper Palaeolithic Magdalenian saw a flourishing of such depictions, encompassing cave art, engraving of stone, bone and antler blanks and decoration of tools and weapons. Though Magdalenian settlement exists as far northwest as Britain, there is a limited range of art known from this region, possibly associated with only fleeting occupation of Britain during this period. Stone plaquettes, flat fragments of stone engraved on at least one surface, have been found in large quantities at numerous sites spanning the temporal and geographical spread of the Magdalenian, but they have been absent so far from the archaeological record of the British Isles. Between 2015 and 2018, ten fragments of stone plaquettes extensively engraved with abstract designs were uncovered at the Magdalenian site of Les Varines, Jersey, Channel Islands. In this paper, we report detailed analyses of these finds, which provide new evidence for technologies of abstract mark-making, and their significance within the lives of people on the edge of the Magdalenian world. These engraved stone fragments represent important, rare evidence of artistic expression in what is the far northern and western range of the Magdalenian and add new insight to the wider significance of dynamic practices of artistic expression during the Upper Palaeolithic.Publisher PDFPeer reviewe

An inclusive approach to raising standards in general practice: working with a 'community of practice' in Western Australia

<p>Abstract</p> <p>Background</p> <p>In this study we explored the challenges to establishing a community of practice (CoP) to address standards in general practice. We focused on the issue of improving referral letters which are the main form of communication between general practitioners (GPs) and specialists. There is evidence to suggest that the information relayed to specialists at the time of referral could be improved.</p> <p>Methods</p> <p>We aimed to develop a community of practice consisting of GPs in Western Australia to improve the quality of referral letters to six specialty clinics. Three phases included: establishing the CoP, monitoring the progress of the CoP and sustaining and managing the CoP. The CoP's activity centred on referral letters to each of six selected specialties. A local measure for the quality of the referral letters was developed from a survey of participants about specific items of history and weighted for their perceived importance in the referral letter. Referral letters by participants written before and after the benchmarking exercise were scored for quality based on the standards set by the CoP. Feedback to participants regarding the 'quality' of their individual referrals was provided by a nominated member of the CoP, including a comparison of before and after scores.</p> <p>Results</p> <p>15 GPs were recruited. Only five GPs submitted referral letters both before and after benchmarking. The five GPs that participated in both study phases submitted a total of 102 referral letters (53 before and 49 after). There was a 26 point (95% CI 11–41) improvement in the average scores of the second set of letters after taking clustering by speciality into account, indicating the quality of referral letters improved substantially after feedback.</p> <p>Conclusion</p> <p>There are many challenges to forming a CoP to focus on improving a specific issue in general practice. However we were able to demonstrate that those practitioners who participated in all aspects of the project substantially improved the quality of their referral letters. For recruitment it was important to work with a champion for the project from within the practice. The project took several months to complete therefore some GPs became disengaged. Some were very disappointed by their performance when compared to colleagues. This reaction may be an important motivation to change, however it needs to be sensitively handled if participants are not to become disillusioned or disheartened.</p

Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and re‐emerging phenotype is associated with graft function

Islet transplantation is an effective therapy for life‐threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet‐specific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fifty‐eight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with islet‐specific T cell responses was not significantly different over time (pre‐Tx: 59%; 1–6 m posttransplant: 38%; 7–12 m: 44%; 13–24 m: 47%; and >24 m: 45%). However, phenotype shifted significantly, with IFN‐γ–dominated response in the pretransplant group replaced by IL‐10–dominated response in the 1–6 m posttransplant group, reverting to predominantly IFN‐γ–oriented response in the >24 m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFN‐γ and IL‐10 phenotypes, respectively. IL‐10–oriented posttransplant response was associated with relatively low graft function. Recipients within the IL‐10+ cluster had a significant decline in C‐peptide levels in the period preceding the IL‐10 response, but stable graft function following the response. In contrast, an IFN‐γ response was associated with subsequently decreased C‐peptide. Islet transplantation favoring ATZ induction is associated with an initial altered islet‐specific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function