Evaluation of molecular descriptors for antitumor drugs with respect to noncovalent binding to DNA and antiproliferative activity

34 pages, 6 additional files, 5 tables, 4 figures.[Background ] Small molecules that bind reversibly to DNA are among the antitumor drugs currently used in chemotherapy. In the pursuit of a more rational approach to cancer chemotherapy based upon these molecules, it is necessary to exploit the interdependency between DNA-binding affinity, sequence selectivity and cytotoxicity. For drugs binding noncovalently to DNA, it is worth exploring whether molecular descriptors, such as their molecular weight or the number of potential hydrogen acceptors/donors, can account for their DNA-binding affinity and cytotoxicity.[Results] Fifteen antitumor agents, which are in clinical use or being evaluated as part of the National Cancer Institute’s drug screening effort, were analyzed in silico to assess the contribution of various molecular descriptors to their DNA-binding affinity, and the capacity of the descriptors and DNA-binding constants for predicting cell cytotoxicity. Equations to predict drug-DNA binding constants and growth-inhibitory concentrations were obtained by multiple regression following rigorous statistical procedures.[Conclusions] For drugs binding reversibly to DNA, both their strength of binding and their cytoxicity are fairly predicted from molecular descriptors by using multiple regression methods. The equations derived may be useful for rational drug design. The results obtained agree with that compounds more active across the National Cancer Institute’s 60-cell line data set tend to have common structural features.Supported by a grant from the former Spanish Ministry of Education and Science (BFU2007-60998) and the FEDER program of the European Community.Peer reviewe

Analysis of pharmaceuticals in wastewater and removal using a membrane bioreactor

Much attention has recently been devoted to the life and behaviour of pharmaceuticals in the water cycle. In this study the behaviour of several pharmaceutical products in different therapeutic categories (analgesics and anti-inflammatory drugs, lipid regulators, antibiotics, etc.) was monitored during treatment of wastewater in a laboratory-scale membrane bioreactor (MBR). The results were compared with removal in a conventional activated-sludge (CAS) process in a wastewater-treatment facility. The performance of an MBR was monitored for approximately two months to investigate the long-term operational stability of the system and possible effects of solids retention time on the efficiency of removal of target compounds. Pharmaceuticals were, in general, removed to a greater extent by the MBR integrated system than during the CAS process. For most of the compounds investigated the performance of MBR treatment was better (removal rates >80%) and effluent concentrations of, e.g., diclofenac, ketoprofen, ranitidine, gemfibrozil, bezafibrate, pravastatin, and ofloxacin were steadier than for the conventional system. Occasionally removal efficiency was very similar, and high, for both treatments (e.g. for ibuprofen, naproxen, acetaminophen, paroxetine, and hydrochlorothiazide). The antiepileptic drug carbamazepine was the most persistent pharmaceutical and it passed through both the MBR and CAS systems untransformed. Because there was no washout of biomass from the reactor, high-quality effluent in terms of chemical oxygen demand (COD), ammonium content (N-NH(4)), total suspended solids (TSS), and total organic carbon (TOC) was obtained

Analogue Transformations in Physics and their Application to Acoustics

Transformation optics has shaped up a revolutionary electromagnetic design paradigm, enabling scientists to build astonishing devices such as invisibility cloaks. Unfortunately, the application of transformation techniques to other branches of physics is often constrained by the structure of the field equations. We develop here a complete transformation method using the idea of analogue spacetimes. The method is general and could be considered as a new paradigm for controlling waves in different branches of physics, from acoustics in quantum fluids to graphene electronics. As an application, we derive an analogue transformation acoustics formalism that naturally allows the use of transformations mixing space and time or involving moving fluids, both of which were impossible with the standard approach. To demonstrate the power of our method, we give explicit designs of a dynamic compressor, a spacetime cloak for acoustic waves and a carpet cloak for a moving aircraft.This work was developed under the framework of the ARIADNA contract 4000104572/11/NL/KML of the European Space Agency. A. M. and J. S.-D. also acknowledge support from Consolider EMET project (CSD2008-00066), A. M. from project TEC2011-28664-C02-02, J.S.-D. from US Office of Naval Research, and C. B. and G. J. from the project FIS2008-06078-C03-01. We thank Reme Miralles for her help with Fig. 2.García Meca, C.; Carloni, S.; Barcelo, C.; Jannes, G.; Sánchez-Dehesa Moreno-Cid, J.; Martínez Abietar, AJ. (2013). Analogue Transformations in Physics and their Application to Acoustics. Scientific Reports. 3(2009):1-5. https://doi.org/10.1038/srep02009S1532009Pendry, J. B., Schurig, D. & Smith, D. R. Controlling electromagnetic fields. Science 312, 1780–1782 (2006).Leonhardt, U. Optical conformal mapping. Science 312, 1777–1780 (2006).Schurig, D. et al. Metamaterial Electromagnetic Cloak at Microwave Frequencies. Science 314, 977–980 (2006).Shalaev, V. M. Transforming Light. Science 322, 384–386 (2008).Greenleaf, A., Kurylev, Y., Lassas, M. & Uhlmann, G. Invisibility and inverse problems. B. Am. Math. Soc. 46, 55–97 (2009).Genov, D. A., Zhang, S. & Zhang, X. Mimicking celestial mechanics in metamaterials. Nat. Phys. 5, 687–692 (2009).Chen, H., Chan, C. T. & Sheng, P. Transformation optics and metamaterials. Nat. Mater. 9, 387–396 (2010).Leonhardt, U. & Philbin, T. Geometry and light. The science of invisibility (Dover Publications, 2010).Pendry, J. B., Aubry, A., Smith, D. R. & Maier, S. A. Transformation Optics and Subwavelength Control of Light. Science 337, 549 (2012).Post, E. G. Formal Structure of Electromagnetics: General Covariance and Electromagnetics (Interscience Publishers, New York, 1962).Cummer, S. A. & Schurig, D. One path to acoustic cloaking. New J. Phys. 9, 45 (2007).Chen, H. & Chan, C. T. Acoustic cloaking in three dimensions using acoustic metamaterials. Appl. Phys. Lett. 91, 183518 (2007).Norris, A. N. Acoustic metafluids. J. Acoust. Soc. Am. 125, 839 (2009).Chen, H. & Chan, C. T. Acoustic cloaking and transformation acoustics. J. Phys. D: Appl. Phys. 43, 113001 (2010).Zhang, S., Genov, D. A., Sun, C. & Zhang, X. Cloaking of Matter Waves. Phys. Rev. Lett. 100, 123002 (2008).McCall, M. W., Favaro, A., Kinsler, P. & Boardman, A. A spacetime cloak, or a history editor. J. Opt. 13, 024003 (2011).Fridman, M., Farsi, A., Okawachi, Y. & Gaeta, A. L. Demonstration of temporal cloaking. Nature 481, 62–65 (2012).Cummer, S. A. & Thompson, R. T. Frequency conversion by exploiting time in transformation optics. J. Opt. 13, 024007 (2011).Barceló, C., Liberati, S. & Visser, M. Analogue Gravity. Living Rev. Relativity 14, 3 (2011).Visser, M. Acoustic black holes: Horizons, ergospheres and Hawking radiation. Class. Quant. Grav. 15, 1767 (1998).Barceló, C. & Jannes, G. A Real Lorentz-FitzGerald contraction. Found. Phys. 38, 191 (2008).Bergmann, P. G. The Wave Equation in a Medium with a Variable Index of Refraction. J. Acoust. Soc. Am. 17, 329 (1946).Torrent, D., Håkansson, A., Cervera, F. & Sánchez-Dehesa, J. Homogenization of two-dimensional clusters of rigid rods in air. Phys. Rev. Lett. 96, 204302 (2006).Torrent, D. & Sánchez-Dehesa, J. Effective parameters of clusters of cylinders embedded in a nonviscous fluid or gas. Phys. Rev. B 74, 224305 (2006).Unruh, W. G. Experimental black hole evaporation? Phys. Rev. Lett. 46, 1351 (1981).Li, J. & Pendry, J. B. Hiding under the Carpet: A New Strategy for Cloaking. Phys. Rev. Lett. 101, 203901 (2008).Popa, B. I., Zigoneanu, L. & Cummer, S. A. Experimental acoustic ground cloak in air. Phys. Rev. Lett. 106, 253901 (2011).Garay, L. J., Anglin, J. R., Cirac, J. I. & Zoller, P. Black holes in Bose-Einstein condensates. Phys. Rev. Lett. 85, 4643 (2000).Lahav, O., Itah, A., Blumkin, A., Gordon, C. & Steinhauer, J. Realization of a sonic black hole analogue in a Bose-Einstein condensate. Phys. Rev. Lett. 105, 240401 (2010).Castro Neto, A. H., Guinea, F., Peres, N. M. R., Novoselov, K. S. & Geim, A. K. The electronic properties of graphene. Rev. Mod. Phys. 81, 109 (2009).Cortijo, A. & Vozmediano, M. A. H. Electronic properties of curved graphene sheets. Europhys. Lett. 77, 47002 (2007).Vakil, A. & Engheta, N. Transformation optics using graphene. Science 332, 1291 (2011)

Stochastic Gravity: Theory and Applications

Whereas semiclassical gravity is based on the semiclassical Einstein equation with sources given by the expectation value of the stress-energy tensor of quantum fields, stochastic semiclassical gravity is based on the Einstein-Langevin equation, which has in addition sources due to the noise kernel. In the first part, we describe the fundamentals of this new theory via two approaches: the axiomatic and the functional. In the second part, we describe three applications of stochastic gravity theory. First, we consider metric perturbations in a Minkowski spacetime, compute the two-point correlation functions of these perturbations and prove that Minkowski spacetime is a stable solution of semiclassical gravity. Second, we discuss structure formation from the stochastic gravity viewpoint. Third, we discuss the backreaction of Hawking radiation in the gravitational background of a black hole and describe the metric fluctuations near the event horizon of an evaporating black holeComment: 100 pages, no figures; an update of the 2003 review in Living Reviews in Relativity gr-qc/0307032 ; it includes new sections on the Validity of Semiclassical Gravity, the Stability of Minkowski Spacetime, and the Metric Fluctuations of an Evaporating Black Hol

Metabolic control in a nationally representative diabetic elderly sample in Costa Rica: patients at community health centers vs. patients at other health care settings

<p>Abstract</p> <p>Background</p> <p>Costa Rica, like other developing countries, is experiencing an increasing burden of chronic conditions such as diabetes mellitus (DM), especially among its elderly population. This article has two goals: (1) to assess the level of metabolic control among the diabetic population age ≥ 60 years old in Costa Rica, and (2) to test whether diabetic elderly patients of community health centers differ from patients in other health care settings in terms of the level of metabolic control.</p> <p>Methods</p> <p>Data come from the project CRELES, a nationally representative study of people aged 60 and over in Costa Rica. This article analyzes a subsample of 542 participants in CRELES with self-reported diagnosis of diabetes mellitus. Odds ratios of poor levels of metabolic control at different health care settings are computed using logistic regressions.</p> <p>Results</p> <p>Lack of metabolic control among elderly diabetic population in Costa Rica is described as follows: 37% have glycated hemoglobin ≥ 7%; 78% have systolic blood pressure ≥ 130 mmHg; 66% have diastolic blood pressure ≥ 80 mmHg; 48% have triglycerides ≥ 150 mg/dl; 78% have LDL ≥ 100 mg/dl; 70% have HDL ≤ 40 mg/dl. Elevated levels of triglycerides and LDL were higher in patients of community health centers than in patients of other clinical settings. There were no statistical differences in the other metabolic control indicators across health care settings.</p> <p>Conclusion</p> <p>Levels of metabolic control among elderly population with DM in Costa Rica are not that different from those observed in industrialized countries. Elevated levels of triglycerides and LDL at community health centers may indicate problems of dyslipidemia treatment among diabetic patients; these problems are not observed in other health care settings. The Costa Rican health care system should address this problem, given that community health centers constitute a means of democratizing access to primary health care to underserved and poor areas.</p

Passive smoking in babies: The BIBE study (Brief Intervention in babies. Effectiveness)

Background: There is evidence that exposure to passive smoking in general, and in babies in particular, is an important cause of morbimortality. Passive smoking is related to an increased risk of pediatric diseases such as sudden death syndrome, acute respiratory diseases, worsening of asthma, acute-chronic middle ear disease and slowing of lung growth. The objective of this article is to describe the BIBE study protocol. The BIBE study aims to determine the effectiveness of a brief intervention within the context of Primary Care, directed to mothers and fathers that smoke, in order to reduce the exposure of babies to passive smoking (ETS). Methods/Design: Cluster randomized field trial (control and intervention group), multicentric and open. Subject: Fathers and/or mothers who are smokers and their babies (under 18 months) that attend pediatric services in Primary Care in Catalonia. The measurements will be taken at three points in time, in each of the fathers and/or mothers who respond to a questionnaire regarding their baby's clinical background and characteristics of the baby's exposure, together with variables related to the parents' tobacco consumption. A hair sample of the baby will be taken at the beginning of the study and at six months after the initial visit (biological determination of nicotine). The intervention group will apply a brief intervention in passive smoking after specific training and the control group will apply the habitual care. Discussion: Exposure to ETS is an avoidable factor related to infant morbimortality. Interventions to reduce exposure to ETS in babies are potentially beneficial for their health. The BIBE study evaluates an intervention to reduce exposure to ETS that takes advantage of pediatric visits. Interventions in the form of advice, conducted by pediatric professionals, are an excellent opportunity for prevention and protection of infants against the harmful effects of ETS

Chronic Melatonin Administration Reduced Oxidative Damage and Cellular Senescence in the Hippocampus of a Mouse Model of Down Syndrome

Previous studies have demonstrated that melatonin administration improves spatial learning and memory and hippocampal long-term potentiation in the adult Ts65Dn (TS) mouse, a model of Down syndrome (DS). This functional benefit of melatonin was accompanied by protection from cholinergic neurodegeneration and the attenuation of several hippocampal neuromorphological alterations in TS mice. Because oxidative stress contributes to the progression of cognitive deficits and neurodegeneration in DS, this study evaluates the antioxidant effects of melatonin in the brains of TS mice. Melatonin was administered to TS and control mice from 6 to 12 months of age and its effects on the oxidative state and levels of cellular senescence were evaluated. Melatonin treatment induced antioxidant and antiaging effects in the hippocampus of adult TS mice. Although melatonin administration did not regulate the activities of the main antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase) in the cortex or hippocampus, melatonin decreased protein and lipid oxidative damage by reducing the thiobarbituric acid reactive substances (TBARS) and protein carbonyls (PC) levels in the TS hippocampus due to its ability to act as a free radical scavenger. Consistent with this reduction in oxidative stress, melatonin also decreased hippocampal senescence in TS animals by normalizing the density of senescence-associated â-galactosidase positive cells in the hippocampus. These results showed that this treatment attenuated the oxidative damage and cellular senescence in the brain of TS mice and support the use of melatonin as a potential therapeutic agent for age-related cognitive deficits and neurodegeneration in adults with DS

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment

Background High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. Methods We used data for exposure to risk factors by country, age group, and sex from pooled analyses of populationbased health surveys. We obtained relative risks for the eff ects of risk factors on cause-specifi c mortality from metaanalyses of large prospective studies. We calculated the population attributable fractions for- each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the eff ects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specifi c population attributable fractions by the number of disease-specifi c deaths. We obtained cause-specifi c mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the fi nal estimates. Findings In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10\ub78 million deaths, 95% CI 10\ub71\u201311\ub75) of deaths from these diseases in 2010 were attributable to the combined eff ect of these four metabolic risk factors, compared with 67% (7\ub71 million deaths, 6\ub76\u20137\ub76) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined eff ects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. Interpretation The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing eff ect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the globalresponse to non-communicable diseases