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  1. Article ; Online: Safety Assessment of Food Additives: Case Example With Myrcene, a Synthetic Flavoring Agent.

    Mog, Steven R / Zang, Yu Janet

    Toxicologic pathology

    2019  Volume 47, Issue 8, Page(s) 1035–1037

    Abstract: In the United States, the Food and Drug Administration (FDA) regulates the safe use of food ingredients, including food additives. Food additives are subject to FDA premarket review and approval, a process conducted by FDA scientists to evaluate the ... ...

    Abstract In the United States, the Food and Drug Administration (FDA) regulates the safe use of food ingredients, including food additives. Food additives are subject to FDA premarket review and approval, a process conducted by FDA scientists to evaluate the additive's safety for the intended conditions of use. Typically, an acceptable daily intake level is established by toxicologists based on the highest no observable adverse effect level for the most sensitive noncancer toxicity end point determined from a pivotal nonclinical study with application of an appropriate safety factor. Utilizing other information, including the additive's use and exposure levels, a safety determination (reasonable certainty of no harm) is made. During ongoing safety assessments, pathologists are often consulted by toxicologists for case-specific reasons, which may include verifying that an observed pathological effect is treatment related and adverse, confirming the determination of the pivotal study, endorsing a mode of action, or evaluating the human relevance of a toxicological effect found in experimental animals. Last year, the FDA took regulatory action to no longer allow the use of the food additive myrcene, a synthetic flavoring agent, based on results from National Toxicology Program carcinogenicity studies. The cancer and noncancer end points from the rat studies are discussed.
    MeSH term(s) Acyclic Monoterpenes/toxicity ; Alkenes/toxicity ; Animals ; Consumer Product Safety ; Flavoring Agents/toxicity ; Food Additives/toxicity ; Humans ; No-Observed-Adverse-Effect Level ; Rats ; Risk Assessment ; Toxicity Tests ; United States ; United States Food and Drug Administration
    Chemical Substances Acyclic Monoterpenes ; Alkenes ; Flavoring Agents ; Food Additives ; myrcene (3M39CZS25B)
    Language English
    Publishing date 2019-10-23
    Publishing country United States
    Document type Journal Article
    ZDB-ID 841009-4
    ISSN 1533-1601 ; 0192-6233
    ISSN (online) 1533-1601
    ISSN 0192-6233
    DOI 10.1177/0192623319879634
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  2. Article ; Online: Renal Papillary Rarefaction: An Artifact Mimicking Papillary Necrosis.

    Seely, John Curtis / Francke, Sabine / Mog, Steven R / Frazier, Kendall S / Hard, Gordon C

    Toxicologic pathology

    2019  Volume 47, Issue 5, Page(s) 645–648

    Abstract: In histopathology, the presence of a tissue change that does not represent the tissue's normal appearance can often lead to an incorrect diagnosis and interpretation. These changes are collectively known as "artifacts" resulting from postmortem autolysis, ...

    Abstract In histopathology, the presence of a tissue change that does not represent the tissue's normal appearance can often lead to an incorrect diagnosis and interpretation. These changes are collectively known as "artifacts" resulting from postmortem autolysis, improper fixation, problems with tissue handling or slide preparation procedures. Most tissue artifacts are obvious, yet some artifacts may be subtle, occur in relatively well-fixed tissue, and demand careful observation to avoid confusion with real biological lesions. The kidney often contains artifacts that may be observed throughout all regions of the renal parenchyma. Cortical tubule artifacts present the greatest challenge when discerning an artifact versus an induced lesion following exposure to a xenobiotic. However, confounding artifacts observed at the tip of the renal papilla may also be problematic for the pathologist. An uncommon artifact involving tinctorial alteration and rarefaction affecting the papillary tip of the rat kidney is described here and differentiated from treatment induced lesions of renal papillary necrosis.
    MeSH term(s) Animals ; Artifacts ; Kidney Medulla/drug effects ; Kidney Medulla/pathology ; Necrosis ; Rats ; Xenobiotics/toxicity
    Chemical Substances Xenobiotics
    Language English
    Publishing date 2019-05-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 841009-4
    ISSN 1533-1601 ; 0192-6233
    ISSN (online) 1533-1601
    ISSN 0192-6233
    DOI 10.1177/0192623319852291
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Hydrophobic Sand Is a Non-Toxic Method of Urine Collection, Appropriate for Urinary Metal Analysis in the Rat.

    Hoffman, Jessica F / Vergara, Vernieda B / Mog, Steven R / Kalinich, John F

    Toxics

    2017  Volume 5, Issue 4

    Abstract: Hydrophobic sand is a relatively new method of urine collection in the rodent, comparable to the established method using a metabolic cage. Urine samples are often used in rodent research, especially for biomarkers of health changes after internal ... ...

    Abstract Hydrophobic sand is a relatively new method of urine collection in the rodent, comparable to the established method using a metabolic cage. Urine samples are often used in rodent research, especially for biomarkers of health changes after internal contamination from embedded metals, such as in a model of a military shrapnel wound. However, little research has been done on the potential interference of hydrophobic sand with urine metal concentrations either by contamination from the sand particulate, or adsorption of metals from the urine. We compare urine collected from rats using the metabolic cage method and the hydrophobic sand method for differences in metal concentration of common urinary metals, and examine physical properties of the sand material for potential sources of contamination. We found minimal risk of internal contamination of the rat by hydrophobic sand, and no interference of the sand with several common metals of interest (cobalt, strontium, copper, and manganese), although we advise caution in studies of aluminum in urine.
    Language English
    Publishing date 2017-10-11
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2733883-6
    ISSN 2305-6304 ; 2305-6304
    ISSN (online) 2305-6304
    ISSN 2305-6304
    DOI 10.3390/toxics5040025
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Captopril reduces lung inflammation and accelerated senescence in response to thoracic radiation in mice.

    Mungunsukh, Ognoon / George, Jeffy / McCart, Elizabeth A / Snow, Andrew L / Mattapallil, Joseph J / Mog, Steven R / Panganiban, Ronald Allan M / Bolduc, David L / Rittase, W Bradley / Bouten, Roxane M / Day, Regina M

    Journal of radiation research

    2021  Volume 62, Issue 2, Page(s) 236–248

    Abstract: The lung is sensitive to radiation and exhibits several phases of injury, with an initial phase of radiation-induced pneumonitis followed by delayed and irreversible fibrosis. The angiotensin-converting enzyme inhibitor captopril has been demonstrated to ...

    Abstract The lung is sensitive to radiation and exhibits several phases of injury, with an initial phase of radiation-induced pneumonitis followed by delayed and irreversible fibrosis. The angiotensin-converting enzyme inhibitor captopril has been demonstrated to mitigate radiation lung injury and to improve survival in animal models of thoracic irradiation, but the mechanism remains poorly understood. Here we investigated the effect of captopril on early inflammatory events in the lung in female CBA/J mice exposed to thoracic X-ray irradiation of 17-17.9 Gy (0.5-0.745 Gy min-1). For whole-body + thoracic irradiation, mice were exposed to 7.5 Gy (0.6 Gy min-1) total-body 60Co irradiation and 9.5 Gy thoracic irradiation. Captopril was administered orally (110 mg kg-1 day-1) in the drinking water, initiated 4 h through to150 days post-irradiation. Captopril treatment increased survival from thoracic irradiation to 75% at 150 days compared with 0% survival in vehicle-treated animals. Survival was characterized by a significant decrease in radiation-induced pneumonitis and fibrosis. Investigation of early inflammatory events showed that captopril significantly attenuated macrophage accumulation and decreased the synthesis of radiation-induced interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) pro-inflammatory cytokines in the lungs of irradiated mice. Suppression of IL-1β and TNF-α correlated with an increase of the anti-inflammatory cytokine IL-10 in the spleen with captopril treatment. We also found that captopril decreased markers for radiation-induced accelerated senescence in the lung tissue. Our data suggest that suppression of inflammation and senescence markers, combined with an increase of anti-inflammatory factors, are a part of the mechanism for captopril-induced survival in thoracic irradiated mice.
    MeSH term(s) Aging/pathology ; Animals ; Apoptosis/drug effects ; Apoptosis/radiation effects ; Biomarkers/metabolism ; Captopril/pharmacology ; Captopril/therapeutic use ; Cytokines/metabolism ; Female ; Inflammation Mediators/metabolism ; Lung/drug effects ; Lung/radiation effects ; Macrophages, Alveolar/drug effects ; Macrophages, Alveolar/pathology ; Macrophages, Alveolar/radiation effects ; Mice, Inbred CBA ; Pneumonia/drug therapy ; Pulmonary Fibrosis/pathology ; Spleen/drug effects ; Spleen/radiation effects ; Survival Analysis ; Thorax/radiation effects ; Whole-Body Irradiation ; X-Rays ; Mice
    Chemical Substances Biomarkers ; Cytokines ; Inflammation Mediators ; Captopril (9G64RSX1XD)
    Language English
    Publishing date 2021-02-22
    Publishing country England
    Document type Journal Article
    ZDB-ID 603983-2
    ISSN 1349-9157 ; 0449-3060
    ISSN (online) 1349-9157
    ISSN 0449-3060
    DOI 10.1093/jrr/rraa142
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: The Role of the Component Metals in the Toxicity of Military-Grade Tungsten Alloy.

    Emond, Christy A / Vergara, Vernieda B / Lombardini, Eric D / Mog, Steven R / Kalinich, John F

    Toxics

    2015  Volume 3, Issue 4, Page(s) 499–514

    Abstract: Tungsten-based composites have been recommended as a suitable replacement for depleted uranium. Unfortunately, one of these mixtures composed of tungsten (W), nickel (Ni) and cobalt (Co) induced rhabdomyosarcomas when implanted into the leg muscle of ... ...

    Abstract Tungsten-based composites have been recommended as a suitable replacement for depleted uranium. Unfortunately, one of these mixtures composed of tungsten (W), nickel (Ni) and cobalt (Co) induced rhabdomyosarcomas when implanted into the leg muscle of laboratory rats and mice to simulate a shrapnel wound. The question arose as to whether the neoplastic effect of the mixture could be solely attributed to one or more of the metal components. To investigate this possibility, pellets with one or two of the component metals replaced with an identical amount of the biologically-inert metal tantalum (Ta) were manufactured and implanted into the quadriceps of B6C3F₁ mice. The mice were followed for two years to assess potential adverse health effects. Implantation with WTa, CoTa or WNiTa resulted in decreased survival, but not to the level reported for WNiCo. Sarcomas in the implanted muscle were found in 20% of the CoTa-implanted mice and 5% of the WTa- and WCoTa-implanted rats and mice, far below the 80% reported for WNiCo-implanted mice. The data obtained from this study suggested that no single metal is solely responsible for the neoplastic effects of WNiCo and that a synergistic effect of the three metals in tumor development was likely.
    Language English
    Publishing date 2015-12-08
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2733883-6
    ISSN 2305-6304 ; 2305-6304
    ISSN (online) 2305-6304
    ISSN 2305-6304
    DOI 10.3390/toxics3040499
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  6. Article ; Online: Induction of rhabdomyosarcoma by embedded military-grade tungsten/nickel/cobalt not by tungsten/nickel/iron in the B6C3F1 mouse.

    Emond, Christy A / Vergara, Vernieda B / Lombardini, Eric D / Mog, Steven R / Kalinich, John F

    International journal of toxicology

    2015  Volume 34, Issue 1, Page(s) 44–54

    Abstract: Continued improvements in the ballistic properties of military munitions have led to metal formulations for which little are known about the long-term health effects. Previously we have shown that a military-grade tungsten alloy comprised of tungsten, ... ...

    Abstract Continued improvements in the ballistic properties of military munitions have led to metal formulations for which little are known about the long-term health effects. Previously we have shown that a military-grade tungsten alloy comprised of tungsten, nickel, and cobalt, when embedded into the leg muscle of F344 rats to simulate a fragment wound, induces highly aggressive metastatic rhabdomyosarcomas. An important follow-up when assessing a compound's carcinogenic potential is to test it in a second rodent species. In this study, we assessed the health effects of embedded fragments of 2 military-grade tungsten alloys, tungsten/nickel/cobalt and tungsten/nickel/iron, in the B6C3F1 mouse. Implantation of tungsten/nickel/cobalt pellets into the quadriceps muscle resulted in the formation of a rhabdomyosarcoma around the pellet. Conversely, implantation of tungsten/nickel/iron did not result in tumor formation. Unlike what was seen in the rat model, the tumors induced by the tungsten/nickel/cobalt did not exhibit aggressive growth patterns and did not metastasize.
    MeSH term(s) Alloys/pharmacokinetics ; Alloys/toxicity ; Animals ; Foreign Bodies ; Male ; Metals, Heavy/pharmacokinetics ; Metals, Heavy/toxicity ; Metals, Heavy/urine ; Mice ; Muscle Neoplasms/chemically induced ; Muscle Neoplasms/metabolism ; Muscle Neoplasms/pathology ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/pathology ; Rhabdomyosarcoma/chemically induced ; Rhabdomyosarcoma/metabolism ; Rhabdomyosarcoma/pathology ; Tissue Distribution ; Weapons
    Chemical Substances Alloys ; Metals, Heavy
    Language English
    Publishing date 2015-01
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1379845-5
    ISSN 1092-874X ; 1091-5818
    ISSN (online) 1092-874X
    ISSN 1091-5818
    DOI 10.1177/1091581814565038
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  7. Article ; Online: Tocopherol succinate: modulation of antioxidant enzymes and oncogene expression, and hematopoietic recovery.

    Singh, Vijay K / Parekh, Vaishali I / Brown, Darren S / Kao, Tzu-Cheg / Mog, Steven R

    International journal of radiation oncology, biology, physics

    2011  Volume 79, Issue 2, Page(s) 571–578

    Abstract: Purpose: A class of naturally occurring isoforms of tocopherol (tocols) was shown to have varying degrees of protection when administered before radiation exposure. We recently demonstrated that α-tocopherol succinate (TS) is a potential radiation ... ...

    Abstract Purpose: A class of naturally occurring isoforms of tocopherol (tocols) was shown to have varying degrees of protection when administered before radiation exposure. We recently demonstrated that α-tocopherol succinate (TS) is a potential radiation prophylactic agent. Our objective in this study was to further investigate the mechanism of action of TS in mice exposed to (60)Co γ-radiation.
    Methods and materials: We evaluated the effects of TS on expression of antioxidant enzymes and oncogenes by quantitative RT-PCR in bone marrow cells of (60)Co γ-irradiated mice. Further, we tested the ability of TS to rescue and repopulate hematopoietic stem cells by analyzing bone marrow cellularity and spleen colony forming unit in spleen of TS-injected and irradiated mice.
    Results: Our results demonstrate that TS modulated the expression of antioxidant enzymes and inhibited expression of oncogenes in irradiated mice at different time points. TS also increased colony forming unit-spleen numbers and bone marrow cellularity in irradiated mice.
    Conclusions: Results provide additional support for the observed radioprotective efficacy of TS and insight into mechanisms.
    MeSH term(s) Animals ; Antioxidants/pharmacology ; Bone Marrow Cells/cytology ; Bone Marrow Cells/drug effects ; Bone Marrow Cells/metabolism ; Bone Marrow Cells/radiation effects ; Cobalt Radioisotopes/pharmacology ; Colony-Forming Units Assay/methods ; DNA Primers/genetics ; Genes, jun/drug effects ; Genes, jun/radiation effects ; Glutathione Peroxidase/drug effects ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/drug effects ; Glutathione Reductase/metabolism ; Glutathione Transferase/drug effects ; Glutathione Transferase/metabolism ; Hematopoietic Stem Cells/drug effects ; Hematopoietic Stem Cells/metabolism ; Hematopoietic Stem Cells/physiology ; Hematopoietic Stem Cells/radiation effects ; Male ; Mice ; Proto-Oncogene Proteins c-fos/metabolism ; Proto-Oncogene Proteins c-jun/metabolism ; Proto-Oncogene Proteins c-myc/metabolism ; Radiation-Protective Agents/pharmacology ; Spleen/cytology ; Spleen/drug effects ; Spleen/radiation effects ; Sternum/cytology ; Sternum/drug effects ; Sternum/radiation effects ; Superoxide Dismutase/drug effects ; Superoxide Dismutase/metabolism ; alpha-Tocopherol/pharmacology
    Chemical Substances Antioxidants ; Cobalt Radioisotopes ; DNA Primers ; Proto-Oncogene Proteins c-fos ; Proto-Oncogene Proteins c-jun ; Proto-Oncogene Proteins c-myc ; Radiation-Protective Agents ; Glutathione Peroxidase (EC 1.11.1.9) ; Superoxide Dismutase (EC 1.15.1.1) ; Glutathione Reductase (EC 1.8.1.7) ; Glutathione Transferase (EC 2.5.1.18) ; alpha-Tocopherol (H4N855PNZ1)
    Language English
    Publishing date 2011-02-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 197614-x
    ISSN 1879-355X ; 0360-3016
    ISSN (online) 1879-355X
    ISSN 0360-3016
    DOI 10.1016/j.ijrobp.2010.08.019
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  8. Article: Subcutaneous administration of genistein prior to lethal irradiation supports multilineage, hematopoietic progenitor cell recovery and survival.

    Davis, Thomas A / Clarke, Tara K / Mog, Steven R / Landauer, Michael R

    International journal of radiation biology

    2007  Volume 83, Issue 3, Page(s) 141–151

    Abstract: Purpose: Genistein, a non-toxic isoflavone from soybeans, has immunomodulating and radioprotective properties. In this study we investigated the mechanism for genistein-induced radioprotection by evaluating the recovery of bone marrow cells and ... ...

    Abstract Purpose: Genistein, a non-toxic isoflavone from soybeans, has immunomodulating and radioprotective properties. In this study we investigated the mechanism for genistein-induced radioprotection by evaluating the recovery of bone marrow cells and peripheral blood hematology in lethally irradiated mice.
    Materials and methods: CD2F1 male mice received a single subcutaneous injection of genistein (200 mg/kg) 24 h prior to a lethal, total body irradiation dose (8.75 Gy) of cobalt-60 gamma radiation. Survival and hematopoietic reconstitution were evaluated over nine weeks post-irradiation. Hematopoietic progenitor colony-forming cell assays were used to assess the reconstitution of bone marrow after radiation-induced myelosuppression.
    Results: A total of 97% of genistein-treated mice survived after 30 days while 31% of vehicle-treated and 0% of untreated mice survived. The improvement in survival was related to accelerated neutrophil and platelet recovery, resulting from earlier and more pronounced multilineage, hematopoietic progenitor cell reconstitution in the femoral marrow compartment. Myeloid and erythroid progenitor cell numbers at day 15 post-irradiation were 6-fold to 20-fold higher in genistein-treated animals than in control animals.
    Conclusions: These results demonstrate that a single subcutaneous administration of genistein 24 h before irradiation provides significant radioprotection to the hematopoietic progenitor cell compartment.
    MeSH term(s) Animals ; Bone Marrow Cells/cytology ; Bone Marrow Cells/drug effects ; Bone Marrow Cells/radiation effects ; Cell Survival/drug effects ; Cell Survival/radiation effects ; Colony-Forming Units Assay ; Gamma Rays ; Genistein/administration & dosage ; Genistein/pharmacology ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/drug effects ; Hematopoietic Stem Cells/radiation effects ; Injections, Subcutaneous ; Kinetics ; Male ; Mice ; Radiation-Protective Agents/administration & dosage ; Radiation-Protective Agents/pharmacology ; Time Factors ; Whole-Body Irradiation
    Chemical Substances Radiation-Protective Agents ; Genistein (DH2M523P0H)
    Language English
    Publishing date 2007-03-07
    Publishing country England
    Document type Journal Article
    ZDB-ID 3065-x
    ISSN 1362-3095 ; 0955-3002 ; 0020-7616
    ISSN (online) 1362-3095
    ISSN 0955-3002 ; 0020-7616
    DOI 10.1080/09553000601132642
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  9. Article: Pathogenicity and immune response measured in mice following intranasal challenge with enterotoxigenic Escherichia coli strains H10407 and B7A.

    Byrd, Wyatt / Mog, Steven R / Cassels, Frederick J

    Infection and immunity

    2002  Volume 71, Issue 1, Page(s) 13–21

    Abstract: The pathogenicity and immunogenicity induced in BALB/c mice by intranasal (i.n.) inoculation of enterotoxigenic Escherichia coli (ETEC) strains H10407 (O78:H11:CFA/I:LT(+):ST(+)) and B7A (O148:H28:CS6:LT(+):ST(+)) (two ETEC strains previously used in ... ...

    Abstract The pathogenicity and immunogenicity induced in BALB/c mice by intranasal (i.n.) inoculation of enterotoxigenic Escherichia coli (ETEC) strains H10407 (O78:H11:CFA/I:LT(+):ST(+)) and B7A (O148:H28:CS6:LT(+):ST(+)) (two ETEC strains previously used in human challenge trials) were studied. The i.n. inoculation of BALB/c mice with large doses of ETEC strains H10407 and B7A caused illness and death. The H10407 strain was found to be consistently more virulent than the B7A strain. Following i.n. challenge with nonlethal doses of H10407 and B7A, the bacteria were cleared from the lungs of the mice at a steady rate over a 2-week period. Macrophages and neutrophils were observed in the alveoli and bronchioles, and lymphocytes were observed in the septa, around vessels, and in the pleura of the lungs in mice challenged with H10407 and B7A. In mice i.n. challenged with H10407, serum immunoglobulin G (IgG) and IgM antibodies were measured at high titers to the CFA/I and O78 lipopolysaccharide (LPS) antigens. In mice i.n. challenged with B7A, low serum IgG antibody titers were detected against CS6, and low serum IgG and IgM antibody titers were detected against O148 LPS. The serum IgG and IgM antibody titers against the heat-labile enterotoxin were equivalent in the H10407- and B7A-challenged mice. The CFA/I and O78 LPS antigens gave mixed T-helper cell 1-T-helper cell 2 (Th1-Th2) responses in which the Th2 response was greater than the Th1 response (i.e., stimulated primarily an antibody response). These studies indicate that the i.n. challenge of BALB/c mice with ETEC strains may provide a useful animal model to better understand the immunogenicity and pathogenicity of ETEC and its virulence determinants. This model may also be useful in providing selection criteria for vaccine candidates for use in primate and human trials.
    MeSH term(s) Administration, Intranasal ; Animals ; Antibodies, Bacterial/blood ; Antigens, Bacterial/immunology ; Bacterial Toxins/immunology ; Bacterial Toxins/metabolism ; Disease Models, Animal ; Enterotoxins/immunology ; Enterotoxins/metabolism ; Escherichia coli/immunology ; Escherichia coli/pathogenicity ; Escherichia coli Infections/immunology ; Escherichia coli Infections/microbiology ; Escherichia coli Infections/mortality ; Escherichia coli Proteins ; Female ; Humans ; Immunoglobulin G/blood ; Immunoglobulin M/blood ; Kinetics ; Lung/immunology ; Lung/pathology ; Mice ; Mice, Inbred BALB C ; Virulence
    Chemical Substances Antibodies, Bacterial ; Antigens, Bacterial ; Bacterial Toxins ; Enterotoxins ; Escherichia coli Proteins ; Immunoglobulin G ; Immunoglobulin M ; heat-labile enterotoxin, E coli (D9K3SN2LNY)
    Language English
    Publishing date 2002-10-08
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 218698-6
    ISSN 1098-5522 ; 0019-9567
    ISSN (online) 1098-5522
    ISSN 0019-9567
    DOI 10.1128/IAI.71.1.13-21.2003
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  10. Article ; Online: Accelerated senescence in skin in a murine model of radiation-induced multi-organ injury.

    McCart, Elizabeth A / Thangapazham, Rajesh L / Lombardini, Eric D / Mog, Steven R / Panganiban, Ronald Allan M / Dickson, Kelley M / Mansur, Rihab A / Nagy, Vitaly / Kim, Sung-Yop / Selwyn, Reed / Landauer, Michael R / Darling, Thomas N / Day, Regina M

    Journal of radiation research

    2017  Volume 58, Issue 5, Page(s) 636–646

    Abstract: Accidental high-dose radiation exposures can lead to multi-organ injuries, including radiation dermatitis. The types of cellular damage leading to radiation dermatitis are not completely understood. To identify the cellular mechanisms that underlie ... ...

    Abstract Accidental high-dose radiation exposures can lead to multi-organ injuries, including radiation dermatitis. The types of cellular damage leading to radiation dermatitis are not completely understood. To identify the cellular mechanisms that underlie radiation-induced skin injury in vivo, we evaluated the time-course of cellular effects of radiation (14, 16 or 17 Gy X-rays; 0.5 Gy/min) in the skin of C57BL/6 mice. Irradiation of 14 Gy induced mild inflammation, observed histologically, but no visible hair loss or erythema. However, 16 or 17 Gy radiation induced dry desquamation, erythema and mild ulceration, detectable within 14 days post-irradiation. Histological evaluation revealed inflammation with mast cell infiltration within 14 days. Fibrosis occurred 80 days following 17 Gy irradiation, with collagen deposition, admixed with neutrophilic dermatitis, and necrotic debris. We found that in cultures of normal human keratinocytes, exposure to 17.9 Gy irradiation caused the upregulation of p21/waf1, a marker of senescence. Using western blot analysis of 17.9 Gy-irradiated mice skin samples, we also detected a marker of accelerated senescence (p21/waf1) 7 days post-irradiation, and a marker of cellular apoptosis (activated caspase-3) at 30 days, both preceding histological evidence of inflammatory infiltrates. Immunohistochemistry revealed reduced epithelial stem cells from hair follicles 14-30 days post-irradiation. Furthermore, p21/waf1 expression was increased in the region of the hair follicle stem cells at 14 days post 17 Gy irradiation. These data indicate that radiation induces accelerated cellular senescence in the region of the stem cell population of the skin.
    MeSH term(s) Adult Stem Cells/radiation effects ; Aging ; Animals ; Apoptosis/radiation effects ; Cellular Senescence/radiation effects ; Disease Models, Animal ; Dose-Response Relationship, Radiation ; Female ; Fibrosis ; Hair Follicle/pathology ; Hair Follicle/radiation effects ; Keratinocytes/pathology ; Keratinocytes/radiation effects ; Mice, Inbred C57BL ; Organ Specificity/radiation effects ; Radiation Injuries/pathology ; Skin/pathology ; Skin/radiation effects ; Skin Aging/radiation effects ; Ulcer/pathology
    Language English
    Publishing date 2017-03-16
    Publishing country England
    Document type Journal Article
    ZDB-ID 603983-2
    ISSN 1349-9157 ; 0449-3060
    ISSN (online) 1349-9157
    ISSN 0449-3060
    DOI 10.1093/jrr/rrx008
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