Determination of the safety and efficacy of therapeutic neutralization of tumor necrosis factor-α (TNF-α) using AZD9773, an anti-TNF-α immune Fab, in murine CLP sepsis.

Objective And Design: TNF-α neutralization is associated with increased mortality in mouse cecal ligation puncture (CLP) models. AZD9773 is an ovine polyclonal human TNF-α immune Fab, with pharmacological properties that differ from previously studied anti-TNF-α agents. We explored the safety and efficacy of therapeutically administered AZD9773 in mouse CLP sepsis.

Quantitative histopathological assessment of retardation of islets of langerhans degeneration in rosiglitazone-dosed obese ZDF rats using combined insulin and collagens (I and III) immunohistochemistry with automated image analysis and statistical modeling.

Islets of Langerhans represent a heterogeneous population in insulin resistant and diabetic animals and humans as histological appearances and function vary substantially. Mathematical representation that reflects this morphological diversity will assist in assessment of degeneration and regeneration, enabling comparisons between species, strains, and experimental investigations. Our investigative approach used a model of islet degeneration in diabetic male obese Zucker Diabetic Fatty (ZDF) rats and evaluated its prevention using rosiglitazone treatment.

The development of an immunohistochemical method to detect the autophagy-associated protein LC3-II in human tumor xenografts.

Autophagy is believed to be an important process during tumorgenesis, and in recent years it has been shown to be modulated in response to a number of conventional anticancer agents. Furthermore, the development of targeted small molecule inhibitors, such as those to the PI3K-AKT-mTOR pathway, has presented a molecular link between the disruption of this signalling cascade and the process of autophagy. The cellular consequence of stimulating or inhibiting autophagy in cancer cells is not completely understood, so it is important that this process be monitored, along with antiproliferative and apoptotic biomarkers, in the preclinical setting.

Explant culture of gastrointestinal tissue: a review of methods and applications.

The gastrointestinal (GI) tract is an important target organ for the toxicity of xenobiotics. The toxic effects of xenobiotics on this complex, heterogeneous structure have been difficult to model in vitro and have traditionally been assessed in vivo. The explant culture of GI tissue offers an alternative approach.

Time-course study of the immunotoxic effects of the anticancer drug chlorambucil in the rat.

In 2005, the International conference on harmonization (ICH) recommended that all new human pharmaceuticals be tested for unintended immunomodulatory potential via a tiered approach. Included in this approach is a semiquantitative description of changes in the separate compartments of lymphoid tissue (also called enhanced histopathology). Chlorambucil was administered to Hanover Wistar rats at regular time points, followed by a treatment-free (recovery) period.

Urinary retention and cystitis associated with subcutaneous estradiol pellets in female nude mice.

Unexpected deaths occurred in studies involving a nude mouse model of mammary cancer that required subcutaneous implantation of 0.5 mg twenty-one-day release estrogen pellets for growth of the estrogen-dependent mammary tumor xenograft BT474c. Early deaths occurred in female nude mice and were associated with urinary retention, frequently with cystitis.

A dual-label technique for the immunohistochemical demonstration of T-lymphocyte subsets in formalin-fixed, paraffin-embedded rat lymphoid tissue.

Immunotoxicology has developed into an integral regulatory requirement of the toxicological assessment of xenobiotics. Histopathological assessment of lymphoid tissues can provide genuine insight into perturbations of lymphoid cell populations. To facilitate retrospective examination of lymphoid organs should concerns over immunotoxicity be raised, we have endeavored to develop a panel of immunohistochemical techniques to demonstrate T-cells and T-cell subsets in formalin-fixed, paraffin-embedded rat lymphoid tissues.

The demonstration of immunohistochemical biomarkers in methyl methacrylate-embedded plucked human hair follicles.

Plucked human hair follicles have been proposed as a potential surrogate for tumour tissue for measuring the effect of drugs on pharmacodynamic biomarkers in drug intervention studies. We describe a new technique of embedding plucked hair follicles in the acrylic resin, methyl methacrylate, and the immunohistochemical demonstration of six potential biomarkers (Ki67, EGFR, phospho-p27, phospho-histone H3, phospho-MAPK and phospho-Rb) in de-plasticised sections. The advantages of this technique over those that have been used in support of clinical drug trials, such as skin and tumour biopsies, whole blood and whole hair samples is discussed.