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  1. Article ; Online: Fitness benefits of low infectivity in a spatially structured population of bacteriophages.

    Roychoudhury, Pavitra / Shrestha, Neelima / Wiss, Valorie R / Krone, Stephen M

    Proceedings. Biological sciences

    2013  Volume 281, Issue 1774, Page(s) 20132563

    Abstract: For a parasite evolving in a spatially structured environment, an evolutionarily advantageous strategy may be to reduce its transmission rate or infectivity. We demonstrate this empirically using bacteriophage (phage) from an evolution experiment where ... ...

    Abstract For a parasite evolving in a spatially structured environment, an evolutionarily advantageous strategy may be to reduce its transmission rate or infectivity. We demonstrate this empirically using bacteriophage (phage) from an evolution experiment where spatial structure was maintained over 550 phage generations on agar plates. We found that a single substitution in the major capsid protein led to slower adsorption of phage to host cells with no change in lysis time or burst size. Plaques formed by phage isolates containing this mutation were not only larger but also contained more phage per unit area. Using a spatially explicit, individual-based model, we showed that when there is a trade-off between adsorption and diffusion (i.e. less 'sticky' phage diffuse further), slow adsorption can maximize plaque size, plaque density and overall productivity. These findings suggest that less infective pathogens may have an advantage in spatially structured populations, even when well-mixed models predict that they will not.
    MeSH term(s) Biological Evolution ; Environment ; Escherichia coli/virology ; Host-Pathogen Interactions ; Microviridae/genetics ; Microviridae/pathogenicity ; Microviridae/ultrastructure ; Models, Biological ; Mutation ; Phenotype
    Language English
    Publishing date 2013-11-13
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209242-6
    ISSN 1471-2954 ; 0080-4649 ; 0962-8452 ; 0950-1193
    ISSN (online) 1471-2954
    ISSN 0080-4649 ; 0962-8452 ; 0950-1193
    DOI 10.1098/rspb.2013.2563
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1364: Show issues Location:
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  2. Article ; Online: The impact of spatial structure on viral genomic diversity generated during adaptation to thermal stress.

    Ally, Dilara / Wiss, Valorie R / Deckert, Gail E / Green, Danielle / Roychoudhury, Pavitra / Wichman, Holly A / Brown, Celeste J / Krone, Stephen M

    PloS one

    2014  Volume 9, Issue 2, Page(s) e88702

    Abstract: Background: Most clinical and natural microbial communities live and evolve in spatially structured environments. When changes in environmental conditions trigger evolutionary responses, spatial structure can impact the types of adaptive response and ... ...

    Abstract Background: Most clinical and natural microbial communities live and evolve in spatially structured environments. When changes in environmental conditions trigger evolutionary responses, spatial structure can impact the types of adaptive response and the extent to which they spread. In particular, localized competition in a spatial landscape can lead to the emergence of a larger number of different adaptive trajectories than would be found in well-mixed populations. Our goal was to determine how two levels of spatial structure affect genomic diversity in a population and how this diversity is manifested spatially.
    Methodology/principal findings: We serially transferred bacteriophage populations growing at high temperatures (40°C) on agar plates for 550 generations at two levels of spatial structure. The level of spatial structure was determined by whether the physical locations of the phage subsamples were preserved or disrupted at each passage to fresh bacterial host populations. When spatial structure of the phage populations was preserved, there was significantly greater diversity on a global scale with restricted and patchy distribution. When spatial structure was disrupted with passaging to fresh hosts, beneficial mutants were spread across the entire plate. This resulted in reduced diversity, possibly due to clonal interference as the most fit mutants entered into competition on a global scale. Almost all substitutions present at the end of the adaptation in the populations with disrupted spatial structure were also present in the populations with structure preserved.
    Conclusions/significance: Our results are consistent with the patchy nature of the spread of adaptive mutants in a spatial landscape. Spatial structure enhances diversity and slows fixation of beneficial mutants. This added diversity could be beneficial in fluctuating environments. We also connect observed substitutions and their effects on fitness to aspects of phage biology, and we provide evidence that some substitutions exclude each other.
    MeSH term(s) Acclimatization/genetics ; Bacteriophages/genetics ; Bacteriophages/physiology ; Cluster Analysis ; Environment ; Escherichia coli/virology ; Genetic Variation ; Genome, Viral ; Genotype ; Hot Temperature ; Mutation ; Oligonucleotides/chemistry ; Phenotype ; Sequence Analysis, DNA
    Chemical Substances Oligonucleotides
    Language English
    Publishing date 2014-02-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0088702
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Nonclinical Profile of BLZ-100, a Tumor-Targeting Fluorescent Imaging Agent.

    Parrish-Novak, Julia / Byrnes-Blake, Kelly / Lalayeva, Narine / Burleson, Stefanie / Fidel, Janean / Gilmore, Rhonda / Gayheart-Walsten, Pamela / Bricker, Gregory A / Crumb, William J / Tarlo, K S / Hansen, Stacey / Wiss, Valorie / Malta, Errol / Dernell, William S / Olson, James M / Miller, Dennis M

    International journal of toxicology

    2017  Volume 36, Issue 2, Page(s) 104–112

    Abstract: BLZ-100 is a single intravenous use, fluorescent imaging agent that labels tumor tissue to enable more complete and precise surgical resection. It is composed of a chlorotoxin peptide covalently bound to the near-infrared fluorophore indocyanine green. ... ...

    Abstract BLZ-100 is a single intravenous use, fluorescent imaging agent that labels tumor tissue to enable more complete and precise surgical resection. It is composed of a chlorotoxin peptide covalently bound to the near-infrared fluorophore indocyanine green. BLZ-100 is in clinical development for intraoperative visualization of human tumors. The nonclinical safety and pharmacokinetic (PK) profile of BLZ-100 was evaluated in mice, rats, canines, and nonhuman primates (NHP). Single bolus intravenous administration of BLZ-100 was well tolerated, and no adverse changes were observed in cardiovascular safety pharmacology, PK, and toxicology studies in rats and NHP. The single-dose no-observed-adverse-effect-levels (NOAELs) were 7 mg (28 mg/kg) in rats and 60 mg (20 mg/kg) in NHP, corresponding to peak concentration values of 89 400 and 436 000 ng/mL and area-under-the-curve exposure values of 130 000 and 1 240 000 h·ng/mL, respectively. Based on a human imaging dose of 3 mg, dose safety margins are >100 for rat and monkey. BLZ-100 produced hypersensitivity reactions in canine imaging studies (lethargy, pruritus, swollen muzzle, etc). The severity of the reactions was not dose related. In a follow-up study in dogs, plasma histamine concentrations were increased 5 to 60 minutes after BLZ-100 injection; this coincided with signs of hypersensitivity, supporting the conclusion that the reactions were histamine based. Hypersensitivity reactions were not observed in other species or in BLZ-100 human clinical studies conducted to date. The combined imaging, safety pharmacology, PK, and toxicology studies contributed to an extensive initial nonclinical profile for BLZ-100, supporting first-in-human clinical trials.
    MeSH term(s) Animals ; Complement System Proteins/analysis ; Dogs ; Drug Hypersensitivity/blood ; Female ; Fluorescent Dyes/pharmacokinetics ; Fluorescent Dyes/toxicity ; HEK293 Cells ; Histamine/blood ; Humans ; Indocyanine Green/analogs & derivatives ; Indocyanine Green/pharmacokinetics ; Indocyanine Green/toxicity ; Macaca fascicularis ; Male ; Mice ; Neoplasms/diagnostic imaging ; Neoplasms/metabolism ; Rats, Sprague-Dawley ; Scorpion Venoms/blood ; Scorpion Venoms/pharmacokinetics ; Scorpion Venoms/toxicity
    Chemical Substances Fluorescent Dyes ; Scorpion Venoms ; Histamine (820484N8I3) ; tozuleristide (835UH424TU) ; Complement System Proteins (9007-36-7) ; Indocyanine Green (IX6J1063HV)
    Language English
    Publishing date 2017-03-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1379845-5
    ISSN 1092-874X ; 1091-5818
    ISSN (online) 1092-874X
    ISSN 1091-5818
    DOI 10.1177/1091581817697685
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1870: Show issues Location:
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  4. Article ; Online: Preclinical Validation of the Utility of BLZ-100 in Providing Fluorescence Contrast for Imaging Spontaneous Solid Tumors.

    Fidel, Janean / Kennedy, Katie C / Dernell, William S / Hansen, Stacey / Wiss, Valorie / Stroud, Mark R / Molho, Joshua I / Knoblaugh, Sue E / Meganck, Jeffrey / Olson, James M / Rice, Brad / Parrish-Novak, Julia

    Cancer research

    2014  Volume 75, Issue 20, Page(s) 4283–4291

    Abstract: There is a need in surgical oncology for contrast agents that can enable real-time intraoperative visualization of solid tumors that can enable complete resections while sparing normal surrounding tissues. The Tumor Paint agent BLZ-100 is a peptide- ... ...

    Abstract There is a need in surgical oncology for contrast agents that can enable real-time intraoperative visualization of solid tumors that can enable complete resections while sparing normal surrounding tissues. The Tumor Paint agent BLZ-100 is a peptide-fluorophore conjugate that can specifically bind solid tumors and fluoresce in the near-infrared range, minimizing light scatter and signal attenuation. In this study, we provide a preclinical proof of concept for use of this imaging contrast agent as administered before surgery to dogs with a variety of naturally occurring spontaneous tumors. Imaging was performed on excised tissues as well as intraoperatively in a subset of cases. Actionable contrast was achieved between tumor tissue and surrounding normal tissues in adenocarcinomas, squamous cell carcinomas, mast cell tumors, and soft tissue sarcomas. Subcutaneous soft tissue sarcomas were labeled with the highest fluorescence intensity and greatest tumor-to-background signal ratio. Our results establish a foundation that rationalizes clinical studies in humans with soft tissue sarcoma, an indication with a notably high unmet need.
    MeSH term(s) Adolescent ; Animals ; Child ; Child, Preschool ; Contrast Media/administration & dosage ; Diagnostic Imaging/instrumentation ; Diagnostic Imaging/methods ; Disease Models, Animal ; Dogs ; Female ; Fluorescent Dyes/administration & dosage ; Humans ; Indocyanine Green/administration & dosage ; Indocyanine Green/analogs & derivatives ; Intraoperative Care ; Male ; Neoplasms/diagnosis ; Neoplasms/pathology ; Reproducibility of Results ; Scorpion Venoms/administration & dosage
    Chemical Substances Contrast Media ; Fluorescent Dyes ; Scorpion Venoms ; tozuleristide (835UH424TU) ; Indocyanine Green (IX6J1063HV)
    Language English
    Publishing date 2014-08-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-15-0471
    Database MEDical Literature Analysis and Retrieval System OnLINE

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