Role of novel hormonal therapies in the management of non-metastatic castration-resistant prostate cancer:a literature-based meta-analysis of randomized trials

BACKGROUND: Novel hormonal therapies have been recently investigated in non-metastatic castration-resistant prostate cancer (CRPC). We performed a meta-analysis to assess the efficacy and safety of novel hormonal therapies in non-metastatic CRPC.MATERIALS AND METHODS: The primary outcome was metastasis-free survival (MFS). The secondary endpoints were overall survival (OS), time to PSA progression and safety. We planned a subgroup analysis according to the PSA doubling time (&gt; 6 vs &lt; 6 months), Eastern Cooperative Oncology Group (ECOG) performance status (1 vs 0) and concomitant use of bone-targeting agent (yes vs no).RESULTS: Pooled analysis of novel hormonal therapies revealed significantly increased MFS compared with placebo (hazard ratio (HR): HR = 0.32, 95% CI 0.25-0.41; p &lt; 0.00001). The subgroup analysis showed a statistically significant MFS advantage in favour of men with the lower ECOG performance status. Other secondary endpoints favoured the novel hormonal therapies. The relative risk (RR) of grade ≥ 3 adverse events and ≥ 3 hypertension was 1.31 and 1.39, respectively.CONCLUSIONS: This study confirmed the efficacy and safety of the novel hormonal therapies in non-metastatic CRPC.</p

Involvement of β3-Adrenoceptor in Altered β-Adrenergic Response in Senescent Heart: Role of Nitric Oxide Synthase 1–derived Nitric Oxide

Background: In senescent heart, β-adrenergic response is altered in parallel with β1- and β2-adrenoceptor down-regulation. A negative inotropic effect of β3-adrenoceptor could be involved. In this study, the authors tested the hypothesis that β3-adrenoceptor plays a role in β-adrenergic dysfunction in senescent heart.Methods: β-Adrenergic responses were investigated in vivo (echocardiography–dobutamine, electron paramagnetic resonance) and in vitro (isolated left ventricular papillary muscle, electron paramagnetic resonance) in young adult (3-month-old) and senescent (24-month-old) rats. Nitric oxide synthase (NOS) immunolabeling (confocal microscopy), nitric oxide production (electron paramagnetic resonance) and β-adrenoceptor Western blots were performed in vitro. Data are mean percentages of baseline ± SD. Results: An impaired positive inotropic effect (isoproterenol) was confirmed in senescent hearts in vivo (117 ± 23 vs. 162 ± 16%; P &lt; 0.05) and in vitro (127 ± 10 vs. 179 ± 15%; P &lt; 0.05). In the young adult group, the positive inotropic effect was not significantly modified by the nonselective NOS inhibitor NG-nitro-l-arginine methylester (l-NAME; 183 ± 19%), the selective NOS1 inhibitor vinyl-l-N-5(1-imino-3-butenyl)-l-ornithine (l-VNIO; 172 ± 13%), or the selective NOS2 inhibitor 1400W (183 ± 19%). In the senescent group, in parallel with β3-adrenoceptor up-regulation and increased nitric oxide production, the positive inotropic effect was partially restored by l-NAME (151 ± 8%; P &lt; 0.05) and l-VNIO (149 ± 7%; P &lt; 0.05) but not by 1400W (132 ± 11%; not significant). The positive inotropic effect induced by dibutyryl-cyclic adenosine monophosphate was decreased in the senescent group with the specific β3-adrenoceptor agonist BRL 37344 (167 ± 10 vs. 142 ± 10%; P &lt; 0.05). NOS1 and NOS2 were significantly up-regulated in the senescent rat. Conclusions: In senescent cardiomyopathy, β3-adrenoceptor overexpression plays an important role in the altered β-adrenergic response via induction of NOS1-nitric oxide

SOPHIE velocimetry of Kepler transit candidates XII. KOI-1257 b: a highly eccentric three-month period transiting exoplanet

In this paper we report a new transiting warm giant planet: KOI-1257 b. It was first detected in photometry as a planet-candidate by the ${\it Kepler}$ space telescope and then validated thanks to a radial velocity follow-up with the SOPHIE spectrograph. It orbits its host star with a period of 86.647661 d $\pm$ 3 s and a high eccentricity of 0.772 $\pm$ 0.045. The planet transits the main star of a metal-rich, relatively old binary system with stars of mass of 0.99 $\pm$ 0.05 Msun and 0.70 $\pm$ 0.07 Msun for the primary and secondary, respectively. This binary system is constrained thanks to a self-consistent modelling of the ${\it Kepler}$ transit light curve, the SOPHIE radial velocities, line bisector and full-width half maximum (FWHM) variations, and the spectral energy distribution. However, future observations are needed to confirm it. The PASTIS fully-Bayesian software was used to validate the nature of the planet and to determine which star of the binary system is the transit host. By accounting for the dilution from the binary both in photometry and in radial velocity, we find that the planet has a mass of 1.45 $\pm$ 0.35 Mjup, and a radius of 0.94 $\pm$ 0.12 Rjup, and thus a bulk density of 2.1 $\pm$ 1.2 g.cm$^{-3}$. The planet has an equilibrium temperature of 511 $\pm$ 50 K, making it one of the few known members of the warm-jupiter population. The HARPS-N spectrograph was also used to observe a transit of KOI-1257 b, simultaneously with a joint amateur and professional photometric follow-up, with the aim of constraining the orbital obliquity of the planet. However, the Rossiter-McLaughlin effect was not clearly detected, resulting in poor constraints on the orbital obliquity of the planet.Comment: 39 pages, 17 figures, accepted for publication in Astronomy & Astrophysic

Role of novel hormonal therapies in the management of non-metastatic castration-resistant prostate cancer:a literature-based meta-analysis of randomized trials

BACKGROUND: Novel hormonal therapies have been recently investigated in non-metastatic castration-resistant prostate cancer (CRPC). We performed a meta-analysis to assess the efficacy and safety of novel hormonal therapies in non-metastatic CRPC.MATERIALS AND METHODS: The primary outcome was metastasis-free survival (MFS). The secondary endpoints were overall survival (OS), time to PSA progression and safety. We planned a subgroup analysis according to the PSA doubling time (&gt; 6 vs &lt; 6 months), Eastern Cooperative Oncology Group (ECOG) performance status (1 vs 0) and concomitant use of bone-targeting agent (yes vs no).RESULTS: Pooled analysis of novel hormonal therapies revealed significantly increased MFS compared with placebo (hazard ratio (HR): HR = 0.32, 95% CI 0.25-0.41; p &lt; 0.00001). The subgroup analysis showed a statistically significant MFS advantage in favour of men with the lower ECOG performance status. Other secondary endpoints favoured the novel hormonal therapies. The relative risk (RR) of grade ≥ 3 adverse events and ≥ 3 hypertension was 1.31 and 1.39, respectively.CONCLUSIONS: This study confirmed the efficacy and safety of the novel hormonal therapies in non-metastatic CRPC.</p

Spin states of asteroids in the Eos collisional family

Eos family was created during a catastrophic impact about 1.3 Gyr ago. Rotation states of individual family members contain information about the history of the whole population. We aim to increase the number of asteroid shape models and rotation states within the Eos collision family, as well as to revise previously published shape models from the literature. Such results can be used to constrain theoretical collisional and evolution models of the family, or to estimate other physical parameters by a thermophysical modeling of the thermal infrared data. We use all available disk-integrated optical data (i.e., classical dense-in-time photometry obtained from public databases and through a large collaboration network as well as sparse-in-time individual measurements from a few sky surveys) as input for the convex inversion method, and derive 3D shape models of asteroids together with their rotation periods and orientations of rotation axes. We present updated shape models for 15 asteroids and new shape model determinations for 16 asteroids. Together with the already published models from the publicly available DAMIT database, we compiled a sample of 56 Eos family members with known shape models that we used in our analysis of physical properties within the family. Rotation states of asteroids smaller than ~20 km are heavily influenced by the YORP effect, whilst the large objects more or less retained their rotation state properties since the family creation. Moreover, we also present a shape model and bulk density of asteroid (423) Diotima, an interloper in the Eos family, based on the disk-resolved data obtained by the Near InfraRed Camera (Nirc2) mounted on the W.M. Keck II telescope.Comment: Accepted for publication in ICARUS Special Issue - Asteroids: Origin, Evolution & Characterizatio

The malleable brain: plasticity of neural circuits and behavior: A review from students to students

One of the most intriguing features of the brain is its ability to be malleable, allowing it to adapt continually to changes in the environment. Specific neuronal activity patterns drive long-lasting increases or decreases in the strength of synaptic connections, referred to as long-term potentiation (LTP) and long-term depression (LTD) respectively. Such phenomena have been described in a variety of model organisms, which are used to study molecular, structural, and functional aspects of synaptic plasticity. This review originated from the first International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Alpbach, Austria (Sep 2016), and will use its curriculum and discussions as a framework to review some of the current knowledge in the field of synaptic plasticity. First, we describe the role of plasticity during development and the persistent changes of neural circuitry occurring when sensory input is altered during critical developmental stages. We then outline the signaling cascades resulting in the synthesis of new plasticity-related proteins, which ultimately enable sustained changes in synaptic strength. Going beyond the traditional understanding of synaptic plasticity conceptualized by LTP and LTD, we discuss system-wide modifications and recently unveiled homeostatic mechanisms, such as synaptic scaling. Finally, we describe the neural circuits and synaptic plasticity mechanisms driving associative memory and motor learning. Evidence summarized in this review provides a current view of synaptic plasticity in its various forms, offers new insights into the underlying mechanisms and behavioral relevance, and provides directions for future research in the field of synaptic plasticity.Fil: Schaefer, Natascha. University of Wuerzburg; AlemaniaFil: Rotermund, Carola. University of Tuebingen; AlemaniaFil: Blumrich, Eva Maria. Universitat Bremen; AlemaniaFil: Lourenco, Mychael V.. Universidade Federal do Rio de Janeiro; BrasilFil: Joshi, Pooja. Robert Debre Hospital; FranciaFil: Hegemann, Regina U.. University of Otago; Nueva ZelandaFil: Jamwal, Sumit. ISF College of Pharmacy; IndiaFil: Ali, Nilufar. Augusta University; Estados UnidosFil: García Romero, Ezra Michelet. Universidad Veracruzana; MéxicoFil: Sharma, Sorabh. Birla Institute of Technology and Science; IndiaFil: Ghosh, Shampa. Indian Council of Medical Research; IndiaFil: Sinha, Jitendra K.. Indian Council of Medical Research; IndiaFil: Loke, Hannah. Hudson Institute of Medical Research; AustraliaFil: Jain, Vishal. Defence Institute of Physiology and Allied Sciences; IndiaFil: Lepeta, Katarzyna. Polish Academy of Sciences; ArgentinaFil: Salamian, Ahmad. Polish Academy of Sciences; ArgentinaFil: Sharma, Mahima. Polish Academy of Sciences; ArgentinaFil: Golpich, Mojtaba. University Kebangsaan Malaysia Medical Centre; MalasiaFil: Nawrotek, Katarzyna. University Of Lodz; ArgentinaFil: Paid, Ramesh K.. Indian Institute of Chemical Biology; IndiaFil: Shahidzadeh, Sheila M.. Syracuse University; Estados UnidosFil: Piermartiri, Tetsade. Universidade Federal de Santa Catarina; BrasilFil: Amini, Elham. University Kebangsaan Malaysia Medical Centre; MalasiaFil: Pastor, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; ArgentinaFil: Wilson, Yvette. University of Melbourne; AustraliaFil: Adeniyi, Philip A.. Afe Babalola University; NigeriaFil: Datusalia, Ashok K.. National Brain Research Centre; IndiaFil: Vafadari, Benham. Polish Academy of Sciences; ArgentinaFil: Saini, Vedangana. University of Nebraska; Estados UnidosFil: Suárez Pozos, Edna. Instituto Politécnico Nacional; MéxicoFil: Kushwah, Neetu. Defence Institute of Physiology and Allied Sciences; IndiaFil: Fontanet, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; ArgentinaFil: Turner, Anthony J.. University of Leeds; Reino Unid

High-throughput screening of tick-borne pathogens in Europe

Due to increased travel, climatic, and environmental changes, the incidence of tick-borne disease in both humans and animals is increasing throughout Europe. Therefore, extended surveillance tools are desirable. To accurately screen tick-borne pathogens (TBPs), a large scale epidemiological study was conducted on 7050 Ixodes ricinus nymphs collected from France, Denmark, and the Netherlands using a powerful new high-throughput approach. This advanced methodology permitted the simultaneous detection of 25 bacterial, and 12 parasitic species (including; Borrelia, Anaplasma, Ehrlichia, Rickettsia, Bartonella, Candidatus Neoehrlichia, Coxiella, Francisella, Babesia, and Theileria genus) across 94 samples. We successfully determined the prevalence of expected (Borrelia burgdorferi sensu lato, Anaplasma phagocytophilum, Rickettsia helvetica, Candidatus Neoehrlichia mikurensis, Babesia divergens, Babesia venatorum), unexpected (Borrelia miyamotoi), and rare (Bartonella henselae) pathogens in the three European countries. Moreover we detected Borrelia spielmanii, Borrelia miyamotoi, Babesia divergens, and Babesia venatorum for the first time in Danish ticks. This surveillance method represents a major improvement in epidemiological studies, able to facilitate comprehensive testing of TBPs, and which can also be customized to monitor emerging diseases

The field high-amplitude SX Phe variable BL Cam: results from a multisite photometric campaign. II. Evidence of a binary - possibly triple - system

Short-period high-amplitude pulsating stars of Population I ($\delta$ Sct stars) and II (SX Phe variables) exist in the lower part of the classical (Cepheid) instability strip. Most of them have very simple pulsational behaviours, only one or two radial modes being excited. Nevertheless, BL Cam is a unique object among them, being an extreme metal-deficient field high-amplitude SX Phe variable with a large number of frequencies. Based on a frequency analysis, a pulsational interpretation was previously given. aims heading (mandatory) We attempt to interpret the long-term behaviour of the residuals that were not taken into account in the previous Observed-Calculated (O-C) short-term analyses. methods heading (mandatory) An investigation of the O-C times has been carried out, using a data set based on the previous published times of light maxima, largely enriched by those obtained during an intensive multisite photometric campaign of BL Cam lasting several months. results heading (mandatory) In addition to a positive (161 $\pm$ 3) x 10$^{-9}$ yr$^{-1}$ secular relative increase in the main pulsation period of BL Cam, we detected in the O-C data short- (144.2 d) and long-term ($\sim$ 3400 d) variations, both incompatible with a scenario of stellar evolution. conclusions heading (mandatory) Interpreted as a light travel-time effect, the short-term O-C variation is indicative of a massive stellar component (0.46 to 1 M_{\sun}) with a short period orbit (144.2 d), within a distance of 0.7 AU from the primary. More observations are needed to confirm the long-term O-C variations: if they were also to be caused by a light travel-time effect, they could be interpreted in terms of a third component, in this case probably a brown dwarf star ($\geq$ 0.03 \ M_{\sun}), orbiting in $\sim$ 3400 d at a distance of 4.5 AU from the primary.Comment: 7 pages, 5 figures, accepted for publication in A&

Asteroids' physical models from combined dense and sparse photometry and scaling of the YORP effect by the observed obliquity distribution

The larger number of models of asteroid shapes and their rotational states derived by the lightcurve inversion give us better insight into both the nature of individual objects and the whole asteroid population. With a larger statistical sample we can study the physical properties of asteroid populations, such as main-belt asteroids or individual asteroid families, in more detail. Shape models can also be used in combination with other types of observational data (IR, adaptive optics images, stellar occultations), e.g., to determine sizes and thermal properties. We use all available photometric data of asteroids to derive their physical models by the lightcurve inversion method and compare the observed pole latitude distributions of all asteroids with known convex shape models with the simulated pole latitude distributions. We used classical dense photometric lightcurves from several sources and sparse-in-time photometry from the U.S. Naval Observatory in Flagstaff, Catalina Sky Survey, and La Palma surveys (IAU codes 689, 703, 950) in the lightcurve inversion method to determine asteroid convex models and their rotational states. We also extended a simple dynamical model for the spin evolution of asteroids used in our previous paper. We present 119 new asteroid models derived from combined dense and sparse-in-time photometry. We discuss the reliability of asteroid shape models derived only from Catalina Sky Survey data (IAU code 703) and present 20 such models. By using different values for a scaling parameter cYORP (corresponds to the magnitude of the YORP momentum) in the dynamical model for the spin evolution and by comparing synthetics and observed pole-latitude distributions, we were able to constrain the typical values of the cYORP parameter as between 0.05 and 0.6.Comment: Accepted for publication in A&A, January 15, 201