A study of the impact of the Ceramic Materials Research program at the University of Washington Final report, 15 Jun. 1968 - 15 Sep. 1969

Impact of Ceramic Materials Research Program at University of Washingto

Acyclovir inhibition of IDO to decrease Tregs as a glioblastoma treatment adjunct

Regulatory T cells, Tregs, are a subset of lymphocytes that have immunosuppressive attributes. They are elevated in blood of glioblastoma patients and within this tumor's tissue itself. Indoleamine 2,3-dioxygenase, IDO, converts tryptophan to kynurenine. IDO activity enhances Treg formation by pathways that are unknown. Experimentally, inhibition of IDO decreases Treg function and number in rodents. The common anti-viral agent acyclovir inhibits IDO. Acyclovir may thereby decrease Treg function in glioblastoma. If it can be confirmed that Treg counts are elevated in glioblastoma patients' tumor tissue, and if we can document acyclovir's lowering of tissue Treg counts by a small trial of acyclovir in pre-operative glioblastoma patients, a trial of acyclovir effect on survival should be done given the current poor prognosis of glioblastoma and the well-established safety and low side effect burden of acyclovir

The RootScope: A Simple High-Throughput Screening System For Quantitating Gene Expression Dynamics In Plant Roots

Background: High temperature stress responses are vital for plant survival. The mechanisms that plants use to sense high temperatures are only partially understood and involve multiple sensing and signaling pathways. Here we describe the development of the RootScope, an automated microscopy system for quantitating heat shock responses in plant roots.Results: The promoter of Hsp17.6 was used to build a Hsp17.6(p):GFP transcriptional reporter that is induced by heat shock in Arabidopsis. An automated fluorescence microscopy system which enables multiple roots to be imaged in rapid succession was used to quantitate Hsp17.6p: GFP response dynamics. Hsp17.6(p):GFP signal increased with temperature increases from 28 degrees C to 37 degrees C. At 40 degrees C the kinetics and localization of the response are markedly different from those at 37 degrees C. This suggests that different mechanisms mediate heat shock responses above and below 37 degrees C. Finally, we demonstrate that Hsp17.6(p):GFP expression exhibits wave like dynamics in growing roots.Conclusions: The RootScope system is a simple and powerful platform for investigating the heat shock response in plants

A conceptually new treatment approach for relapsed glioblastoma: Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care

Kast, Richard E. et al.To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma’s compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed.Peer Reviewe

2010-2011 Veterans Law Update

Part I will cover updates related directly to veterans\u27 benefits and rights. Part II will focus on updates to rules involving veterans\u27 caregivers and healthcare facilities. Part III will cover proposed rules dealing with veterans\u27 claims and insurance. Part IV will focus on rules and case law covering the VA\u27s procedures and operating regulations

Fluorescence assisted capillary electrophoresis of glycans enabled by the negatively charged auxochromes in 1-Aminopyrenes

A compact and negatively charged acceptor group, N-(cyanamino)sulfonyl, is introduced for dye design and its influence on the absorption and emission spectra of the “push–pull” chromophores is demonstrated with 1,3,6-tris[(cyanamino)sulfonyl]-8-aminopyrene. The new sulfonamides, including O-phosphorylated (3-hydroxyazetidine)-N-sulfonyl, are negatively charged electron acceptors and auxochromes. 1-Aminopyrenes decorated with the new sulfonamides have three or six negative charges (pH ≥8), low m/z ratios, high mobilities in an electric field, and yellow to orange emission. We labeled maltodextrin oligomers by reductive amination, separated the products by electrophoresis, and demonstrated their high brightness in a commercial DNA analyzer and the distribution of the emission signal among the detection channels

Inflight Pharmacokinetic and Pharmacodynamic Responses to Medications Commonly Used in Spaceflight

Researchers do not know if medications act the same in the spaceflight environment as they do on Earth. Aspects of the spaceflight environment (low gravity, radiation exposure, closed environment, stress) have been shown to alter human physiology. Some of these physiological changes could be expected to alter either pharmacokinetics (PK, how the body absorbs, distributes, metabolizes and excretes administered medications) or pharmacodynamics (PD, receptors or signaling systems that are the targets of medication action). Anecdotal data has suggested that, at least for certain medications or indications, inflight medication efficacy is poor. In order to prepare for exploration missions where speedy evacuation to Earth may not be a possibility, the likelihood of unexpected medication action must be determined

Toward a noncytotoxic glioblastoma therapy: blocking MCP-1 with the MTZ Regimen

To improve the prognosis of glioblastoma, we developed an adjuvant treatment directed to a neglected aspect of glioblastoma growth, the contribution of nonmalignant monocyte lineage cells (MLCs) (monocyte, macrophage, microglia, dendritic cells) that infiltrated a main tumor mass. These nonmalignant cells contribute to glioblastoma growth and tumor homeostasis. MLCs comprise of approximately 10%-30% of glioblastoma by volume. After integration into the tumor mass, these become polarized toward an M2 immunosuppressive, pro-angiogenic phenotype that promotes continued tumor growth. Glioblastoma cells initiate and promote this process by synthesizing 13 kDa MCP-1 that attracts circulating monocytes to the tumor. Infiltrating monocytes, after polarizing toward an M2 phenotype, synthesize more MCP-1, forming an amplification loop. Three noncytotoxic drugs, an antibiotic - minocycline, an antihypertensive drug - telmisartan, and a bisphosphonate - zoledronic acid, have ancillary attributes of MCP-1 synthesis inhibition and could be re-purposed, singly or in combination, to inhibit or reverse MLC-mediated immunosuppression, angiogenesis, and other growth-enhancing aspects. Minocycline, telmisartan, and zoledronic acid - the MTZ Regimen - have low-toxicity profiles and could be added to standard radiotherapy and temozolomide. Re-purposing older drugs has advantages of established safety and low drug cost. Four core observations support this approach: 1) malignant glioblastoma cells require a reciprocal trophic relationship with nonmalignant macrophages or microglia to thrive;2) glioblastoma cells secrete MCP-1 to start the cycle, attracting MLCs, which subsequently also secrete MCP-1 perpetuating the recruitment cycle;3) increasing cytokine levels in the tumor environment generate further immunosuppression and tumor growth;and 4) MTZ regimen may impede MCP-1-driven processes, thereby interfering with glioblastoma growth

Evidence that Amphotericin B Mediates Reactivation of Latent Epstein-Barr Virus in Hodgkin's Lymphoma Allowing Cytotoxicity by Acyclovir

This brief communication focuses on aspects of a recent case report (Yonsei Med J 2005;46:425-30) on a full and sustained remission of Hodgkin's lymphoma (HL) after a single day of chemotherapy. A septic episode required stopping chemotherapy and starting amphotericin B and acyclovir. Remission evidence was seen within days of starting these. A review of research supporting the notion that amphotericin B can reactivate latent Epstein-Barr virus and thus allow acyclovir to kill infected HL cells is given. Experimental work is required to confirm or refute this possibility. If successful, amphotericin B and acyclovir treatment could be extended to other EBV-driven cancers such as Burkitt's lymphoma, nasopharyngeal carcinoma and the occasional EBV-related epithelial cancer of the breast, colon, prostate, and others