The Long and Short of MicroRNA Yates, Luke A.; Norbury, Chris J.; Gilbert, Robert J.C.
Cell,
04/2013, Letnik:
153, Številka:
3
Journal Article
Recenzirano
Odprti dostop
MicroRNAs (miRNAs) are versatile regulators of gene expression in higher eukaryotes. In order to silence many different mRNAs in a precise manner, miRNA stability and efficacy is controlled by highly ...developed regulatory pathways and fine-tuning mechanisms both affecting miRNA processing and altering mature miRNA target specificity.
Homologous recombination repair deficiency (HRD) is a frequent feature of high-grade serous ovarian, fallopian tube and peritoneal carcinoma (HGSC) and is associated with sensitivity to PARP ...inhibitor (PARPi) therapy. HRD testing provides an opportunity to optimise PARPi use in HGSC but methodologies are diverse and clinical application remains controversial.
To define best practice for HRD testing in HGSC the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project that incorporated a systematic review approach. The main aims were to (i) define the term ‘HRD test’; (ii) provide an overview of the biological rationale and the level of evidence supporting currently available HRD tests; (iii) provide recommendations on the clinical utility of HRD tests in clinical management of HGSC.
A broad range of repair genes, genomic scars, mutational signatures and functional assays are associated with a history of HRD. Currently, the clinical validity of HRD tests in ovarian cancer is best assessed, not in terms of biological HRD status per se, but in terms of PARPi benefit. Clinical trials evidence supports the use of BRCA mutation testing and two commercially available assays that also incorporate genomic instability for identifying subgroups of HGSCs that derive different magnitudes of benefit from PARPi therapy, albeit with some variation by clinical scenario. These tests can be used to inform treatment selection and scheduling but their use is limited by a failure to consistently identify a subgroup of patients who derive no benefit from PARPis in most studies. Existing tests lack negative predictive value and inadequately address the complex and dynamic nature of the HRD phenotype.
Currently available HRD tests are useful for predicting likely magnitude of benefit from PARPis but better biomarkers are urgently needed to better identify current homologous recombination proficiency status and stratify HGSC management.
•Homologous recombination repair deficiency (HRD) is a common feature of high-grade serous gynaecological cancers (HGSC).•Currently, the clinical validity of HRD tests in ovarian cancer is best assessed in terms of PARPi benefit.•Germline and somatic BRCA mutation and genomic instability tests help to predict likely magnitude of benefit from a PARPi.•Existing HRD tests fail to consistently identify a subgroup of patients who derive no benefit from PARPis in most studies.•HRD is a dynamic entity and better biomarkers that capture current homologous recombination proficiency status are needed.
Seascape ecology, the marine-centric counterpart to landscape ecology, is rapidly emerging as an interdisciplinary and spatially explicit ecological science with relevance to marine management, ...biodiversity conservation, and restoration. While important progress in this field has been made in the past decade, there has been no coherent prioritisation of key research questions to help set the future research agenda for seascape ecology. We used a 2-stage modified Delphi method to solicit applied research questions from academic experts in seascape ecology and then asked respondents to identify priority questions across 9 interrelated research themes using 2 rounds of selection. We also invited senior management/conservation practitioners to prioritise the same research questions. Analyses highlighted congruence and discrepancies in perceived priorities for applied research. Themes related to both ecological concepts and management practice, and those identified as priorities include seascape change, seascape connectivity, spatial and temporal scale, ecosystem-based management, and emerging technologies and metrics. Highest-priority questions (upper tercile) received 50% agreement between respondent groups, and lowest priorities (lower tercile) received 58% agreement. Across all 3 priority tiers, 36 of the 55 questions were within a ±10% band of agreement. We present the most important applied research questions as determined by the proportion of votes received. For each theme, we provide a synthesis of the research challenges and the potential role of seascape ecology. These priority questions and themes serve as a roadmap for advancing applied seascape ecology during, and beyond, the UN Decade of Ocean Science for Sustainable Development (2021-2030).
Aims. Future astrophysics and cosmic microwave background space missions operating in the far-infrared to millimetre part of the spectrum will require very large arrays of ultra-sensitive detectors ...in combination with high multiplexing factors and efficient low-noise and low-power readout systems. We have developed a demonstrator system suitable for such applications. Methods. The system combines a 961 pixel imaging array based upon Microwave Kinetic Inductance Detectors (MKIDs) with a readout system capable of reading out all pixels simultaneously with only one readout cable pair and a single cryogenic amplifier. We evaluate, in a representative environment, the system performance in terms of sensitivity, dynamic range, optical efficiency, cosmic ray rejection, pixel-pixel crosstalk and overall yield at an observation centre frequency of 850 GHz and 20% fractional bandwidth. Results. The overall system has an excellent sensitivity, with an average detector sensitivity \hbox{$\mathrm{\langle NEP_{det}\rangle =3\times10^{-19}\;\WHz}$}⟨NEPdet⟩=3×10-19W/Hz measured using a thermal calibration source. At a loading power per pixel of 50 fW we demonstrate white, photon noise limited detector noise down to 300 mHz. The dynamic range would allow the detection of ~1 Jy bright sources within the field of view without tuning the readout of the detectors. The expected dead time due to cosmic ray interactions, when operated in an L2 or a similar far-Earth orbit, is found to be <4%. Additionally, the achieved pixel yield is 83% and the crosstalk between the pixels is <−30 dB. Conclusions. This demonstrates that MKID technology can provide multiplexing ratios on the order of a 1000 with state-of-the-art single pixel performance, and that the technology is now mature enough to be considered for future space based observatories and experiments.
Little is known about adherence to inhaled medication in chronic obstructive pulmonary disease (COPD) and the impact on mortality and morbidity.
Data on drug adherence from a randomised double-blind ...trial comparing inhaled salmeterol 50 microg + fluticasone propionate 500 microg twice daily with placebo and each drug individually in 6112 patients with moderate to severe COPD over 3 years in the TORCH study were used. All-cause mortality and exacerbations leading to hospital admission were primary and secondary end points. The study of adherence was not specified a priori as an ancillary study.
Of the 4880 patients (79.8%) with good adherence defined as >80% use of study medication, 11.3% died compared with 26.4% of the 1232 patients (20.2%) with poor adherence. The annual rates of hospital admission for exacerbations were 0.15 and 0.27, respectively. The association between adherence and mortality remained unchanged and statistically significant after adjusting for other factors related to prognosis (hazard ratio 0.40 (95% CI 0.35 to 0.46), p<0.001). The association was even stronger when analysing on-treatment deaths only. Similarly, the association between adherence and hospital admission remained unchanged and significant in a multivariate analysis (rate ratio 0.58 (95% CI 0.44 to 0.73, p<0.001). The association between increased adherence and improved mortality and reduction in hospital admission was independent of study treatment. The effect of treatment was more pronounced in patients with good adherence than in those with poor adherence.
Adherence to inhaled medication is significantly associated with reduced risk of death and admission to hospital due to exacerbations in COPD. Further research is needed to understand these strong associations.
Inhaled corticosteroids (ICS) are important in reducing exacerbation frequency associated with chronic obstructive pulmonary disease (COPD). However, little is known about the risk of associated ...infections. In a post hoc analysis of the TOwards a Revolution in COPD Health (TORCH) study, we analysed and identified potential risk factors for adverse event reports of pneumonia in this randomised, double-blind trial comparing twice-daily inhaled salmeterol (SAL) 50 microg, fluticasone propionate (FP) 500 microg, and the combination (SFC) with placebo in 6,184 patients with moderate-to-severe COPD over 3 yrs. Despite a higher withdrawal rate in the placebo arm, after adjusting for time on treatment, a greater rate of pneumonia was reported in the FP and SFC treatment arms (84 and 88 per 1,000 treatment-yrs, respectively) compared with SAL and placebo (52 and 52 per 1,000 treatment-yrs, respectively). Risk factors for pneumonia were age > or =55 yrs, forced expiratory volume in 1 s <50% predicted, COPD exacerbations in the year prior to the study, worse Medical Research Council dyspnoea scores and body mass index <25 kg.m(-2). No increase in pneumonia deaths with SFC was observed; this could not be concluded for FP. Despite the benefits of ICS-containing regimens in COPD management, healthcare providers should remain vigilant regarding the possible development of pneumonia as a complication in COPD patients receiving such therapies.
We have directly measured quasiparticle number fluctuations in a thin film superconducting Al resonator in thermal equilibrium. The spectrum of these fluctuations provides a measure of both the ...density and the lifetime of the quasiparticles. We observe that the quasiparticle density decreases exponentially with decreasing temperature, as theoretically predicted, but saturates below 160 mK to 25-55/μm(3). We show that this saturation is consistent with the measured saturation in the quasiparticle lifetime, which also explains similar observations in qubit decoherence times.
We investigated the impact of season relative to other determinants of chronic obstructive pulmonary disease (COPD) exacerbation frequency in a long-term international study of patients with forced ...expiratory volume in 1 s (FEV(1)) <60% predicted. COPD exacerbations were defined by worsening symptoms requiring systemic corticosteroids and/or antibiotics (moderate) or hospital admission (severe). Seasonality effect was calculated as the proportion of patients experiencing an exacerbation each month. Exacerbations in the northern and southern regions showed an almost two-fold increase in the winter months. No seasonal pattern occurred in the tropics. Overall, 38% of exacerbations were treated with antibiotics only, 19% with systemic corticosteroids only and 43% with both, while 20% required hospital admission irrespective of the season. Exacerbation frequency was associated with older age, lower body mass index, lower FEV(1) % pred and history of prior exacerbations. Females and patients with worse baseline breathlessness, assessed using the Medical Research Council (MRC) dyspnoea scale, exacerbated more often (rate ratio (RR) for male versus female 0.7, 95% CI 0.7-0.8 (p<0.001); RR for MRC dyspnoea score 3 versus 1 and 2 combined 1.1, 95% CI 1.1-1.2 (p<0.001)). The effect of season was independent of these risk factors. COPD exacerbations and hospitalisations were more frequent in winter.
A variant on complement factor 3 is associated with age-related macular degeneration, with a population attributable risk of 22%. This finding underlines the importance of complement activation in ...the pathogenesis of the disease.
A variant on complement factor 3 is associated with age-related macular degeneration, with a population attributable risk of 22%.
Age-related macular degeneration is the leading cause of visual impairment in the elderly and the most common cause of blindness in Western countries.
1
It affects the macular region of the retina. The macula has a high density of photoreceptors and provides detailed central vision. In the early stages of the disease (referred to as age-related maculopathy), deposits called drusen develop between the retinal pigment epithelium and underlying choroid.
1
Later, the disease is manifested as either extensive atrophy of the retinal pigment epithelium and overlying photoreceptor cells (geographic atrophy) or aberrant choroidal angiogenesis (choroidal neovascularization).
1
Both of these conditions can lead . . .
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