Ischemia-reperfusion increases transfection efficiency of intracoronary adenovirus type 5 in pig heart in situ.

Efficiency of intracoronary (IC) adenoviral vector transfection is impaired by the vascular endothelium. Ischemia and substances that increase vascular permeability (sodium nitroprusside, nitroglycerin) may augment adenoviral vector transfection efficiency (TE). We tested whether TE of adenoviral vector following IC infusion is improved by nitrates or by ischemia.

Enigmol: a novel sphingolipid analogue with anticancer activity against cancer cell lines and in vivo models for intestinal and prostate cancer.

Sphingoid bases are cytotoxic for many cancer cell lines and are thought to contribute to suppression of intestinal tumorigenesis in vivo by ingested sphingolipids. This study explored the behavior of a sphingoid base analogue, (2S,3S,5S)-2-amino-3,5-dihydroxyoctadecane (Enigmol), that cannot be phosphorylated by sphingosine kinases and is slowly N-acylated and therefore is more persistent than natural sphingoid bases. Enigmol had potential anticancer activity in a National Cancer Institute (NCI-60) cell line screen and was confirmed to be more cytotoxic and persistent than naturally occurring sphingoid bases using HT29 cells, a colon cancer cell line.

Pathogenic virus-specific T cells cause disease during treatment with the calcineurin inhibitor FK506: implications for transplantation.

Recently, several cases of fatal lymphocytic choriomeningitis virus (LCMV) infection occurred in transplant recipients being treated with the immunosuppressive calcineurin inhibitor FK506. These findings were surprising because LCMV is a noncytolytic virus. To understand how a noncytolytic virus can cause disease under conditions of immunosuppression, we used the mouse LCMV model and found that, similar to the observations in human transplant recipients, LCMV infection of FK506-treated mice resulted in a lethal disease characterized by viremia, lack of seroconversion, and minimal lymphocytic infiltrates in the tissues.

PIKE-A is required for prolactin-mediated STAT5a activation in mammary gland development.

PI 3-kinase enhancer A (PIKE-A) is critical for the activation of Akt signalling, and has an essential function in promoting cancer cell survival. However, its physiological functions are poorly understood. Here, we show that PIKE-A directly associates with both signal transducer and activator of transcription 5a (STAT5a) and prolactin (PRL) receptor, which is essential for PRL-provoked STAT5a activation and the subsequent gene transcription.

Regulation of hepatic cytochrome P450 expression in mice with intestinal or systemic infections of citrobacter rodentium.

We reported previously that infection of C3H/HeOuJ (HeOu) mice with the murine intestinal pathogen Citrobacter rodentium caused a selective modulation of hepatic cytochrome P450 (P450) gene expression in the liver that was independent of the Toll-like receptor 4. However, HeOu mice are much more sensitive to the pathogenic effects of C. rodentium infection, and the P450 down-regulation was associated with significant morbidity in the animals.

Suppression of NF-kappaB activation blocks osteoclastic bone resorption during estrogen deficiency.

Postmenopausal osteoporosis stems from an imbalance in osteoclastic bone resorption with respect to osteoblastic bone formation, a consequence of estrogen deficiency. The nuclear factor-kappaB (NF-kappaB) signal transduction pathway is critical for osteoclast formation and resorption, and suppression of NF-kappaB activation has been shown to block bone resorption in vitro, and to ameliorate inflammatory bone loss in vivo. The use of NF-kappaB antagonists to blunt the bone loss associated with estrogen deficiency however, has not been previously reported.

Safingol toxicology after oral administration to TRAMP mice: demonstration of safingol uptake and metabolism by N-acylation and N-methylation.

Safingol [(2S,3S)-2-amino-1,3-octadecanediol] is an unnatural l-threo-stereoisomer of sphinganine that is cytotoxic for cancer cells in culture and is being tested in phase 1 human clinical trials. To determine if safingol can be absorbed orally and if it affects prostate cancer in a mouse strain used in prostate cancer studies, safingol was fed to TRAMP (transgenic adenocarcinoma of mouse prostate) mice for 2 weeks at 0.0125% to 0.

Cytokine-mediated disruption of lymphocyte trafficking, hemopoiesis, and induction of lymphopenia, anemia, and thrombocytopenia in anti-CD137-treated mice.

CD137-mediated signals costimulate T cells and protect them from activation-induced apoptosis; they induce curative antitumor immunity and enhance antiviral immune responses in mice. In contrast, anti-CD137 agonistic mAbs can suppress T-dependent humoral immunity and reverse the course of established autoimmune disease. These results have provided a rationale for assessing the therapeutic potential of CD137 ligands in human clinical trials.

Investigation of appropriate sanitization frequency for rodent caging accessories: evidence supporting less-frequent cleaning.

The Guide for the Care and Use of Laboratory Animals states that sanitization of caging accessories (for example, filter tops and wire-bar lids) should be done every 2 wk. In this study we tested the hypothesis that organic contamination measured by the presence of ATP associated with organic material (measured with luciferase test swabs) and the number of bacterial colony-forming units (as determined by use of replicate organism detection and counting plates) on caging accessories did not differ significantly at 2 wk versus several months of use. The study evaluated 4 groups: mouse and rat ventilated and static wire-bar cages with or without filter tops (n = 10 per group).

Use of broad-spectrum antimicrobials in the eradication of unknown aquatic pathogens in a zebrafish larval rearing system.

A zebrafish larval rearing system experienced a surge in mortality rates soon after the introduction of new stocks. A comprehensive water analysis of pH, nitrites, nitrates, ammonia, chlorine, carbonate hardness, general hardness, and conductivity identified no anomalies. Observations via light microscopy of affected fry revealed consistent signs of impaired mobility, blood clotting, and eventual heart hemorrhage resulting in the death of 90 to 100% of the fry by the age of 2 weeks.

Cutaneous acariasis in the African clawed frog (Xenopus laevis).

Increased mortality was observed in a single colony of 50 Xenopus laevis. The frogs were used as oocyte donors in developmental biology studies. Necropsy findings included dermal erythema and petechiation consistent with red leg syndrome; dermal ulcerations and white, filamentous growths on the skin were consistent with Saprolegnia sp.

Urolithiasis associated with experimental lymphocytic choriomeningitis virus inoculation in Lewis rats.

A high frequency of struvite urolithiasis, hydronephrosis, and other urinary tract lesions developed in a group of Lewis rats inoculated intracranially with lymphocytic choriomeningitis virus (LCMV). Initially, clinically ill rats were referred to necropsy: 30 rats over 3 years. These rats had high frequency of urolithiasis (8/30, 27%), hydronephrosis (12/30, 40%), cystitis (9/30, 30%), transitional cell carcinoma (4/30, 13%), and pyelonephritis (19/30, 63%).

Dietary soy sphingolipids suppress tumorigenesis and gene expression in 1,2-dimethylhydrazine-treated CF1 mice and ApcMin/+ mice.

Dietary supplementation with milk sphingolipids inhibits colon tumorigenesis in CF1 mice treated with a colon carcinogen [1,2-dimethylhydrazine (DMH)] and in multiple intestinal neoplasia (Min) mice, which develop intestinal tumors spontaneously. Plant sphingolipids differ structurally from those of mammals [soy glucosylceramide (GlcCer) consists predominantly of a 4,8-sphingadiene backbone and alpha-hydroxy-palmitic acid], which might affect their bioactivity. Soy GlcCer was added to the AIN-76A diet (which contains <0.

Ectopical expression of human MUC18 increases metastasis of human prostate cancer cells.

MUC18, a cell adhesion molecule (CAM), has been reported to be a diagnostic marker for the early detection of the metastatic potential of prostate cancers as well as implicated to be an important determinant for mediating the tumorigenesis and metastasis of prostate cancer. To test the hypothesis, we further investigated the possible role of MUC18 in the malignant progression of human prostate cancer. The human MUC18-minus, non-metastatic human prostate cancer LNCaP cells were transfected with the human cytomegalovirus immediate-early gene (HCMV-IE) promoter-driven human MUC18 (huMUC18) cDNA.

Sphingomyelin in the suppression of colon tumors: prevention versus intervention.

Intestinal cells are regularly exposed to sphingolipid metabolites, i.e., ceramide and sphingoid bases, after hydrolysis of complex sphingolipids from the diet.

Confirmed persistent mouse hepatitis virus infection and transmission by mice with a targeted null mutation of tumor necrosis factor to sentinel mice, using short-term exposure.

Mouse hepatitis virus (MHV) infection in immunocompetent mice is typically self limiting, and transmission is short lived. With the recent surge in the development of genetically engineered mutant mice with alterations in immune system components, however, MHV clearance may be disrupted. We report confirmed persistent transmission of MHV from tumor necrosis factor (TNF) knockout mice, B6.

Postanesthesia death and suspected peracute endotoxic shock due to Pseudomonas putida in a cynomolgous macaque (Macaca fascicularis).

An adult male cynomolgous macaque (Macaca fascicularis) died suddenly after anesthesia for a positron emission tomography scan. Bacteriologic culture of the mucopurulent secretions recovered from the endotracheal tube yielded heavy growth of Pseudomonas putida, a known endotoxin producer. Histologically, the lungs had severe, diffuse perivascular edema and neutrophils marginating to the endothelium.

Sphingoid bases and de novo ceramide synthesis: enzymes involved, pharmacology and mechanisms of action.

The sphingoid base backbones of sphingolipids (sphingosines, sphinganines, 4-hydroxysphinganines and others) are highly bioactive species directly and-in most cases-as their metabolites, the N-acyl-sphingoid bases (ceramides) and sphingoid base 1-phosphates. The complexity of these compounds affords many opportunities to prepare synthetic analogs for studies of sphingolipid metabolism and the functions of the sphingoid bases and metabolites. Described in this review are methods for the preparation of libraries of sphingoid bases, including a series of 1-deoxy-analogs, as well as information about their metabolism and biological activities.

High Mortality in Zebrafish (Danio rerio).

A group of 100 adult zebrafish were housed in a new system at a stocking density of 20 fish per tank. Four weeks after arrival, 15 fish presented with petechial hemorrhages and ulceration on the surfaces of the skin. Samples of the fish were collected for histopathology, fungal culture, and bacterial culture and sensitivity.

A cure for murine sickle cell disease through stable mixed chimerism and tolerance induction after nonmyeloablative conditioning and major histocompatibility complex-mismatched bone marrow transplantation.

The morbidity and mortality associated with sickle cell disease (SCD) is caused by hemolytic anemia, vaso-occlusion, and progressive multiorgan damage. Bone marrow transplantation (BMT) is currently the only curative therapy; however, toxic myeloablative preconditioning and barriers to allotransplantation limit this therapy to children with major SCD complications and HLA-matched donors. In trials of myeloablative BMT designed to yield total marrow replacement with donor stem cells, a subset of patients developed mixed chimerism.

Preclinical evaluation of a novel device for delivering brachytherapy to the margins of resected brain tumor cavities.

Object: The objectives of this study were to evaluate the safety and performance of a new brachytherapy applicator in the treatment of resected brain tumors in a canine model.

Methods: The brachytherapy applicator is an inflatable balloon catheter that is implanted in the resection cavity remaining after a brain tumor has been debulked. After implantation the balloon is inflated with Iotrex, a sterile solution containing organically bound iodine-125.