Inhibition of Cardiac Hypertrophy by Triflusal (4-Trifluoromethyl Derivative of Salicylate) and Its Active Metabolite

ABSTRACT The nuclear factor (NF)-B signaling pathway is an important intracellular mediator of cardiac hypertrophy. The aim of the present study was to determine whether triflusal (2-acetoxy-4-trifluoromethylbenzoic acid), a salicylate derivative used as antiplatelet agent, and its active metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) inhibit cardiac hypertrophy in vitro and in vivo by blocking the NF-B signaling pathway. In cultured neonatal rat cardiomyocytes, HTB (300 M, a concentration reached in clinical use) inhibited phenylephrine (PE)-induced protein synthesis ([ 3 H]leucine uptake), induction of the fetal-type gene atrial natriuretic factor (ANF), and sarcomeric disorganization. Assessment of the effects of triflusal in pressure overload-induced cardiac hypertrophy by aortic banding resulted in a significant reduction in the ratio of heart weight to body weight and in a reduction of the mRNA levels of the cardiac hypertrophy markers ANF and ␣-actinin compared with untreated banded rats. Electrophoretic mobility shift assay revealed an increase in the NF-B binding activity in cardiac nuclear extracts of banded rats that was prevented by triflusal treatment. It is noteworthy that banded rats treated with oral triflusal, compared with untreated rats, showed enhanced protein levels of IB␣, which forms a cytoplasmic inactive complex with the p65-p50 heterodimeric complex. Finally, HTB increased phospho-IB␣ levels in neonatal cardiomyocytes and inhibited proteosome activity, suggesting that this drug prevented proteosome-mediated degradation of IB␣. These results indicate that triflusal, a drug with a well characterized pharmacological and safety profile currently used as antiplatelet, inhibits cardiomyocyte growth by interfering with the NF-B signaling pathway through a post-transcriptional mechanism involving reduced-proteosome degradation of IB␣. Cardiac hypertrophy is a response of the heart to a wide range of extrinsic stimuli, such as arterial hypertension, valvular heart disease, myocardial infarction, and cardiomyopathy. Although this process is initially compensatory for an increase workload, its prolongation frequently results in congestive heart failure, arrhythmia, and sudden deat

Hypogonadotropic hypogonadism in Klinefelter syndrome and hypothalamic-pituitary tumor

El síndrome de Klinefelter es la causa más frecuente de hipogonadismo hipergonadotropo en el varón. La supresión en la respuesta al estímulo con hormona liberadora de la hormona luteinizante en estos pacientes debe hacer sospechar como posible etiología una tumoración a nivel hipotalámico. Se presenta el caso de un paciente diagnosticado a los 4 meses con síndrome de Klinefelter mediante cribado neonatal, con cariotipo 47 XXY, en el que se realizan controles clínicos y analíticos seriados y se encuentran, a los 17 años, valores suprimidos de hormona luteinizante y hormona folículo estimulante. Inicia, posteriormente, cefalea y amaurosis de ojo izquierdo, y se encuentra, en una resonancia magnética cerebral, un tumor germinal mixto a nivel hipotalámico, que precisa tratamiento quirúrgico, quimioterapia y radioterapia, con respuesta favorable. Klinefelter Syndrome is the most frequent cause of hypergonadotropic hypogonadism in men. A flat response at luteinizing hormone releasing hormone stimulation test could be the first sign of hypothalamic tumor in these patients. We report the case of a patient diagnosed by neonatal screening with Klinefelter Syndrome, 47 XXY, that at 17 years follow-up presents analytical modification of the response to luteinizing hormone releasing hormone stimulation test with suppressed luteinizing hormone and follicle-stimulating hormone values; lately he presents with headache and loss of left eye vision. A magnetic resonance imaging of the brain showed a mixed germ cell hypothalamus tumor, requiring surgery, chemotherapy and radiotherapy with optimal response

A few StePS forward in unveiling the complexity of galaxy evolution: Light-weighted stellar ages of intermediate-redshift galaxies with WEAVE

The upcoming new generation of optical spectrographs on four-meter-class telescopes will provide invaluable information for reconstructing the history of star formation in individual galaxies up to redshifts of about 0.7. We aim at defining simple but robust and meaningful physical parameters that can be used to trace the coexistence of widely diverse stellar components: younger stellar populations superimposed on the bulk of older ones. We produce spectra of galaxies closely mimicking data from the forthcoming Stellar Populations at intermediate redshifts Survey (StePS), a survey that uses the WEAVE spectrograph on the William Herschel Telescope. First, we assess our ability to reliably measure both ultraviolet and optical spectral indices in galaxies of different spectral types for typically expected signal-to-noise levels. Then, we analyze such mock spectra with a Bayesian approach, deriving the probability density function of r- and u-band light-weighted ages as well as of their difference. We find that the ultraviolet indices significantly narrow the uncertainties in estimating the r- and u-band light-weighted ages and their difference in individual galaxies. These diagnostics, robustly retrievable for large galaxy samples even when observed at moderate signal-to-noise ratios, allow us to identify secondary episodes of star formation up to an age of ~0.1 Gyr for stellar populations older than ~1.5 Gyr, pushing up to an age of ~1 Gyr for stellar populations older than ~5 Gyr. The difference between r-band and u-band light-weighted ages is shown to be a powerful diagnostic to characterize and constrain extended star-formation histories and the presence of young stellar populations on top of older ones. This parameter can be used to explore the interplay between different galaxy star-formation histories and physical parameters such as galaxy mass, size, morphology, and environment

WEAVE-StePS. A stellar population survey using WEAVE at WHT

The upcoming new generation of optical spectrographs on four-meter-class telescopes will provide valuable opportunities for forthcoming galaxy surveys through their huge multiplexing capabilities, excellent spectral resolution, and unprecedented wavelength coverage. WEAVE is a new wide-field spectroscopic facility mounted on the 4.2 m William Herschel Telescope in La Palma. WEAVE-StePS is one of the five extragalactic surveys that will use WEAVE during its first five years of operations. It will observe galaxies using WEAVE MOS (~950 fibres across a field of view of ~3 deg2 on the sky) in low-resolution mode (R~5000, spanning the wavelength range 3660-9590 AA). WEAVE-StePS will obtain high-quality spectra (S/N ~ 10 per AA at R~5000) for a magnitude-limited (I_AB = 20.5) sample of ~25,000 galaxies, the majority selected at z>=0.3. The survey goal is to provide precise spectral measurements in the crucial interval that bridges the gap between LEGA-C and SDSS data. The wide area coverage of ~25 deg2 will enable us to observe galaxies in a variety of environments. The ancillary data available in each observed field (including X-ray coverage, multi-narrow-band photometry and spectroscopic redshift information) will provide an environmental characterisation for each observed galaxy. This paper presents the science case of WEAVE-StePS, the fields to be observed, the parent catalogues used to define the target sample, and the observing strategy chosen after a forecast of the expected performance of the instrument for our typical targets. WEAVE-StePS will go back further in cosmic time than SDSS, extending its reach to encompass more than ~6 Gyr, nearly half of the age of the Universe. The spectral and redshift range covered by WEAVE-StePS will open a new observational window by continuously tracing the evolutionary path of galaxies in the largely unexplored intermediate-redshift range.Comment: 15 pages, 9 figures, A&A in pres

Predicting long-term disease control in transplant-ineligible patients with multiple myeloma: impact of an MGUS-like signature

Disease control at 5 years would be a desirable endpoint for elderly multiple myeloma (MM) patients, but biomarkers predicting this are not defined. Therefore, to gain further insights in this endpoint, a population of 498 newly diagnosed transplant-ineligible patients enrolled in two Spanish trials (GEM2005MAS65 and GEM2010MAS65), has been analyzed. Among the 435 patients included in this post-hoc study, 18.6% remained alive and progression free after 5 years of treatment initiation. In these patients, overall survival (OS) rate at 10 years was 60.8% as compared with 11.8% for those progressing within the first 5 years. Hemoglobin (Hb) = 12 g/dl (OR 2.74, p = 0.001) and MGUS-like profile (OR 4.18, p = 0.005) were the two baseline variables associated with long-term disease-free survival. Upon including depth of response (and MRD), Hb = 12 g/dl (OR 2.27) and MGUS-like signature (OR 7.48) retained their predictive value along with MRD negativity (OR 5.18). This study shows that despite the use of novel agents, the probability of disease control at 5 years is still restricted to a small fraction (18.6%) of elderly MM patients. Since this endpoint is associated with higher rates of OS, this study provides important information about diagnostic and post-treatment biomarkers helpful in predicting the likelihood of disease control at 5 years

EuroFlow Standardized Approach to Diagnostic Immunopheneotyping of Severe PID in Newborns and Young Children

The EuroFlow PID consortium developed a set of flow cytometry tests for evaluation of patients with suspicion of primary immunodeficiency (PID). In this technical report we evaluate the performance of the SCID-RTE tube that explores the presence of recent thymic emigrants (RTE) together with T-cell activation status and maturation stages and discuss its applicability in the context of the broader EuroFlow PID flow cytometry testing algorithm for diagnostic orientation of PID of the lymphoid system. We have analyzed peripheral blood cells of 26 patients diagnosed between birth and 2 years of age with a genetically defined primary immunodeficiency disorder: 1

Prognostic utility of serum free light chain ratios and heavy-light chain ratios in multiple myeloma in three PETHEMA/GEM phase III clinical trials

We investigated the prognostic impact and clinical utility of serum free light chains (sFLC) and serum heavy-light chains (sHLC) in patients with multiple myeloma treated according to the GEM2005MENOS65, GEM2005MAS65, and GEM2010MAS65 PETHEMA/GEM phase III clinical trials. Serum samples collected at diagnosis were retrospectively analyzed for sFLC (n = 623) and sHLC (n = 183). After induction or autologous transplantation, 309 and 89 samples respectively were available for sFLC and sHLC assays. At diagnosis, a highly abnormal (HA) sFLC ratio (sFLCr) (32) was not associated with higher risk of progression. After therapy, persistence of involved-sFLC levels >100 mg/L implied worse survival (overall survival [OS], P = 0.03; progression-free survival [PFS], P = 0.007). Among patients that achieved a complete response, sFLCr normalization did not necessarily indicate a higher quality response. We conducted sHLC investigations for IgG and IgA MM. Absolute sHLC values were correlated with monoclonal protein levels measured with serum protein electrophoresis. At diagnosis, HA-sHLCrs (73) showed a higher risk of progression (P = 0.006). Additionally, involved-sHLC levels >5 g/L after treatment were associated with shorter survival (OS, P = 0.001; PFS, P = 0.018). The HA-sHLCr could have prognostic value at diagnosis; absolute values of involved-sFLC >100 mg/L and involved-sHLC >5 g/L could have prognostic value after treatment

Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression

New treatment options offering enhanced activity in elderly, newly diagnosed patients with multiple myeloma are required. One strategy is to combine melphalan and prednisone with novel agents. We previously reported an 89% response rate, including 32% complete responses and 11% near complete responses, in our phase 1/2 study of bortezomib plus melphalan and prednisone (VMP) in 60 newly diagnosed multiple myeloma patients with a median age of 75 years. Here, we report updated time-to-events data and the impact of poor prognosis factors on outcome