Drugs affecting the renin-angiotensin system and survival from cancer: a population based study of breast, colorectal and prostate cancer patient cohorts

Background: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are commonly prescribed to the growing number of cancer patients (more than two million in the UK alone) often to treat hypertension. However, increased fatal cancer in ARB users in a randomized trial and increased breast cancer recurrence rates in ACEI users in a recent observational study have raised concerns about their safety in cancer patients. We investigated whether ACEI or ARB use after breast, colorectal or prostate cancer diagnosis was associated with increased risk of cancer-specific mortality.

Methods: Population-based cohorts of 9,814 breast, 4,762 colorectal and 6,339 prostate cancer patients newly diagnosed from 1998 to 2006 were identified in the UK Clinical Practice Research Datalink and confirmed by cancer registry linkage. Cancer-specific and all-cause mortality were identified from Office of National Statistics mortality data in 2011 (allowing up to 13 years of follow-up). A nested case–control analysis was conducted to compare ACEI/ARB use (from general practitioner prescription records) in cancer patients dying from cancer with up to five controls (not dying from cancer). Conditional logistic regression estimated the risk of cancer-specific, and all-cause, death in ACEI/ARB users compared with non-users.

Results: The main analysis included 1,435 breast, 1,511 colorectal and 1,184 prostate cancer-specific deaths (and 7,106 breast, 7,291 colorectal and 5,849 prostate cancer controls). There was no increase in cancer-specific mortality in patients using ARBs after diagnosis of breast (adjusted odds ratio (OR) = 1.06 95% confidence interval (CI) 0.84, 1.35), colorectal (adjusted OR = 0.82 95% CI 0.64, 1.07) or prostate cancer (adjusted OR = 0.79 95% CI 0.61, 1.03). There was also no evidence of increases in cancer-specific mortality with ACEI use for breast (adjusted OR = 1.06 95% CI 0.89, 1.27), colorectal (adjusted OR = 0.78 95% CI 0.66, 0.92) or prostate cancer (adjusted OR = 0.78 95% CI 0.66, 0.92).

Conclusions: Overall, we found no evidence of increased risks of cancer-specific mortality in breast, colorectal or prostate cancer patients who used ACEI or ARBs after diagnosis. These results provide some reassurance that these medications are safe in patients diagnosed with these cancers.

Keywords: Colorectal cancer; Breast cancer; Prostate cancer; Mortality; Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers

Creating an Inclusive Society… How Close are We in Relation to Autism Spectrum Disorder? A General Population Survey

BackgroundChildren with autism spectrum disorder are increasingly educated in mainstream classrooms in the United Kingdom (Wilkinson & Twist, Autism and Educational Assessment: UK Policy and Practice. NFER, Slough, 2010), and some employers are now specifically seeking out staff on the autism spectrum. Does that mean that we are living in an inclusive society' [United Nations Department of Economic and Social Affairs (UNDESA), Creating an Inclusive Society: Practical Strategies to Promote Social Integration 2008], in the sense that inequalities are reduced and full economic, social and cultural participation is advanced for individuals with autism?

MethodsA general population survey was conducted to assess how close we, as a society, are to an inclusive society for individuals with autism in Northern Ireland. Public attitudes were examined to (i) visibility and social interaction, (ii) aetiology, needs and interventions, and (iii) rights and resources.

ResultsA stratified, representative sample of 1204 adults took part in the survey; of these, 989 were aware of autism and their attitudes and behavioural projections reflected a mix of acceptance and denunciation. The level of confusion with regard to interventions reflected the general uncertainty within UK policy regarding meeting the needs of individuals on the autism spectrum (International Journal of Disability, Development and Education 61, 134, 2014a).

ConclusionTherefore, it seems that inclusion is working to an extent, but more clarity is needed with regard to adequate education, intervention and support for individuals with autism.

Exercise training protects the LDLI subfraction from oxidation susceptibility in an aged human population

Background Exercise training is considered an effective strategy to improve metabolic disease. Despite this, less is known regarding exercise training in the prevention and susceptibility of LDL subfraction oxidation, particularly in an aged population. 
Methods Eleven aged (55 ± 4 yrs) and twelve young (21 ± 2 yrs) participants were randomly separated into an experimental or control group as follows: young exercise (n = 6); young control (n = 6); aged exercise (n = 6) and aged control (n = 5). The participants assigned to the exercise groups performed 12 weeks of moderate intensity (55–65% VO2max) exercise training. Venous blood was extracted at baseline, and 48 h following 12 weeks of exercise and assayed for a range of metabolites associated with lipid composition and lipoprotein susceptibility to oxidation. 
Results Although there was no difference in the oxidation potential (time ½ max) of LDL I, II or III between groups at baseline (p > 0.05), there was an increase in time ½ max for LDL I following exercise within the aged exercise group (p < 0.05). Moreover, α-tocopherol concentration was selectively lower in the aged exercise group, compared to the young exercise at baseline. The lipid composition of LDL I, LDL II, LDL III, VLDL, HDL2, HDL3 and serum lipid hydroperoxides remained unchanged as a function of exercise training and ageing (p > 0.05). 
Conclusion The primary finding of this study demonstrates that adaptations in LDL resistance to oxidation occur following 12 weeks of exercise training in the aged, and this may be of clinical significance, as oxidation of LDL has been implicated in atherosclerosis.

Observational Constraints on the Progenitors of Core-Collapse Supernovae: The Case for Missing High-Mass Stars

Over the last 15 years, the supernova community has endeavoured to directly identify progenitor stars for core-collapse supernovae discovered in nearby galaxies. These precursors are often visible as resolved stars in high-resolution images from space-and ground-based telescopes. The discovery rate of progenitor stars is limited by the local supernova rate and the availability and depth of archive images of galaxies, with 18 detections of precursor objects and 27 upper limits. This review compiles these results (from 1999 to 2013) in a distance-limited sample and discusses the implications of the findings. The vast majority of the detections of progenitor stars are of type II-P, II-L, or IIb with one type Ib progenitor system detected and many more upper limits for progenitors of Ibc supernovae (14 in all). The data for these 45 supernovae progenitors illustrate a remarkable deficit of high-luminosity stars above an apparent limit of log L/L-circle dot similar or equal to 5.1 dex. For a typical Salpeter initial mass function, one would expect to have found 13 high-luminosity and high-mass progenitors by now. There is, possibly, only one object in this time-and volume-limited sample that is unambiguously high-mass (the progenitor of SN2009ip) although the nature of that supernovae is still debated. The possible biases due to the influence of circumstellar dust, the luminosity analysis, and sample selection methods are reviewed. It does not appear likely that these can explain the missing high-mass progenitor stars. This review concludes that the community's work to date shows that the observed populations of supernovae in the local Universe are not, on the whole, produced by high-mass (M greater than or similar to 18 M-circle dot) stars. Theoretical explosions of model stars also predict that black hole formation and failed supernovae tend to occur above an initial mass of M similar or equal to 18 M-circle dot. The models also suggest there is no simple single mass division for neutron star or black-hole formation and that there are islands of explodability for stars in the 8-120 M-circle dot range. The observational constraints are quite consistent with the bulk of stars above M similar or equal to 18 M-circle dot collapsing to form black holes with no visible supernovae.

Early-type stars observed in the ESO UVES Paranal Observatory Project - V. Time-variable interstellar absorption

The structure and properties of the diffuse interstellar medium (ISM) on small scales, sub-au to 1 pc, are poorly understood. We compare interstellar absorption-lines, observed towards a selection of O- and B-type stars at two or more epochs, to search for variations over time caused by the transverse motion of each star combined with changes in the structure in the foreground ISM. Two sets of data were used: 83 VLT- UVES spectra with approximately 6 yr between epochs and 21 McDonald observatory 2.7m telescope echelle spectra with 6 - 20 yr between epochs, over a range of scales from 0 - 360 au. The interstellar absorption-lines observed at the two epochs were subtracted and searched for any residuals due to changes in the foreground ISM. Of the 104 sightlines investigated with typically five or more components in Na I D, possible temporal variation was identified in five UVES spectra (six components), in Ca II, Ca I and/or Na I absorption-lines. The variations detected range from 7\% to a factor of 3.6 in column density. No variation was found in any other interstellar species. Most sightlines show no variation, with 3{\sigma} upper limits to changes of the order 0.1 - 0.3 dex in Ca II and Na I. These variations observed imply that fine-scale structure is present in the ISM, but at the resolution available in this study, is not very common at visible wavelengths. A determination of the electron densities and lower limits to the total number density of a sample of the sightlines implies that there is no striking difference between these parameters in sightlines with, and sightlines without, varying components.

SN 2009ib: a Type II-P supernova with an unusually long plateau

We present optical and near-infrared photometry and spectroscopy of SN 2009ib, a Type II-P supernova in NGC 1559. This object has moderate brightness, similar to those of the intermediate-luminosity SNe 2008in and 2009N. Its plateau phase is unusually long, lasting for about 130 d after explosion. The spectra are similar to those of the subluminous SN 2002gd, with moderate expansion velocities. We estimate the Ni-56 mass produced as 0.046 +/- A 0.015 M-aS (TM). We determine the distance to SN 2009ib using both the expanding photosphere method (EPM) and the standard candle method. We also apply EPM to SN 1986L, a Type II-P SN that exploded in the same galaxy. Combining the results of different methods, we conclude the distance to NGC 1559 as D = 19.8 +/- A 3.0 Mpc. We examine archival, pre-explosion images of the field taken with the Hubble Space Telescope, and find a faint source at the position of the SN, which has a yellow colour [(V - I)(0) = 0.85 mag]. Assuming it is a single star, we estimate its initial mass as M-ZAMS = 20 M-aS (TM). We also examine the possibility, that instead of the yellow source the progenitor of SN 2009ib is a red supergiant star too faint to be detected. In this case, we estimate the upper limit for the initial zero-age main sequence (ZAMS) mass of the progenitor to be similar to 14-17 M-aS (TM). In addition, we infer the physical properties of the progenitor at the explosion via hydrodynamical modelling of the observables, and estimate the total energy as similar to 0.55 x 10(51) erg, the pre-explosion radius as similar to 400 R-aS (TM), and the ejected envelope mass as similar to 15 M-aS (TM), which implies that the mass of the progenitor before explosion was similar to 16.5-17 M-aS (TM).

Massive stars exploding in a He-rich circumstellar medium - V. Observations of the slow-evolving SN Ibn OGLE-2012-SN-006

We present optical observations of the peculiar Type Ibn supernova (SN Ibn) OGLE-2012-SN-006, discovered and monitored by the Optical Gravitational Lensing Experiment-IV survey, and spectroscopically followed by Public ESO Spectroscopic Survey of Transient Objects (PESSTO) at late phases. Stringent pre-discovery limits constrain the explosion epoch with fair precision to JD = 245 6203.8 +/- 4.0. The rise time to the I-band light-curve maximum is about two weeks. The object reaches the peak absolute magnitude M-I = -19.65 +/- 0.19 on JD = 245 6218.1 +/- 1.8. After maximum, the light curve declines for about 25 d with a rate of 4 mag (100 d)(-1). The symmetric I-band peak resembles that of canonical Type Ib/c supernovae (SNe), whereas SNe Ibn usually exhibit asymmetric and narrower early-time light curves. Since 25 d past maximum, the light curve flattens with a decline rate slower than that of the Co-56-Fe-56 decay, although at very late phases it steepens to approach that rate. However, other observables suggest that the match with the Co-56 decay rate is a mere coincidence, and the radioactive decay is not the main mechanism powering the light curve of OGLE-2012-SN-006. An early-time spectrum is dominated by a blue continuum, with only a marginal evidence for the presence of He I lines marking this SN type. This spectrum shows broad absorptions bluewards than 5000 angstrom, likely O II lines, which are similar to spectral features observed in superluminous SNe at early epochs. The object has been spectroscopically monitored by PESSTO from 90 to 180 d after peak, and these spectra show the typical features observed in a number of SN 2006jc-like events, including a blue spectral energy distribution and prominent and narrow (v(FWHM) approximate to 1900 km s(-1)) He I emission lines. This suggests that the ejecta are interacting with He-rich circumstellar material. The detection of broad (10(4) km s(-1)) O I and Ca II features likely produced in the SN ejecta (including the [OI] lambda lambda 6300,6364 doublet in the latest spectra) lends support to the interpretation of OGLE-2012-SN-006 as a core-collapse event.

Low luminosity TypeII supernovae-II. Pointing towards moderate mass precursors

We present new data for five underluminous Type II-plateau supernovae (SNe IIP), namely SN 1999gn, SN 2002gd, SN 2003Z, SN 2004eg and SN 2006ov. This new sample of lowluminosity SNe IIP (LL SNe IIP) is analysed together with similar objects studied in the past. All of them show a flat light-curve plateau lasting about 100 d, an underluminous late-time exponential tail, intrinsic colours that are unusually red, and spectra showing prominent and narrow P Cygni lines. A velocity of the ejected material below 10³ km s^-1 is inferred from measurements at the end of the plateau. The 56Ni masses ejected in the explosion are very small (≤10^-2 M⊙). We investigate the correlations among ⁵⁶Ni mass, expansion velocity of the ejecta and absolute magnitude in the middle of the plateau, confirming the main findings of Hamuy, according to which events showing brighter plateau and larger expansion velocities are expected to produce more 56Ni. We propose that these faint objects represent the LL tail of a continuous distribution in parameters space of SNe IIP. The physical properties of the progenitors at the explosion are estimated through the hydrodynamical modelling of the observables for two representative events of this class, namely SN 2005cs and SN 2008in. We find that the majority of LL SNe IIP, and quite possibly all, originate in the core collapse of intermediate-mass stars, in the mass range 10-15 M⊙. 

HPV prevalence and type-distribution in cervical cancer and premalignant lesions of the cervix: A population-based study from Northern Ireland

Assessment of Human papillomavirus (HPV) prevalence and genotype distribution is important for monitoring the impact of prophylactic HPV vaccination. This study aimed to demonstrate the HPV genotypes predominating in pre-malignant and cervical cancers in Northern Ireland (NI) before the vaccination campaign has effect. Formalin fixed paraffin embedded tissue blocks from 2,303 women aged 16-93 years throughout NI were collated between April 2011 and February 2013. HPV DNA was amplified by PCR and HPV genotyping undertaken using the Roche^® linear array detection kit. In total, 1,241 out of 1,830 eligible samples (68.0%) tested positive for HPV, with the majority of these [1,181/1,830 (64.5%)] having high-risk (HR) HPV infection; 37.4% were positive for HPV-16 (n=684) and 5.1% for HPV-18 (n=93). HPV type-specific prevalence was 48.1%, 65.9%, 81.3%, 92.2%, and 64.3% among cervical intraepithelial neoplasias (CIN) Grades I-III, squamous cell carcinomas (SCC) and adenocarcinoma (AC) cases, respectively. Most SCC cases (81.3%) had only one HPV genotype detected and almost a third (32.0%) of all cervical pathologies were HPV negative including 51.9% of CIN I (n=283), 34.1% CIN II (n=145), 18.7% of CIN III (n=146), 7.8% of SCC (n=5), and 35.7% of AC (n=5) cases. This study provides important baseline data for monitoring the effect of HPV vaccination in NI and for comparison with other UK regions. The coverage of other HR-HPV genotypes apart from 16 and 18, including HPV-45, 31, 39, and 52, and the potential for cross protection, should be considered when considering future polyvalent vaccines.

Ultraviolet emission lines of Si II in cool star and solar spectra

Recent atomic physics calculations for Si II are employed within the CLOUDY modelling code to analyse Hubble Space Telescope (HST) STIS ultraviolet spectra of three cool stars, β Geminorum, α Centauri A and B, as well as previously published HST/GHRS observations of α Tau, plus solar quiet Sun data from the High Resolution Telescope and Spectrograph. Discrepancies found previously between theory and observation for line intensity ratios involving the 3s²3p ²PJ-3s3p^{2 4}P^J' intercombination multiplet of Si II at ~ 2335 Å are significantly reduced, as are those for ratios containing the 3s²3p ²PJ-3s3p^{2 2}DJ ~ transitions at ~1816 Å. This is primarily due to the effect of the new Si II transition probabilities. However, these atomic data are not only very different from previous calculations, but also show large disagreements with measurements, specifically those of Calamai et al. for the intercombination lines. New measurements of transition probabilities for Si II are hence urgently required to confirm (or otherwise) the accuracy of the recently calculated values. If the new calculations are confirmed, then a long-standing discrepancy between theory and observation will have finally been resolved. However, if the older measurements are found to be correct, then the agreement between theory and observation is simply a coincidence and the existing discrepancies remain.

The Fenix II Study: A longitudinal study of psychopathology among burn patients

Psychological symptoms are common among burn survivors. However, knowledge about epidemiology and predictors of psychopathology has shown great heterogeneity in this population. The Fenix-II Project was the first epidemiological study on the psychopathological consequences of burn injuries developed in Spain, providing a detailed analysis of the progression of psychological symptoms during the first six months after injury. Three hundred and thirty-three patients were monitored and 183 were included in this study. Posttraumatic, depression and anxiety symptoms showed a general decreasing tendency across time. At 6 months, 34 patients showed clinically significant Posttraumatic Stress Disorder (PTSD) symptoms (20.5% of 166 patients reached at 6 months) as measured with the MINI Neuropsychiatric Interview. Within this group of patients, anxiety, depression and hyperarousal increased at 30 days, and avoidance 90 days after injury. The most accurate predictors of PTSD were found to be being burned in a Motor Vehicle Accident, risk of social exclusion, low body-image adjustment, anterior trunk location of the burn injury and life threat perception during the burn-shock period. Considering these factors, clinicians may identify patients at risk of PTSD development, allowing an adequate follow up and preventive interventions which may minimize the psychological consequences of burn injuries.

Restriction site-associated DNA sequencing, genotyping error estimation and de novo assembly optimization for population genetic inference.

Restriction site-associated DNA sequencing (RADseq) provides researchers with the ability to record genetic polymorphism across thousands of loci for nonmodel organisms, potentially revolutionizing the field of molecular ecology. However, as with other genotyping methods, RADseq is prone to a number of sources of error that may have consequential effects for population genetic inferences, and these have received only limited attention in terms of the estimation and reporting of genotyping error rates. Here we use individual sample replicates, under the expectation of identical genotypes, to quantify genotyping error in the absence of a reference genome. We then use sample replicates to (i) optimize de novo assembly parameters within the program Stacks, by minimizing error and maximizing the retrieval of informative loci; and (ii) quantify error rates for loci, alleles and single-nucleotide polymorphisms. As an empirical example, we use a double-digest RAD data set of a nonmodel plant species, Berberis alpina, collected from high-altitude mountains in Mexico.

Safety and immunogenicity of the M72/AS01 candidate tuberculosis vaccine in HIV-infected adults on combination antiretroviral therapy: a phase I/II, randomized trial.

OBJECTIVE: Tuberculosis (TB) is highly prevalent among HIV-infected people, including those receiving combination antiretroviral therapy (cART), necessitating a well tolerated and efficacious TB vaccine for these populations. We evaluated the safety and immunogenicity of the candidate TB vaccine M72/AS01 in adults with well controlled HIV infection on cART. DESIGN: A randomized, observer-blind, controlled trial (NCT00707967). METHODS: HIV-infected adults on cART in Switzerland were randomized 3 : 1 : 1 to receive two doses, 1 month apart, of M72/AS01, AS01 or 0.9% physiological saline (N = 22, N = 8 and N = 7, respectively) and were followed up to 6 months postdose 2 (D210). Individuals with CD4⁺ cell counts below 200 cells/μl were excluded. Adverse events (AEs) including HIV-specific and laboratory safety parameters were recorded. Cell-mediated (ICS) and humoral (ELISA) responses were evaluated before vaccination, 1 month after each dose (D30, D60) and D210. RESULTS: Thirty-seven individuals [interquartile range (IQR) CD4⁺ cell counts at screening: 438-872 cells/μl; undetectable HIV-1 viremia] were enrolled; 73% of individuals reported previous BCG vaccination, 97.3% tested negative for the QuantiFERON-TB assay. For M72/AS01 recipients, no vaccine-related serious AEs or cART-regimen adjustments were recorded, and there were no clinically relevant effects on laboratory safety parameters, HIV-1 viral loads or CD4⁺ cell counts. M72/AS01 was immunogenic, inducing persistent and polyfunctional M72-specific CD4⁺ T-cell responses [medians 0.70% (IQR 0.37-1.07) at D60] and 0.42% (0.24-0.61) at D210, predominantly CD40L⁺IL-2⁺TNF-α⁺, CD40L⁺IL-2⁺ and CD40L⁺IL-2⁺TNF-α⁺IFN-γ⁺]. All M72/AS01 vaccines were seropositive for anti-M72 IgG after second vaccination until study end. CONCLUSION: M72/AS01 was clinically well tolerated and immunogenic in this population, supporting further clinical evaluation in HIV-infected individuals in TB-endemic settings.

Dilated cardiomyopathy and impaired cardiac hypertrophic response to angiotensin II in mice lacking FGF-2.

FGF-2 has been implicated in the cardiac response to hypertrophic stimuli. Angiotensin II (Ang II) contributes to maintain elevated blood pressure in hypertensive individuals and exerts direct trophic effects on cardiac cells. However, the role of FGF-2 in Ang II-induced cardiac hypertrophy has not been established. Therefore, mice deficient in FGF-2 expression were studied using a model of Ang II-dependent hypertension and cardiac hypertrophy. Echocardiographic measurements show the presence of dilated cardiomyopathy in normotensive mice lacking FGF-2. Moreover, hypertensive mice without FGF-2 developed no compensatory cardiac hypertrophy. In wild-type mice, hypertrophy was associated with a stimulation of the c-Jun N-terminal kinase, the extracellular signal regulated kinase, and the p38 kinase pathways. In contrast, mitogen-activated protein kinase (MAPK) activation was markedly attenuated in FGF-2-deficient mice. In vitro, FGF-2 of fibroblast origin was demonstrated to be essential in the paracrine stimulation of MAPK activation in cardiomyocytes. Indeed, fibroblasts lacking FGF-2 expression have a defective capacity for releasing growth factors to induce hypertrophic responses in cardiomyocytes. Therefore, these results identify the cardiac fibroblast population as a primary integrator of hypertrophic stimuli in the heart, and suggest that FGF-2 is a crucial mediator of cardiac hypertrophy via autocrine/paracrine actions on cardiac cells.