Skeletal and Uterotrophic Effects of Endoxifen in Female Rats.

Endoxifen, the primary active metabolite of tamoxifen, is currently being investigated as a novel endocrine therapy for the treatment of breast cancer. Tamoxifen is a selective estrogen receptor modulator that elicits potent anti-breast cancer effects. However, long-term use of tamoxifen also induces bone loss in premenopausal women and is associated with an increased risk of endometrial cancer in postmenopausal women.

Chronic Phenotype Characterization of a Large-Animal Model of Hereditary Tyrosinemia Type 1.

Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disease caused by deficiency in fumarylacetoacetate hydrolase, the last enzyme in the tyrosine catabolic pathway. In this study, we investigated whether fumarylacetoacetate hydrolase deficient (FAH) pigs, a novel large-animal model of HT1, develop fibrosis and cirrhosis characteristic of the human disease. FAH pigs were treated with the protective drug 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3 cyclohexandione (NTBC) at a dose of 1 mg/kg per day initially after birth.

Curative ex vivo liver-directed gene therapy in a pig model of hereditary tyrosinemia type 1.

We tested the hypothesis that ex vivo hepatocyte gene therapy can correct the metabolic disorder in fumarylacetoacetate hydrolase-deficient (Fah(-/-)) pigs, a large animal model of hereditary tyrosinemia type 1 (HT1). Recipient Fah(-/-) pigs underwent partial liver resection and hepatocyte isolation by collagenase digestion. Hepatocytes were transduced with one or both of the lentiviral vectors expressing the therapeutic Fah and the reporter sodium-iodide symporter (Nis) genes under control of the thyroxine-binding globulin promoter.

Low-Dose Gamma Irradiation of Decellularized Heart Valves Results in Tissue Injury In Vitro and In Vivo.

Background: Decellularized heart valves are emerging as a potential alternative to current bioprostheses for valve replacement. Whereas techniques of decellularization have been thoroughly examined, terminal sterilization techniques have not received the same scrutiny.

Methods: This study evaluated low-dose gamma irradiation as a sterilization method for decellularized heart valves.

Development of an Endometrial Ablation Model in New Zealand White Rabbits.

Objective: To develop an animal model for radiofrequency endometrial ablation (EA) and evaluate histopathologic outcomes of EA in New Zealand White (NZW) rabbits.

Study Design: A pilot study was conducted. A radiofrequency EA device was developed and a variety of EA settings were tested on euthanized NZW rabbits.

EUS-guided portal injection chemotherapy for treatment of hepatic metastases: feasibility in the acute porcine model.

Background And Aims: Direct injection of chemotherapy into the portal vein for treatment of liver metastases may increase hepatic tissue levels while decreasing systemic levels and toxicities. We aimed to evaluate EUS-guided portal injection chemotherapy (EPIC) by using drug-eluting microbeads or nanoparticles and compare it with systemic injection.

Methods: We conducted a comparative feasibility trial in the acute porcine model (24 anesthetized pigs).

Pregnancy-associated plasma protein-A deficiency improves survival of mice on a high fat diet.

Obesity is on the rise in westernized countries, and visceral obesity in particular is associated with enhanced risk of developing metabolic disease and accelerated aging. Various dietary restriction regimens have been shown to extend healthy lifespan in a variety of species. However, identification of alternative approaches that could be more acceptable to humans is actively being pursued.

Endoscopic band ligation for closure of GI perforations in a porcine animal model (with video).

Background: GI perforations occur rarely during endoscopy but have life-threatening implications.

Objective: To evaluate endoscopic band ligation (EBL) for closure of acute GI perforations by using a porcine model.

Design: Investigator-initiated interventional pilot study by using an in vivo porcine model.

Fumarylacetoacetate hydrolase deficient pigs are a novel large animal model of metabolic liver disease.

Hereditary tyrosinemia type I (HT1) is caused by deficiency in fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the last step of tyrosine metabolism. The most severe form of the disease presents acutely during infancy, and is characterized by severe liver involvement, most commonly resulting in death if untreated. Generation of FAH(+/-) pigs was previously accomplished by adeno-associated virus-mediated gene knockout in fibroblasts and somatic cell nuclear transfer.

Inactivation of the transcription factor GLI1 accelerates pancreatic cancer progression.

The role of GLI1 in pancreatic tumor initiation promoting the progression of preneoplastic lesions into tumors is well established. However, its function at later stages of pancreatic carcinogenesis remains poorly understood. To address this issue, we crossed the gli1 knock-out (GKO) animal with cre-dependent pancreatic activation of oncogenic kras concomitant with loss of the tumor suppressor tp53 (KPC).

Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy.

We investigated pregnancy-associated plasma protein-A (PAPP-A) in diabetic nephropathy. Normal human kidney showed specific staining for PAPP-A in glomeruli, and this staining was markedly increased in diabetic kidney. To assess the possible contribution of PAPP-A in the development of diabetic nephropathy, we induced diabetes with streptozotocin in 14-month-old WT and Papp-A knockout (KO) mice.

Downregulation of hematopoietic MUC1 during experimental colitis increases tumor-promoting myeloid-derived suppressor cells.

Purpose: MUC1 is a tumor-associated antigen that is aberrantly expressed in cancer and inflammatory bowel disease (IBD). Even though immune cells express low MUC1 levels, their modulations of MUC1 are important in tumor progression. Consistent with previous clinical data that show increased myeloid-derived suppressor cells (MDSCs) in IBD, we now show that downregulation of MUC1 on hematopoietic cells increases MDSCs in IBD, similar to our data in tumor-bearing mice.

Loss of the transcription factor GLI1 identifies a signaling network in the tumor microenvironment mediating KRAS oncogene-induced transformation.

Although the biological role of KRAS is clearly established in carcinogenesis, the molecular mechanisms underlying this phenomenon are not completely understood. In this study, we provide evidence of a novel signaling network regulated by the transcription factor GLI1 mediating KRAS-induced carcinogenesis. Using pancreatic cancer (a disease with high prevalence of KRAS mutations) as a model, we show that loss of GLI1 blocks the progression of KRAS-induced pancreatic preneoplastic lesions in mice with pancreas-specific Cre-activated oncogenic mutant kras.

Detection of progressive myocardial tissue injury by ultrasonic integrated backscatter immediately after coronary reperfusion.

Myocardial reperfusion following ischemia may paradoxically cause additional injury, including microvascular damage and edema. These structural alterations augment tissue echogenicity, which is measurable by ultrasonic integrated backscatter (IB). We sought to characterize alterations in myocardial IB in an ischemic and reperfused region of the rat heart.

Longevity and age-related pathology of mice deficient in pregnancy-associated plasma protein-A.

The pregnancy-associated plasma protein-A knockout (PAPP-A KO) mouse is a model of reduced local insulin-like growth factor (IGF)-I activity with normal circulating IGF-I levels. In this study, PAPP-A KO mice had significantly increased mean (27%), median (27%), and maximum (35%) life span compared with wild-type (WT) littermates. End-of-life pathology indicated that the incidence of neoplastic disease was not significantly different in the two groups of mice; however, it occurred in older aged PAPP-A KO compared with WT mice.

Intravitreal alemtuzumab penetrates full-thickness retina in rabbit eyes.

Purpose: The purpose of this study was to assess whether alemtuzamab, a large antibody of 150 kDa, would be able to penetrate through the full-thickness retina of Dutch-belted rabbits.

Methods: Four Dutch-belted rabbits had intravitreal injections of alemtuzumab (1.5 mg in 0.

Reprogrammed FoxP3+ T regulatory cells become IL-17+ antigen-specific autoimmune effectors in vitro and in vivo.

Lymphocyte differentiation from naive CD4(+) T cells into mature Th1, Th2, Th17, or T regulatory cell (Treg) phenotypes has been considered end stage in character. In this study, we demonstrate that dendritic cells (DCs) activated with a novel immune modulator B7-DC XAb (DC(XAb)) can reprogram Tregs into T effector cells. Down-regulation of FoxP3 expression after either in vitro or in vivo Treg-DC(XAb) interaction is Ag-specific, IL-6-dependent, and results in the functional reprogramming of the mature T cell phenotype.

Spontaneous vulvar papillomas in a colony of mice used for pancreatic cancer research.

Mice in a colony used for pancreatic cancer research and maintained in a barrier animal facility presented with vulvar masses. A census and examination of all colony animals was conducted on 17 February 2006; line, gender, and mass location were recorded; a slide caliper was used to measure the width, length, and height of each mass; and the volume of each mass was calculated. Progeny female mice from crossbreeding of the B6.

Absence of histologic retinal toxicity of intravitreal nanogold in a rabbit model.

Purpose: To evaluate the retinal toxicity of intravitreal nanogold, a novel antiangiogenic and long-term delivery agent.

Methods: One eye of each of 16 Dutch-belted rabbits was injected with intravitreal nanogold; the other eye served as a control. Eight rabbits received a dose of 67 micromol/0.

The MUC1 Cytoplasmic Tail and Tandem Repeat Domains Contribute to Mammary Oncogenesis in FVB Mice.

Background: Though the importance of the transmembrane mucin MUC1 in mammary oncogenesis has long been recognized, the relative contributions of the cytoplasmic tail and tandem repeat domains are poorly understood.

Methods: To address this, mouse models of mammary carcinogenesis were created expressing full-length, cytoplasmic tail-deleted, or tandem repeat-deleted MUC1 constructs.

Results: Overexpression of full-length MUC1 resulted in tumor formation in young mice (≤12 months); however, loss of either the cytoplasmic tail or the tandem repeat domain abrogated this oncogenic capacity.

Submucosal endoscopy with mucosal flap safety valve.

Background: There is no reliable endoscopic method to selectively resect deeper layers of the gut wall or to access the peritoneal cavity and prevent peritoneal soiling.

Objectives: To determine the technical feasibility and safety of submucosal endoscopy with mucosal flap (SEMF) in accessing the peritoneal cavity through a large full-thickness gastric-muscle-wall resection.

Design: Ex vivo feasibility exploration and survival animal study.

Absence of histologic retinal toxicity of intravitreal bevacizumab in a rabbit model.

Purpose: To evaluate the retinal toxicity of intravitreal bevacizumab in an animal model.

Design: Animal study.

Methods: Bevacizumab was injected into the vitreous of one eye of each of eight Dutch-belted rabbits; the other eye served as a control.