Electronic Structure and Spectro-Structural Correlations of Fe(III)Zn(II) Biomimetics for Purple Acid Phosphatases: Relevance to DNA Cleavage and Cytotoxic Activity

Purple acid phosphatases (PAPs) are a group of metallohydrolases that contain a dinuclear Fe(II)M(II) center (M(II) = Fe, Mn, Zn) in the active site and are able to catalyze the hydrolysis of a variety of phosphoric acid esters. The dinuclear complex [(H(2)O)Fe(III)(mu-OH)Zn(II)(L-H)](CIO(4))(2) (2) with the ligand 2-[N-bis(2-pyridylmethyl)aminomethyl]-4-methyl-6-[N-(2-pyridylmethyl)(2-hydroxybenzyl) aminomethyl]phenol (H(2)L-H) has recently been prepared and is found to closely mimic the coordination environment of the Fe(III)Zn(II) active site found in red kidney bean PAP (Neves et al. J. Am. Chem. Soc. 2007, 129, 7486). The biomimetic shows significant catalytic activity in hydrolytic reactions. By using a variety of structural, spectroscopic, and computational techniques the electronic structure of the Fe(III) center of this biomimetic complex was determined. In the solid state the electronic ground state reflects the rhombically distorted Fe(III)N(2)O(4) octahedron with a dominant tetragonal compression align ad along the mu-OH-Fe-O(phenolate) direction. To probe the role of the Fe-O(phenolate) bond, the phenolate moiety was modified to contain electron-donating or -withdrawing groups (-CH(3), -H, -Br, -NO(2)) in the 5-position. Tie effects of the substituents on the electronic properties of the biomimetic complexes were studied with a range of experimental and computational techniques. This study establishes benchmarks against accurate crystallographic struck ral information using spectroscopic techniques that are not restricted to single crystals. Kinetic studies on the hydrolysis reaction revealed that the phosphodiesterase activity increases in the order -NO(2)<- Br <- H <- CH(3) when 2,4-bis(dinitrophenyl)phosphate (2,4-bdnpp) was used as substrate, and a linear free energy relationship is found when log(k(cat)/k(0)) is plotted against the Hammett parameter a. However, nuclease activity measurements in the cleavage of double stranded DNA showed that the complexes containing the electron-withdrawing -NO(2) and electron-donating CH3 groups are the most active while the cytotoxic activity of the biomimetics on leukemia and lung tumoral cells is highest for complexes with electron-donating groups.

Relação da imunoexpressão da bmp-2, bmpr-ia e bmpr-ii com o perfil clínico-patológico em carcinoma epidermóide de lábio inferior

Currently, bone morphogenetic proteins (BMPs) have effective participation in the growth of malignancies. Knowing that there are few studies involving BMPs and oral squamous cell carcinoma, this work constitutes an immunohistochemical study of BMP-2, BMPR IA and BMPR II in squamous cell carcinomas (SCC) of the lower lip relating to the clinical and pathological aspects of this lesion. The sample consisted of 40 cases of SCC of the lower lip, being 20 cases of SCC of the lower lip with regional metastasis and 20 cases without metastasis. We evaluated the intensity of expression (score 1 to mark absent / weak, score 2 for high ) and was found the percentage of labeled cells, where the score was 1 cases with 0 to 50% of positive cells, score 2 with 51 to 75% of positive cells, and score 3 more than 75% of positive cells. The sample comprised 72.5% of men with a mean age of 65.8 years, there was a predominance of stage II and 52.5% of the carcinomas were classified as low grade, being carcinoma with metastasis presenting most cases (70%) as carcinomas of high malignancy grade (p = 0.004). The largest number of cases of SCC of the lower lip that were in stages I / II (61, 9%) were classified as carcinomas of low grade malignancy and carcinomas in stages III / IV were classified as high-grade tumors (p = 0, 024). The BMP-2 showed strong intensity of immunostaining in 82.5%, BMPR-IA showed 55% of cases with an intensity of immunostaining absent / weak and BMPR-II showed 85% of cases with an intensity of immunostaining absent / weak. Only the protein BMPR-IA were significantly associated with all clinic-pathological parameters studied, metastasis (p <0.001), TNM (p <0.001) and histological grade of malignancy with (p = 0.028). The percentage of positive cells, all markers showed the highest number of cases with more than 75% of positive cells (score 3) and only BMPR-II showed statistical difference when related to the presence and absence of metastasis (p = 0.049 ). We conclude that there is disturbance in the BMP signaling pathway in EC-mediated lower lip and that high expression of BMP-2 associated with the expression of BMPR-IA and BMPR-II are associated with metastasis in carcinoma

Economia política da arte moderna II/ notas para uma sistematização provisória

Paradigma tradicional de excelência artesanal, com que meios pode a pintura responder à abstração do trabalho e à sua ordenação serial, inerentes à modernização capitalista? O texto presente busca sistematizar os momentos decisivos de um percurso que se estende de Manet (1832-1883) a Rothko (1903-1970). Constitui o capítulo conclusivo de uma investigação sobre a transformação crítica do modo de pintar em modo de fabricação, fundado na superação reflexiva da dicotomia entre trabalho intelectual e corporal, imposta historicamente à sociedade. Atualizada criticamente e assinalando um fecho possível do processo da arte moderna, a pintura de Rothko põe-se como a negação de todo aspecto individual da pintura e de unidade orgânica e monádica da obra. Alcança-se assim o último termo de um processo; termo que assinala o fim do ciclo da autonomia estética como forma ligada à liberdade do sujeito, idealizado como natureza desinteressada. Para o trabalho de resistência contra a aceleração da barbárie é fundamental doravante levar em conta os fatores de heteronomia supraindividuais que, se não logram controlar toda a produção, detêm a hegemonia na esfera da circulação.

Cediranib Plus FOLFOX/CAPOX Versus Placebo Plus FOLFOX/CAPOX in Patients With Previously Untreated Metastatic Colorectal Cancer: A Randomized, Double-Blind, Phase III Study (HORIZON II)

Purpose Cediranib is a highly potent inhibitor of vascular endothelial growth factor (VEGF) signaling with activity against all three VEGF receptors. HORIZON II [Cediranib (AZD2171, RECENTIN) in Addition to Chemotherapy Versus Placebo Plus Chemotherapy in Patients With Untreated Metastatic Colorectal Cancer] assessed infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (FOLFOX/CAPOX) with or without cediranib in patients with previously untreated metastatic colorectal cancer (mCRC). Patients and Methods Eligible patients were initially randomly assigned 1:1:1 to receive cediranib (20 or 30 mg per day) or placebo plus FOLFOX/CAPOX. In an early analysis of this and two other cediranib studies (HORIZON I [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Previously Treated Metastatic Colorectal Cancer] and HORIZON III [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Untreated Metastatic Colorectal Cancer]), the 20-mg dose met the predefined criteria for continuation. Subsequent patients were randomly assigned 2: 1 to the cediranib 20 mg or placebo arms. Progression-free survival (PFS) and overall survival (OS) were coprimary end points. Results In all, 860 patients received cediranib 20 mg (n = 502) or placebo (n = 358). The addition of cediranib to FOLFOX/CAPOX resulted in PFS prolongation (hazard ratio [HR], 0.84; 95% CI, 0.73 to 0.98; P = .0121; median PFS, 8.6 months for cediranib v 8.3 months for placebo) but had no impact on OS (HR, 0.94; 95% CI, 0.79 to 1.12; P = .5707; median OS, 19.7 months for cediranib v 18.9 months for placebo). There were no significant differences in the secondary end points of objective response rate, duration of response, or liver resection rate. Median chemotherapy dose-intensity was decreased by approximately 10% in patients treated with cediranib. Adverse events (AEs) associated with cediranib were manageable. Conclusion Addition of cediranib 20 mg to FOLFOX/CAPOX resulted in a modest PFS prolongation, but no significant difference in OS. The cediranib AE profile was consistent with those from previous studies. Because of the lack of improvement in OS, cediranib plus an oxaliplatin-based regimen cannot be recommended as a treatment for patients with mCRC. J Clin Oncol 30:3596-3603. (C) 2012 by American Society of Clinical Oncology

Cost-Effectiveness Analysis for Surgical, Angioplasty, or Medical Therapeutics for Coronary Artery Disease 5-Year Follow-Up of Medicine, Angioplasty, or Surgery Study (MASS) II Trial

Background-The Second Medicine, Angioplasty, or Surgery Study (MASS II) included patients with multivessel coronary artery disease and normal systolic ventricular function. Patients underwent coronary artery bypass graft surgery (CABG, n = 203), percutaneous coronary intervention (PCI, n = 205), or medical treatment alone (MT, n = 203). This investigation compares the economic outcome at 5-year follow-up of the 3 therapeutic strategies. Methods and Results-We analyzed cumulative costs during a 5-year follow-up period. To analyze the cost-effectiveness, adjustment was made on the cumulative costs for average event-free time and angina-free proportion. Respectively, for event-free survival and event plus angina-free survival, MT presented 3.79 quality-adjusted life-years and 2.07 quality-adjusted life-years; PCI presented 3.59 and 2.77 quality-adjusted life-years; and CABG demonstrated 4.4 and 2.81 quality-adjusted life-years. The event-free costs were $9071.00 for MT; $19 967.00 for PCI; and $18 263.00 for CABG. The paired comparison of the event-free costs showed that there was a significant difference favoring MT versus PCI (P<0.01) and versus CABG (P<0.01) and CABG versus PCI (P<0.01). The event-free plus angina-free costs were $16 553.00, $25 831.00, and $24 614.00, respectively. The paired comparison of the event-free plus angina-free costs showed that there was a significant difference favoring MT versus PCI (P=0.04), and versus CABG (P<0.001); there was no difference between CABG and PCI (P>0.05). Conclusions-In the long-term economic analysis, for the prevention of a composite primary end point, MT was more cost effective than CABG, and CABG was more cost-effective than PCI.

La gestione dei beni fiscali da parte di Federico II di Svevia: Il "Quaternus excadenciarum capitinate". Edizione e commento

La ricerca è stata incentrata su di una fonte di grande importanza per una più puntuale comprensione della vita del regno di Federico II: il Quaternus excadenciarum Capitinate. Essa ha tenuto presenti le altre fonti coeve: Liber Augustalis, Registro della Cancelleria di Federico II degli anni 1239-1240, fonti cronachistiche. Il Quaternus è un inventario di talune particolari categorie di beni demaniali, le excadencie, la cui concessione è scaduta e pertanto ritornano al fisco. Tali beni sono situati in 33 località del Giustizierato di Capitanata. Senza data, è stato redatto tra il 1249 e il 1250 (risultano inseriti i beni confiscati a Pier della Vigna, bollato di tradimento nel febbraio 1249). Obiettivo della ricerca è stato duplice: 1) analizzare e approfondire le questioni di natura giuridico-istituzionale ed economica implicate nel documento e tentare di ricostruire uno spaccato della Capitanata del XIII sec.; 2) offrire una nuova e più corretta edizione del testo. La prima parte dello studio ha inteso inquadrare il documento nel contesto delle esigenze proprie delle monarchie del tempo di tenere sotto controllo i beni immobili di ciascun regno ed analizzare la politica economica fridericiana (capp. I, II). La seconda parte è stata dedicata agli approfondimenti innanzi ricordati. Essa è struttura in sette capitoli (I. Il Quaternus excadenciarum Capitinate; II. Beni e diritti costituenti le excadencie Capitinate; III. Il Quaternus come specchio di una politica dispotica; IV. La gestione delle excadencie; V. Pesi e misure; VI. Monete e valori; VII. Il Quaternus come documento sullo stato della Capitanata nel XIII secolo). In appendice: tabelle che offrono per ciascuna delle 33 località considerate, puntuali indicazioni dei beni e diritti censiti, dei nomi dei titolari delle concessioni (spesso personaggi di rango) e delle relative rendite.

Normare la vita. Biocontrollo e nuove tecnologie

Questa ricerca, suddivisa in due parti, si concentra sulle problematiche connesse alla normazione della vita e dei corpi delle donne al tempo delle biotecnologie. La Parte I è una genealogia filosofico-politica che ripercorre le tappe analitico-concettuali del dibattito intorno a biopolitica e tecnoscienza, a partire dai contributi teorici di poststrutturalismo e femminismo neomaterialista, e risponde alle domande: Cosa sono diventati i corpi nell’attuale società bio-info-modificata? Qual'è il ruolo delle scienze nelle metamorfosi che interessano soggettività e rapporti di potere? La Parte II è una cartografia dei modi in cui le biotecnologie, riguardanti i corpi delle donne, si sono sviluppate e diffuse. Essa indaga in modo transdisciplinare come in Italia, e più in generale in Europa, sono state normate le tecniche di interruzione volontaria di gravidanza e fecondazione in vitro. Ampio spazio è dedicato ai modi in cui gli attori della bioetica, istituzionale e non, i medici, laici e cattolici, e le case farmaceutiche hanno affrontato questi temi e quello della contraccezione ormonale maschile. Medicina riproduttiva e rigenerativa sono tematizzate sempre in relazione al quadro normativo, per mostrare in che modo esso influenzi l’accesso ai diritti alla salute e all’autodeterminazione delle donne. Il quadro normativo è analizzato, a sua volta, alla luce dei fatti storici più rilevanti e delle culture più diffuse. L’obiettivo della ricerca è duplice: da un lato essa ha il fine di mostrare il modo in cui i corpi delle donne, e la relativa potenza generatrice, siano diventati uno snodo fondamentale nell’articolazione del biocontrollo e nell'apertura dei nuovi mercati legati a medicina riproduttiva e rigenerativa; dall’altro si propone di argomentare come un biodiritto flessibile, a contenuto storico variabile, condiviso e partecipato, sia un’ipotesi praticabile e virtuosa, utile all'eliminazione del gender gap ancora esistente in materia di diritti riproduttivi e sessuali.

Le stelle di Beatrice. Astronomia e astrologia nella "Vita Nova"

Ci sono due luoghi astronomici nella Vita Nova con i quali Dante calcola il tempo in cui si verificano gli episodi principali della storia narrata. Queste nozioni scientifiche contengono implicito un significato astrologico, connesso all’influsso del segno zodiacale dei Gemelli, configurazione astrologica che torna ad ogni anniversario. I Gemelli è il segno zodiacale di Dante, come il poeta afferma nella Commedia: l’invocazione del pellegrino alla costellazione omonima, alla cui influenza egli deve il suo ingegno (Par. XXII, 112-123), riconosce all’astrologia, attraverso il motivo delle qualità personali instillate dagli astri, il compito di esaltare il suo ruolo di poeta divinamente ispirato. L’importanza di questo segno è evidente nella Vita Nova: I Gemelli è probabilmente il segno zodiacale di Beatrice, come il poeta sembra suggerire in VN 1, 3 [II, 2], se si considera il fatto che, al verificarsi del primo incontro tra Dante e Beatrice, la fanciulla non aveva ancora iniziato il suo nono anno di vita («quasi»). Il colore dell’abito di Beatrice, «sanguigno» (VN 1, 4; II, 3), può riferirsi al temperamento della donna, e confermare così la sua appartenenza a quel segno. In seguito, la buona influenza del segno torna in VN 19, 4 [XXIX, 1], il capitolo dedicato alla morte di Beatrice. La donna muore l’8 giugno 1290, così anche la sua morte accade in Gemelli. Tutti gli eventi della Vita Nova sono garantiti dalle stelle, e Dante nel «libello» non fa che esaltare l’importanza dell’azione dei cieli influenti sulla vita umana.

XIAP discriminates between type I and type II FAS-induced apoptosis

FAS (also called APO-1 and CD95) and its physiological ligand, FASL, regulate apoptosis of unwanted or dangerous cells, functioning as a guardian against autoimmunity and cancer development. Distinct cell types differ in the mechanisms by which the 'death receptor' FAS triggers their apoptosis. In type I cells, such as lymphocytes, activation of 'effector caspases' by FAS-induced activation of caspase-8 suffices for cell killing, whereas in type II cells, including hepatocytes and pancreatic beta-cells, caspase cascade amplification through caspase-8-mediated activation of the pro-apoptotic BCL-2 family member BID (BH3 interacting domain death agonist) is essential. Here we show that loss of XIAP (X-chromosome linked inhibitor of apoptosis protein) function by gene targeting or treatment with a second mitochondria-derived activator of caspases (SMAC, also called DIABLO; direct IAP-binding protein with low pI) mimetic drug in mice rendered hepatocytes and beta-cells independent of BID for FAS-induced apoptosis. These results show that XIAP is the critical discriminator between type I and type II apoptosis signalling and suggest that IAP inhibitors should be used with caution in cancer patients with underlying liver conditions.

Historia de' riti Ebraici : vita, & osservanza degli Ebrei di questi tempi ; nuovamente ristampata, e con diligenza ricorretta

di Leon Modena

SwissScoring--a nationwide survey of SAPS II assessing practices and its accuracy.

OBJECTIVE The first description of the simplified acute physiology score (SAPS) II dates back to 1993, but little is known about its accuracy in daily practice. Our purpose was to evaluate the accuracy of scoring and the factors that affect it in a nationwide survey. METHODS Twenty clinical scenarios, covering a broad range of illness severities, were randomly assigned to a convenience sample of physicians or nurses in Swiss adult intensive care units (ICUs), who were asked to assess the SAPS II score for a single scenario. These data were compared to a reference that was defined by five experienced researchers. The results were cross-matched with demographic characteristics and data on the training and quality control for the scoring, structural and organisational properties of each participating ICU. RESULTS A total of 345 caregivers from 53 adult ICU providers completed the SAPS II evaluation of one clinical scenario. The mean SAPS II scoring was 42.6 ± 23.4, with a bias of +5.74 (95%CI 2.0-9.5) compared to the reference score. There was no evidence of bias variation according to the case severity, ICU size, linguistic area, profession (physician vs. nurse), experience, initial SAPS II training, or presence of a quality control system. CONCLUSION This nationwide survey revealed substantial variability in the SAPS II scoring results. On average, SAPS II scoring was overestimated by more than 13%, irrespective of the profession or experience of the scorer or of the structural characteristics of the ICUs.

Gruppe in Silber ausgeführt [Illustration] : (Geschenk der Petersburger Juden an Kaiser Nikolaus II. anlässlich seiner Krönung)

Mark Antokolski

Ms. germ. qu. 103 - Vita Jesu Christi in deutscher Bearbeitung

Vorbesitzer: Familie von Schellenberg; W.V. Villenbach; Universität Frankfurt am Main

Description and chemical composition of ferromanganese encrustations and deposits in the Atlantic Ocean from R/V Atlantis II cruises 20, 42, 60, 85; R/V Chain cruise 35; R/V Knorr cruise 61 and RRS Shackleton cruise 75/1 stations

Chemical and mineralogical compositions of ferromanganese oxide coatings on rocks dredged from the New England Seamounts, the Sierra Leone Rise and the Mid-Atlantic Ridge near the Equator have been determined in an investigation of regional differences in Atlantic ferromanganese deposits. Most encrustations are clearly of hydrogenous origin, consisting mainly of todorokite and delta MnO2, but several recovered from the equatorial fracture zones may be hydrothermal accumulations. Differences in the chemistry of the water column and in growth rates of the ferromanganese coatings may be important in producing this regional contrast in composition. Fine-scale changes in element abundances within the encrustations indicate that the nature of the substrate has little influence on compositional variations.