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Concerning computational physics, web services are conceived as mathematical units that are experienced in different systems that offer service composition. Due to the exponential growth of web services and their deployment on cloud platforms, quality of service parameters have now become an essential factor when searching for and selecting services that must satisfy specific non-functional requirements of a user application. A variety of service components are highly configurable and are dynamic scenarios because a significant number of services can meet these requirements. This work analyzes the systemic perspective of approaches for the selecting and searching of web services that have specifications of optimization strategies based on the configurable quality of service parameters with test scenarios in cloud environments that have a considerable number of services as input. The study shows that policies based on artificial intelligence and related areas are the ones with the most significant convergence, and the approaches analyzed to give a perspective of future work aimed at strategies based on automatic learning.

Background There is limited information describing the presenting characteristics and outcomes of patients with schizophrenia (SCZ) requiring hospitalization for coronavirus disease 2019 (COVID-19). Aims We aimed to compare the clinical characteristics and outcomes of COVID-19 SCZ patients with those of non-SCZ patients. Method This was a case-control study of COVID-19 patients admitted to 4 AP–HM/AMU acute care hospitals in Marseille, southern France. COVID-19 infection was confirmed by a positive result on polymerase chain reaction testing of a nasopharyngeal sample and/or on chest computed scan among patients requiring hospital admission. The primary outcome was in-hospital mortality. The secondary outcome was intensive care unit (ICU) admission. Results A total of 1092 patients were included. The overall in-hospital mortality rate was 9.0%. The SCZ patients had an increased mortality compared to the non-SCZ patients (26.7% vs. 8.7%, P = 0.039), which was confirmed by the multivariable analysis after adjustment for age, sex, smoking status, obesity and comorbidity (adjusted odds ratio 4.36 [95% CI: 1.09–17.44]; P = 0.038). In contrast, the SCZ patients were not more frequently admitted to the ICU than the non-SCZ patients. Importantly, the SCZ patients were mostly institutionalized (63.6%, 100% of those who died), and they were more likely to have cancers and respiratory comorbidities. Conclusions This study suggests that SCZ is not overrepresented among COVID-19 hospitalized patients, but SCZ is associated with excess COVID-19 mortality, confirming the existence of health disparities described in other somatic diseases.

Introduction: It has been reported that overeating may be the greatest avoidable cause of cancer in nonsmokers and obesity increases postmenopausal breast cancer (BC) risk. Calorie restriction reduces BC incidence in experimental animals, but the evidence in humans is more limited. This study analyzes the association between female BC risk and excessive or restricted calorie consumption in Spain. Methods: EpiGEICAM is a multicenter case-control study including 1017 matched pairs (age & town) of incident BC cases and healthy controls in 14 regions in Spain. Participants filled a structured questionnaire. Average calorie intake (cals) during the 5 years previous to diagnosis (cases) or interview (controls) was estimated using a validated 117-item semiquantitative food-frequency questionnaire. Expected calorie intake (cals_exp) was calculated from a linear regression model taking into account the basal metabolic rate (Sabounchi's meta-regression) and the amount of physical activity performed by each woman (5 categories). For each woman the prediction interval (99%) of cals_exp was used to consider her calorie intake as “normal” (NCI) (cals inside this interval –the reference group-), “excesive” (ECI) (cals>upper limit of the interval) or “restricted” (RCI) (cals Results: After excluding participants with extreme calorie intake, 973 case-control pairs were considered. Average number of calories was higher in BC cases (1990 kcals) than controls (1897 kcals) P=0.001). Women with RCI (cals40% of the predicted limit) showed increased BC risk (OR=1.92; P=0.001), being this effect stronger in postmenopausal women (OR=2.81; Pheterogenity=0.001). By pathologic subtypes, no statistically significant differences were observed, but ECI (over 40%) was strongly associated with HER2+ tumors (OR=2.05, P=0.021). No differences in the effect of ECI or RCI were observed by levels of BMI, tobacco or HRT. Conclusion: After taking BMI into account, excessive energy intake increases BC risk, while relative caloric restriction seems to have a protective effect. Moderate calorie restriction, in combination with regular physical activity, could be a good strategy for BC prevention. Funding:Scientific Foundation of the Spanish Association Against Cancer (AECC), SEOM, FECMA, Cerveza y Salud Foundation, FIS CD110/00018 Citation Format: Pollán M, Castelló A, Martín M, Ruiz A, Casas AM, Baena JM, Antolin S, Ramos M, Garcia-Saénz JA, Muñoz M, Lluch A, de Juan A, Jara C, Sánchez Rovira P, Antón A, Chacón JI, Arcusa A, Jimeno MA, Bezares S, Carrasco E, Pérez-Gómez B, Lope V. Overeating and breast cancer risk by pathologic subtypes: EpiGEICAM study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-09-08.

Based on the monoamine oxidase (MAO) inhibition properties of aminoheterocycles with a carbonitrile group we have carried out a systematic exploration to discover new classes of carbonitriles endowed with dual MAO and AChE inhibitory activities, and Aβ anti-aggregating properties. Eighty-three nitrile-containing compounds, 13 of which are new, were synthesized and evaluated. in vitro screening revealed that 31, a new compound, presented the best lead for trifunctional inhibition against MAO A (0.34 μM), MAO B (0.26 μM), and AChE (52 μM), while 32 exhibited a lead for selective MAO A (0.12 μM) inhibition coupled to AChE (48 μM) inhibition. Computational analysis revealed that the malononitrile group can find an advantageous position with the aromatic cleft and FAD of MAO A or MAO B. However, the total binding energy can be handicapped by an internal penalty caused by twisting of the ligand molecule and subsequent disruption of the conjugation (32 in MAO B compared to the conjugated 31). Conjugation is also important for AChE as well as the hydrophilic character of malononitrile that allows this group to be in close contact with the aqueous environment as seen for 83. Although the effect of 31 and 32 against Aβ, was very weak, the effect of 63 and 65, and of the new compound 75, indicated that these compounds were able to disaggregate Aβ fibrils. The most effective was 63, a (phenylhydrazinylidene)propanedinitrile derivative that also inhibited MAO A (1.65 μM), making it a potential lead for Alzheimer's disease application., European Cooperation in Science and Technology, Grant/Award Numbers: STSM CM1103-29512, STSM D34-05989, STSMCM1103- 29510; Portuguese Foundation for Science and Technology, Grant/Award Number: FCT -Project PTDC/SAUNEU/ 64151/2006 (MCC); Slovak Research and Development Agency (MM); Slovak Research and Development Agency; Foundation for Science and Technology

The lack of polarity sensing fluorophores with OFF-ON features when increasing the environment polarity has limited the monitoring of biological processes that involve an increase in local hydrophilicity. In this work, replacement of a hydroxyl group by a dimethylamino group transformed solvatochromic ICT naphthalimide- and quinolimide-based fluorophores into reversed solvatochromic ones, with higher emission in polar than in apolar environments. Excited-state dynamics studies, TD-DFT calculations, X-ray and NMR support the existence of a folded conformation for the 2-(dimethylamino)ethyl chain upon the imide ring in apolar solvents, where the dimethylamino group would quench the fluorescence by a PET effect, while in polar solvents the chain has an extended conformation, where the PET is hindered. These PET fluorophores have given rise to H2O and pH sensors in organic solvents as well as to bright macrophage cytoplasm imaging probes.

There are optimization problems in the Cloud for the selection of web services, due to the large number of services available by different cloud providers and the diversity of quality of service parameters of each of them. This work proposes the adaptation of a pattern recognition model based on the systematic functioning of the brain called Ar2p for the selection of web services in composition activities in Cloud environments. The web serice are represented as patterns to be recognized by Ar2p, which determines the necessary and sufficient web services that constitute the composition of services that meet its functional and non-functional requirements. The services composition and activity selection have been formalized through a logical-mathematical model of web service recognition mechanisms in two steps, one that describes the syntactic search of the service and the second, which offers filtering through quality of service parameters. An adaptive implementation of the final model allows its recognition modules to be provided with any desired optimization strategy.

Efficient enzymatic synthesis of lactosyl-oligofructosides (LFOS) with a degree of polymerization from 4 to 8 was achieved in the presence of sucrose:lactosucrose and sucrose:lactose mixtures by transfructosylation reaction. The main synthesized LFOS which consist of β-2,1-linked fructose to lactosucrose: β-d-galactopyranosyl-(1 → 4)-α-d-glucopyranosyl-[(1 → 2)-β-d-fructofuranosyl]n-(1 → 2)-β-d-fructofuranoside (where n refers to the number of transferred fructose moieties) was structurally characterized by nuclear magnetic resonance (NMR). The maximum formation of LFOS was 81% (in weight with respect to the initial amount of lactosucrose) and was obtained after 24 h of transfructosylation reaction based on sucrose:lactosucrose (250 g L− 1 each) catalyzed by an inulosucrase from Lactobacillus gasseri DSM 20604 (IS). The production of LFOS in the presence of sucrose:lactose mixtures required a previous high-yield lactosucrose synthesis step catalyzed by using a levansucrase from Bacillus subtilis CECT 39 (LS) before the inulosucrase-catalyzed reaction. This novel one-pot bi-enzymatic system led to the synthesis of about 22% LFOS in weight, with respect to the initial amount of lactose (250 g L− 1). The results revealed a high specificity for the substrate involved in the inulosucrase-catalyzed reaction given that, although lactosucrose (O-β-d-galactopyranosyl-(1 → 4)-O-α-d-glucopyranosyl-(1 → 2)-β-d-fructofuranoside) acted as a strong acceptor of β-2,1-linked fructose, lactose (β-d-galactopyranosyl-(1 → 4)-α-d-glucose) was found to be an extremely weak acceptor., This work has been financed by project AGL2011-27884 from the Ministerio de Ciencia e Innovación. M. Díez-Municio is supported by CSIC through JAE-Pre Programme co-funded by ESF. M. Herrero thanks MICINN for his “Ramón y Cajal” contract.

Stereochemical and steric control of the relative spatial arrangement of the chromophoric units in multichromophoric systems offers an interesting strategy for raising unusual and appealing light-induced emission states. To explore and exploit this strategy, a series of conformationally restricted boron–dipyrromethene (BODIPY) dimers were designed by using tartaric acid as a symmetrical connector between the boron atoms of the dyes. The variety of stereoisomeric forms available for this bis(hydroxy acid) allows the relative spatial orientation of the chromophoric units in the dimer to be modified, which thus opens the door to modulation of the photophysical and chiroptical properties of the new bichromophoric systems. Chromophore alkylation introduces an additional level of control through distance-dependent steric interactions between the BODIPY units in the dimer, which also modulates their relative spatial disposition and properties.

Background: Bone is the most common lesion in metastatic breast cancer (MBC) patients. Pain due to bone disease is a very limiting and frequent symptom. We evaluated prospectively the BOMET-QoL questionnaire in the context of normal clinical practice, irrespectively of the treatment received, in order to assess the impact of bone metastasis on the Health-Related Quality of Life (HRQoL) of patients with MBC. Material and Methods: This is an observational, prospective, multicenter study conducted in Spain. Patients diagnosed of MBC with bone disease and a life expectancy ≥ 8 months were eligible. Patients completed the bone metastasis Quality of life questionnaire (BOMET-QoL), a Visual Analogue Scale (VAS) for pain and a self-perception of health status item at baseline and 4, 8, 12, 16, 20 and 24 months thereafter. Socio-demographic, clinical and therapeutic data were also collected. Assuming a level of significance of 0.05 and a 20% drop-out rate, 174 patients were to be included in the study in order to estimate the QoL with a precision of ±3.75. Results: From October-2007 to May-2010 172 evaluable patients were included in 15 Spanish institutions. Median age was 58 years (29.6-88.6). Bone disease was most frequently localized in the backbone (76.2% of patients), pelvis (53.5%) and ribs (45.3%). Seventy patients (40.5%) had visceral disease. Most patients (147, 88.5%) had ECOG 0-1. At study entry, 65 patients were receiving analgesic therapy (44 with NSAIDs and 21 with opioids) and 136 were receiving bisphosphonates. The values obtained on the BOMET-QoL and pain VAS scores at the different visits showed a moderate positive correlation (0.2-0.5; p Conclusions: The BOMET-QoL questionnaire is a consistent instrument to evaluate the HRQoL of patients with bone metastasis from breast cancer in regular clinical practice conditions, with regards to cross-sectional and longitudinal validity, feasibility and sensitivity to change. BOMET-QoL is easy to understand and can be completed in a short time by the majority of patients. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-10-02.

Nonafluorobutanesulfonyl azide is an advantageous alternative to triflyl azide for the efficient synthesis of sulfonyl azides from sulfonamides in terms of its higher reactivity, lower cost, and non-hazardous nature. The reagent has proven its utility in a novel synthesis of N,N′-disulfonylamidines from available sulfonamides by a copper-catalyzed two-step, one-pot sequential process with added terminal alkynes. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The preparation of the first structurally well-defined Janus nanocube showing two chemically distinct opposed faces is described. The synthetic approach is based on a highly efficient and symmetrycontrolled CuAAC functionalization of an octa-azido cubic silsesquioxane with a conformationally constrained tetra-alkyne with an appropriate spatial orientation of the triple bonds., with two sets of orthogonally reactive functional groups. We gratefully acknowledge financial support by the Spanish Ministerio de Ciencia e Innovación (project MAT2010-20646- C04-03) and Ministerio de Economía y Competitividad (project MAT2014-51937-C3-1-P). We also acknowledge the Spanish Ministerio de Economía y Competitividad for a FPI contract to A. B., and CSIC for a JAEDOC contract to J. R. S. and a JAEPRE contract to M. E. P.-O., and for support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).

We report herein the silver-catalyzed cycloisomerization of readily available N-(prop-2-yn-1-yl)pyridine-2-amines as a new and practical method for the synthesis of differently substituted 3-methylimidazo[1,2-a]pyridines. The isomerization reactions proceeded under mild reactions conditions to give good yields and excellent regioselectivity. A DFT-based mechanistic analysis is also reported.

The production of new bioactive oligosaccharides is currently garnering much attention for their potential use as functional ingredients. This work addresses the enzymatic synthesis and NMR structural characterization of 2-α-d-glucopyranosyl-lactose derived from sucrose:lactose and sucrose:cheese whey permeate mixtures by using a Leuconostoc mesenteroides B-512F dextransucrase. The effect of synthesis conditions, including concentration of substrates, molar ratio of donor/acceptor, enzyme concentration, reaction time, and temperature, on the formation of transfer products is evaluated. Results indicated that cheese whey permeate is a suitable material for the synthesis of 2-α-d-glucopyranosyl-lactose, giving rise to yields around 50% (in weight respect to the initial amount of lactose) under the optimum reaction conditions. According to its structure, this trisaccharide is an excellent candidate for a new prebiotic ingredient, due to the reported high resistance of α-(1→2) linkages to the digestive enzymes in humans and animals, as well as to its potential selective stimulation of beneficial bacteria in the large intestine mainly attributed to the two linked glucose units located at the reducing end that reflects the disaccharide kojibiose (2-α-d-glucopyranosyl-d-glucose). These findings could contribute to broadening the use of important agricultural raw materials, such as sucrose or cheese whey permeates, as renewable substrates for enzymatic synthesis of oligosaccharides of nutritional interest., This work has been financed by projects POII10-0178-4685 from Junta de Comunidades de Castilla-La Mancha and European regional development fund (ERDF) and projects AGL2011-27884 and Consolider Ingenio 2010 FUN-C-FOOD CSD2007-00063 both from Ministerio de Ciencia e Innovación. M.D.-M. thanks CSIC for a JAE predoctoral fellowship.

We report the photo-oxidation of some di-2-benzothiazolylmethane derivatives and discuss the structure of the isolated methanols and ketones.

Background Thanks to an automated treatment of the medical information of the Departmental Commission of the Special Education in the Var, set up since 1999, under the responsability of an epidemiologist doctor, it is possible to measure the incidence rates of the children recognized as been handicapped. Methods This study is the first one performed on the basis of good-quality and reliable medical and administrative informations. Moreover, this study has yielded thinking on the criteria of handicap definition and nomenclature to be used to define psychic deficiency. Results The occurrence rate of children recognized as handicapped by the Departmental Commission of the Var is 2.04%. The rate of children with a psychic deficiency recognized by the Commission is 1.25%. These rates are 2.5 times higher among boys than girls. Psychic deficiencies occurs mainly between five and nine years of age, at the entry to the primary school. The western part of the department displays rates of nevrotic, reactional, instrumental functions, and training disorders that are higher than those of the other geographical areas. For the eastern part of the department, the rates of psychoses, pathologies of the personality and evolutionary disorders are the highest. The distribution of declared pathologies probably reflects equipment of the medical sector of childpsychiatry and distribution of the liberal assumptions of responsability. The geographical area of Draguignan is significantly under-equipped with medico-social structures but is characterized by a high rate of children with a psychic handicap. Conclusion The Law of February 11 2005 for chance and equal right, stipulates a counting of the people affected by handicap and the underlying pathologies, to define the ethiology of the handicap, to improve the accompaniment of those people and to develop actions aimed at reducing the incapacities and at the prevention of risks. It is within the Departmental houses of the handicapped person that the information systems will have to collect a minimum common set of standardized data to meet requirements of the Law of February 2005 and to take part in the planification of the means of medico-social establishment.

BACKGROUND: According to the "World Cancer Research Fund" and the "American Institute of Cancer Research" (WCRF/AICR) one in four cancer cases could be prevented through a healthy diet, weight control and physical activity. OBJECTIVE: To explore the association between the WCRF/AICR recommendations and risk of breast cancer. METHODS: During the period 2006 to 2011 we recruited 973 incident cases of breast cancer and 973 controls from 17 Spanish Regions. We constructed a score based on 9 of the WCRF/AICR recommendations for cancer prevention:: 1)Maintain adequate body weight; 2)Be physically active; 3)Limit the intake of high density foods; 4)Eat mostly plant foods; 5)Limit the intake of animal foods; 6)Limit alcohol intake; 7)Limit salt and salt preserved food intake; 8)Meet nutritional needs through diet; S1)Breastfeed infants exclusively up to 6 months. We explored its association with BC by menopausal status and by intrinsic tumor subtypes (ER+/PR+ & HER2-; HER2+; ER&PR-&HER2-) using conditional and multinomial logistic models respectively. RESULTS: Our results point to a linear association between the degree of noncompliance and breast cancer risk. Taking women who met 6 or more recommendations as reference, those meeting less than 3 showed a three-fold excess risk (OR=2.98(CI95%:1.59-5.59)), especially for postmenopausal women (OR=3.60(CI95%:1.24;10.47)) and ER+/PR+&HER2- (OR=3.60(CI95%:1.84;7.05)) and HER2+ (OR=4.23(CI95%:1.66;10.78)) tumors. Noncompliance of recommendations regarding the consumption of foods and drinks that promote weight gain in premenopausal women (OR=2.24(CI95%:1.18;4.28); p for interaction=0.014) and triple negative tumors (OR=2.93(CI95%:1.12-7.63)); the intake of plant foods in postmenopausal women (OR=2.35(CI95%:1.24;4.44)) and triple negative tumors (OR=3.48(CI95%:1.46-8.31)); and the alcohol consumption in ER+/PR+&HER2- tumors (OR=1.52 (CI95%:1.06-2.19)) showed the strongest associations. CONCLUSION: Breast cancer prevention might be possible by following the "World Cancer Research Fund" and the "American Institute of Cancer Research" recommendations, even in settings like Spain, where a high percentage of women already comply with many of them. This study was funded by Fundación Científica Asociación Española Contra el Cáncer (AECC) (Scientific Foundation of the Spanish Association Against Cancer), Fundación Cerveza y Salud 2005 (Beer and Health Foundation 2005), Sociedad Española de Oncología Médica (SEOM) (Spanish Society of Medical Oncology), Fondo de Investigación Sanitaria (FIS) (Health Research Fund) CD110/00018, Federación de Mujeres con Cáncer de Mama (FECMA) (Association of Women with Breast Cancer). None of the funders intervened in the design, data collection and analysis, decision to publish, or preparation of the manuscript Sí

A suitable solid-phase approach, based on Fmoc/tBu methodology and on the use of 2-chlorotrityl resin, allowed a rapid and efficient preparation of new GPE analogues. Most of the synthesized tripeptides displayed glutamate receptor binding affinity comparable to that of GPE, but only a few derivatives showed significant neuroprotective activity., This work has been supported by the Spanish Ministry of Education and Science (SAF 2003-07207-C02 and CT2004-5358), Comunidad de Madrid (GR/SAL/0850/ 2004), and UTE project FIMA. S.A.A.D.D. holds a predoctoral fellowship from the Ministry of Education for Associated Units to CSIC. D.C. thanks CSIC for a I3P Grant.

We have reinvestigated the reaction of α-pyranosides-2-uloses 13 , 14 , 19 and 24 with DAST and shown that the 1,2-difluorinated compounds 17 , 18 and 25 are produced by a ring-contraction reaction. The reaction of 18 with benzyl alcohol gives the tri-benzyl derivative 26 or compound 27 , depending on the reaction conditions. Treating 17 with 2-naphthol produced the spiranic compounds 29 – 31 . The reaction of 17 with bis(trimethylsilyl)uracil produced the mononucleoside 28 , which preserves the fluorine atom in the more substituted carbon.

Two novel diglycosylated steroidal alkaloids of 5Δ-pregnene nucleus, named obtusine-20(R)-O-[β-thevetopyranosyl-(1→4)-β-cymaropyranoside] and obtusolactam-20(R)-O-[β-thevetopyranosyl-(1→4)-β-cymaropyranoside], together with the known β-sitosteryl-3-O-β-glucopyranoside were isolated from the roots of Cryptolepis obtusa N. E. Br., We thank Mr. Daniel Zunguza of the Faculty of Bi- ology, Eduardo Mondlane University, Mozambique, for his kindly collaboration in plant collection; Mrs. J. Hawkes of the Intercollegiate NMR Service Unit, Department of Chemistry, King's College London; Mr. Peter Haycock of the NMR Service of Queen Mary and West®eld College, London and Mr. Mark Domin of the Mass Spectrometry Service of School of Pharmacy, London. We want also to acknowledge INVOTAN-Portugal for a Ph.D. grant (13/A/94/PO) to Alexandra Paulo.

Il contributo descrive una scultura monolitica in forma di guerriero stante, rinvenuta dagli autori nella valle del Rio Negro della reginoe dei Chimalapas, nella zona di frontiera tra Chiapas e Oaxaca (Messico). Sebbene la scultura sia stata rinvenuta fuori dal suo contesto originale, alcuni elementi stilistici permettono di datarla tentativamente al periodo Postclassico Antico (ca. 1000-1250 d.C.).

The oxidative cyclization of (E,E)-2′-hydroxycinnamylideneacetophenones 1a–e, and (E, E)-2′-benzyloxy-6′-hydroxycinnamylideneacetophenones 1i–l with DMSO/iodine, gave (E)-2-styrylchromones 3a–e,i–l. However, in the case of (E, E)-γ-alkyl-2′-hydroxycinnamylideneacetophenones 1f–h, (E)- and (Z)-2-styrylchromones 3f–h and 4f–h were obtained. The stereochemistry of the (E,E)-cinnamylideneacetophenones 1 and (E)- and (Z)-2-styrylchromones 3 and 4 was established by NOE experiments. The induced daylight photooxidative cyclization of some (E)-2-styrylchromones 3a,f–h gave 12H-benzo[a]xanthene-12-ones 6a,f–h.

Although almost 200-years-old, several unknown aspects remain to be explored of colchicine, the unique available drug for acute flares of gout. In this article, we report density-functional theory (DFT) studies of geometry, energy, and NMR; 1H-, 13C-, and 15N-NMR chemical shifts and some spin-spin coupling constants, including the complete analysis of the saturated part (ring B); the assignment of both enantiomers by NMR using a chiral solvating agent; solid-state NMR experiments of the different forms of natural and racemic colchicine, and IR and vibrational circular dichroism (VCD) studies of these same forms. Copyright © 2014 Verlag Helvetica Chimica Acta AG, Zürich.

BACKGROUND: Although there are solid findings regarding the detrimental effect of alcohol consumption, the existing evidence on the effect of other dietary factors on breast cancer (BC) risk is inconclusive. This study aimed to evaluate the association between dietary patterns and risk of BC in Spanish women, stratifying by menopausal status and tumour subtype, and to compare the results with those of Alternate Healthy Index (AHEI) and Alternate Mediterranean Diet Score (aMED). METHODS: We recruited 1017 incident BC cases and 1017 matched healthy controls of similar age (±5 years) without a history of BC. The association between 'a priori' and 'a posteriori' developed dietary patterns and BC in general and according to menopausal status and intrinsic tumour subtypes (ER+/PR+ and HER2-; HER2+; and ER-/PR- and HER2-) was evaluated using logistic and multinomial regression models. RESULTS: Adherence to the Western dietary pattern was related to higher risk of BC (OR for the top vs the bottom quartile 1.46 (95% CI 1.06-2.01)), especially in premenopausal women (OR=1.75; 95% CI 1.14-2.67). In contrast, the Mediterranean pattern was related to a lower risk (OR for the top quartile vs the bottom quartile 0.56 (95% CI 0.40-0.79)). Although the deleterious effect of the Western pattern was similarly observed in all tumour subtypes, the protective effect of our Mediterranean pattern was stronger for triple-negative tumours (OR=0.32; 95% CI 0.15-0.66 and Pheterogeneity=0.04). No association was found between adherence to the Prudent pattern and BC risk. The associations between 'a priori' indices and BC risk were less marked (OR for the top vs the bottom quartile of AHEI=0.69; 95% CI 0.51-0.94 and aMED=0.74; 95% CI 0.46-1.18)). CONCLUSIONS: Our results confirm the harmful effect of a Western diet on BC risk, and add new evidence on the benefits of a diet rich in fruits, vegetables, legumes, oily fish and vegetable oils for preventing all BC subtypes, and particularly triple-negative tumours. This work was supported by the Fundación Científica Asociación Española Contra el Cáncer (AECC) (Scientific Foundation of the Spanish Association Against Cancer); Fundación Cerveza y Salud 2005 (Beer and Health Foundation 2005); Sociedad Española de Oncología Médica (SEOM) (Spanish Society of Medical Oncology); Federación de Mujeres con Cáncer de Mama (FECMA) (Association of Women with Breast Cancer) and Fondo de Investigación Sanitaria (FIS) (Health Research Fund) CD110/00018.

Nonafluorobutanesulfonyl azide is an advantageous alternative to triflyl azide for the efficient synthesis of sulfonyl azides from sulfonamides in terms of its higher reactivity, lower cost, and non-hazardous nature. The reagent has proven its utility in a novel synthesis of N,N′-disulfonylamidines from available sulfonamides by a copper-catalyzed two-step, one-pot sequential process with added terminal alkynes.

We report herein the silver-catalyzed cycloisomerization of readily available N-(prop-2-yn-1-yl)pyridine-2-amines as a new and practical method for the synthesis of differently substituted 3-methylimidazo[1,2-a]pyridines. The isomerization reactions proceeded under mild reactions conditions to give good yields and excellent regioselectivity. A DFT-based mechanistic analysis is also reported.

We gratefully acknowledge the DGICYT of Spain for financial support (Project No. 92/19) and Dr Jose G. de la Campa for help with the MM+ calculations.

An interesting aspect of neural networks is shown in the elaboration of an evaluation scale for pain in cerebral palsy with severe mental retardation. Because of the diversity of cases, the number of items had to be limited in the final step of statistical validation. Classical analysis on prior data did not allow to decide whether the variability in results is more likely due to the type of disability (i. e., the possibility of pain expression) than to the actual presence of pain. A neural network was used to find implicit relations between the data, with the advantage of having total control on the variables’ status by applying variations in the network architecture. This allowed for the rapid identification more significant item combinations as a function of degree of relationship to pain in cerebral palsy.

The nucleocapsid protein NCp7 of human immunodeficiency virus, type 1, is a key component in the viral life cycle. Since, the first common step of all reported NCp7 activities corresponds to a nucleic acid-binding step, the NCp7 binding parameters to the natural primer tRNA(3Lys) were investigated. Using NCp7 intrinsic fluorescence, we found that (i) in 0.1 M NaCl, NCp7 bound noncooperatively to tRNA(3Lys) with a Kobs = 3.2 x 10(6) M-1 association constant and a n = 6 binding site size, (ii) four ionic interactions were formed in the NCp7.tRNA(3Lys) complex, and (iii) nonelectrostatic factors provided about 60% of the binding energy. These binding parameters were not significantly altered when the natural tRNA(3Lys) was replaced by either an in vitro synthetic tRNA(3Lys) transcript, the heterologous yeast tRNA(Phe) or the structurally unrelated 5 S RNA from Escherichia coli. Moreover, the environment of the intrinsic fluorescent reporters (Trp37 and Trp61) was similar in the various complexes. Finally, experiments performed at low protein concentration provide no evidence of high affinity binding sites. Taken together, our data strongly suggested an essentially nonspecific binding of NCp7 to tRNA(3Lys) and thus did not seem to support a direct role of NCp7, per se, in the selection of tRNA(3Lys) from the pool of cellular tRNAs.

Polyhedral oligosilsesquioxanes (POSS) have recently attracted attention as scaffolds for the synthesis of multivalent bioconjugates. The synthesis of glycosyl-octasilsesquioxanes (glyco-POSS) using a copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition approach is reported. The problems associated with the use of bases or aqueous media in their preparation are investigated and a comprehensive study of the multivalent interaction between the mannosyl-octasilsesquioxanes and a model lectin, concanavalin A (Con A), using an array of complementary biophysical techniques is presented. The possibility to modulate the half-life of POSS conjugates in aqueous solution and the low toxicity of their constituent monomeric organosilanes offers an advantage over other scaffolds in vivo, preventing bioaccumulation and saturation of complementary receptors (lectins). Despite the hydrolysis in water, the octamannosyl-POSS studied shows a 50-fold higher binding affinity to Con A than methyl α-D-mannopyranoside. These experiments suggest that the novel glyco-POSS are attractive compounds for in vivo applications that require multivalent display of glycans., The authors thank the Spanish Ministerio de Ciencia e Innovación (projects CTQ-2006-15515-C02-02/BQU, CTQ2009-14551-C02-02, MAT2010-20646-C04-03, SAF2010-15670, and CTQ2010-15848), the Comunidad de Madrid (project S2009/PPQ-1634 “AVANCAT”), the Junta de Andalucía, and the European Union (FEDER and FSE) for fi nancial support. The authors also thank Ministerio de Ciencia e Innovación for FPU predoctoral contracts to B.T. and A.M.-A., and C.S.I.C. for a JAEPREDOC contract to M.E.P.-O.

The nmr and X-ray diffraction data of the novel ring system furo[3,2-e]imidazo[1,2-c]pyrimidine are reported in this paper. The crystal and molecular structure of this compound (C9H7N3O2·1/2H2O) has been solved at room temperature. Crystals are monoclinic in a space group of P2/n with cell constants a = 9.982(8), b = 13.526(9) and c = 13.981(9) A, β = 107.44(5)°, V = 1800.9 A3, Z = 8, Dx = 1.462 Mg·m−3. The structure was solved by full matrix least square refinement giving a final R = 0.054 (Rw = 0.069) for 1263 reflections (I>3.0σ(I)). The compound is essentially planar, existing in two slightly structural different forms, A and B. These are held in pairs with symmetry related molecules by hydrogen bonds formed with two water molecules. Then the dimeric units are stacked parallel to the c axis to form the tridimensional packing.

Background.The approved capecitabine regimen as monotherapyinmetastaticbreastcancer(MBC)is1,250mg/m 2 twice daily for 2 weeks on and 1 weekoff (Cint). Dose modifications are often required because of severe hand-foot syndrome (HFS).Wetestedacontinuousregimenwithalowerdailydose but a similar cumulative dose in an attempt to reduce the severity of adverse events (AEs) while maintaining efficacy. Methods.We randomized 195 patients with HER-2/neunegativeMBCtocapecitabine800mg/m 2 twicedailythroughoutthe 21-daycycle (Ccont) or to Cintto assess noninferiority in the percentage of patients free of progression at 1 year. Secondary endpoints included efficacy and safety. Associations between polymorphisms in capecitabine metabolismrelated genes and drug response were assessed. Results.The percentage of patients free of progression at 1 year was 27.3% with Cint versus 25.3% with Ccont (difference of 22.0%; 95% confidence interval: 215.5% to 11.5%, exceeding the 15% deemed noninferior). Differences regarding other efficacy variables were also not found. Grade 3–4 HFS was the most frequent AE (41.1% in Cint vs. 42.3% in Ccont). Grade 3–4 neutropenia, thrombocytopenia, diarrhea, and stomatitis were more frequent with Cint. A 59 untranslated region polymorphism in the carboxylesterase 2 gene was associated with HFS. One polymorphism in cytidine deaminase and two in thymidine phosphorylase were associated with survival. Conclusion. Ourstudywasunabletoshow noninferioritywith the continuous capecitabine regimen (Ccont) compared with the approved intermittent regimen (Cint). Further investigation is required to improve HFS. Polymorphisms in several genes might contribute to interindividual differences in response to capecitabine.The Oncologist 2015;20:1–2 DISCUSSION In this patient population (Table 1), continuous, lower daily dosesofcapecitabinewerenotshowntobenoninferiorinefficacy tothestandardscheduledespitemaintainingthesamecumulative dose and dose intensity (Fig. 1).The percentage of patients free ofprogressionat1yearwere27.3%with1,250mg/m 2 twicedaily for 2 weeks on and 1 week off versus 25.3% with 800 mg/m 2 twice daily throughout the 21-day cycle (difference of 22.0%; 95% confidence interval: 215.5 to 11.5%), meaning that the margin deemed noninferior by the study design (15%) was exceeded. Median progression-free survival (PFS) and overall survival (OS) were numerically superior (although nonsignificant) with the approved intermittent administration schedule. Hand-foot syndrome (HFS) was not different between arms.

The tributyltin hydride mediated free radical cyclization of sugar derivatives 4–6 gives the annulated furanoses 9–11 in good yield and high diastereoselectivity. This protocol is a new synthetic route for the preparation of complex cyclopentanoid molecules.

Two novel diglycosylated steroidal alkaloids of 5D-pregnene nucleus, named obtusine-20(R)-O-[b-thevetopyranosyl-(1 44)-b-cymaropyranoside] and obtusolactam-20(R)-O-[b-thevetopyranosyl-(1 44)-b-cymaropyranoside], together with the known b-sitosteryl-3-O-b-glucopyranoside were isolated from the roots of Cryptolepis obtusa N. E. Br. # 2000 Elsevier Science Ltd. Allrights reserved. Keywords: Cryptolepis obtusa; Periplocaceae or Asclepiadaceae; Saponins; 5D-pregnene steroidal alkaloids 1. IntroductionThe genus Cryptolepis R. Br. includes about 20species distributed throughout the tropical regions ofAfrica, Madagascar, Asia, Australia and Papua NewGuinea. The genus is assigned either to the Periplocoi-deae subfamily of the Asclepiadaceae or to the newlycreated family Periplocaceae (Hutchinson & Dalziel,1963; Cronquist, 1981), a taxon poorly investigatedfrom the chemical point of view. Continuing our stu-dies on the chemistry and biological activity of Crypto-lepis species (Paulo, Pimentel, Viegas, Pires, Duarte C Paulo, Duarte & Gomes, 1994; Paulo,Gomes & Houghton, 1995; Paulo, Gomes, Duarte,Perrett & Houghton, 1997; Paulo, Gomes, Steele, War-hurst & Houghton, in press) the roots of Cryptolepisobtusa N. E. Br. were analysed for their major second-ary metabolites. The aqueous extracts of roots of C.obtusa are traditionally used in Mozambique as ananti-abortive remedy, vermifuge and to treat abdomi-nal pains (Mendes & Jansen, 1984). To our knowledge,no phytochemical work has been reported on the rootsof this species. We describe herein the isolation andstructural elucidation, on the basis of extensive high-field NMR studies, of two new diglycosylated steroidalalkaloids (1 and 2) with a novel 5D-pregnene skeleton.2. Results and discussionTLC using general spray reagents (Wagner, Bladt &Zgainski, 1984) of the chloroformic crude extract ofthe roots of C. obtusa revealed the presence of alka-loidal and non-alkaloidal saponins as major constitu-ents. The chloroformic extract was chromatographedon a silica gel column and the alkaloid fractionobtained was further fractionated and purified bysemi-preparative HPLC and prep. TLC to a•ord com-pounds 1 and 2.Compound 1 gave positive reaction with the Dra-gendor• spray reagent and for that reason it was sus-pected to be an alkaloid. The molecular formula ofC

We have reinvestigated the reaction of α-pyranosides-2-uloses 13 , 14 , 19 and 24 with DAST and shown that the 1,2-difluorinated compounds 17 , 18 and 25 are produced by a ring-contraction reaction. The reaction of 18 with benzyl alcohol gives the tri-benzyl derivative 26 or compound 27 , depending on the reaction conditions. Treating 17 with 2-naphthol produced the spiranic compounds 29 – 31 . The reaction of 17 with bis(trimethylsilyl)uracil produced the mononucleoside 28 , which preserves the fluorine atom in the more substituted carbon.

The tributyltin hydride mediated free radical cyclization of sugar derivatives 4–6 gives the annulated furanoses 9–11 in good yield and high diastereoselectivity. This protocol is a new synthetic route for the preparation of complex cyclopentanoid molecules.

3,4,5-Triamino-2 H -l,2,6-thiadiazine 1,1-dioxide 1 undergoes intermolecular cyclization, under different reaction conditions, to give a novel tricyclic system which shows interesting chelating properties toward ammonium ion. A spectroscopic study of this new tricycle and a mechanistic study of the reaction using an 15N-labelled intermediate has been carried out.

Glucopyranosides of methyl-1,2,6-thiadiazin-3(2H)-one 1,1-dioxides have been synthesized and their rotational isomerism studied. Two of them exist, in solution, as mixtures of syn : anti rotamers, at room temperature. In the case of the diglucoside, the barriers to rotation about both glycosidic bonds have been calculated by dynamic 13C NMR.