New potential antitumoral fluorescent tetracyclic thieno[3,2-b]pyridine derivatives: interaction with DNA and nanosized liposomes

Fluorescence properties of two new potential antitumoral tetracyclic thieno[3,2-b]pyridine derivatives were studied in solution and in liposomes of DPPC (dipalmitoyl phosphatidylcholine), egg lecithin (phosphatidylcholine from egg yolk; Egg-PC) and DODAB (dioctadecyldimethylammonium bromide). Compound 1, pyrido[2',3':3,2]thieno[4,5-d]pyrido[1,2-a]pyrimidin-6-one, exhibits reasonably high fluorescence quantum yields in all solvents studied (0.20 ≤ ΦF ≤ 0.30), while for compound 2, 3-[(p-methoxyphenyl)ethynyl]pyrido[2',3':3,2]thieno[4,5-d]pyrido[1,2-a]pyrimidin-6-one, the values are much lower (0.01 ≤ ΦF ≤ 0.05). The interaction of these compounds with salmon sperm DNA was studied using spectroscopic methods, allowing the determination of intrinsic binding constants, Ki = (8.7 ± 0.9) × 103 M-1 for compound 1 and Ki = (5.9 ± 0.6) × 103 M-1 for 2, and binding site sizes of n = 11 ± 3 and n = 7 ± 2 base pairs, respectively. Compound 2 is the most intercalative compound in salmon sperm DNA (35%), while for compound 1 only 11% of the molecules are intercalated. Studies of incorporation of both compounds in liposomes of DPPC, Egg-PC and DODAB revealed that compound 2 is mainly located in the hydrophobic region of the lipid bilayer, while compound 1 prefers a hydrated and fluid environment

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

Indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (KP1019) and its Na+ analogue (KP1339) are two of the most prominent non-platinum antitumor metal complexes currently undergoing clinical trials. After intravenous administration, they are known to bind to human serum albumin (HSA) in a noncovalent manner. To elucidate their HSA binding sites, displacement reactions with the established site markers warfarin and dansylglycine as well as bilirubin were monitored by spectrofluorimetry, ultrafiltration-UV-vis spectrophotometry, and/or capillary zone electrophoresis. Conditional stability constants for the binding of KP1019 and KP1339 to sites I and II of HSA were determined, indicating that both Ru(III) compounds bind to both sites with moderately strong affinity (log K (1)' = 5.3-5.8). No preference for either binding site was found, and similar results were obtained for both metal complexes, demonstrating low influence of the counter ion on the binding event

Experimental Gastric Carcinogenesis in Cebus apella Nonhuman Primates

The evolution of gastric carcinogenesis remains largely unknown. We established two gastric carcinogenesis models in New-World nonhuman primates. In the first model, ACP03 gastric cancer cell line was inoculated in 18 animals. In the second model, we treated 6 animals with N-methyl-nitrosourea (MNU). Animals with gastric cancer were also treated with Canova immunomodulator. Clinical, hematologic, and biochemical, including C-reactive protein, folic acid, and homocysteine, analyses were performed in this study. MYC expression and copy number was also evaluated. We observed that all animals inoculated with ACP03 developed gastric cancer on the 9th day though on the 14th day presented total tumor remission. In the second model, all animals developed pre-neoplastic lesions and five died of drug intoxication before the development of cancer. The last surviving MNU-treated animal developed intestinal-type gastric adenocarcinoma observed by endoscopy on the 940th day. The level of C-reactive protein level and homocysteine concentration increased while the level of folic acid decreased with the presence of tumors in ACP03-inoculated animals and MNU treatment. ACP03 inoculation also led to anemia and leukocytosis. The hematologic and biochemical results corroborate those observed in patients with gastric cancer, supporting that our in vivo models are potentially useful to study this neoplasia. In cell line inoculated animals, we detected MYC immunoreactivity, mRNA overexpression, and amplification, as previously observed in vitro. In MNU-treated animals, mRNA expression and MYC copy number increased during the sequential steps of intestinal-type gastric carcinogenesis and immunoreactivity was only observed in intestinal metaplasia and gastric cancer. Thus, MYC deregulation supports the gastric carcinogenesis process. Canova immunomodulator restored several hematologic measurements and therefore, can be applied during/after chemotherapy to increase the tolerability and duration of anticancer treatments

A quantitative synthesis of the medicinal ethnobotany of the Malinké of Mali and the Asháninka of Peru, with a new theoretical framework

<p>Abstract</p> <p>Background</p> <p>Although ethnomedically and taxonomically guided searches for new medicinal plants can improve the percentage of plants found containing active compounds when compared to random sampling, ethnobotany has fulfilled little of its promise in the last few decades to deliver a bounty of new, laboratory-proven medicinal plants and compounds. It is quite difficult to test, isolate, and elucidate the structure and mechanism of compounds from the plethora of new medicinal plant uses described each year with limited laboratory time and resources and the high cost of clinical trials of new drug candidates.</p> <p>Methods</p> <p>A new quantitative theoretical framework of mathematical formulas called "relational efficacy" is proposed that should narrow down this search for new plant-derived medicines based on the hypothesis that closely related plants used to treat closely related diseases in distantly related cultures have a higher probability of being effective because they are more likely to be independent discoveries of similar plant compounds and disease mechanisms. A prerequisite to this hypothesis, the idea that empirical testing in traditional medicine will lead to choosing similar medicinal plants and therefore the medicinal flora of two distant cultures will prove to be more similar than their general flora, is tested using resampling statistics on cross-cultural field data of the plants used by the Malinké of Mali and the Asháninka of Peru to treat the diseases malaria, African sleeping sickness, Chagas' disease, leishmaniasis, diabetes, eczema, asthma, and uterine fibroids.</p> <p>Results</p> <p>In this case, the similarity of the medicinal floras is found to be significantly greater than the similarity of the general floras, but only when the diseases in question are grouped into the categories of parasitic and autoimmune diseases.</p> <p>Conclusion</p> <p>If the central theoretical framework of this hypothesis is shown to be true, it will allow the synthesis of medicinal plant information from around the world to pinpoint the species with the highest potential efficacy to take into the laboratory and analyze further, ultimately saving much field and laboratory time and resources.</p> <p><b>Spanish abstract</b></p> <p>Las búsquedas que utilizan la etnomedicina y la taxonomía para descubrir nuevas plantas medicinales, pueden aumentar la probabilidad de éxito de encontrar compuestos químicos activos en plantas, en comparación con las búsquedas aleatorias. A pesar de lo anterior, en las últimas décadas, la etnobotánica no ha cumplido con las expectativas de proveer numerosas plantas medicinales y químicos nuevos una vez examinados en el laboratorio. Cada año se describen una plétora de plantas medicinales y sus usos, sin embargo las limitaciones de tiempo y recursos en los laboratorios, unidos al alto coste de los ensayos clínicos de las drogas potenciales, hacen muy difícil probar, aislar, y elucidar la estructura y el mecanismo de los compuestos de estas plantas. Se propone un nuevo marco teórico cuantitativo cuyo fin es focalizar la búsqueda de nueva plantas medicinales. Este marco teórico está basado en la hipótesis que las plantas cercanamente relacionadas, usadas para tratar enfermedades cercanamente relacionadas en culturas distantemente relacionadas, tienen una eficacia potencial más alta, debido a que es más probable que estos hallazgos sean descubrimientos independientes de compuestos químicos similares. Parte de esta hipótesis, que las escogencias racionales se hacen para elegir plantas medicinales similares y que la flora medicinal de dos culturas distantes es más similar que su flora general, se probó usando métodos estadísticos de remuestreo con datos de campo de la comunidad Malinké de Malí y de la Asháninka de Perú, y las enfermedades de paludismo, enfermedad africana del sueño, enfermedad de Chagas, leishmania, diabetes, eczema, asma, y fibromas uterinos. Se encontró, en este caso, que la similitud de las floras medicinales es significativamente mayor a la similitud de las floras generales, solamente cuando las enfermedades analizadas se agruparon en las categorías de enfermedades parasitarias y enfermedades autoinmunes. Si se demostrara que las otras partes de esta hipótesis son ciertas, se podría sintetizar la información sobre plantas medicinales alrededor del mundo, para establecer así las plantas potencialmente más eficaces para llevarlas al laboratorio y analizarlas más profundamente.</p> <p><b>French abstract</b></p> <p>Par rapport aux recherches menées de façon aléatoire, les recherches effectuées par des critères ethnobotaniques et taxonomiques ont de meilleures chances à découvrir de nouvelles plantes médicinales à produit chimique actifs. Pendant les dernières décennies pourtant, l'ethnobotanique a réalisé peu de ces promesses à révéler un grand nombre de plantes médicinales et de nouveaux produits chimiques, testés au laboratoire. Avec les ressources limitées pour la recherche au laboratoire et le coût élevé des épreuves cliniques pour trouver de nouveaux candidats aux médicaments, il est difficile d'étudier, d'isoler et d'élucider la structure et le mécanisme des produits chimiques de chacune des nombreuses plantes médicinales (et les utilisations de ces plantes) décrites chaque année. Nous proposons une nouvelle technique théorique et quantitative pour préciser la recherche de nouvelles plantes médicinales; elle est basée sur l'hypothèse que les plantes étroitement apparentées, employées pour traiter les maladies étroitement apparentées dans les cultures très éloignées les unes des autres, ont une potentialité d'efficacité supérieure parce qu'elles représentent la découverte indépendante des propriétés chimiques semblables des plantes. Une partie de cette hypothèse-qui démontre que la sélection des plantes médicinales semblables est un choix rationnel et qu'il y a davantage de ressemblance dans la flore médicinale de deux cultures éloignées que dans leur flore générale-est examinée par un re-échantillonnage des données de recherches effectuées parmi les Malinké au Mali et les Asháninka au Pérou, en particulier sur la malaria, la maladie africaine du sommeil, la maladie de Chagas, la leishmania, le diabète, l'eczéma, l'asthme et les fibromes utérins. Dans ces cas précis, la similitude de la flore médicinale s'avère sensiblement plus grande que la similitude de la flore générale, mais seulement quand les maladies en question sont regroupées ensemble comme maladies parasitaires et auto-immunitaires. Si cette hypothèse est prouvée, elle permettra la synthèse des informations recueillies sur les plantes médicinales du monde entier pour en sélectionner de façon plus précise celles qui sont les plus efficaces et qui méritent analyse plus approfondie au laboratoire.</p> <p><b>Asháninka abstract</b></p> <p>Aayiantyarori iròpero aavintane, ontzimatye ancovacovatero ayotero ovaqueraripaye incashi iyoyetziri ashaninka, ayotzityaro aajatzi iyotane viracocha paitachari "quimica" ancantero aaca oshintsinka inchashipaye. Atziri yotacotzirori cametsa, ishtoriajacotzirori iyotane ashaninkapaye te iroñàrantero maaroni ocaratzi yamenacotaqueri laboratorioki. Aaviantyarori cametsa, ayotacotero aavintarontsiyetatsiri osamani antzimaventero ishtoriatacotaro, aajatzi osheki opinata ampinaventero aparopaye inchashi, acoviriqui ayotacotero, osaretsikipaye. Tzimatsi ovaquerari quenquishiriantsitatsiri ero opinata osheki ashitoriatacotero aparopaye inchashi, asampiyetatyrey pashinipaye atziri saicatsiri intaina puitarika inchasshi yavintari, ajatzirica oshiyaro ayotzi aaca, quemetachari atziri saikatsiri nampitsiki malinke aajatzi ishiyari ashaninka saicatsiri peruki, tzimatsi inchashi aajatzi yaavintari osheki okamètsatzi aririka anteri mantsiyarentsi icantaitziri ompetarentsi catsirentsi, pochokirentsi, patsarontsi(matatsi) ashipetate maaroni, ampochavathate, ancainikentsite, oncatsithakite tsinani. Aririka añaker aajatzi ahiyaro inchashi yaavintayetari pashinipaye atziri intainasatzi irdotake ahitoriatacoperoteri anàashityard aavintarontsi ovamairiri shithanentsi, onàshitaavintarontsi tzicaacoventairi ero antane mantsiyarentsi. Omanperotatyarica iròperotzi avintarontsi, oshitovake laboratorioki aritaque iyoitanaquero maaroni quipatsiki iroperori avintarontsi.</p

Evaluating the Psychometric Quality of Social Skills Measures: A Systematic Review

Introduction - Impairments in social functioning are associated with an array of adverse outcomes. Social skills measures are commonly used by health professionals to assess and plan the treatment of social skills difficulties. There is a need to comprehensively evaluate the quality of psychometric properties reported across these measures to guide assessment and treatment planning. Objective - To conduct a systematic review of the literature on the psychometric properties of social skills and behaviours measures for both children and adults. Methods - A systematic search was performed using four electronic databases: CINAHL, PsycINFO, Embase and Pubmed; the Health and Psychosocial Instruments database; and grey literature using PsycExtra and Google Scholar. The psychometric properties of the social skills measures were evaluated against the COSMIN taxonomy of measurement properties using pre-set psychometric criteria. Results - Thirty-Six studies and nine manuals were included to assess the psychometric properties of thirteen social skills measures that met the inclusion criteria. Most measures obtained excellent overall methodological quality scores for internal consistency and reliability. However, eight measures did not report measurement error, nine measures did not report cross-cultural validity and eleven measures did not report criterion validity. Conclusions - The overall quality of the psychometric properties of most measures was satisfactory. The SSBS-2, HCSBS and PKBS-2 were the three measures with the most robust evidence of sound psychometric quality in at least seven of the eight psychometric properties that were appraised. A universal working definition of social functioning as an overarching construct is recommended. There is a need for ongoing research in the area of the psychometric properties of social skills and behaviours instruments

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years