Efficacy and Safety of Radium-223 Dichloride in Symptomatic Castration-resistant Prostate Cancer Patients With or Without Baseline Opioid Use From the Phase 3 ALSYMPCA Trial

Background: The phase 3 ALSYMPCA trial enrolled metastatic castration-resistant prostate cancer patients with or without baseline opioid use. Objective: To assess the efficacy and safety of radium-223 dichloride (radium-223) versus placebo in ALSYMPCA patients by baseline opioid use. Design, setting, and participants: Nine hundred and twenty one patients enrolled at 136 centers globally. Intervention: Radium-223 (50 kBq/kg, intravenous injection) every 4 wk for six cycles or matching placebo, each plus best standard of care. Outcome measurements and statistical analysis: Primary endpoint (overall survival [OS]), main secondary efficacy endpoints, and safety were evaluated by baseline opioid use. Additional analyses included time to first opioid use, time to first external beam radiation therapy for bone pain, and safety of concomitant external beam radiation therapy. Results and limitations: At baseline, 408 (44%) patients had no pain and no analgesic use or mild pain with nonopioid therapy (World Health Organization ladder pain score 0–1 [nonopioid subgroup]), and 513 (56%) had moderate pain with occasional opioids or severe pain with regular daily opioids (World Health Organization ladder pain score 2–3 [opioid subgroup]). Radium-223 significantly prolonged OS versus placebo in nonopioid (hazard ratio [HR] = 0.70; 95% confidence interval [CI]: 0.52–0.93; p = 0.013) and opioid (HR = 0.68; 95% CI: 0.54–0.86; p = 0.001) subgroups, and significantly reduced risk of symptomatic skeletal events versus placebo, regardless of baseline opioid use (nonopioid subgroup: HR = 0.56, 95% CI: 0.39– 0.82, p = 0.002; opioid subgroup: HR = 0.72, 95% CI: 0.53–0.98, p = 0.038). Time to first opioid use for bone pain was significantly delayed with radium-223 versus placebo (HR = 0.62, 95% CI: 0.46–0.85, p = 0.002). Adverse event incidences were similar between opioid subgroups. Conclusions: Radium-223 versus placebo significantly prolonged OS and reduced symptomatic skeletal event risk with a favorable safety profile in castration-resistant prostate cancer patients with symptomatic bone metastases, regardless of baseline opioid use. Patient summary: In this ALSYMPCA opioid subgroup analysis, baseline symptom levels did not appear to impact radium-223 dichloride efficacy or safet

Nonequilibrium evolution in scalar O(N) models with spontaneous symmetry breaking

We consider the out-of-equilibrium evolution of a classical condensate field and its quantum fluctuations for a scalar O(N) model with spontaneously broken symmetry. In contrast to previous studies we do not consider the large N limit, but the case of finite N, including N=1, i.e., plain $\lambda \phi^ 4$ theory. The instabilities encountered in the one-loop approximation are prevented, as in the large-N limit, by back reaction of the fluctuations on themselves, or, equivalently, by including a resummation of bubble diagrams. For this resummation and its renormalization we use formulations developed recently based on the effective action formalism of Cornwall, Jackiw and Tomboulis. The formulation of renormalized equations for finite N derived here represents a useful tool for simulations with realistic models. Here we concentrate on the phase structure of such models. We observe the transition between the spontaneously broken and the symmetric phase at low and high energy densities, respectively. This shows that the typical structures expected in thermal equilibrium are encountered in nonequilibrium dynamics even at early times, i.e., before an efficient rescattering can lead to thermalization.Comment: 31 pages, 19 Figures, LaTeX; extended discussion on the basis of: fluctuations, eff. potential, correlations, analytic calculation of parametric resonance for "pion"_and_ "sigma" field

Multi-Objective Optimization with an Adaptive Resonance Theory-Based Estimation of Distribution Algorithm: A Comparative Study

Proceedings of: 5th International Conference, LION 5, Rome, Italy, January 17-21, 2011.The introduction of learning to the search mechanisms of optimization algorithms has been nominated as one of the viable approaches when dealing with complex optimization problems, in particular with multi-objective ones. One of the forms of carrying out this hybridization process is by using multi-objective optimization estimation of distribution algorithms (MOEDAs). However, it has been pointed out that current MOEDAs have a intrinsic shortcoming in their model-building algorithms that hamper their performance. In this work we argue that error-based learning, the class of learning most commonly used in MOEDAs is responsible for current MOEDA underachievement. We present adaptive resonance theory (ART) as a suitable learning paradigm alternative and present a novel algorithm called multi-objective ART-based EDA (MARTEDA) that uses a Gaussian ART neural network for model-building and an hypervolume-based selector as described for the HypE algorithm. In order to assert the improvement obtained by combining two cutting-edge approaches to optimization an extensive set of experiments are carried out. These experiments also test the scalability of MARTEDA as the number of objective functions increases.This work was supported by projects CICYT TIN2008-06742-C02-02/TSI, CICYT TEC2008-06732-C02-02/TEC, CAM CONTEXTS (S2009/TIC-1485) and DPS2008-07029-C02-02.Publicad

A review on probabilistic graphical models in evolutionary computation

Thanks to their inherent properties, probabilistic graphical models are one of the prime candidates for machine learning and decision making tasks especially in uncertain domains. Their capabilities, like representation, inference and learning, if used effectively, can greatly help to build intelligent systems that are able to act accordingly in different problem domains. Evolutionary algorithms is one such discipline that has employed probabilistic graphical models to improve the search for optimal solutions in complex problems. This paper shows how probabilistic graphical models have been used in evolutionary algorithms to improve their performance in solving complex problems. Specifically, we give a survey of probabilistic model building-based evolutionary algorithms, called estimation of distribution algorithms, and compare different methods for probabilistic modeling in these algorithms

The chemical compound 'Heatin' stimulates hypocotyl elongation and interferes with the Arabidopsis NIT1-subfamily of nitrilases

Temperature passively affects biological processes involved in plant growth. Therefore, it is challenging to study the dedicated temperature signalling pathways that orchestrate thermomorphogenesis, a suite of elongation growth-based adaptations that enhance leaf-cooling capacity. We screened a chemical library for compounds that restored hypocotyl elongation in the pif4-2-deficient mutant background at warm temperature conditions in Arabidopsis thaliana to identify modulators of thermomorphogenesis. The small aromatic compound 'Heatin', containing 1-iminomethyl-2-naphthol as a pharmacophore, was selected as an enhancer of elongation growth. We show that ARABIDOPSIS ALDEHYDE OXIDASES redundantly contribute to Heatin-mediated hypocotyl elongation. Following a chemical proteomics approach, the members of the NITRILASE1-subfamily of auxin biosynthesis enzymes were identified among the molecular targets of Heatin. Our data reveal that nitrilases are involved in promotion of hypocotyl elongation in response to high temperature and Heatin-mediated hypocotyl elongation requires the NITRILASE1-subfamily members, NIT1 and NIT2. Heatin inhibits NIT1-subfamily enzymatic activity in vitro and the application of Heatin accordingly results in the accumulation of NIT1-subfamily substrate indole-3-acetonitrile in vivo. However, levels of the NIT1-subfamily product, bioactive auxin (indole-3-acetic acid), were also significantly increased. It is likely that the stimulation of hypocotyl elongation by Heatin might be independent of its observed interaction with NITRILASE1-subfamily members. However, nitrilases may contribute to the Heatin response by stimulating indole-3-acetic acid biosynthesis in an indirect way. Heatin and its functional analogues present novel chemical entities for studying auxin biology

Assessment of alcohol consumption, fat and sodium intake in selected group of outpatients with primary arterial hypertension

Nadciśnienie tętnicze znacząco zwiększa ryzyko chorób układu krążenia, które stanowią główne zagrożenie zdrowia i życia człowieka. W prewencji i terapii wysokiego ciśnienia tętniczego istotną rolę odgrywa prawidłowy sposób żywienia. Celem pracy była ocena spożycia alkoholu, tłuszczu i sodu w wybranej grupie pacjentów z pierwotnym nadciśnieniem tętniczym. W badaniu uczestniczyło 33 pacjentów z pierwotnym nadciśnieniem tętniczym, bez chorób współistniejących. W celach porównawczych i właściwej interpretacji uzyskanych wyników, w badaniu wzięło również udział 35 zdrowych osób, wolontariuszy, wchodzących w skład grupy kontrolnej. W obu grupach przeprowadzono badania ankietowe dotyczące nawyków żywieniowych respondentów m.in. charakterystyki spożycia alkoholu i sodu. Przeprowadzono również ocenę sposobu żywienia na podstawie trzykrotnego 24-godzinnego wywiadu żywieniowego, z wykorzystaniem „Album fotografii produktów i potraw”. Ocenę wartości energetycznej i oszacowanie ilości wybranych składników odżywczych, występujących w całodziennych racjach pokarmowych, przeprowadzono przy użyciu komputerowego programu Dietetyk. Stwierdzono istotnie wyższą (p<0,05) podaż energii oraz większe spożycie tłuszczu, w tym nasyconych i jednonienasyconych kwasów tłuszczowych oraz NNKT, w grupie pacjentów z nadciśnieniem tętniczym pijących alkohol aniżeli u chorych niespożywających alkoholu. Wśród osób pijących alkohol stwierdzono ponadto spożycie cholesterolu przekraczające zalecane normy żywieniowe. Wśród osób z pierwotnym nadciśnieniem tętniczym zaobserwowano dużą podaż sodu w diecie, w tym również częste dosalanie posiłków. W grupie kontrolnej istotności statystyczne dotyczyły większego spożycia nasyconych kwasów tłuszczowych wśród badanych spożywających alkohol. Podsumowując, można stwierdzić, że osoby pijące alkohol spożywają również większą ilość żywieniowych czynników hipertensyjnych, jak tłuszcz (m.in. nasycone kwasy tłuszczowe, cholesterol) i sód, co może nasilać wzrost wartości ciśnienia tętniczego i znacząco utrudniać terapię.Arterial hypertension significantly increases the risk of cardiovascular diseases presenting major threats to human life and health. In the prevention and treatment of high arterial blood tension, the proper diet plays a significant role. The objective of this study was to evaluate the alcohol consumption, as well as the fat and sodium intakes in a selected group of adult outpatients with primary arterial hypertension. 33 outpatients with primary arterial hypertension and with no coexisting diseases participated in the survey. Also in order to compare and appropriately interpret the results obtained, 35 healthy people, the volunteers, participated in this survey as a control group. The participants of the 2 groups were polled on their dietary habits, among other things they had to characterize their consumption of alcohol and the intake of sodium. Moreover, their eating habits were assessed based on their dietary history obtained from a 24h survey conducted three times with the application of an ‘Album with photos of products and dishes’. The energy value was evaluated and the amounts of selected nutrients covered by daily food rations were assessed using ‘DIETETYK’ computer software. It was found that, in the group of outpatients with arterial hypertension who did not drink alcohol, the supply of energy was significantly higher (p<0.05), as was the fat intake, including the intake of saturated and monounsaturated fatty acids, and essential fatty acids (EFA), compared to non-drinking outpatients. Furthermore, amidst the persons drinking alcohol, the cholesterol intake was found to exceed the recommended nutritional norms. Among the people with primary arterial hypertension, a high dietary sodium intake was reported, and those outpatients often salted more their dishes. In the control group, the statistical significances referred to a higher intake of saturated fatty acids by the polled who consumed alcohol. The conclusion is that the persons who drink alcohol also intake higher amounts of dietary “prohypertension” factors, such as fat (among other things saturated fats and cholesterol) and sodium, and, therefore, the increase in their arterial blood pressure can be intensified and significantly hinder treatment