“The potential role of CXCR4 and SDF-1 as indicators of tumor aggressiviness in patients with conventional papillary thyroid carcinoma”

Background: Functional chemokine receptors are expressed in many malignant tumors, including papillary thyroid carcinoma (PTC). These receptors promote tumor growth and metastasis in response to endogenous chemokines. The purpose of this study was to examine the expression of SDF-1 and its chemokine receptors, CXCR4, in a series of PTCs, considered as low risk for tumor size and hystotypes. In this study, we correlated CXCR4 and SDF-1 with indicators of clinical and tumor aggressiveness, including age, gender, tumor size, extrathyroidal extension, multifocality and lymph node metastasis. Methods: CXCR4 as well as its specific chemokine ligand, SDF-1 , were assessed in 48 PTCs using a semiquantitative measure of immunohistochemical (IHC) staining intensity for each molecule. Staining intensity was compared with clinicopathological features. Expression in CXCR4 and SDF-1 mRNA levels were sought in a subset of tumors, using gene microarrays and quantitative RTPCR. Results: In 29 cases, the PTC was associated with chronic thyroiditis. High-intensity IHC staining for CXCR4 correleted with T1 (p=0.003), classical variant (p=0.02) and lymph node metastasis at initial diagnosis (p=0.01). In contrast SDF 1 correlated with female gender (p =0.05), but this association was not shown following multivariate analyses. Conclusion: In our study, the expression of CXCR4 and its ligand are more frequent in tumors that have a smaller dimension and a classical variant of PTC. Therefore, CXCR4 and its ligand are associated with lymph node metastasis involvement at the initial diagnosis, which is an indicator of negative prognosis. Finally, the chemokine pathways may be expressed early in PTC tumorigenesis. Although these markers are found in a less aggressive PTC variant, they may be responsible for early and preferential lymphnode neck metastases. Further studies are necessary to define the mechanisms underlying this association and to determine its potential prognostic and therapeutic implications

Folic acid-layered double hydroxides hybrids in skin formulations: Technological, photochemical and in vitro cytotoxicity on human keratinocytes and fibroblasts

Abstract Folic acid (FA) is a key factor in the physiological processes of cell metabolism; as it is involved in DNA synthesis and repair, it can be used in the treatment of aged and photo-damaged skin. The main drawbacks associated to FA use, particularly for topical applications, are the limited solubility and the sensitivity to UV rays. Hybrids of FA with two kinds of layered double hydroxides (ZnAl-LDH and MgAl-LDH) were prepared and characterized showing suitable particle size, flow properties and UV photoprotection. The introduction of FA-LDHs in the external water phase of O/W emulgels produced an enhancement of their flow properties; moreover, the spectrophotometric analyses showed that very good photostability is maintained even after their introduction into the formulations. In-vitro release studies showed that the FA-LDH containing emulgels promoted a sustained FA release as expected. Finally, the safety of FA-LDH was evaluated by in-vitro studies performed on human keratinocytes (HaCaT) and human primary dermal fibroblasts (as a skin representative). The obtained results showed a high cytotoxic effect of ZnAl-LDH-FA in both cell lines

Endothelial-mediated coronary flow reserve in patients with mild thyroid hormone deficiency

ContextAlthough coronary flow reserve (CFR) is reduced in patients with subclinical hypothyroidism (SHypo), the endothelial response of coronary vasomotion has never been explored in this clinical setting.ObjectiveTo investigate the endothelial response of coronary flow in young and middle-aged patients with SHypo, without associated cardiovascular risk factors compared with healthy control subjects.Patients and methodsThe study population consisted of 20 women (mean age 38.4+12.1 years) with newly diagnosed, untreated and persistent SHypo due to Hashimoto's thyroiditis. A total of 15 volunteers served as controls. Age, gender, body surface area, glucose, insulin levels, heart rate, systolic, diastolic, and mean blood pressure were similar in patients and controls. Body mass index was significantly higher in SHypo patients. Total cholesterol and low-density lipoprotein cholesterol, despite not significant, tended to be higher, and high-density lipoprotein cholesterol to be lower in SHypo. Coronary blood flow velocities were recorded in patients at rest and after the cold pressor test (CPT), a stimulus that can be considered totally endothelium-dependent. CFR was calculated as the ratio of hyperemic-to-resting diastolic peak velocities.ResultsCoronary diastolic peak velocities at rest did not differ between the two groups but were significantly lower after CPT in patients with SHypo, thereby resulting in a lower CFR. The difference remained significant after adjusting resting and CPT velocities for the respective mean blood pressures. TSH was inversely correlated with CFR in the pooled population.ConclusionPatients with SHypo without associated cardiovascular risk factors have a coronary endothelial dysfunction that appears in response to a physiological stimulus (the CPT)

Minimal Extrathyroidal Extension in Predicting 1-Year Outcomes: A Longitudinal Multicenter Study of Low-to-Intermediate-Risk Papillary Thyroid Carcinoma (ITCO#4)

Background: The role of minimal extrathyroidal extension (mETE) as a risk factor for persistent papillary thyroid carcinoma (PTC) is still debated. The aim of this study was to assess the clinical impact of mETE as a predictor of worse initial treatment response in PTC patients and to verify the impact of radioiodine therapy after surgery in patients with mETE. Methods: We reviewed all records in the Italian Thyroid Cancer Observatory (ITCO) database and selected 2237 consecutive patients with PTC who satisfied the inclusion criteria (PTC with no lymph node metastases and at least 1 year of follow-up). For each case, we considered initial surgery, histological variant of PTC, tumor diameter, recurrence risk class according to the American Thyroid Association (ATA) risk stratification system, use of radioiodine therapy, and initial therapy response, as suggested by ATA guidelines. Results: At 1-year follow-up, 1831 patients (81.8%) had an excellent response, 296 (13.2%) had an indeterminate response, 55 (2.5%) had a biochemical incomplete response, and 55 (2.5%) had a structural incomplete response. Statistical analysis suggested that mETE (odds ratio [OR] 1.16, p=0.65), tumor size >2 cm (OR 1.45, p=0.34), aggressive PTC histology (OR 0.55, p=0.15), and age at diagnosis (OR 0.90, p=0.32) were not significant risk factors for a worse initial therapy response. When evaluating the combination of mETE, tumor size, and aggressive PTC histology, the presence of mETE with a >2 cm tumor was significantly associated with a worse outcome (OR 5.27, 95% CI, p=0.014). The role of radioiodine ablation in patients with mETE was also evaluated. When considering radioiodine treatment, propensity score-based matching was performed, and no significant differences were found between treated and non-treated patients (p=0.24). Conclusions: This study failed to show the prognostic value of mETE in predicting initial therapy response in a large cohort of PTC patients without lymph node metastases. The study suggests that the combination of tumor diameter and mETE can be used as a reliable prognostic factor for persistence and could be easily applied in clinical practice to manage PTC patients with low-to-intermediate risk of recurrent/persistent disease

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio

Stellar parameters of early-M dwarfs from ratios of spectral features at optical wavelengths

Context. Low-mass stars have been recognised as promising targets in the search for rocky, small planets with the potential of supporting life. As a consequence, Doppler search programmes using high-resolution spectrographs like HARPS or HARPS-N are providing huge quantities of optical spectra of M dwarfs. However, determining the stellar parameters of M dwarfs using optical spectra has proven to be challenging. Aims: We aim to calibrate empirical relationships to determine accurate stellar parameters for early-M dwarfs (spectral types M0-M4.5) using the same spectra as those that are used for radial velocity determinations, without the necessity of acquiring IR spectra or relying on atmospheric models and/or photometric calibrations. Methods: Our methodology consists of using ratios of pseudo-equivalent widths of spectral features as a temperature diagnostic, a technique frequently used in solar-type stars. Stars with effective temperatures obtained from interferometric estimates of their radii are used as calibrators. Empirical calibrations for the spectral type are also provided. Combinations of features and ratios of features are used to derive calibrations for the stellar metallicity. Our methods are then applied to a large sample of M dwarfs that are currently being observed in the framework of the HARPS GTO search for extrasolar planets. The derived temperatures and metallicities are used together with photometric estimates of mass, radius, and surface gravity to calibrate empirical relationships for these parameters. Results: A long list of spectral features in the optical spectra of early-M dwarfs was identified. This list shows that the pseudo-equivalent width of roughly 43% of the features is strongly anticorrelated with the effective temperature. The correlation with the stellar metallicity is weaker. A total of 112 temperature sensitive ratios were identified and calibrated over the range 3100-3950 K, providing effective temperatures with typical uncertainties of about 70 K. Eighty-two ratios of pseudo-equivalent widths of features were calibrated to derive spectral types within 0.5 subtypes for stars with spectral types between K7V and M4.5V. We calibrated 696 combinations of the pseudo-equivalent widths of individual features and temperature-sensitive ratios for the stellar metallicity over a metallicity range from -0.54 to +0.24 dex, with estimated uncertainties in the range of 0.07-0.10 dex. We provide our own empirical calibrations for stellar mass, radius, and surface gravity. These parameters depend on the stellar metallicity. For a given effective temperature, lower metallicities predict lower masses and radii as well as higher gravities. Based on data products from observations made with ESO Telescopes at the La Silla Paranal Observatory under programmes ID 072.C-0488(E), 082.C-0718(B), 085.C-0019(A), 180.C-0886(A), 183.C-0437(A), and 191.C-0505(A), as well as data from the Italian Telescopio Nazionale Galileo (TNG) Archive (programmes ID CAT-147, and A27CAT_83).Our computational codes including the full version of Tables 2, 4, and 6 are only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/577/A132Appendix A is available in electronic form at http://www.aanda.org</A

Epigenetic suppression of FBXL7 promotes metastasis

Epigenetic reprogramming is emerging as a key mechanism for metastasis development. Our study identified a novel regulatory mechanism whereby promoter methylation-mediated epigenetic silencing of the gene encoding the ubiquitin ligase subunit F-box/LRR-repeat protein 7 (FBXL7) induces accumulation of active c-SRC, which, in turn, activates epithelial-to-mesenchymal transition and supports cancer cell invasion and metastasis

The pattern of TSH and fT4 levels across different BMI ranges in a large cohort of euthyroid patients with obesity

PurposeA multifold association relates the hypothalamo-pituitary-thyroid axis to body weight. The potential underlying mechanisms are incompletely understood. Further, the mild severity of obesity and the small proportion of individuals with obesity in so far published cohort studies provide little insights on metabolic correlates of thyroid function in obesity. MethodsWe retrospectively enrolled 5009 adults with obesity (F/M, 3448/1561; age range, 18-87 years; BMI range, 30.0-82.7 kg/m(2)), without known thyroid disease in a study on TSH and fT4 levels, lipid profile, glucose homeostasis and insulin resistance, anthropometric parameters including BIA-derived fat mass (%FM) and fat-free mass (FFM). ResultsThe overall reference interval for TSH in our obese cohort was 0.58-5.07 mIU/L. As subgroups, females and non-smokers showed higher TSH levels as compared to their counterparts (p<0.0001 for both), while fT4 values were comparable between groups. There was a significant upward trend for TSH levels across incremental BMI classes in females, while the opposite trend was seen for fT4 levels in males (p<0.0001 for both). Expectedly, TSH was associated with %FM and FFM (p<0,0001 for both). TSH and fT4 showed correlations with several metabolic variables, and both declined with aging (TSH, p<0.0001; fT4, p<0.01). In a subgroup undergoing leptin measurement, leptin levels were positively associated with TSH levels (p<0.01). At the multivariable regression analysis, in the group as a whole, smoking habit emerged as the main independent predictor of TSH (beta=-0.24, p<0.0001) and fT4 (beta=-0.25, p<0.0001) levels. In non-smokers, %FM (beta=0.08, p<0.0001) and age (beta=-0.05, p<0.001) were the main significant predictors of TSH levels. In the subset of nonsmokers having leptin measured, leptin emerged as the strongest predictor of TSH levels (beta=0.17, p<0.01). ConclusionsOur study provides evidence of a gender- and smoking-dependent regulation of TSH levels in obesity