235 research outputs found
State of Utah v. Layne Kenneth Lundstrom : Brief of Appellant
No full textBRIEF OF APPELLANT, LAYNE KENNETH LUNDSTROM Appeal of Layne Kenneth Lundstrom from a Final Judgment of guilty on Revocation, entered August 4, 1987, by the Sixth Circuit Court of Tooele County, Honorable Edward A. Watson
New frontiers in oncolytic viruses: optimizing and selecting for virus strains with improved efficacy
No full textKenneth Lundstrom PanTherapeutics, Lutry, Switzerland Abstract: Oncolytic viruses have demonstrated selective replication and killing of tumor cells. Different types of oncolytic viruses – adenoviruses, alphaviruses, herpes simplex viruses, Newcastle disease viruses, rhabdoviruses, Coxsackie viruses, and vaccinia viruses – have been applied as either naturally occurring or engineered vectors. Numerous studies in animal-tumor models have demonstrated substantial tumor regression and prolonged survival rates. Moreover, clinical trials have confirmed good safety profiles and therapeutic efficacy for oncolytic viruses. Most encouragingly, the first cancer gene-therapy drug – Gendicine, based on oncolytic adenovirus type 5 – was approved in China. Likewise, a second-generation oncolytic herpes simplex virus-based drug for the treatment of melanoma has been registered in the US and Europe as talimogene laherparepvec. Keywords: immunotherapy, viral vectors, clinical trials, drug approva
Alphaviruses in Immunotherapy and Anticancer Therapy
No full textAlphaviruses have been engineered as expression vectors for vaccine development and gene therapy. Due to the feature of RNA self-replication, alphaviruses can provide exceptional direct cytoplasmic expression of transgenes based on the delivery of recombinant particles, naked or nanoparticle-encapsulated RNA or plasmid-based DNA replicons. Alphavirus vectors have been utilized for the expression of various antigens targeting different types of cancers, and cytotoxic and antitumor genes. The most common alphavirus vectors are based on the Semliki Forest virus, Sindbis virus and Venezuelan equine encephalitis virus, but the oncolytic M1 alphavirus has also been used. Delivery of immunostimulatory cytokine genes has been the basis for immunotherapy demonstrating efficacy in different animal tumor models for brain, breast, cervical, colon, lung, ovarian, pancreatic, prostate and skin cancers. Typically, therapeutic effects including tumor regression, tumor eradication and complete cure as well as protection against tumor challenges have been observed. Alphavirus vectors have also been subjected to clinical evaluations. For example, therapeutic responses in all cervical cancer patients treated with an alphavirus vector expressing the human papilloma virus E6 and E7 envelope proteins have been achieved
Therapeutic Applications for Oncolytic Self-Replicating RNA Viruses
No full textSelf-replicating RNA viruses have become attractive delivery vehicles for therapeutic applications. They are easy to handle, can be rapidly produced in large quantities, and can be delivered as recombinant viral particles, naked or nanoparticle-encapsulated RNA, or plasmid DNA-based vectors. The self-replication of RNA in infected host cells provides the means for generating much higher transgene expression levels and the possibility to apply substantially reduced amounts of RNA to achieve similar expression levels or immune responses compared to conventional synthetic mRNA. Alphaviruses and flaviviruses, possessing a single-stranded RNA genome of positive polarity, as well as measles viruses and rhabdoviruses with a negative-stranded RNA genome, have frequently been utilized for therapeutic applications. Both naturally and engineered oncolytic self-replicating RNA viruses providing specific replication in tumor cells have been evaluated for cancer therapy. Therapeutic efficacy has been demonstrated in animal models. Furthermore, the safe application of oncolytic viruses has been confirmed in clinical trials. Multiple myeloma patients treated with an oncolytic measles virus (MV-NIS) resulted in increased T-cell responses against the measles virus and several tumor-associated antigen responses and complete remission in one patient. Furthermore, MV-CEA administration to patients with ovarian cancer resulted in a stable disease and more than doubled the median overall survival
Investigation of iron isotope variability in the bimodal Aztec Wash Pluton, Eldorado Mountains, Nevada
No full textOver the course of the past decade, our understanding of silicic plutons has undergone a fundamental shift, from envisioning pluton emplacement as one large magmatic intrusion to the concept of incremental emplacement, in which plutons form from multiple smaller injections of magma over hundreds of thousands to million-year time scales (Coleman et al., 2004; Glazner et al., 2004). While this concept helps to assuage previously held concerns about pluton emplacement, it also raises questions about the formation of features shared by many felsic intrusions, such as compositional zonation and the presence of significant volumes of relatively homogeneous granite.
Water-rich temperature gradient experiments (Huang et al., 2009) have been able to produce compositional zonation similar to that found in zoned plutons. The process that alters andesitic starting material to granitic and mafic end members within a temperature gradient is called thermal migration zone refining (Lundstrom, 2009). In addition to the compositional changes that occur within the temperature gradient, an isotopic signature was also observed: heavy isotopes of Fe, Mg, O, H and Li became enriched in the cold, felsic end of the gradient (Bindeman, et al., 2013; Huang et al., 2009). This isotopic trend is strikingly similar to one found in igneous systems, in which non-traditional stable isotopes such as Fe and Si become increasingly heavy as the silica content increases (Poitrasson and Freydier, 2005; Schoenberg and von Blanckenburg, 2006; Heimann et al., 2008; Savage, et al., 2011). Could the isotopic trend found in magmatic systems be related to temperature gradients formed as a result of multiple intrusions? There are only a few investigations of the role that temperature gradients have in driving isotopic fractionation within magmatic systems (Zambardi et al., 2014; Gajos, 2014).
In order to test this hypothesis, I have analyzed samples collected from transects oriented paleo-vertically and paleohorizontally through the Miocene-aged Aztec Wash Pluton (AW). AW is a bimodal, reversely zoned pluton, consisting of an outer “rim” of granite (the granite zone) underlain by the heterogeneous zone, which contains co-existing mafic, felsic and intermediate rocks. Rotation of the intrusion during Basin and Range extension exposed a sub-vertical slice of AW from the roof downwards, allowing for the paleovertical and paleohorizontal transects. Major element compositions and iron isotope ratios were measured for samples from four transects: PV, a paleovertical transect through the top of the pluton, ELT and 11-22, two paleohorizontal transects, and 11-20, a short transect through monzonite and monzodiorite layers. Fe isotope ratio results do not match reasonable Rayleigh fractionation models for fractional crystallization or fluid exsolution. The scattering of a range of iron isotope compositions of samples throughout the transects may be indicative of thermal diffusion signatures. However, the complicated open system history of AW has likely obscured the presence of simple diffusional gradients like those seen in the experiments (Huang et al. 2009; Bindeman et al. 2013).Item withdrawn by Laura Spradlin ([email protected]) on 2014-12-10T17:41:46Z
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Self-Amplifying RNA Viruses as RNA Vaccines
No full textSingle-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses and rhabdoviruses are characterized by their capacity of highly efficient self-amplification of RNA in host cells, which make them attractive vehicles for vaccine development. Particularly, alphaviruses and flaviviruses can be administered as recombinant particles, layered DNA/RNA plasmid vectors carrying the RNA replicon and even RNA replicon molecules. Self-amplifying RNA viral vectors have been used for high level expression of viral and tumor antigens, which in immunization studies have elicited strong cellular and humoral immune responses in animal models. Vaccination has provided protection against challenges with lethal doses of viral pathogens and tumor cells. Moreover, clinical trials have demonstrated safe application of RNA viral vectors and even promising results in rhabdovirus-based phase III trials on an Ebola virus vaccine. Preclinical and clinical applications of self-amplifying RNA viral vectors have proven efficient for vaccine development and due to the presence of RNA replicons, amplification of RNA in host cells will generate superior immune responses with significantly reduced amounts of RNA delivered. The need for novel and efficient vaccines has become even more evident due to the global COVID-19 pandemic, which has further highlighted the urgency in challenging emerging diseases
Application of DNA Replicons in Gene Therapy and Vaccine Development
No full textDNA-based gene therapy and vaccine development has received plenty of attention lately. DNA replicons based on self-replicating RNA viruses such as alphaviruses and flaviviruses have been of particular interest due to the amplification of RNA transcripts leading to enhanced transgene expression in transfected host cells. Moreover, significantly reduced doses of DNA replicons compared to conventional DNA plasmids can elicit equivalent immune responses. DNA replicons have been evaluated in preclinical animal models for cancer immunotherapy and for vaccines against infectious diseases and various cancers. Strong immune responses and tumor regression have been obtained in rodent tumor models. Immunization with DNA replicons has provided robust immune responses and protection against challenges with pathogens and tumor cells. DNA replicon-based COVID-19 vaccines have shown positive results in preclinical animal models
Replicon RNA Viral Vectors as Vaccines
No full textSingle-stranded RNA viruses of both positive and negative polarity have been used as vectors for vaccine development. In this context, alphaviruses, flaviviruses, measles virus and rhabdoviruses have been engineered for expression of surface protein genes and antigens. Administration of replicon RNA vectors has resulted in strong immune responses and generation of neutralizing antibodies in various animal models. Immunization of mice, chicken, pigs and primates with virus-like particles, naked RNA or layered DNA/RNA plasmids has provided protection against challenges with lethal doses of infectious agents and administered tumor cells. Both prophylactic and therapeutic efficacy has been achieved in cancer immunotherapy. Moreover, recombinant particles and replicon RNAs have been encapsulated by liposomes to improve delivery and targeting. Replicon RNA vectors have also been subjected to clinical trials. Overall, immunization with self-replicating RNA viruses provides high transient expression levels of antigens resulting in generation of neutralizing antibody responses and protection against lethal challenges under safe conditions
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