Oncolytic Adenoviruses for Gynecologic Cancer

Gene therapy is a promising novel approach for treating cancers resistant to or escaping currently available modalities. Treatment approaches are based on taking advantage of molecular differences between normal and tumor cells. Various strategies are currently in clinical development with adenoviruses as the most popular vehicle. Recent developments include improving targeting strategies for gene delivery to tumor cells with tumor specific promoters or infectivity enhancement. A rapidly developing field is as well replication competent agents, which allow improved tumor penetration and local amplification of the anti-tumor effect. Adenoviral cancer gene therapy approaches lack cross-resistance with other treatment options and therefore synergistic effects are possible. This study focused on development of adenoviral vectors suitable for treatment of various gynecologic cancer types, describing the development of the field from non-replicating adenoviral vectors to multiple-modified conditional replicating viruses. Transcriptional targeting of gynecologic cancer cells by the use of the promoter of vascular endothelial growth factor receptor type 1 (flt-1) was evaluated. Flt-1 is not expressed in the liver and thus an ideal promoter for transcriptional targeting of adenoviruses. Our studies implied that the flt-1 promoter is active in teratocarcinomas.and therefore a good candidate for development of oncolytic adenoviruses for treatment of this often problematic disease with then poor outcome. A tropism modified conditionally replicating adenovirus (CRAd), Ad5-Δ24RGD, was studied in gynecologic cancers. Ad5-Δ24RGD is an adenovirus selectively replication competent in cells defective in the p16/Rb pathway, including many or most tumor cells. The fiber of Ad5-Δ24RGD contains an integrin binding arginine-glycine-aspartic acid motif (RGD-4C), allowing coxackie-adenovirus receptor independent infection of cancer cells. This approach is attractive because expression levels of CAR are highly variable and often low on primary gynecological cancer cells. Oncolysis could be shown for a wide variety of ovarian and cervical cancer cell lines as well as primary ovarian cancer cell spheroids, a novel system developed for in vitro analysis of CRAds on primary tumor substrates. Biodistribution was evaluated and preclinical safety data was obtained by demonstrating lack of replication in human peripheral blood mononuclear cells. The efficicacy of Ad5-Δ24RGD was shown in different orthotopic murine models including a highly aggressive intraperitoneal model of disseminated ovarian cancer cells, where Ad5-Δ24RGD resulted in complete eradication of intraperitoneal disease in half of the mice. To further improve the selectivity and specificity of CRAds, triple-targeted oncolytic adenoviruses were cloned, featuring the cyclo-oxygenase-2 (cox-2) promoter, E1A transcomplementation and serotype chimerism. Those viruses were evaluated on ovarian cancer cells for specificity and oncolytic potency with regard to two different cox2 versions and three different variants of E1A (wild type, delta24 and delta2delta24). Ad5/3cox2Ld24 emerged as the best combination due to enhanced selectivity without potency lost in vitro or in an aggressive intraperitoneal orthotopic ovarian tumor model. In summary, the preclinical therapeutic efficacy of the CRAds tested in this study, taken together with promising biodistribution and safety data, suggest that these CRAds are interesting candidates for translation into clinical trials for gynecologic cancer.

Chronic disease risks and use of a smartphone application during a physical activity and dietary intervention in Australian truck drivers

- Objective This study examined chronic disease risks and the use of a smartphone activity tracking application during an intervention in Australian truck drivers (April-October 2014). - Methods Forty-four men (mean age=47.5 [SD 9.8] years) completed baseline health measures, and were subsequently offered access to a free wrist-worn activity tracker and smartphone application (Jawbone UP) to monitor step counts and dietary choices during a 20-week intervention. Chronic disease risks were evaluated against guidelines; weekly step count and dietary logs registered by drivers in the application were analysed to evaluate use of the Jawbone UP. - Results Chronic disease risks were high (e.g. 97% high waist circumference [≥94 cm]). Eighteen drivers (41%) did not start the intervention; smartphone technical barriers were the main reason for drop out. Across 20-weeks, drivers who used the Jawbone UP logged step counts for an average of 6 [SD 1] days/week; mean step counts remained consistent across the intervention (weeks 1–4=8,743[SD 2,867] steps/day; weeks 17–20=8,994[SD 3,478] steps/day). The median number of dietary logs significantly decreased from start (17 [IQR 38] logs/weeks) to end of the intervention (0 [IQR 23] logs/week; p<0.01); the median proportion of healthy diet choices relative to total diet choices logged increased across the intervention (weeks 1–4=38[IQR 21]%; weeks 17–20=58[IQR 18]%). - Conclusions Step counts were more successfully monitored than dietary choices in those drivers who used the Jawbone UP. - Implications Smartphone technology facilitated active living and healthy dietary choices, but also prohibited intervention engagement in a number of these high-risk Australian truck drivers.

Franks family papers, 1711-1821, [1965-1968].

Contains business correspondence, accounts and documents relating to Jacob Franks of New York, his two sons, Moses and David, a nephew, Isaac, and a John Franks of Halifax, possibly a member of the family.

Pennsylvania Packet and Daily Advertiser. Containing anecdote regarding Oliver Cromwell and the Jew

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Petition of Abraham I. Abrahams

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Letter from Jeoshua His DeCordova regarding kosher meat

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Valistus suomalaisessa kirjakulttuurissa 1700-luvulla

The dissertation discusses the history of the book and the Enlightenment in Finland by studying the reception and diffusion of eighteenth-century books and by approaching the discourse on the Enlightenment in Finnish source material. The methods used relate to historian Robert Darnton s studies on eighteenth-century print culture and his analyses of the relations between print culture and society. The study is based on diverse eighteenth-century sources: books, pamphlets and dissertations, bibliographies, book auction protocols, parliamentary documents, estate inventory deeds, newspapers, letters, lectures, memoirs and commonplace books. By the end of the eighteenth century, book production had increased and secular literature had begun to challenge the dominance of religious literature. The books of the Enlightenment belonged to the new literature that found its way into Finnish book collections previously dominated by religious literature. Enlightenment literature is not a set selection of books but rather diverse works from different genres. Thus the study introduces a variety of printed material, from philosophical tracts and textbooks to novels and pornography. In the case of books of the Enlightenment, the works of French Voltaire and German Christian Wolff were among the most widely read and circulated books in Finland. First and foremost, the Enlightenment was an era of intellectual debate. These debates carried strong criticism of the prevailing systems of thought. Enlightenment ideas challenged the Lutheran society of Sweden and especially its sense of conformity. Contemporaries saw many of the books of the Enlightenment as vessels of new ideas and criticism. Furthermore, this kind of print material was interpreted as being dangerous for uneducated readers. Belonging to a certain estate and social class had a major impact on individuals reading habits and their acquisition of books. One specific social group stands out in the Finnish source material: the officers at the Sveaborg naval fortress possessed and distributed Enlightenment books more than the members of any other social class. Other essential social groups were scholars, the nobility and the clergy, who took part in debates concerning the ideas and benefits of the Enlightenment. In the Finnish debates at the time, the concept of Enlightenment involved three primary notions. Firstly, it referred to the French philosophers, les philosophes, and to their works as well as to the social changes that took place during the French revolution. It also carried the idea of philosophical light or the light of reason, in a sense similar to Immanuel Kant s writings. Most importantly, it referred to a belief in progress and to a trust in true knowledge that would supercede ignorance and fanaticism. Hence, it is impossible to speak about the Enlightenment era in the Swedish realm without such concepts as reason, benefit or progress. These concepts likewise marked the books of the Enlightenment in eighteenth-century Finland.

Study of temperature distribution along an artificially polluted insulator string

Insulator becomes wet partially or completely, and the pollution layer on it becomes conductive, when collecting pollutants for an extended period during dew, light rain, mist, fog or snow melting. Heavy rain is a complicated factor that it may wash away the pollution layer without initiating other stages of breakdown or it may bridge the gaps between sheds to promote flashover. The insulator with a conducting pollution layer being energized, can cause a surface leakage current to flow (also temperature-rise). As the surface conductivity is non-uniform, the conducting pollution layer becomes broken by dry bands (at spots of high current density), interrupting the flow of leakage current. Voltage across insulator gets concentrated across dry bands, and causes high electric stress and breakdown (dry band arcing). If the resistance of the insulator surface is sufficiently low, the dry band arcs can be propagated to bridge the terminals causing flashover. The present paper concerns the evaluation of the temperature distribution along the surface of an energized artificially polluted insulator string.

Preliminary X-ray crystallographic studies on acetate kinase (AckA) from Salmonella typhimurium in two crystal forms

Acetate kinase (AckA) catalyzes the reversible transfer of a phosphate group from acetyl phosphate to ADP, generating acetate and ATP, and plays a central role in carbon metabolism. In the present work, the gene corresponding to AckA from Salmonella typhimurium (StAckA) was cloned in the IPTG-inducible pRSET C vector, resulting in the attachment of a hexahistidine tag to the N-terminus of the expressed enzyme. The recombinant protein was overexpressed, purified and crystallized in two different crystal forms using the microbatch-under-oil method. Form I crystals diffracted to 2.70 angstrom resolution when examined using X-rays from a rotating-anode X-ray generator and belonged to the monoclinic space group C2, with unit-cell parameters a = 283.16, b = 62.17, c = 91.69 angstrom, beta = 93.57 degrees. Form II crystals, which diffracted to a higher resolution of 2.35 angstrom on the rotating-anode X-ray generator and to 1.90 angstrom on beamline BM14 of the ESRF, Grenoble, also belonged to space group C2 but with smaller unit-cell parameters (a = 151.01, b = 78.50, c = 97.48 angstrom, beta = 116.37 degrees). Calculation of Matthews coefficients for the two crystal forms suggested the presence of four and two protomers of StAckA in the asymmetric units of forms I and II, respectively. Initial phases for the form I diffraction data were obtained by molecular replacement using the coordinates of Thermotoga maritima AckA (TmAckA) as the search model. The form II structure was phased using a monomer of form I as the phasing model. Inspection of the initial electron-density maps suggests dramatic conformational differences between residues 230 and 300 of the two crystal forms and warrants further investigation.

Structural and kinetic studies on adenylosuccinate lyase from Mycobacterium smegmatis and Mycobacterium tuberculosis provide new insights on the catalytic residues of the enzyme

Adenylosuccinate lyase (ASL), an enzyme involved in purine biosynthesis, has been recognized as a drug target against microbial infections. In the present study, ASL from Mycobacteriumsmegmatis (MsASL) and Mycobacteriumtuberculosis (MtbASL) were cloned, purified and crystallized. The X-ray crystal structure of MsASL was determined at a resolution of 2.16 angstrom. It is the first report of an apo-ASL structure with a partially ordered active site C3 loop. Diffracting crystals of MtbASL could not be obtained and a model for its structure was derived using MsASL as a template. These structures suggest that His149 and either Lys285 or Ser279 of MsASL are the residues most likely to function as the catalytic acid and base, respectively. Most of the active site residues were found to be conserved, with the exception of Ser148 and Gly319 of MsASL. Ser148 is structurally equivalent to a threonine in most other ASLs. Gly319 is replaced by an arginine residue in most ASLs. The two enzymes were catalytically much less active compared to ASLs from other organisms. Arg319Gly substitution and reduced flexibility of the C3 loop might account for the low catalytic activity of mycobacterial ASLs. The low activity is consistent with the slow growth rate of Mycobacteria and their high GC containing genomes, as well as their dependence on other salvage pathways for the supply of purine nucleotides. Structured digital abstract andby()

高水分煤在流化床中燃烧时NOx的排放特性

通过数值计算，研究了高水分煤在流化床中燃烧时ＮＯ的排放特性及其形成的主要影响因素。结果表明煤中的水分，床内的ＣＯ浓度和空－燃比等都对于ＮＯ转换率有较大影响。

Combined effect of surface tension, gravity and van der Waals force induced by a non-contact probe tip on the shape of liquid surface

Aiming at understanding how a liquid film on a substrate affects the atomic force microscopic image in experiments, we present an analytical representation of the shape of liquid surface under van der Waals interaction induced by a non-contact probe tip. The analytical expression shows good consistence with the corresponding numerical results. According to the expression, we find that the vertical scale of the liquid dome is mainly governed by a combination of van der Waals force, surface tension and probe tip radius, and is weekly related to gravity. However, its horizontal extension is determined by the capillary length.

La participación de la mujer y los niños en el manejo integrado de plagas en las regiones I y II de Nicaragua

El presente trabajo es el resultado de un diagnostico realizado en las regiones I y II de Nicaragua. El objetivo del estudio fue conocer el rol que juegan las mujeres y los niños en las prácticas de control de plagas y en particular en el manejo de los plaguicidas. Para obtener la información del estudio se realizó una encuesta dirigida a mujeres y niños en 18 comunidades de los departamentos de Estelí, Nueva Segovia, León y Chinandega. En el estudio resultó que la participación de la mujer y los menores es alta, los resultados muestran que el 96% de la mujer y el 85% de los niños tienen participación en todas las fases agrícolas. Las prácticas de manejo integrado de plagas implementadas por las productoras son mayoritariamente recuentos de plagas, rotación de cultivos, cultivos en asocio y variedades mejoradas. Generalmente la aplicación de plaguicidas, lavado de la ropa contaminada, preparación de la mezcla y acarreo del plaguicida al lugar de aplicación. En el manejo y exposición al riesgo de los plaguicidas el 65% de las productoras en la región II contestó que conocían de personas intoxicadas, además identificaron la intoxicación laboral como la más común. En la región I, 42% de las productoras mencionó conocer de personas intoxicadas. Cuatro de los plaguicidas reportados en existencia por las agricultoras son altamente a extremadamente peligrosos, estos plaguicidas son almacenados principalmente dentro de la casa, 15% de las productoras utilizan los envases de plaguicidas para almacenar agua y alimento y el 8% para echar más veneno. Además el 88% de las productoras mencionaron conocer de los efectos adversos de la utilización de los plaguicidas, sobre todo en la salud humana. Finalmente la encuesta indica que las capacitaciones en MIP son dirigidas en su gran mayoría a los hombres y cuando incluyen a las mujeres los lugares y hora escogida para las capacitaciones eran uno los factores que obstaculizaba su participación. La falta de títulos de propiedad, que limita el acceso al crédito para la siembra, fue otro factor limitante para participar en actividades MIP. Las instituciones y los programas radiales educativos, así como la comunicación directa, juegan un papel importante en la transmisión de conocimientos MIP

Determinación de la capacidad de extracción de nutrientes, acumulación de materia seca y fijación biológica de nitrógeno por cuatro variedades de frijol común (Phaseolus vulgaris L.)

El presente trabajo fue realizado en la estación experimental "La Compañía" Carazo, en época de primera (junio - agosto de 1994), en suelos jóvenes de origen volcánico con altos contenidos de Potasio y deficiente en fósforo. El propósito del experimento fue determinar la variación en la cantidad de Nitrógeno fijado, así como la extracción de nutrientes y acumulación de materia seca, por cuatro variedades de frijol común. Las variedades evaluadas fueron: DOR-364, ESTELÍ 90-A, BRUNCA, CRIOLLA y variedad TESTIGO. El diseño utilizado fue bloques completos al azar (B.C.A) con cuatro tratamientos y cuatro repeticiones. Las variables evaluadas fueron: altura de planta, número de plantas cosechadas por ha, número de vainas por planta, rendimiento de grano, número de nódulos, acumulación de materia seca, concentraciones de nutrientes en la planta y cantidades exportadas por ha. Los datos se procesaron usando análisis de varianza (ANDEVA) y se utilizó la prueba de rangos múltiples de DUNCAN (p 0.05). Los resultados obtenidos se pueden sintetizar de la siguiente forma: La variedad DOR-364 alcanzó una mayor altura así como también una mayor concentración de P y Zn en sus tejidos y acumuló más materia seca, sin embargo disminuyó tanto en el rendimiento de grano como en el número de vainas, además fue deficiente en la población. Esta variedad extrajo la mayor cantidad de N, sin embargo la mayor concentración de este elemento en el follaje la presentó la variedad (testigo. La ESTELÍ 90-A, presentó un mayor número de plantas por ha y un alto rendimiento de grano, fue la variedad más eficiente en la nodulación. Las variedades DOR-364 y ESTELI 90-A exportaron más nutrientes que el resto de las variedades evaluadas. Se desarrolló una tendencia por parte de la variedad TESTIGO a presentar una mayor concentración de K, S, Ca, Mg, Fe, Cu y Mn en sus tejidos en comparación con las otras variedades estudiadas. Se realizaron correlaciones entre cada uno de los elementos y variables en estudio, las cuales mostraron resultados positivos en su mayoría a excepción de la relación entre el número de vainas y los elementos Cu y Fe. El rendimiento se relacionó solamente con el número de nódulos en la segunda evaluación.