Validation of a Preclinical Model of Diethylnitrosamine-Induced Hepatic Neoplasia in Yucatan Miniature Pigs.

Objective: The purpose of this study was to reduce the time to tumor onset in a diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) swine model via partial liver embolization (PLE) and to characterize the model for use in translational research.

Methods: Eight Yucatan miniature pigs were injected intraperitoneally with either saline (n = 2) or DEN (n = 6) solution weekly for 12 weeks. Three of the DEN-treated pigs underwent PLE.

Pharmacokinetics, clearance, and biosafety of polyethylene glycol-coated hollow gold nanospheres.

Objective: Gold nanoparticles have attracted enormous interest as potential theranostic agents. However, little is known about the long-term elimination and systemic toxicity of gold nanoparticles in the literature. Hollow gold nanospheres (HAuNS) is a class of photothermal conducting agent that have shown promises in photoacoustic imaging, photothermal ablation therapy, and drug delivery.

Tissue-specific and age-dependent effects of global Mdm2 loss.

Mdm2, an E3 ubiquitin ligase, negatively regulates the tumour suppressor p53. In this study we utilized a conditional Mdm2 allele, Mdm2(FM) , and a CAG-CreER tamoxifen-inducible recombination system to examine the effects of global Mdm2 loss in adult mice. Two different tamoxifen injection regimens caused 100% lethality of Mdm2(FM) (/-) ;CAG-CreER mice; both radio-sensitive and radio-insensitive tissues were impaired.

A biodistribution and toxicity study of cobalt dichloride-N-acetyl cysteine in an implantable MRI marker for prostate cancer treatment.

Purpose: C4, a cobalt dichloride-N-acetyl cysteine complex, is being developed as a positive-signal magnetic resonance imaging (MRI) marker to localize implanted radioactive seeds in prostate brachytherapy. We evaluated the toxicity and biodistribution of C4 in rats with the goal of simulating the systemic effects of potential leakage from C4 MRI markers within the prostate.

Methods And Materials: 9-μL doses (equivalent to leakage from 120 markers in a human) of control solution (0.

Enhancement of lung tumorigenesis in a Gprc5a Knockout mouse by chronic extrinsic airway inflammation.

Background: Although cigarette smoking is the principal cause of lung carcinogenesis, chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, has been identified as an independent risk factor for lung cancer. Bacterial colonization, particularly with non-typeable Haemophilus influenzae (NTHi), has been implicated as a cause of airway inflammation in COPD besides cigarette smoke. Accordingly, we hypothesized that lung cancer promotion may occur in a chronic inflammatory environment in the absence of concurrent carcinogen exposure.

Photothermal-chemotherapy with doxorubicin-loaded hollow gold nanospheres: A platform for near-infrared light-trigged drug release.

Photothermal ablation (PTA) is an emerging technique that uses near-infrared (NIR) laser light-generated heat to destroy tumor cells. However, complete eradication of tumor cells with PTA is difficult because of uneven heat distribution in the treatment volume. We hypothesized that combining PTA with chemotherapy using a single multifunctional nanoconstruct that mediates simultaneous photothermal cell killing and drug release (photothermal-chemotherapy) would result in enhanced antitumor activity and reduced toxicity compared to chemotherapy alone.

Multiple stress signals activate mutant p53 in vivo.

p53 levels are tightly regulated in normal cells, and thus, the wild-type p53 protein is nearly undetectable until stimulated through a variety of stresses. In response to stress, p53 is released from its negative regulators, mainly murine double minute 2 (Mdm2), allowing p53 to be stabilized to activate cell-cycle arrest, senescence, and apoptosis programs. Many of the upstream signals that regulate wild-type p53 are known; however, limited information for the regulation of mutant p53 exists.

Hepatic arterial embolization with doxorubicin-loaded superabsorbent polymer microspheres in a rabbit liver tumor model.

Objectives: The pharmacokinetic profile after hepatic arterial embolization with superabsorbent microspheres (QuadraSpheres) loaded with doxorubicin was studied.

Methods: Rabbits with hepatic VX2 tumors were treated with intra-arterial administration of QuadraSpheres loaded with doxorubicin, or transarterial chemoembolization (TACE) using doxorubicin, Lipiodol and Embospheres, or hepatic arterial infusion (HAI) of doxorubicin. Tumor specimens were evaluated by fluorescence microscopy, and plasma and tumor concentrations of doxorubicin were measured.

Differential impacts of insulin-like growth factor-binding protein-3 (IGFBP-3) in epithelial IGF-induced lung cancer development.

The IGF axis has been implicated in the risk of various cancers. We previously reported a potential role of tissue-derived IGF in lung tumor formation and progression. However, the role of IGF-binding protein (IGFBP)-3, a major IGFBP, on the activity of tissue-driven IGF in lung cancer development is largely unknown.

Cdk2 is required for breast cancer mediated by the low-molecular-weight isoform of cyclin E.

Cyclin E activates Cdk2, controls centrosome duplication, and regulates histone gene transcription. Cyclin E is deregulated in cancer and appears as low-molecular-weight (LMW) isoforms that correlate strongly with decreased survival in breast cancer patients. Transgenic mice overexpressing LMW-cyclin E have increased incidence of mammary tumors and distant metastasis when compared with mice that had full-length cyclin E.

Spontaneous tumorigenesis in mice overexpressing the p53-negative regulator Mdm4.

High levels of the critical p53 inhibitor Mdm4 is common in tumors that retain a wild-type p53 allele, suggesting that Mdm4 overexpression is an important mechanism for p53 inactivation during tumorigenesis. To test this hypothesis in vivo, we generated transgenic mice with widespread expression of Mdm4. Two independent lines of transgenic mice, Mdm4(Tg1) and Mdm4(Tg15), developed spontaneous tumors, the most prevalent of which were sarcomas.

Comparative functional genomics analysis of NNK tobacco-carcinogen induced lung adenocarcinoma development in Gprc5a-knockout mice.

Background: Improved understanding of lung cancer development and progression, including insights from studies of animal models, are needed to combat this fatal disease. Previously, we found that mice with a knockout (KO) of G-protein coupled receptor 5A (Gprc5a) develop lung tumors after a long latent period (12 to 24 months).

Methodology/principal Findings: To determine whether a tobacco carcinogen will enhance tumorigenesis in this model, we administered 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) i.

Knockout of the tumor suppressor gene Gprc5a in mice leads to NF-kappaB activation in airway epithelium and promotes lung inflammation and tumorigenesis.

Mouse models can be useful for increasing the understanding of lung tumorigenesis and assessing the potential of chemopreventive agents. We explored the role of inflammation in lung tumor development in mice with knockout of the tumor suppressor Gprc5a. Examination of normal lung tissue and tumors from 51 Gprc5a(+/+) (adenoma incidence, 9.

Low molecular weight cyclin E is specific in breast cancer and is associated with mechanisms of tumor progression.

Low molecular weight (LMW) isoforms of cyclin E are post-translationally generated in breast cancer cells and are associated with aggressive disease and poor prognosis. In this study, the specificity of LMW cyclin E to cancer cells was determined by measuring cyclin E expression in tumor and non-tumor tissue from 340 breast cancer patients. Our results reveal the LMW isoforms were detected significantly more frequently in breast tumor tissue than in adjacent non-tumor breast tissues (p < 0.

The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss.

The p53 tumor suppressor is often disrupted in human cancers by the acquisition of missense mutations. We generated mice with a missense mutation at codon 172 that mimics the p53R175H hot spot mutation in human cancer. p53 homozygous mutant mice have unstable mutant p53 in normal cells and stabilize mutant p53 in some but not all tumors.

Identification of the retinoic acid-inducible Gprc5a as a new lung tumor suppressor gene.

Background: Lung cancers develop via multiple genetic and epigenetic changes, including inactivation of tumor suppressor genes. We previously cloned human G protein-coupled receptor family C type 5A (GPRC5A), whose expression is suppressed in some human lung carcinoma cells, and its mouse homolog Gprc5a.

Methods: We generated Gprc5a knockout mice by homologous recombination and studied their phenotype by macroscopic observation and microscopic histologic analysis of embryos and lungs of 1- to 2-year-old mice.

Overexpression of the low molecular weight cyclin E in transgenic mice induces metastatic mammary carcinomas through the disruption of the ARF-p53 pathway.

In tumor cells, cyclin E deregulation results in the appearance of five low molecular weight (LMW) isoforms. When overexpressed in breast cancer cells, these forms of cyclin E induce genomic instability, resistance to inhibition by p21 and p27, and resistance to antiestrogen therapy. Additionally, the LMW forms of cyclin E strongly correlate with decreased survival in patients with breast cancer.

Loss of Mdm4 results in p53-dependent dilated cardiomyopathy.

Background: Although several loci for familial dilated cardiomyopathy (DCM) have been mapped, the origin of a large percentage of DCM remains unclear. Mdm2, a p53-negative regulator, protects cardiomyocytes from ischemic and reperfusion-induced cell death. Mdm4, a homolog of Mdm2, inhibits p53 activity in numerous cell types.

Haploinsufficiency of Mdm2 and Mdm4 in tumorigenesis and development.

The tumor suppressor p53 is inactivated by multiple mechanisms that include mutations of the p53 gene itself and increased levels of the p53 inhibitors MDM2 and MDM4. Mice lacking Mdm2 or Mdm4 exhibit embryo-lethal phenotypes that are completely rescued by concomitant deletion of p53. Here we show that Mdm2 and Mdm4 haploinsufficiency leads to increased p53 activity, exhibited as increased sensitivity to DNA damage and decreased transformation potential.

Transcatheter arterial embolization of renal VX-2 carcinoma: ethiodol-ethanol capillary embolization combined with carboplatin.

Objective: We wanted to determine whether transcatheter Ethiodol-based capillary embolization in combination with carboplatin could improve the efficiency of a 1:1 Ethiodol-ethanol mixture (EEM) to ablate kidneys that been inoculated with VX-2 carcinoma.

Materials And Methods: The right kidney in 34 New Zealand white rabbits were inoculated with fresh VX-2 tumor fragments. One week later, the kidneys were subjected to transarterial treatment (4-5 rabbits/group): Saline infusion (Group 1); carboplatin infusion (5 or 10 mg, Groups 2A and 2B); carboplatin-Ethiodol (CE) alone (Group 3) and followed by main renal artery occlusion with ethanol (RAO) (Group 4); carboplatin-EEM (C-EEM) followed by RAO (Group 5); carboplatin infusion followed by EEM plus RAO (Group 6); and EEM followed by RAO (Group 7).

Impaired angiogenesis in aminopeptidase N-null mice.

Aminopeptidase N (APN, CD13; EC 3.4.11.

The antimelanoma immunocytokine scFvMEL/TNF shows reduced toxicity and potent antitumor activity against human tumor xenografts.

The immunocytokine scFvMEL/TNF, a fusion protein composed of human tumor necrosis factor (TNF) and a single-chain Fv antibody (scFv) scFvMEL targeting the melanoma gp240 antigen, demonstrates impressive cytotoxic effects against human melanoma cell lines in vitro. Pharmacokinetic studies of 125I-scFvMEL/TNF in BALB/c mice showed that the construct clears from the circulation with a terminal-phase half-life of 17.6 hours after intravenous administration.

Synergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development.

Loss of Mdm2 or Mdm4 leads to embryo lethal phenotypes that are p53-dependent. To determine whether Mdm2 and Mdm4 inhibit p53 function redundantly in a more restricted cell type, conditional alleles were crossed to a neuronal specific Cre transgene to delete Mdm2 and Mdm4 in the CNS. Mice lacking Mdm2 in the CNS developed hydranencephaly at embryonic day 12.

Use of the i-STAT portable clinical analyzer in mice.

The use of portable chemistry analyzers is an attractive option for obtaining clinical pathology panels in mice, because these analyzers require only small volumes of whole blood. However, in studies with other animals, portable analyzers do not always agree with results obtained using standard laboratory equipment. The authors evaluated the use of the i-STAT handheld portable clinical analyzer compared to the use of standard nonportable laboratory instruments in mice.

Evaluation of targeted arterial delivery of the branched chain fatty acid 12-methyltetradecanoic acid as a novel therapy for solid tumors.

The purpose of this research was to evaluate the effects of targeted arterial delivery of the branched chain fatty acid 12-methyltetradecanoic acid (12-MTA) on the VX2 squamous cell carcinoma in rabbits. An intramuscular VX2 squamous cell carcinoma was induced at a single site in the right thigh of 39 New Zealand white rabbits. Approximately 10 days after inoculation, a 3-French catheter was introduced into the right common carotid artery and positioned using fluoroscopic guidance in the right deep femoral artery, which was the main, if not exclusive, artery supplying the tumor.