Phosphorothioate antisense oligonucleotides induce the formation of nuclear bodies

Antisense oligonucleotides are powerful tools for the in vivo regulation of gene expression. We have characterized the intracellular distribution of fluorescently tagged phosphorothioate oligodeoxynucleotides (PS-ONs) at high resolution under conditions in which PS-ONs have the potential to display antisense activity. Under these conditions PS-ONs predominantly localized to the cell nucleus where they accumulated in 20-30 bright spherical foci designated phosphorothioate bodies (PS bodies), which were set against a diffuse nucleoplasmic population excluding nucleoli. PS bodies are nuclear structures that formed in cells after PS-ON delivery by transfection agents or microinjection but were observed irrespectively of antisense activity or sequence. Ultrastructurally, PS bodies corresponded to electron-dense structures of 150-300 nm diameter and resembled nuclear bodies that were found with lower frequency in cells lacking PS-ONs. The environment of a living cell was required for the de novo formation of PS bodies, which occurred within minutes after the introduction of PS-ONs. PS bodies were stable entities that underwent noticeable reorganization only during mitosis. Upon exit from mitosis, PS bodies were assembled de novo from diffuse PS-ON pools in the daughter nuclei. In situ fractionation demonstrated an association of PS-ONs with the nuclear matrix. Taken together, our data provide evidence for the formation of a nuclear body in cells after introduction of phosphorothioate oligodeoxynucleotides

K2-140b - An eccentric 6.57 d transiting hot Jupiter in Virgo

We present the discovery of K2-140b, a P = 6.57 d Jupiter-mass (MP = 1.019 ± 0.070MJup) planet transiting a V = 12.5 (G5-spectral type) star in an eccentric orbit (e = 0.120-0.046 +0.056) detected using a combination of K2 photometry and ground-based observations. With a radius of 1.095 ± 0.018 RJup, the planet has a bulk density of 0.726 ± 0.062 ρJup. The host star has a [Fe/H] of 0.12 ± 0.045, and from the K2 light curve, we find a rotation period for the star of 16.3 ± 0.1 d. This discovery is the 9th hot Jupiter from K2 and highlights K2's ability to detect transiting giant planets at periods slightly longer than traditional, ground-based surveys. This planet is slightly inflated, but much less than others with similar incident fluxes. These are of interest for investigating the inflation mechanism of hot Jupiters

Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1

High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10−9) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10−8), with the alleles showing opposite effects on the risks of the two cancers

Use of SMS texts for facilitating access to online alcohol interventions: a feasibility study

A41 Use of SMS texts for facilitating access to online alcohol interventions: a feasibility study In: Addiction Science & Clinical Practice 2017, 12(Suppl 1): A4

Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

HD 213885b: A transiting 1-d-period super-Earth with an Earth-like composition around a bright (V = 7.9) star unveiled by TESS

We report the discovery of the 1.008-d, ultrashort period (USP) super-Earth HD 213885b (TOI-141b) orbiting the bright (V= 7.9) star HD 213885 (TOI-141, TIC 403224672), detected using photometry from the recently launched TESS mission. Using FEROS, HARPS, and CORALIE radial velocities, we measure a precise mass of 8.8 ±0.6M⊙ for this 1.74±0.05R⊙ exoplanet, which provides enough information to constrain its bulk composition - similar to Earth's but enriched in iron. The radius, mass, and stellar irradiation of HD 213885b are, given our data, very similar to 55 Cancri e, making this exoplanet a good target to perform comparative exoplanetology of short period, highly irradiated super-Earths. Our precise radial velocities reveal an additional 4.78-d signal which we interpret as arising from a second, non-transiting planet in the system, HD 213885c, whose minimum mass of 19.9 ± 1.4 M⊙ makes it consistent with being a Neptune-mass exoplanet. The HD 213885 system is very interesting from the perspective of future atmospheric characterization, being the second brightest star to host an USP transiting super-Earth (with the brightest star being, in fact, 55 Cancri). Prospects for characterization with present and future observatories are discussed

Data on the catalytic mechanism of thiol peroxidase mimics

We have recently reported SAR data describing the pharmacological activity of a series of phenyl alkyl selenides and tellurides which catalyse the oxidation of thiols by hydrogen peroxide (H2O2), “The design of redox active thiol peroxidase mimics: dihydrolipoic acid recognition correlates with cytotoxicity and prooxidant action” B. Zadehvakili, S.M. McNeill, J.P. Fawcett, G.I. Giles (2016) [1]. This thiol peroxidase (TPx) activity is potentially useful for a number of therapeutic applications, as it can alter the outcome of oxidative stress related pathologies and modify redox signalling. This article presents data describing the molecular changes that occur to a TPx mimic upon exposure to H2O2, and then the thiol mercaptoethanol, as characterised by UV–vis spectroscopy and HPLC retention time

Mercury(II) mediated cyclisation of R-1-(1′-hydroxyethyl)-2-(1″-propenyl)-3-alkoxy-4-methoxybenzenes to chiral isochromanes

A protocol has been established for the transformation of chiral ortho 1-hydroxyethyl propenyl benzenes under both anaerobic and oxidative mercury(II) mediated conditions to produce chiral isochromanes. Further transformations of the former products yielded chiral isochromanquinones, while the latter afforded the corresponding chiral 4-hydroxyisochromanquinones