Estudo sobre o manejo dos resíduos biológicos classe A4.

A complexidade na implantação de processos seguros para o manejo dos resíduos biológicos em diversas classes de riscos, conforme a Resolução RDC no. 306/2004 ANVISA, é um desafio para administrações públicas e Unidades de Serviços de Saúde (USS) do país. O objetivo deste trabalho é avaliar o atual manejo destes resíduos, em particular os da classe de risco A4. A pesquisa tem caráter exploratório e qualitativo consistindo de revisão bibliográfica do estado da arte sobre o tema e de levantamento de dados. A coleta das informações foi realizada em Unidades de Serviços de Saúde (USS); órgãos ambientais; nas visitas técnicas em empresas tratadoras de resíduos; em gerenciadores de aterros sanitários; e através de entrevistas com especialistas no assunto. A título de exemplo, dois casos sobre o manejo dos resíduos biológicos foram estudados: no Rio de Janeiro (RJ) e em Orlando (Flórida - USA). A relevância da pesquisa está na constatação das mudanças em andamento no setor de saneamento no país, como o passo importante que esta sendo dado com a aprovação da Política Nacional de Resíduos Sólidos (PNRS). Para se atingir melhores indicadores de saúde e meio ambiente, torna-se imprescindível o gerenciamento integrado dos resíduos com a incorporação de métodos, técnicas e abordagens atuais. Quanto aos resíduos biológicos, existe aqui uma tendência em se adotar o modelo americano, mais rígido, que considera vários resíduos, comuns para nós, como sendo infectantes, e não separa estes resíduos biológicos em classes, colocando-os todos no mesmo grau de risco. Para a realidade brasileira tal rigidez de conceitos aumenta o risco no manejo para todos os envolvidos na cadeia e o custo da operação como um todo, tornando-a impraticável na maior parte do país. No Brasil a gestão inadequada dos resíduos em muitas USS e a grande quantidade de lixões existentes, com a presença de catadores de materiais recicláveis, são processos inseguros e para melhorar este quadro, é fundamental a implementação da PNRS. Nossa legislação se mostra eficiente, mas necessitamos de maior monitoramento e avaliação, e uma consequente ação educativa. Em complemento deve haver maior determinação de responsabilidades, aplicação de punições e empreender reformas substanciais nas áreas de educação e saúde pública. Espera-se que este trabalho contribua com a construção de um modelo de manejo adequado dos resíduos biológicos, sobretudo os de classe A4, de forma mais sustentável e segura. Para estudos futuros, indica-se uma avaliação estratégica sobre a sustentabilidade técnica e econômica do modelo de gerenciamento destes resíduos a ser realizada em contexto mais amplo. Para tal, recomenda-se a extensão da pesquisa a outros estados da federação, assim como o acompanhamento das tendências mundiais para classificação dos riscos dos Resíduos de Serviços de Saúde e de sua destinação mais adequada, principalmente em países com realidades semelhantes à nossa.

BubR1 is required for the mitotic block induced by combretastatin-A4 and a novel cis-restricted ß-lactam analogue in human cancer cells

BubR1 is a well-defined guardian of the mitotic spindle, initiating mitotic arrest in response to the lack of tension and/or chromosome alignment across the mitotic plate. However, the role of BubR1 in combretastatin-induced cell death remains unknown. In this study, we describe the effects of combretastatin A-4 (CA-4) and a synthetic cis-restricted 3,4-diaryl-2-azetidinone (ß-lactam) analogue (CA-432) on the modulation and phosphorylation of BubR1 in human cervical cancer-derived cells. We demonstrate that CA-4 and CA-432 depolymerise the microtubular network of human cervical carcinoma-derived cells. Both compounds induced the disassembly of the microtubules and the loss of microtubule tension led to the early phosphorylation of BubR1 and the late cleavage of BubR1. The phosphorylation of BubR1 correlated with the onset of G2M cell cycle arrest whilst the cleavage of BubR1 coincided with apoptosis induced by the combretastatins. The combretastatin-induced apoptosis and the BubR1 cleavage were caspase-dependent. In vitro enzyme digests demonstrated that combretastatin-activated BubR1 is a substrate for caspase-3. Gene silencing of BubR1 with small interfering RNA severely compromised combretastatin-induced G2M cell cycle arrest with a corresponding increase in the formation of polyploid cells in both cervical and breast cancer-derived cells. In summary, BubR1 is required to maintain the G2M arrest and limit the formation of polyploid cells in response to continued combretastatin exposure. Moreover, substitution of the ethylene bridge with 3,4-diaryl-2-azetidinone did not alter the tubulin depolymerising properties or the subsequent mitotic spindle checkpoint response to CA-4 in human cancer cells.

The vascular targeting agent combretastatin-A4 and a novel cis-Restricted {beta}-Lactam Analogue, CA-432, induce apoptosis in human chronic myeloid leukemia cells and ex vivo patient samples including those displaying multidrug resistance

Combretastatin-A4 (CA-4) is a natural derivative of the African willow tree Combretum caffrum. CA-4 is one of the most potent antimitotic components of natural origin, but it is, however, intrinsically unstable. A novel series of CA-4 analogs incorporating a 3,4-diaryl-2-azetidinone (β-lactam) ring were designed and synthesized with the objective to prevent cis -trans isomerization and improve the intrinsic stability without altering the biological activity of CA-4. Evaluation of selected β-lactam CA-4 analogs demonstrated potent antitubulin, antiproliferative, and antimitotic effects in human leukemia cells. A lead β-lactam analog, CA-432, displayed comparable antiproliferative activities with CA-4. CA-432 induced rapid apoptosis in HL-60 acute myeloid leukemia cells, which was accompanied by depolymerization of the microtubular network, poly(ADP-ribose) polymerase cleavage, caspase-3 activation, and Bcl-2 cleavage. A prolonged G(2)M cell cycle arrest accompanied by a sustained phosphorylation of mitotic spindle checkpoint protein, BubR1, and the antiapoptotic proteins Bcl-2 and Bcl-x(L) preceded apoptotic events in K562 chronic myeloid leukemia (CML) cells. Molecular docking studies in conjunction with comprehensive cell line data rule out CA-4 and β-lactam derivatives as P-glycoprotein substrates. Furthermore, both CA-4 and CA-432 induced significantly more apoptosis compared with imatinib mesylate in ex vivo samples from patients with CML, including those positive for the T315I mutation displaying resistance to imatinib mesylate and dasatinib. In summary, synthetic intrinsically stable analogs of CA-4 that display significant clinical potential as antileukemic agents have been designed and synthesized.

Karta öfver Finland (Sektionen A4)

1 kartta :, vär. ;, 50,4 x 43,1 cm, lehti 58 x 50,6 cm

Expression of cancer-testis antigens MAGE-A4 and MAGE-C1 in oral squamous cell carcinoma

Background Tumor markers are genes or their products expressed exclusively or preferentially in tumor cells and cancer-testis antigens (CTAs) form a group of genes with a typical expression pattern expressed in a variety of malignant neoplasms. CTAs are considered potential targets for cancer vaccines. It is possible that the CTA MAGE-A4 (melanoma antigen) and MAGE-C1 are expressed in carcinoma of the oral cavity and are related with survival. Methods This study involved immunohistochemical analysis of 23 patients with oral squamous cell carcinoma (SCC) and was carried out using antibodies for MAGE-A4 and MAGE-C1. Fisher's exact test and log-rank test were used to evaluate the results. Results The expression of the MAGE-A4 and MAGE-C1 were 56.5% and 47.8% without statistical difference in studied variables and survival. Conclusion The expression of at least 1 CTA was present in 78.3% of the patients, however, without correlation with clinicopathologic variables and survival. (c) 2011 Wiley Periodicals, Inc. Head Neck, 2012

Concept and realization of the A4 compton backscattering polarimeter at MAMI

The main concern of the A4 parity violation experiment at the Mainzer Microtron accelerator facility is to study the electric and magnetic contributions of strange quarks to the charge and magnetism of the nucleons at the low momentum transfer region. More precisely, the A4 collaboration investigates the strange quarks' contribution to the electric and magnetic vector form factors of the nucleons. Thus, it is important that the A4 experiment uses an adequate and precise non-destructive online monitoring tool for the electron beam polarization when measuring single spin asymmetries in elastic scattering of polarized electrons from unpolarized nucleons. As a consequence, the A4 Compton backscattering polarimeter was designed and installed such that we can take the absolute measurement of the electron beam polarization without interruption to the parity violation experiment. The present study shows the development of an electron beam line that is called the chicane for the A4 Compton backscattering polarimeter. The chicane is an electron beam transport line and provides an interaction region where the electron beam and the laser beam overlap. After studying the properties of beam line components carefully, we developed an electron beam control system that makes a beam overlap between the electron beam and the laser beam. Using the system, we can easily achieve the beam overlap in a short time. The electron control system, of which the performance is outstanding, is being used in production beam times. And the study presents the development of a scintillating fiber electron detector that reduces the statistical error in the electron polarization measurement. We totally redesigned the scintillating fiber detector. The data that were taken during a 2008 beam time shows a huge background suppression, approximately 80 percent, while leaving the Compton spectra almost unchanged when a coincidence between the fiber detector and the photon detector is used. Thus, the statistical error of the polarization measurement is reduced by about 40 percent in the preliminary result. They are the significant progress in measuring a degree of polarization of the electron beam.

Bestimmung der Analysierstärke des A4-Compton-Rückstreupolarimeters zur Messung der longitudinalen Spinpolarisation des MAMI-Elektronenstrahls

Das A4-Experiment bestimmt den Beitrag der Strangequarks zu den elektromagnetischen Formfaktoren des Nukleons durch Messung der Paritätsverletzung in der elastischen Elektron-Nukleon-Streuung. Diese Messungen werden mit dem spinpolarisierten Elektronenstrahl des Mainzer Mikrotrons (MAMI) bei Strahlenergien zwischen 315 und 1508 MeV ndurchgeführt. Die Bestimmung des Strahlpolarisationsgrades ist für die Analyse der Daten unerläßlich, um die physikalische Asymmetrie aus der gemessenen paritätsverletzenden Asymmetrie extrahieren zu können. Aus diesem Grund wird von der A4-Kollaboration ein neuartiges Compton-Laserrückstreupolarimeter entwickelt, das eine zerstörungsfreie Messung der Strahlpolarisation, parallel zum laufenden Paritätsexperiment erlaubt. Um den zuverlässigen Dauerbetrieb des Polarimeters zu ermöglichen, wurde das Polarimeter im Rahmen dieser Arbeit weiterentwickelt. Das Datenerfassungssystem für Photonen- und Elektronendetektor wurde neu aufgebaut und im Hinblick auf die Verarbeitung hoher Raten optimiert. Zum Nachweis der rückgestreuten Photonen wurde ein neuartiger Detektor (LYSO) in Betrieb genommen. Darüber hinaus wurden GEANT4-Simulationen der Detektoren durchgeführt und eine Analyseumgebung für die Extraktion von Comptonasymmetrien aus den Rückstreudaten entwickelt. Das Analyseverfahren nutzt die Möglichkeit, die rückgestreuten Photonen durch koinzidente Detektion der gestreuten Elektronen energiemarkiert nachzuweisen (Tagging). Durch die von der Energiemarkierung eingeführte differentielle Energieskala wird somit eine präzise Bestimmung der Analysierstärke möglich. In der vorliegenden Arbeit wurde die Analysierstärke des Polarimeters bestimmt, so daß nun das Produkt von Elektronen- und Laserstrahlpolarisation bei einem Strahlstrom von 20 muA, parallel zum laufenden Paritätsexperiment, mit einer statistischen Genauigkeit von 1% in 24 Stunden bei 855 MeV bzw. <1% in 12 Stunden bei 1508 MeV gemessen werden kann. In Kombination mit der Bestimmung der Laserpolarisation in einer parallelen Arbeit (Y. Imai) auf 1% kann die statistische Unsicherheit der Strahlpolarisation im A4-Experiment von zuvor 5% auf nun 1,5% bei 1508MeV verringert werden. Für die Daten zur Messung der paritätsverletzenden Elektronenstreuung bei einem Viererimpulsübertrag von $Q^2=0,6 (GeV/c)^2$ beträgt die Rohasymmetrie beim derzeitigen Stand der Analyse $A_{PV}^{Roh} = ( -20,0 pm 0,9_{stat} ) cdot 10^{-6}$. Für eine Strahlpolarisation von 80% erhält man einen Gesamtfehler von $1,68 cdot 10^{-6}$ für $Delta P_e/P_e = 5 %$. Als Ergebnis dieser Arbeit wird sich dieser Fehler durch Analyse der Daten des Compton-Laserrückstreupolarimeters um 29% auf $1,19 cdot 10^{-6}$ ($Delta P_e/P_e = 1,5 %$) verringern lassen.

Phase I trial of combretastatin A4 phosphate (CA4P) in combination with bevacizumab in patients with advanced cancer

The vascular disrupting agent (VDA) combretastatin A4 phosphate (CA4P) induces significant tumor necrosis as a single agent. Preclinical models have shown that the addition of an anti-VEGF antibody to a VDA attenuates the revascularization of the surviving tumor rim and thus significantly increases antitumor activity.

Phenotypic associations of Crohn's disease with antibodies to flagellins A4-Fla2 and Fla-X, ASCA, p-ANCA, PAB, and NOD2 mutations in a Swiss Cohort

BACKGROUND: Distinct Crohn's disease (CD) phenotypes correlate with antibody reactivity to microbial antigens. We examined the association between antibody response to 2 new flagellins called A4-Fla2 and Fla-X, anti-Saccharomyces cerevisiae antibodies (ASCA), anti-neutrophil cytoplasmic antibodies (p-ANCA), anti-pancreas antibodies (PAB), NOD2 mutations (R702W, G908R, and L1007fsinsC), and clinical CD phenotypes (according to Vienna criteria). METHODS: All the above-mentioned antibodies as well as NOD2 mutations were determined in 252 CD patients, 53 with ulcerative colitis (UC), and 43 healthy controls (HC) and correlated with clinical data. RESULTS: A seroreactivity for A4-Fla2/Fla-X/ASCA/p-ANCA/PAB (in percent) was found in 59/57/62/12/22 of CD patients, 6/6/4/51/0 of UC patients, and 0/2/5/0/0 of healthy controls. CD behavior: 37% B1, 36% B2, and 27% B3. In multivariate logistic regression, antibodies to A4-Fla2, Fla-X, and ASCA were significantly associated with stricturing phenotype (P = 0.027, P = 0.041, P < 0.001), negative associations were found with inflammatory phenotype (P = 0.001, P = 0.005, P < 0.001). Antibodies to A4-Fla2, Fla-X, ASCA, and NOD2 mutations were significantly associated with small bowel disease (P = 0.013, P = 0.01, P < 0.001, P = 0.04), whereas ASCA was correlated with fistulizing disease (P = 0.007), and small bowel surgery (P = 0.009). Multiple antibody responses against microbial antigens were associated with stricturing (P < 0.001), fistulizing disease (P = 0.002), and small bowel surgery (P = 0.002). CONCLUSIONS: Anti-flagellin antibodies and ASCA are strongly associated with complicated CD phenotypes. CD patients with serum reactivity against multiple microbes have the greatest frequency of strictures, perforations, and small bowel surgery. Further prospective longitudinal studies are needed to show that antibody-based risk stratification improves the clinical outcome of CD patients.