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Geoffrey D Girnun

Publications and source records attributed to Geoffrey D Girnun.

6 recordsLinked to original sources
PubMed2005

Hic-5 regulates an epithelial program mediated by PPARgamma.

PPARgamma is a dominant regulator of fat cell differentiation. However, this nuclear receptor also plays an important role in the differentiation of intestinal and other epithelial cell types. The mechanism by which PPARgamma can influence the differentiation of such diverse cell lineages is unknown. We show here that PPARgamma interacts with Hic-5, a coactivator protein expressed in gut epithelial cells. Hic-5 and PPARgamma colocalize to the villus epithelium of the small intestine, and their expression during embryonic gut development correlates with the transition from endoderm to a specialized epithelium; expression of both these factors is reduced in tumors. Forced expression of Hic-5 in colon cancer cells enhances the PPARgamma-mediated induction of several gut epithelial differentiation/maturation markers such as L-FABP, kruppel-like factor 4 (KLF4), and keratin 20. siRNA directed against Hic-5 specifically reduces PPARgamma-mediated induction of gut epithelial genes in colon cells and in an ex vivo model of embryonic gut differentiation. Finally, forced expression of Hic-5 during 3T3-L1 preadipocyte differentiation inhibits adipogenesis while inducing inappropriate expression of several mRNAs characteristic of gut epithelium in these mesenchymal cells. These results indicate that Hic5 is an important component in determining an epithelial differentiation program induced by PPARgamma.

Adipocytes↗
PubMed2003

Percutaneous tumor ablation: reduced tumor growth with combined radio-frequency ablation and liposomal doxorubicin in a rat breast tumor model.

PURPOSE: To determine whether combined intravenous liposomal doxorubicin and radio-frequency (RF) ablation decreases tumor growth and increases endpoint survival over those with RF or liposomal doxorubicin alone in an animal tumor model. MATERIALS AND METHODS: Subcutaneous R3230 mammary adenocarcinoma (1.1-1.4 cm) was implanted in female Fischer rats. Initially, 35 tumors were randomized into four experimental groups: (a) conventional monopolar RF (70 degrees C for 5 minutes) alone, (b) liposomal doxorubicin (1 mg) alone, (c) RF ablation followed by liposomal doxorubicin, and (d) no treatment. Ten additional tumors were randomized into two groups that received a 90 degrees C RF dose either with or without liposomal doxorubicin. Tumor growth rates and the defined survival endpoint, the time at which the tumor reached 3.0 cm in diameter, were recorded. The effect of treatments on endpoint survival and tumor doubling time were analyzed by means of the Kaplan-Meier method and analysis of variance statistics. RESULTS: Differences in endpoint survival and tumor doubling time in the six groups were highly significant (P <.001). Endpoint survivals were 9.1 days +/- 2.5 for the control group, 16 days +/- 3.7 for tumors treated with 70 degrees C RF alone, 16.5 days +/- 3.2 for tumors treated with liposomal doxorubicin alone, and 26.6 +/- 5.3 days with combined treatment. For 90 degrees C RF ablation, endpoint survivals were 16.6 days +/- 1.2 and 31.5 days +/- 3.0 without and with liposomal doxorubicin (P <.01). Mean endpoint survival and tumor doubling times for the three RF levels (0, 70 degrees C, and 90 degrees C) were all significantly different (P =.01). Additionally, animals that received combined liposomal doxorubicin and 90 degrees C RF ablation survived longer than did animals that received combined liposomal doxorubicin and 70 degrees C RF ablation (P <.01). CONCLUSION: Combined RF ablation and liposomal doxorubicin retards tumor growth and may increase animal survival compared with that with either therapy alone or no therapy.

Animals↗
PubMed2002

APC-dependent suppression of colon carcinogenesis by PPARgamma.

Activation of PPARgamma by synthetic ligands, such as thiazolidinediones, stimulates adipogenesis and improves insulin sensitivity. Although thiazolidinediones represent a major therapy for type 2 diabetes, conflicting studies showing that these agents can increase or decrease colonic tumors in mice have raised concerns about the role of PPARgamma in colon cancer. To analyze critically the role of this receptor, we have used mice heterozygous for Ppargamma with both chemical and genetic models of this malignancy. Heterozygous loss of PPARgamma causes an increase in beta-catenin levels and a greater incidence of colon cancer when animals are treated with azoxymethane. However, mice with preexisting damage to Apc, a regulator of beta-catenin, develop tumors in a manner insensitive to the status of PPARgamma. These data show that PPARgamma can suppress beta-catenin levels and colon carcinogenesis but only before damage to the APC/beta-catenin pathway. This finding suggests a potentially important use for PPARgamma ligands as chemopreventative agents in colon cancer.

Animals↗
PubMed2002

Radio-frequency ablation increases intratumoral liposomal doxorubicin accumulation in a rat breast tumor model.

PURPOSE: To determine whether intratumoral accumulation of liposomal doxorubicin or free unencapsulated doxorubicin is increased when combined with radio-frequency (RF) ablation. MATERIALS AND METHODS: Two 1.2-1.5-cm R3230 mammary adenocarcinomas were grown within the mammary fat pads of 19 female Fischer rats. One tumor of each pair was treated with RF ablation (tip temperature, 70 degrees C +/- 2 [SD]; 120 mA +/- 75) for 5 minutes, whereas the other tumor was a control. Intravenous liposomal doxorubicin (1 mg in 500 micro L, n = 6) or intravenous free unencapsulated doxorubicin (n = 7) was administered immediately following RF ablation. Doxorubicin was extracted in acid alcohol from tumors 24 hours following RF ablation, and fluorescent spectrophotometry was used to quantify extracted doxorubicin. Comparisons of intratumoral doxorubicin accumulation in tumors treated with RF ablation and in untreated tumors were analyzed with parametric (paired Student t test) and nonparametric (Wilcoxon rank sum test) statistics. Findings at autoradiography with densitometry (six additional tumors) demonstrated the spatial distribution of the intratumoral accumulation of liposomal doxorubicin. RESULTS: When RF ablation preceded administration of liposomal doxorubicin, mean intratumoral doxorubicin concentration was 5.6 micro g/g +/- 2.1 (range, 1.9-7.7 micro g/g), whereas 1.0 micro g/g +/- 0.4 (range, 0.5-1.5 micro g/g) was present in control tumors not treated with RF ablation (P <.05). Thus, there was a mean 7.1-fold +/- 4.9 increase in intratumoral doxorubicin accumulation following RF ablation (range, 2.1-14.5-fold) compared with the amount without RF pretreatment (P <.05). Increased intratumoral accumulation was not seen in animals receiving free doxorubicin with (mean, 0.4 micro g/g +/- 0.1) or without (mean, 0.8 micro g/g +/- 0.4) RF pretreatment (P =.07). Autoradiographic findings demonstrated accumulation of liposomal doxorubicin in a peripheral rim of tumor adjacent to the zone of coagulation. CONCLUSION: RF ablation augments the delivery of systemic antineoplastic agents such as liposomal doxorubicin.

Adenocarcinoma↗
PubMed2002

Identification of a functional peroxisome proliferator-activated receptor response element in the rat catalase promoter.

Peroxisomal proliferator-activated receptor (PPAR)gamma has been shown to decrease the inflammatory response via transrepression of proinflammatory transcription factors. However, the identity of PPARgamma responsive genes that decrease the inflammatory response has remained elusive. Because generation of the reactive oxygen species hydrogen peroxide (H(2)O(2)) plays a role in the inflammatory process and activation of proinflammatory transcription factors, we wanted to determine whether the antioxidant enzyme catalase might be a PPARgamma target gene. We identified a putative PPAR response element (PPRE) containing the canonical direct repeat 1 motif, AGGTGA-A-AGTTGA, in the rat catalase promoter. In vitro translated PPARgamma and retinoic X receptor-alpha proteins were able to bind to the catalase PPRE. Promoter deletion analysis revealed that the PPRE was functional, and a heterologous promoter construct containing a multimerized catalase PPRE demonstrated that the PPRE was necessary and sufficient for PPARgamma-mediated activation. Treatment of microvascular endothelial cells with PPARgamma ligands led to increases in catalase mRNA and activity. These results demonstrate that PPARgamma can alter catalase expression; this occurs via a PPRE in the rat catalase promoter. Thus, in addition to transrepression of proinflammatory transcription factors, PPARgamma may also be modulating catalase expression, and hence down-regulating the inflammatory response via scavenging of reactive oxygen species.

Animals↗