Detection and analysis of tumour biomarkers to strengthen the diagnosis of acute and chronic leukaemias

AbstractMolecular markers in leukaemia are essential to diagnose, establish prognosis factors and determine the correct treatment of patients; therefore, it is imperative to include molecular biology studies, so that, combined with cytomorphology and immunophenotyping studies, they constitute the differential diagnosis of these neoplasias. It is extremely important to implement a panel of molecular markers that allows us to detect oncogenes derived from chromosomal translocations, genes derived from epigenetic alterations and drug-resistant genes.A panel of molecular markers that included 11 genes derived from chromosomal translocations BCR-ABL major and minor breakpoints, E2A-PBX1, MLL-AF4, TEL-AML1, PML-RARα, AML1-ETO was standardised; cancer testis antigens (CTA) derived from NY-ESO1 and MAGE-A3 epigenetic alterations and multi-drug-resistant genes ABCB1 and ABCG2. 30 patients diagnosed with leukaemia from Mexico's General Hospital (Hospital General de Mexico) were included. They suffered from acute lymphoblastic leukaemia (ALL) and acute myeloblastic leukaemia (AML); bone marrow mononuclear cells were used, from which RNA was extracted for the synthesis of cDNA and RT-PCR for each of the markers. In acute lymphoblastic leukaemia (ALL), BCR-ABL biomarkers expressed under 30% (3/10), E2A-PBX1 10% (1/10), ABC-B1 80% (8/10), and ABC-G2 60% (6/10). Patients with acute myeloblastic leukaemia (AML) expressed 30% PML-RARα (3/10), 40% ABC-B1 (4/10), and 10% ABC-G2 (1/10). Lastly, in patients with chronic myeloid leukaemia (CML), BCR-ABL was over 100% (10/10), ABC-B1 20% (2/10), and ABC-G2 50% (5/10). The presence of transcripts from chimeric genes minor BCR-ABL and E2A-PBX1 in ALL; PML-RARα in AML; and major BCR-ABL in CML, confirms the importance that the panel of molecular markers has in strengthening the diagnosis and prognosis of these conditions

<i>Gaia</i> Data Release 1. Summary of the astrometric, photometric, and survey properties

Context. At about 1000 days after the launch of Gaia we present the first Gaia data release, Gaia DR1, consisting of astrometry and photometry for over 1 billion sources brighter than magnitude 20.7. Aims. A summary of Gaia DR1 is presented along with illustrations of the scientific quality of the data, followed by a discussion of the limitations due to the preliminary nature of this release. Methods. The raw data collected by Gaia during the first 14 months of the mission have been processed by the Gaia Data Processing and Analysis Consortium (DPAC) and turned into an astrometric and photometric catalogue. Results. Gaia DR1 consists of three components: a primary astrometric data set which contains the positions, parallaxes, and mean proper motions for about 2 million of the brightest stars in common with the HIPPARCOS and Tycho-2 catalogues – a realisation of the Tycho-Gaia Astrometric Solution (TGAS) – and a secondary astrometric data set containing the positions for an additional 1.1 billion sources. The second component is the photometric data set, consisting of mean G-band magnitudes for all sources. The G-band light curves and the characteristics of ∼3000 Cepheid and RR-Lyrae stars, observed at high cadence around the south ecliptic pole, form the third component. For the primary astrometric data set the typical uncertainty is about 0.3 mas for the positions and parallaxes, and about 1 mas yr−1 for the proper motions. A systematic component of ∼0.3 mas should be added to the parallax uncertainties. For the subset of ∼94 000 HIPPARCOS stars in the primary data set, the proper motions are much more precise at about 0.06 mas yr−1. For the secondary astrometric data set, the typical uncertainty of the positions is ∼10 mas. The median uncertainties on the mean G-band magnitudes range from the mmag level to ∼0.03 mag over the magnitude range 5 to 20.7. Conclusions. Gaia DR1 is an important milestone ahead of the next Gaia data release, which will feature five-parameter astrometry for all sources. Extensive validation shows that Gaia DR1 represents a major advance in the mapping of the heavens and the availability of basic stellar data that underpin observational astrophysics. Nevertheless, the very preliminary nature of this first Gaia data release does lead to a number of important limitations to the data quality which should be carefully considered before drawing conclusions from the data

Differential expression of genes in follicular cells of swines

The main purpose of the present study was to identify for candidate genes related to ovulation in swines. To do so, it was investigated in ovarian follicular cells through quantitative real-time PCR the differential expression of the following genes: steroidogenic acute regulator (STAR), GATA-binding protein 4 (GATA), prostaglandin F2&#945; (PGF2&#945;), progesterone receptor (P4R), follicle-stimulating hormone receptor (FSHR), and cytochrome P450 aromatase (CYP19). These genes encode hormone receptors (FSHR and P4R), hormone (PGF2&#945;), steroidogenic proteins (STAR and CYP19) and transcription factor (GATA). Folicular cells were collected from sows with high and low number of piglets/litters during the follicular phase of the estrus cycle. There was difference in transcript abundance among low and high prolific sows for the STAR, GATA, PGF2&#945;, P4R and CYP19 genes. For the FSHR gene, the fold change was not considered to be significantly different. Because in the present study only the transcript level of the above mentioned genes was analyzed, no inference can be made regarded to protein translation or activity. Therefore, gene sequence trials and other functional studies will be necessary to complement the present results, allowing a better understanding on biological complexity of these genes and their use as markers for prolificity in swines.O objetivo neste trabalho foi identificar genes candidatos relacionados à ovulação em suínos. Para tanto, investigou-se a expressão diferencial dos genes STAR (steroidogenic acute regulator), GATA (GATA-binding protein 4), PGF2&#945; (prostaglandin F2&#945;), P4R (progesterone receptor), FSHR (follicle-stimulating hormone receptor) e CYP19 (cytochrome P450 aromatase) em células foliculares ovarianas por meio de reação em cadeia da polimerase em tempo real (qRT-PCR) quantitativo em tempo real. Esses genes codificam para receptores hormonais (FSHR e P4R) hormônio (PGF2&#945;), proteínas esteroidogênicas (STAR e CYP19) e fator de transcrição (GATA). As células foliculares foram coletadas durante a fase folicular do ciclo estral de porcas com alto e baixo número de leitões/leitegada. Houve diferença na abundância de transcritos entre porcas com alta e baixa prolificidade para os genes STAR, GATA, PGF2&#945;, P4R and CYP19. Para o gene do FSHR, a alteração na abundância dos transcritos não foi significativamente diferente. Considerando que foi analisado somente o nível de transcrição desses genes mencionados, não se pode fazer inferências com relação à tradução ou atividade proteica. Portanto, ensaios de sequenciamento gênico e outras análises funcionais serão necessários para complementar esses achados e possibilitar melhor entendimento da complexidade biológica desses genes e seu uso como marcadores para prolificidade em suínos

Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study

Background: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. Methods: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. Findings: We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2–11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75–1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58–1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91–1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70–1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11–0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50–0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38–0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45–0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. Interpretation: Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. Funding: Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health

Epigenetics and developmental programming of welfare and production traits in farm animals

The concept that postnatal health and development can be influenced by events that occur in utero originated from epidemiological studies in humans supported by numerous mechanistic (including epigenetic) studies in a variety of model species. Referred to as the ‘developmental origins of health and disease’ or ‘DOHaD’ hypothesis, the primary focus of large-animal studies until quite recently had been biomedical. Attention has since turned towards traits of commercial importance in farm animals. Herein we review the evidence that prenatal risk factors, including suboptimal parental nutrition, gestational stress, exposure to environmental chemicals and advanced breeding technologies, can determine traits such as postnatal growth, feed efficiency, milk yield, carcass composition, animal welfare and reproductive potential. We consider the role of epigenetic and cytoplasmic mechanisms of inheritance, and discuss implications for livestock production and future research endeavours. We conclude that although the concept is proven for several traits, issues relating to effect size, and hence commercial importance, remain. Studies have also invariably been conducted under controlled experimental conditions, frequently assessing single risk factors, thereby limiting their translational value for livestock production. We propose concerted international research efforts that consider multiple, concurrent stressors to better represent effects of contemporary animal production systems

Gaia Data Release 1: Testing parallaxes with local Cepheids and RR Lyrae stars

Context. Parallaxes for 331 classical Cepheids, 31 Type II Cepheids, and 364 RR Lyrae stars in common between Gaia and the Hipparcos and Tycho-2 catalogues are published in Gaia Data Release 1 (DR1) as part of the Tycho-Gaia Astrometric Solution (TGAS). Aims. In order to test these first parallax measurements of the primary standard candles of the cosmological distance ladder, which involve astrometry collected by Gaia during the initial 14 months of science operation, we compared them with literature estimates and derived new period-luminosity (PL), period-Wesenheit (PW) relations for classical and Type II Cepheids and infrared PL, PL-metallicity (PLZ), and optical luminosity-metallicity (M V -[Fe/H]) relations for the RR Lyrae stars, with zero points based on TGAS. Methods. Classical Cepheids were carefully selected in order to discard known or suspected binary systems. The final sample comprises 102 fundamental mode pulsators with periods ranging from 1.68 to 51.66 days (of which 33 with σ Ω /Ω < 0.5). The Type II Cepheids include a total of 26 W Virginis and BL Herculis stars spanning the period range from 1.16 to 30.00 days (of which only 7 with σ Ω /Ω < 0.5). The RR Lyrae stars include 200 sources with pulsation period ranging from 0.27 to 0.80 days (of which 112 with σ Ω /Ω < 0.5). The new relations were computed using multi-band (V,I,J,K s ) photometry and spectroscopic metal abundances available in the literature, and by applying three alternative approaches: (i) linear least-squares fitting of the absolute magnitudes inferred from direct transformation of the TGAS parallaxes; (ii) adopting astrometry-based luminosities; and (iii) using a Bayesian fitting approach. The last two methods work in parallax space where parallaxes are used directly, thus maintaining symmetrical errors and allowing negative parallaxes to be used. The TGAS-based PL,PW,PLZ, and M V - [Fe/H] relations are discussed by comparing the distance to the Large Magellanic Cloud provided by different types of pulsating stars and alternative fitting methods. Results. Good agreement is found from direct comparison of the parallaxes of RR Lyrae stars for which both TGAS and HST measurements are available. Similarly, very good agreement is found between the TGAS values and the parallaxes inferred from the absolute magnitudes of Cepheids and RR Lyrae stars analysed with the Baade-Wesselink method. TGAS values also compare favourably with the parallaxes inferred by theoretical model fitting of the multi-band light curves for two of the three classical Cepheids and one RR Lyrae star, which were analysed with this technique in our samples. The K-band PL relations show the significant improvement of the TGAS parallaxes for Cepheids and RR Lyrae stars with respect to the Hipparcos measurements. This is particularly true for the RR Lyrae stars for which improvement in quality and statistics is impressive. Conclusions. TGAS parallaxes bring a significant added value to the previous Hipparcos estimates. The relations presented in this paper represent the first Gaia-calibrated relations and form a work-in-progress milestone report in the wait for Gaia-only parallaxes of which a first solution will become available with Gaia Data Release 2 (DR2) in 2018. © ESO, 2017

A LOFAR census of non-recycled pulsars: average profiles, dispersion measures, flux densities, and spectra

We present first results from a LOFAR census of non-recycled pulsars. The census includes almost all such pulsars known (194 sources) at declinations Dec > 8 and Galactic latitudes jGbj > 3, regardless of their expected flux densities and scattering times. Each pulsar was observed for 20 min in the contiguous frequency range of 110-188 MHz. Full-Stokes data were recorded. We present the dispersion measures, flux densities, and calibrated total intensity profiles for the 158 pulsars detected in the sample. The median uncertainty in census dispersion measures (1:5 × 10-3 pc cm-3) is ten times smaller, on average, than in the ATNF pulsar catalogue. We combined census flux densities with those in the literature and fitted the resulting broadband spectra with single or broken power-law functions. For 48 census pulsars such fits are being published for the first time. Typically, the choice between single and broken power-laws, as well as the location of the spectral break, were highly influenced by the spectral coverage of the available flux density measurements. In particular, the inclusion of measurements below 100MHz appears essential for investigating the lowfrequency turnover in the spectra for most of the census pulsars. For several pulsars, we compared the spectral indices from different works and found the typical spread of values to be within 0.5-1.5, suggesting a prevailing underestimation of spectral index errors in the literature. The census observations yielded some unexpected individual source results, as we describe in the paper. Lastly, we will provide this unique sample of wide-band, low-frequency pulse profiles via the European Pulsar Network Database

Gaia Data Release 1: Open cluster astrometry: performance, limitations, and future prospects

Context. The first Gaia Data Release contains the Tycho-Gaia Astrometric Solution (TGAS). This is a subset of about 2 million stars for which, besides the position and photometry, the proper motion and parallax are calculated using Hipparcos and Tycho-2 positions in 1991.25 as prior information.Aims. We investigate the scientific potential and limitations of the TGAS component by means of the astrometric data for open clusters.Methods. Mean cluster parallax and proper motion values are derived taking into account the error correlations within the astrometric solutions for individual stars, an estimate of the internal velocity dispersion in the cluster, and, where relevant, the effects of the depth of the cluster along the line of sight. Internal consistency of the TGAS data is assessed.Results. Values given for standard uncertainties are still inaccurate and may lead to unrealistic unit-weight standard deviations of least squares solutions for cluster parameters. Reconstructed mean cluster parallax and proper motion values are generally in very good agreement with earlier HIPPARCOS-based determination, although the Gaia mean parallax for the Pleiades is a significant exception. We have no current explanation for that discrepancy. Most clusters are observed to extend to nearly 15 pc from the cluster centre, and it will be up to future Gaia releases to establish whether those potential cluster-member stars are still dynamically bound to the clusters.Conclusions. The Gaia DR1 provides the means to examine open clusters far beyond their more easily visible cores, and can provide membership assessments based on proper motions and parallaxes. A combined HR diagram shows the same features as observed before using the HIPPARCOS data, with clearly increased luminosities for older A and F dwarfs