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  1. Article ; Online: Frameshift mutations in peripheral blood as a biomarker for surveillance of lynch syndrome.

    Song, Yurong / Loomans-Kropp, Holli / Baugher, Ryan N / Somerville, Brandon / Baxter, Shaneen S / Kerr, Travis D / Plona, Teri M / Mellott, Stephanie D / Young, Todd B / Lawhorn, Heidi E / Wei, Lei / Hu, Qiang / Liu, Song / Hutson, Alan / Pinto, Ligia / Potter, John D / Sei, Shizuko / Gelincik, Ozkan / Lipkin, Steven M /
    Gebert, Johannes / Kloor, Matthias / Shoemaker, Robert H

    Journal of the National Cancer Institute

    2024  

    Abstract: Background: Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, which lead to high microsatellite instability (MSI-H) and frameshift mutations (FSMs) at coding ... ...

    Abstract Background: Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, which lead to high microsatellite instability (MSI-H) and frameshift mutations (FSMs) at coding mononucleotide repeats (cMNRs) in the genome. Recurrent FSMs in these regions are thought to play a central role in the increased risk of various cancers. However, there are no biomarkers currently available for the surveillance of MSI-H-associated cancers.
    Methods: An FSM-based biomarker panel was developed and validated by targeted next generation sequencing of supernatant DNA from cultured MSI-H colorectal cancer cells. This supported selection of 122-FSM targets as potential biomarkers. This biomarker panel was then tested using matched tumor, adjacent normal tissue, and buffy coat (53 samples), and blood-derived cell-free DNA (cfDNA; 38 samples) obtained from 45 cases of MSI-H/MMR deficient (MMRd) patients/carriers. cfDNA from 84 healthy individuals was also sequenced to assess background noise.
    Results: Recurrent FSMs at cMNRs were detectable not only in tumors, but also in cfDNA from MSI-H/MMRd cases including a LS carrier with a varying range of target detection (up to 85.2%), whereas they were virtually undetectable in healthy individuals. ROC analysis showed high sensitivity and specificity (AUC = 0.94) of the investigated panel.
    Conclusions: We demonstrated that FSMs can be detected in cfDNA from MSI-H/MMRd cases and asymptomatic carriers. The 122-target FSM panel described here has promise as a tool for improved surveillance of MSI-H/MMRd carriers with the potential to reduce the frequency of invasive screening methods for this high-cancer-risk cohort.
    Language English
    Publishing date 2024-03-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2992-0
    ISSN 1460-2105 ; 0027-8874 ; 0198-0157
    ISSN (online) 1460-2105
    ISSN 0027-8874 ; 0198-0157
    DOI 10.1093/jnci/djae060
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  2. Article ; Online: Small animal jet injection technique results in enhanced immunogenicity of hantavirus DNA vaccines.

    Brocato, Rebecca L / Kwilas, Steven A / Josleyn, Matthew D / Long, Simon / Zeng, Xiankun / Perley, Casey C / Principe, Lucia M / Somerville, Brandon / Cohen, Melanie V / Hooper, Jay W

    Vaccine

    2021  Volume 39, Issue 7, Page(s) 1101–1110

    Abstract: DNA vaccine evaluation in small animals is hampered by low immunogenicity when the vaccines are delivered using a needle and syringe. To overcome this technical hurdle we tested the possibility that a device developed for human intradermal medicine ... ...

    Abstract DNA vaccine evaluation in small animals is hampered by low immunogenicity when the vaccines are delivered using a needle and syringe. To overcome this technical hurdle we tested the possibility that a device developed for human intradermal medicine delivery might be adapted to successfully deliver a DNA vaccine to small animals. Disposable syringe jet injection (DSJI) does not currently exist for small animals. However, a commercialized, human intradermal device used to to administer medicines to the human dermis in a 0.1 mL volume was evaluated in Syrian hamsters. Here, we found that hantavirus DNA vaccines administered to hamsters using DSJI were substantially more immunogenic than the same vaccines delivered by needle/syringe or particle mediated epidermal delivery (gene gun) vaccination. By adjusting how the device was used we could deliver vaccine to either subcutaneous tissues, or through the skin into the muscle. RNA and/or antigen expression was detected in epidermal, subepidermal and fibroblast cells. We directly compared six optimized and non-optimized hantavirus DNA vaccines in hamsters. Optimization, including codon-usage and mRNA stability, did not necessarily result in increased immunogenicity for all vaccines tested; however, optimization of the Andes virus (ANDV) DNA vaccine protected vaccinated hamsters from lethal disease. This is the first time active vaccination with an ANDV DNA vaccine has shown protective efficacy in the hamster model. The adaptation of a human intradermal jet injection device for use as a method of subcutaneous and intramuscular jet injection of DNA vaccines will advance the development of nucleic acid based medical countermeasures for diseases modeled in hamsters.
    MeSH term(s) Animals ; Cricetinae ; Hantavirus/genetics ; Hantavirus Infections/prevention & control ; Immunogenicity, Vaccine ; Injections, Jet ; Vaccination/methods ; Vaccines, DNA/administration & dosage ; Viral Vaccines/administration & dosage
    Chemical Substances Vaccines, DNA ; Viral Vaccines
    Language English
    Publishing date 2021-01-19
    Publishing country Netherlands
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 605674-x
    ISSN 1873-2518 ; 0264-410X
    ISSN (online) 1873-2518
    ISSN 0264-410X
    DOI 10.1016/j.vaccine.2021.01.002
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  3. Article: Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer.

    Song, Yurong / Kerr, Travis D / Sanders, Chelsea / Dai, Lisheng / Baxter, Shaneen S / Somerville, Brandon / Baugher, Ryan N / Mellott, Stephanie D / Young, Todd B / Lawhorn, Heidi E / Plona, Teri M / Xu, Bingfang / Wei, Lei / Hu, Qiang / Liu, Song / Hutson, Alan / Karim, Baktiar / Burkett, Sandra / Difilippantonio, Simone /
    Pinto, Ligia / Gebert, Johannes / Kloor, Matthias / Lipkin, Steven M / Sei, Shizuko / Shoemaker, Robert H

    Frontiers in oncology

    2023  Volume 13, Page(s) 1223915

    Abstract: Background: Genome integrity is essential for the survival of an organism. DNA mismatch repair (MMR) genes (e.g., : Methods: To better understand the biology of MMRd cancers, elucidate the resistance mechanisms to immune modulation, and develop ... ...

    Abstract Background: Genome integrity is essential for the survival of an organism. DNA mismatch repair (MMR) genes (e.g.,
    Methods: To better understand the biology of MMRd cancers, elucidate the resistance mechanisms to immune modulation, and develop vaccines and therapeutic testing platforms for this high-risk population, we generated organoids and an orthotopic mouse model from intestine tumors developed in a Msh2-deficient mouse model, and followed with a detailed characterization.
    Results: The organoids were shown to be of epithelial origin with stem cell features, to have a high frameshift mutation frequency with MSI-H and chromosome instability, and intra- and inter-tumor heterogeneity. An orthotopic model using intra-cecal implantation of tumor fragments derived from organoids showed progressive tumor growth, resulting in the development of adenocarcinomas mixed with mucinous features and distant metastasis in liver and lymph node.
    Conclusions: The established organoids with characteristics of MSI-H cancers can be used to study MMRd cancer biology. The orthotopic model, with its distant metastasis and expressing frameshift peptides, is suitable for evaluating the efficacy of neoantigen-based vaccines or anticancer drugs in combination with other therapies.
    Language English
    Publishing date 2023-09-08
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2023.1223915
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  4. Article: Anti-HFRS Human IgG Produced in Transchromosomic Bovines Has Potent Hantavirus Neutralizing Activity and Is Protective in Animal Models.

    Perley, Casey C / Brocato, Rebecca L / Wu, Hua / Bausch, Christoph / Karmali, Priya P / Vega, Jerel B / Cohen, Melanie V / Somerville, Brandon / Kwilas, Steven A / Principe, Lucia M / Shamblin, Joshua / Chivukula, Padmanabh / Sullivan, Eddie / Hooper, Jay W

    Frontiers in microbiology

    2020  Volume 11, Page(s) 832

    Abstract: We explored an emerging technology to produce anti-Hantaan virus (HTNV) and anti-Puumala virus (PUUV) neutralizing antibodies for use as pre- or post-exposure prophylactics. The technology involves hyperimmunization of transchomosomic bovines (TcB) ... ...

    Abstract We explored an emerging technology to produce anti-Hantaan virus (HTNV) and anti-Puumala virus (PUUV) neutralizing antibodies for use as pre- or post-exposure prophylactics. The technology involves hyperimmunization of transchomosomic bovines (TcB) engineered to express human polyclonal IgG antibodies with HTNV and PUUV DNA vaccines encoding G
    Keywords covid19
    Language English
    Publishing date 2020-05-07
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2587354-4
    ISSN 1664-302X
    ISSN 1664-302X
    DOI 10.3389/fmicb.2020.00832
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  5. Article ; Online: Clindamycin Protects Nonhuman Primates Against Inhalational Anthrax But Does Not Enhance Reduction of Circulating Toxin Levels When Combined With Ciprofloxacin.

    Vietri, Nicholas J / Tobery, Steven A / Chabot, Donald J / Ingavale, Susham / Somerville, Brandon C / Miller, Jeremy A / Schellhase, Chris W / Twenhafel, Nancy A / Fetterer, David P / Cote, Christopher K / Klimko, Christopher P / Boyer, Anne E / Woolfitt, Adrian R / Barr, John R / Wright, Mary E / Friedlander, Arthur M

    The Journal of infectious diseases

    2020  Volume 223, Issue 2, Page(s) 319–325

    Abstract: Background: Inhalational anthrax is rare and clinical experience limited. Expert guidelines recommend treatment with combination antibiotics including protein synthesis-inhibitors to decrease toxin production and increase survival, although evidence is ... ...

    Abstract Background: Inhalational anthrax is rare and clinical experience limited. Expert guidelines recommend treatment with combination antibiotics including protein synthesis-inhibitors to decrease toxin production and increase survival, although evidence is lacking.
    Methods: Rhesus macaques exposed to an aerosol of Bacillus anthracis spores were treated with ciprofloxacin, clindamycin, or ciprofloxacin + clindamycin after becoming bacteremic. Circulating anthrax lethal factor and protective antigen were quantitated pretreatment and 1.5 and 12 hours after beginning antibiotics.
    Results: In the clindamycin group, 8 of 11 (73%) survived demonstrating its efficacy for the first time in inhalational anthrax, compared to 9 of 9 (100%) with ciprofloxacin, and 8 of 11 (73%) with ciprofloxacin + clindamycin. These differences were not statistically significant. There were no significant differences between groups in lethal factor or protective antigen levels from pretreatment to 12 hours after starting antibiotics. Animals that died after clindamycin had a greater incidence of meningitis compared to those given ciprofloxacin or ciprofloxacin + clindamycin, but numbers of animals were very low and no definitive conclusion could be reached.
    Conclusion: Treatment of inhalational anthrax with clindamycin was as effective as ciprofloxacin in the nonhuman primate. Addition of clindamycin to ciprofloxacin did not enhance reduction of circulating toxin levels.
    MeSH term(s) Animals ; Anthrax/blood ; Anthrax/microbiology ; Anthrax/mortality ; Anthrax/prevention & control ; Anti-Bacterial Agents/therapeutic use ; Antigens, Bacterial/blood ; Bacillus anthracis/drug effects ; Bacillus anthracis/physiology ; Bacterial Toxins/blood ; Biomarkers ; Ciprofloxacin/pharmacology ; Ciprofloxacin/therapeutic use ; Clindamycin/pharmacology ; Clindamycin/therapeutic use ; Disease Models, Animal ; Drug Therapy, Combination ; Macaca mulatta ; Prognosis ; Respiratory Tract Infections/blood ; Respiratory Tract Infections/microbiology ; Respiratory Tract Infections/mortality ; Respiratory Tract Infections/prevention & control ; Treatment Outcome
    Chemical Substances Anti-Bacterial Agents ; Antigens, Bacterial ; Bacterial Toxins ; Biomarkers ; anthrax toxin ; Clindamycin (3U02EL437C) ; Ciprofloxacin (5E8K9I0O4U)
    Language English
    Publishing date 2020-07-22
    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 3019-3
    ISSN 1537-6613 ; 0022-1899
    ISSN (online) 1537-6613
    ISSN 0022-1899
    DOI 10.1093/infdis/jiaa365
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  6. Article ; Online: Small Animal Jet Injection Technique Results in Enhanced Immunogenicity of Hantavirus DNA Vaccines

    Brocato, Rebecca L. / Kwilas, Steven A. / Josleyn, Matthew D. / Long, Simon / Zeng, Xiankun / Perley, Casey C. / Principe, Lucia M. / Somerville, Brandon / Cohen, Melanie V. / Hooper, Jay W.

    bioRxiv

    Abstract: DNA vaccine evaluation in small animals is hampered by low immunogenicity when the vaccines are delivered using a needle and syringe. To overcome this technical hurdle we tested the possibility that a device developed for human intradermal medicine ... ...

    Abstract DNA vaccine evaluation in small animals is hampered by low immunogenicity when the vaccines are delivered using a needle and syringe. To overcome this technical hurdle we tested the possibility that a device developed for human intradermal medicine delivery might be adapted to successfully deliver a DNA vaccine to small animals. The PharmaJet® Tropis device is a FDA 510(k)-cleared disposable syringe, needle-free jet injection device designed to administer medicines to the human dermis in a 0.1 mL volume. Here, we found that hantavirus DNA vaccines administered to Syrian hamsters using Tropis were substantially more immunogenic than the same vaccines delivered by needle/syringe or particle mediated epidermal delivery (gene gun) vaccination. By adjusting how the device was used we could deliver vaccine to either subcutaneous tissues, or through the skin into the muscle. RNA and/or antigen expression was detected in epidermal, subepidermal and fibroblast cells. We directly compared six optimized and non-optimized hantavirus DNA vaccines in hamsters. Optimization, including codon-usage and mRNA stability, did not necessarily result in increased immunogenicity for all vaccines tested; however, optimization of the Andes virus (ANDV) DNA vaccine protected vaccinated hamsters from lethal disease. This is the first time active vaccination with an ANDV DNA vaccine has shown protective efficacy in the hamster model. The adaptation of a human intradermal jet injection device for use as a method of subcutaneous and intramuscular jet injection of DNA vaccines will advance the development of nucleic acid based medical countermeasures for diseases modeled in hamsters.
    Keywords covid19
    Publisher BioRxiv
    Document type Article ; Online
    DOI 10.1101/2020.11.09.374439
    Database COVID19

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  7. Article ; Online: Origins of Yersinia pestis sensitivity to the arylomycin antibiotics and the inhibition of type I signal peptidase.

    Steed, Danielle B / Liu, Jian / Wasbrough, Elizabeth / Miller, Lynda / Halasohoris, Stephanie / Miller, Jeremy / Somerville, Brandon / Hershfield, Jeremy R / Romesberg, Floyd E

    Antimicrobial agents and chemotherapy

    2015  Volume 59, Issue 7, Page(s) 3887–3898

    Abstract: Yersinia pestis is the etiologic agent of the plague. Reports of Y. pestis strains that are resistant to each of the currently approved first-line and prophylactic treatments point to the urgent need to develop novel antibiotics with activity against the ...

    Abstract Yersinia pestis is the etiologic agent of the plague. Reports of Y. pestis strains that are resistant to each of the currently approved first-line and prophylactic treatments point to the urgent need to develop novel antibiotics with activity against the pathogen. We previously reported that Y. pestis strain KIM6+, unlike most Enterobacteriaceae, is susceptible to the arylomycins, a novel class of natural-product lipopeptide antibiotics that inhibit signal peptidase I (SPase). In this study, we show that the arylomycin activity is conserved against a broad range of Y. pestis strains and confirm that it results from the inhibition of SPase. We next investigated the origins of this unique arylomycin sensitivity and found that it does not result from an increased affinity of the Y. pestis SPase for the antibiotic and that alterations to each component of the Y. pestis lipopolysaccharide-O antigen, core, and lipid A-make at most only a small contribution. Instead, the origins of the sensitivity can be traced to an increased dependence on SPase activity that results from high levels of protein secretion under physiological conditions. These results highlight the potential of targeting protein secretion in cases where there is a heavy reliance on this process and also have implications for the development of the arylomycins as an antibiotic with activity against Y. pestis and potentially other Gram-negative pathogens.
    MeSH term(s) Anti-Bacterial Agents/pharmacology ; Arabinose/pharmacology ; Bacterial Proteins/biosynthesis ; Cloning, Molecular ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation, Enzymologic/drug effects ; Lipid A/metabolism ; Lipopolysaccharides/metabolism ; Membrane Proteins/antagonists & inhibitors ; Membrane Proteins/genetics ; Microbial Sensitivity Tests ; O Antigens/metabolism ; Peptides, Cyclic/pharmacology ; Plasmids/genetics ; Protein Synthesis Inhibitors/pharmacology ; Serine Endopeptidases/genetics ; Temperature ; Yersinia pestis/drug effects ; Yersinia pestis/genetics
    Chemical Substances Anti-Bacterial Agents ; Bacterial Proteins ; Enzyme Inhibitors ; Lipid A ; Lipopolysaccharides ; Membrane Proteins ; O Antigens ; Peptides, Cyclic ; Protein Synthesis Inhibitors ; arylomycin A-C16 ; Arabinose (B40ROO395Z) ; Serine Endopeptidases (EC 3.4.21.-) ; type I signal peptidase (EC 3.4.21.89)
    Language English
    Publishing date 2015-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 217602-6
    ISSN 1098-6596 ; 0066-4804
    ISSN (online) 1098-6596
    ISSN 0066-4804
    DOI 10.1128/AAC.00181-15
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