Kevin Gerrish

Publications (34) View all

• Source

  Available from: Richard Paules

  Article: Genomic indicators in the blood predict drug-induced liver injury.

  J Huang, W Shi, J Zhang, J W Chou, R S Paules, K Gerrish, J Li, J Luo, R D Wolfinger, W Bao, [......], D Dosymbekov, M O Tsyganova, L Shi, X Fan, J C Corton, M Chen, Y Cheng, W Tong, H Fang, P R Bushel
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  ABSTRACT: Genomic biomarkers for the detection of drug-induced liver injury (DILI) from blood are urgently needed for monitoring drug safety. We used a unique data set as part of the Food and Drug Administration led MicroArray Quality Control Phase-II (MAQC-II) project consisting of gene expression data from the two tissues (blood and liver) to test cross-tissue predictability of genomic indicators to a form of chemically induced liver injury. We then use the genomic indicators from the blood as biomarkers for prediction of acetaminophen-induced liver injury and show that the cross-tissue predictability of a response to the pharmaceutical agent (accuracy as high as 92.1%) is better than, or at least comparable to, that of non-therapeutic compounds. We provide a database of gene expression for the highly informative predictors, which brings biological context to the possible mechanisms involved in DILI. Pathway-based predictors were associated with inflammation, angiogenesis, Toll-like receptor signaling, apoptosis, and mitochondrial damage. The results show for the first time and support the hypothesis that genomic indicators in the blood can serve as potential diagnostic biomarkers predictive of DILI.
  The Pharmacogenomics Journal 08/2010; 10(4):267-77. · 4.54 Impact Factor
• Article: Global gene profiling of spontaneous hepatocellular carcinoma in B6C3F1 mice: similarities in the molecular landscape with human liver cancer.

  Mark J Hoenerhoff, Arun R Pandiri, Stephanie A Lahousse, Hu-Hua Hong, Tai-Vu Ton, Tiwanda Masinde, Scott S Auerbach, Kevin Gerrish, Pierre R Bushel, Keith R Shockley, Shyamal D Peddada, Robert C Sills
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  ABSTRACT: Hepatocellular carcinoma (HCC) is an important cause of morbidity and mortality worldwide. Although the risk factors of human HCC are well known, the molecular pathogenesis of this disease is complex, and in general, treatment options remain poor. The use of rodent models to study human cancer has been extensively pursued, both through genetically engineered rodents and rodent models used in carcinogenicity and toxicology studies. In particular, the B6C3F1 mouse used in the National Toxicology Program (NTP) two-year bioassay has been used to evaluate the carcinogenic effects of environmental and occupational chemicals, and other compounds. The high incidence of spontaneous HCC in the B6C3F1 mouse has challenged its use as a model for chemically induced HCC in terms of relevance to the human disease. Using global gene expression profiling, we identify the dysregulation of several mediators similarly altered in human HCC, including re-expression of fetal oncogenes, upregulation of protooncogenes, downregulation of tumor suppressor genes, and abnormal expression of cell cycle mediators, growth factors, apoptosis regulators, and angiogenesis and extracellular matrix remodeling factors. Although major differences in etiology and pathogenesis remain between human and mouse HCC, there are important similarities in global gene expression and molecular pathways dysregulated in mouse and human HCC. These data provide further support for the use of this model in hazard identification of compounds with potential human carcinogenicity risk, and may help in better understanding the mechanisms of tumorigenesis resulting from chemical exposure in the NTP two-year carcinogenicity bioassay.
  Toxicologic Pathology 06/2011; 39(4):678-99. · 1.91 Impact Factor
• Article: Prevention of photocarcinogenesis and UV-induced immunosuppression in mice by topical tannic acid.

  H L Gensler, K E Gerrish, T Williams, G Rao, J Kittelson
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  ABSTRACT: Topical application of tannic acid, a phenolic antioxidant derived from plants, was found to inhibit the cutaneous carcinogenesis and the immunosuppression induced by ultraviolet B (UVB) irradiation with no visible toxicity. BALB/cAnNTacfBR mice were treated with 200 micrograms of tannic acid three times weekly for two weeks before UV treatments began and throughout the experiment. UVB irradiation consisted of five 30-minute exposures per week to banks of six FS40 Westinghouse sunlamps. In the photocarcinogenesis study, mice received a total dose of approximately 1.09 x 10(6) J/m2. Skin cancer incidence in UV-irradiated mice was 75% at 26 weeks after the first UV exposure; tannic acid reduced this to 42%. Immunosuppression induced by UVB irradiation normally prevents the host from rejecting antigenic syngeneic UV-induced tumors. Immunosuppression in these experiments was measured by a passive transfer assay. Tumor challenges grew to an average of 88 +/- 20, 36 +/- 11, and 20 +/- 8 mm2 in naive recipients of splenocytes from UVB-irradiated mice, nonirradiated control mice, and UVB-irradiated mice treated with tannic acid, respectively. Thus topical tannic acid treatment prevented the transfer of enhanced tumor susceptibility with splenocytes from UVB-irradiated mice.
  Nutrition and Cancer 02/1994; 22(2):121-30. · 2.78 Impact Factor
• Article: Inhibition of DFMO-induced audiogenic seizures by chlordiazepoxide.

  K E Gerrish, D J Fuller, E W Gerner, H L Gensler
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  ABSTRACT: Mice given 1% alpha-difluoromethylornithine (DFMO) in the drinking water for 5 weeks developed a hyperactive behavior characterized by uncontrolled running upon stimulation with noise. The running was followed by seizures and sometimes death. These behaviors are characteristic of audiogenic seizures. Strain differences in susceptibility to DFMO-induced audiogenic seizures were observed. The order of sensitivity to this DFMO effect was: C3HeB/FEJ = C3H/HeN > CBA/J = BALB/c. Chronic DFMO treatment was found to deplete whole brain putrescine and spermidine, but not spermine nor gamma-aminobutyric acid (GABA), in the 2 strains of mice analyzed, C3H/HeN and BALB/c. The audiogenic seizures were eliminated by pretreatment with the benzodiazepine, chlordiazepoxide (Librium) (40 mg/kg, ip) 105 minutes prior to testing for seizures.
  Life Sciences 02/1993; 52(13):1101-8. · 2.53 Impact Factor
• Article: Prevention of photocarcinogenesis by dietary vitamin E.

  K E Gerrish, H L Gensler
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  ABSTRACT: Ultraviolet B (UV-B) irradiation of C3H/HeN mice induces skin cancer. In this study, the ability of dietary d-alpha-tocopheryl acetate to reduce photocarcinogenesis was tested in this murine model. Skin cancers developed in 67.5% of UV-B-irradiated mice by 31 weeks after the first UV exposure. Supplementation with 100 or 200 IU of d-alpha-tocopheryl acetate per kilogram of diet led to a reduction of the incidence to 46% and 19%, respectively. The latter value was significantly different from that found in mice fed the basal diet (p = 0.039, one-sided P value by log-rank test). Skin levels of alpha-tocopherol varied with the dietary dose of d-alpha-tocopheryl acetate. No toxicity was evident in unirradiated mice fed the vitamin E-supplemented diet, but 40% of the UV-B-irradiated mice fed 200 IU of vitamin E per kilogram of diet died by 31 weeks after the first UV-B treatment. Decreased relative spleen weight was observed in the UV-B-irradiated mice fed the vitamin E-supplemented diet. In summary, oral d-alpha-tocopheryl acetate prevented photocarcinogenesis, but at doses that were toxic to inbred C3H/HeN mice after exposure to 8.6 x 10(5) J/m2 of UV-B irradiation.
  Nutrition and Cancer 02/1993; 19(2):125-33. · 2.78 Impact Factor