Prodrugs for Gene-Directed Enzyme-Prodrug Therapy (Suicide Gene Therapy)

This review focuses on the prodrugs used in suicide gene therapy. These prodrugs need to satisfy a number of criteria. They must be efficient and selective substrates for the activating enzyme, and be metabolized to potent cytotoxins preferably able to kill cells at all stages of the cell cycle. Both prodrugs and their activated species should have good distributive properties, so that the resulting bystander effects can maximize the effectiveness of the therapy, since gene transduction efficiencies are generally low. A total of 42 prodrugs explored for use in suicide gene therapy with 12 different enzymes are discussed, particularly in terms of their physiocochemical properties. An important parameter in determining bystander effects generated by passive diffusion is the lipophilicity of the activated form, a property conveniently compared by diffusion coefficients (log P for nonionizable compounds and log D(7) for compounds containing an ionizable centre). Many of the early antimetabolite-based prodrugs provide very polar activated forms that have limited abilities to diffuse across cell membranes, and rely on gap junctions between cells for their bystander effects. Several later studies have shown that more lipophilic, neutral compounds have superior diffusion-based bystander effects. Prodrugs of DNA alkylating agents, that are less cell cycle-specific than antimetabolites and more effective against noncycling tumor cells, appear in general to be more active prodrugs, requiring less prolonged dosing schedules to be effective. It is expected that continued studies to optimize the bystander effects and other properties of prodrugs and the activated species they generate will contribute to improvements in the effectiveness of suicide gene therapy

Who pays business rates?

Non-domestic rates are a tax that is formally levied on the occupiers of nondomestic property in the United Kingdom. This does not imply that it is only the occupiers of business and other non-domestic property who are made worse off by the imposition of ‘business rates’. Some or all of the effective burden of nondomestic rates may be shifted backwards from the occupiers of business property to the owners of business property. This occurs if the rents that property owners can charge their tenants are reduced by the imposition of business rates. In this case, the total cost of occupying a business property (i.e. rent plus rates) is increased by less than the full amount of the non-domestic rates paid by occupiers, and part of the burden of business rates is borne by property owners in the form of lower rental income than they would otherwise have received. The effective incidence of non-domestic rates is then said to fall partly on property owners, and only partly on occupiers.

2-(1,4-Dioxo-1,4-dihydro-2-naphthyl)-2-methylpropanoic acid

The sterically crowded title compound, C₁₄H₁₂O₄, crystallizes as centrosymmetric hydrogen-bonded dimers involving the carboxyl groups. The naphthoquinone ring system is folded by 11.5 (1)° about a vector joining the 1,4-C atoms, and the quinone O atoms are displaced from the ring plane, presumably because of steric interactions with the bulky substituent

Senior Military Leadership in Domestic Operations: An Exploratory Study

The article record as published may be found at https://www.hsaj.org/articles/16927This article reports on an exploratory study on how senior military leaders perceive leadership during a crisis-disaster response in the U.S. Homeland, and the developmental experiences and activities they believe support effective leadership during highly complex civil support operations.Sponsored the U. S. Department of Homeland Security’s National Preparedness Directorate, FEMA, CHDS is part of the Naval Postgraduate School (NPS)

DNA and the chromosome – varied targets for chemotherapy

The nucleus of the cell serves to maintain, regulate, and replicate the critical genetic information encoded by the genome. Genomic DNA is highly associated with proteins that enable simple nuclear structures such as nucleosomes to form higher-order organisation such as chromatin fibres. The temporal association of regulatory proteins with DNA creates a dynamic environment capable of quickly responding to cellular requirements and distress. The response is often mediated through alterations in the chromatin structure, resulting in changed accessibility of specific DNA sequences that are then recognized by specific proteins. Anti-cancer drugs that target cellular DNA have been used clinically for over four decades, but it is only recently that nuclease specific drugs have been developed to not only target the DNA but also other components of the nuclear structure and its regulation. In this review, we discuss some of the new drugs aimed at primary DNA sequences, DNA secondary structures, and associated proteins, keeping in mind that these agents are not only important from a clinical perspective but also as tools for understanding the nuclear environment in normal and cancer cells

Exile Vol. VI No. 1

EDITORIAL 4-6 Ride Through a Mad November Night (story) by Denny Trudell 7-17 Have You Ever Killed Anyone? (poem) by William Bennett 17 State 4 (woodcut) by Pat Wagenhals 18 Deserts (poem) by Chris Condit 19 Ode to a Sleeping Beauty (poem) by Bob Canary 20-29 O Let Me Let the Wild Bird Free (poem) by Chris Condit 30 Undercurrent (poem) by Bob Wehling 30 Afternoon (etching) by Judy Higgins 31 Operation Dump (story) by Christine Onufrock 32-43 Thru the Ages (woodcut) by Dave Bingham 43 Crude Are the Events (poem) by William Bennett 44 Awarded the semi-annual EXILE-Denison Bookstore Writing Prize: Ride Through a Mad November Night by Denny Trudell 7-1

“Propuesta de Creación de un Área Protegida Municipal de Recreación en el Sector las Pozas del Cantón Milagro”

El Sector de Las Pozas del Estero Belín de la ciudad de Milagro es un importante yacimiento de arcilla de origen aluvial, la cual es muy valorada como materia prima para la elaboración artesanal de ladrillos. La tesis “Propuesta de creación de un Área Protegida Municipal de Recreación en el sector Las Pozas del Cantón Milagro”, reviste de mucha importancia, ya que no solamente procuró un manejo integral de servicios ecosistémicos que potencie los recursos naturales, tanto hídricos como del suelo, sino que con ella se pretendió incrementar la calidad de vida de los ciudadanos de Milagro, con la dotación de un espacio natural urbano para la recreación, el ecoturismo y la conservación del entorno natural. La metodología fue cualitativa, documental, de campo y aplicada. Para la obtención de información se realizó una revisión documental, se llevaron a cabo observaciones de campo, se aplicó cualitativamente la Matriz de Leopold y se elaboraron entrevistas a personas claves, para obtener información precisa. La propuesta es viable legalmente y proyecta optimizar el ecosistema formado por la extracción antitécnica de la arcilla de la Zona de influencia del Estero Belín Sector las Pozas, el lacustre. Para la remediación ecosistémica se fomentó, para la reinserción de procesos ecológicos, el cultivo de las especies nativas forestales mangle rojo, tillo blanco y guayabo, así como de especies ornamentales como helechos, orquídeas y del pez huaij

Assessment of Toxoplasma gondii lytic cycle and the impact of a gene deletion using 3D label-free optical diffraction holotomography

Toxoplasma gondii is a widespread single-celled intracellular eukaryotic apicomplexan protozoan parasite primarily associated with mammalian foetal impairment and miscarriage, including in humans. Is estimated that approximately one third of the human population worldwide is infected by this parasite. Here we used cutting-edge, label-free 3D quantitative optical diffraction holotomography to capture and evaluate the Toxoplasma lytic cycle (invasion, proliferation and egress) in real-time based on the refractive index distribution. In addition, we used this technology to analyse an engineered CRISPR-Cas9 Toxoplasma mutant to reveal differences in cellular physical properties when compared to the parental line. Collectively, these data support the use of holotomography as a powerful tool for the study of protozoan parasites and their interactions with their host cells