Plasma Androgen Receptor and Docetaxel for Metastatic Castration-resistant Prostate Cancer

Plasma androgen receptor (AR) gain identifies metastatic castration-resistant prostate cancer (mCRPC) patients with worse outcome on abiraterone/enzalutamide but its relevance in the context of taxane chemotherapy is unknown. We aimed to evaluate whether docetaxel is active regardless of plasma AR and to perform exploratory analysis to compare docetaxel with abiraterone/enzalutamide. This multi-institution study was a pooled analysis of AR status, determined by droplet digital PCR, on pre-treatment plasma samples. We evaluated associations between plasma AR and overall/progression-free survival (OS/PFS) and prostate-specific antigen (PSA) response rate in 163 docetaxel-treated patients. OS was significantly shorter in AR-gain [hazard ratio (HR)=1.61, 95% confidence interval (CI)=1.08-2.39, p=0.018), but not PFS (HR=1.04, 95%CI 0.74-1.46, p=0.8), nor PSA response [odds ratio (OR)=1.14, 95%CI=0.65-1.99, p=0.7)]. We investigated the interaction between plasma AR and treatment type after incorporating updated data from our prior study of 7 chemotherapy-naïve, abiraterone/enzalutamide-treated patients with data from 115 first-line docetaxel patients. In an exploratory analysis of mCRPC receiving first-line therapies, a significant interaction was observed between plasma AR and docetaxel versus abiraterone/enzalutamide for OS (HR=0.27,95%CI=0.11-0.68, p=0.005) and PFS (HR=0.28, 95%CI=0.12-0.64, p=0.002). Specifically, we reported a significant difference for OS favoring abiraterone/enzalutamide for AR-normal (HR=1.93, 95%CI=1.19-3.12, p=0.008) and a suggestion favoring docetaxel for AR-gained patients (HR=0.53, 95%CI=0.24-1.16, p=0.11). These data suggest that AR-normal patients should receive abiraterone/enzalutamide and AR-gained docetaxel. This treatment selection merits prospective evaluation in a randomized trial. // Patient summary: We investigated whether plasma androgen receptor (AR) predicted outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel, and we performed an exploratory analysis in patients treated with docetaxel or AR-directed drugs as first-line mCRPC therapy. We showed that plasma AR normal favored hormonal treatment, whilst plasma AR-gained patients may have had a longer response to docetaxel, suggesting that plasma AR status could be a useful treatment selection biomarker

A search for the K−pp bound state in the 3He(K−in-flight, n) reaction at J-PARC

We have collected the first physics data of an experimental search for the simplest kaonic nuclear bound state, " K − pp", by the 3He( K − n) reaction at J-PARC. We confirmed that our spectrometer system works as designed and observed clear peak structure composed of the quasi-elastic K − " n " → K − n and the charge-exchange K − " p " → ¯ K 0 n reactions in the forward neutron spectrum

The First Post-Kepler Brightness Dips of KIC 8462852

We present a photometric detection of the first brightness dips of the unique variable star KIC 8462852 since the end of the Kepler space mission in 2013 May. Our regular photometric surveillance started in October 2015, and a sequence of dipping began in 2017 May continuing on through the end of 2017, when the star was no longer visible from Earth. We distinguish four main 1-2.5% dips, named "Elsie," "Celeste," "Skara Brae," and "Angkor", which persist on timescales from several days to weeks. Our main results so far are: (i) there are no apparent changes of the stellar spectrum or polarization during the dips; (ii) the multiband photometry of the dips shows differential reddening favoring non-grey extinction. Therefore, our data are inconsistent with dip models that invoke optically thick material, but rather they are in-line with predictions for an occulter consisting primarily of ordinary dust, where much of the material must be optically thin with a size scale <<1um, and may also be consistent with models invoking variations intrinsic to the stellar photosphere. Notably, our data do not place constraints on the color of the longer-term "secular" dimming, which may be caused by independent processes, or probe different regimes of a single process

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

7th Drug hypersensitivity meeting: part two

No abstract availabl

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

Echinoderms from the Museum of Zoology from the Universidad de Costa Rica

El Museo de Zoología de la Universidad de Costa Rica (MZUCR) se funda en 1966 y alberga la colección de organismos vertebrados e invertebrados más completa de Costa Rica. El MZUCR cuenta actualmente con 24 colec-ciones que contienen más de cinco millones de especíme-nes, y más de 13 000 especies identificadas. Las primeras colecciones datan 1960 e incluyen peces, reptiles, anfibios, poliquetos, crustáceos y equinodermos. Para este último grupo, el MZUCR posee un total de 157 especies, en 1 173 lotes y 4 316 ejemplares. Estas 157 especies representan el 54% del total de especies de equinodermos que posee Costa Rica (293 especies). El resto de especies están repar-tidas en las siguientes instituciones: Academia de la Cien-cias de California (CAS) (4.8%), Instituto Oceanográfico Scripps (SIO) (5.2%), en la Colección Nacional de equino-dermos “Dra. Ma. Elena Caso” de la Universidad Nacional Autónoma de México (ICML-UNAM) (12.7%), Museo de Zoología Comparada de Harvard (MZC) (19.2%), y en el Museo Nacional de Historia Natural del Instituto Smithso-niano (USNM) (35.1%). Es posible que haya material de Costa Rica en el Museo de Historia Natural de Dinamarca (NCD) y en el Museo de Historia Natural de los Ángeles (LACM), sin embargo, no hubo acceso a dichas coleccio-nes. A su vez hay 9.6% de especies que no aparecen en ningún museo, pero están reportadas en la literatura. Con base en esta revisión de colecciones se actualizó el listado taxonómico de equinodermos para Costa Rica que consta de 293 especies, 152 géneros, 75 familias, 30 órdenes y cinco clases. La costa Pacífica de Costa Rica posee 153 especies, seguida por la isla del Coco con 134 y la costa Caribe con 65. Holothuria resultó ser el género más rico con 25 especies.The Museum of Zoology, Universidad de Costa Rica (MZUCR) was founded in 1966 and houses the most complete collection of vertebrates and invertebrates in Costa Rica. The MZUCR currently has 24 collections containing more than five million specimens, and more than 13 000 species. The earliest collections date back to 1960 and include fishes, reptiles, amphibians, polychaetes, crustaceans and echinoderms. For the latter group, the MZUCR has a total of 157 species, in 1 173 lots and 4 316 specimens. These 157 species represent 54% of the total species of echino-derms from Costa Rica. The remaining species are distributed in the following institutions: California Academy of Sciences (CAS) (4.8%), Scripps Oceanographic Institute (SIO) (5.2%), National Echinoderm Collection “Dr. Ma. Elena Caso” from the National Autonomous University of Mexico (ICML-UNAM) (12.7%), the National Museum of Natural History, Smithsonian Institute (USNM) (35.1%), and the Harvard Museum of Comparative Zoology (19.2%). There may be material from Costa Rica in the Natural History Museum of Denmark (NCD) and the Natural History Museum of Los Angeles (LACM), however, there was no access to such collections. There are 9.6% that do not appear in museums, but are reported in the literature. Based on this revision, the taxonomic list of echinoderms for Costa Rica is updated to 293 species, 152 genera, 75 families, 30 orders and 5 classes. The Pacific coast of Costa Rica has 153 species, followed by the Isla del Coco with 134 and the Caribbean coast with 65. Holothuria is the most diverse genus with 25 species.UCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de BiologíaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Ciencias del Mar y Limnología (CIMAR)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Artes y Letras::Museo de la Universidad de Costa Ric

Observation of B-c(+) -> J/psi D-(*()) K-(*()) decays

A search for the decays $B_c^+ \to J/\psi D^{(*)0} K^+$ and $B_c^+ \to J/\psi D^{(*)+} K^{*0}$ is performed with data collected at the LHCb experiment corresponding to an integrated luminosity of 3 fb$^{-1}$. The decays $B_c^+ \to J/\psi D^0 K^+$ and $B_c^+ \to J/\psi D^{*0} K^+$ are observed for the first time, while first evidence is reported for the $B_c^+ \to J/\psi D^{*+} K^{*0}$ and $B_c^+ \to J/\psi D^+ K^{*0}$ decays. The branching fractions of these decays are determined relative to the $B_c^+ \to J/\psi \pi^+$ decay. The $B_c^+$ mass is measured, using the $J/\psi D^0 K^+$ final state, to be $6274.28 \pm 1.40 (stat) \pm 0.32 (syst)$ MeV/$c^2$. This is the most precise single measurement of the $B_c^+$ mass to date.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-055.htm

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease