Opinion: A Seven-step Approach to Communication about Animal Research.

Organizations that receive public money to conduct research using animals should be able to explain the importance of and need for that work. More generally, anyone who believes that properly conducted and regulated animal research either does or does not make the world a better place wants the public to understand why they hold their belief. In a world with divided support for animal research, honest communication about these issues is essential to develop sound public policy.

Influence of animal pain and distress on judgments of animal research justifiability among university undergraduate students and faculty.

Acceptance of animal research by the public depends on several characteristics of the specific experimental study. In particular, acceptance decreases as potential animal pain or distress increases. Our objective in this study was to quantify the magnitude of pain/distress that university undergraduate students and faculty would find to be justifiable in animal research, and to see how that justifiability varied according to the purpose of the research, or the species to which the animal belonged.

Attitudes toward animals, and how species and purpose affect animal research justifiability, among undergraduate students and faculty.

As members of a university community that sponsors animal research, we developed a survey to improve our knowledge about factors underlying the perceived justifiability of animal research among faculty and undergraduate students. To accomplish this objective, we gathered quantitative data about their general views on animal use by humans, their specific views about the use of different species to address different categories of scientific questions, and their confidence in the translatability of animal research to humans. Students and faculty did not differ in their reported levels of concern for the human use of animals, but women reported significantly higher levels of concern than men.

Assessing undergraduate student and faculty views on animal research: What do they know, whom do they trust, and how much do they care?

Research using animals is controversial. To develop sound public outreach and policy about this issue, we need information about both the underlying science and people's attitudes and knowledge. To identify attitudes toward this subject at the University of Wisconsin-Madison, we developed and administered a survey to undergraduate students and faculty.

A Simple and Reliable Method for Early Pregnancy Detection in Inbred Mice.

The study of normal and abnormal development typically requires precise embryonic staging. In mice, this task is accomplished through timed matings and the detection of a copulation plug. However, the presence of a plug is not a definitive indicator of true pregnancy, particularly in inbred mice, in which false-pregnancy rates have been reported to be 50% or higher, depending on the strain.

Mutant Hras(G12V) and Kras(G12D) have overlapping, but non-identical effects on hepatocyte growth and transformation frequency in transgenic mice.

Background: Mouse hepatocarcinogenesis is associated with mutations in Hras, but infrequently in Kras. The effect on carcinogenesis of developmental age at the time of ras mutation remains unknown.

Aim: We sought to compare quantitatively the effects of expressing mutant H- or Kras genes in fetal vs.

Minimal cooperation between mutant Hras and c-myc or TGFα in the regulation of mouse hepatocyte growth or transformation in vivo.

Background: Liver carcinogenesis is associated with multiple genetic changes in affected cells, including alterations in the Hras signalling pathway.

Aim: To define the biological contributions of Hras to mouse hepatocarcinogenesis, we quantified in vivo interactions between mutant Hras and other genetic alterations frequently associated with liver cancer, including overexpression of the transcription factor c-myc and the epidermal growth factor receptor ligand transforming growth factor alpha (TGFα).

Methods: To accomplish this aim, we initiated expression of an activated Hras in hepatocytes of adult mice with or without simultaneous overexpression of either c-myc or TGFα.

Acinar-to-ductal metaplasia accompanies c-myc-induced exocrine pancreatic cancer progression in transgenic rodents.

Several important characteristics of exocrine pancreatic tumor pathogenesis remain incompletely defined, including identification of the cell of origin. Most human pancreatic neoplasms are ductal adenocarcinomas. However, acinar cells have been proposed as the source of some ductal neoplasms through a process of acinar-to-ductal metaplasia.

Podocyte injury damages other podocytes.

Loss of podocytes promotes glomerulosclerosis, but whether this results from a continued primary insult or a secondary mechanism triggered by the initial loss of podocytes is unknown. We generated chimeric mice in which only a subpopulation of podocytes expressed hCD25, which is the receptor for the immunotoxin LMB2. In addition, genetic labeling of hCD25-negative cells with human placental alkaline phosphatase allowed the study of these two distinct podocyte populations.

Effect of mutant β-catenin on liver growth homeostasis and hepatocarcinogenesis in transgenic mice.

Background: Mutations in the Wnt signalling pathway molecule β-catenin are associated with liver cancer.

Aims: Our aim was to confirm the effects of stabilized β-catenin on liver growth, identify whether those effects were reversible and cell autonomous or non-cell autonomous and to model β-catenin-induced liver cancer in mice.

Methods: Using a liver-specific inducible promoter, we generated transgenic mice in which the expression of mutant β-catenin can be induced or repressed within hepatocytes in mice of different ages.

Hematopoietic bone marrow cells participate in endothelial, but not epithelial or mesenchymal cell renewal in adult rats.

The extent to which bone marrow (BM) contributes to physiological cell renewal is still controversial. Using the marker human placental alkaline phosphatase (ALPP) which can readily be detected in paraffin and plastic sections by histochemistry or immunohistochemistry, and in ultrathin sections by electron microscopy after pre-embedding staining, we examined the role of endogenous BM in physiological cell renewal by analysing tissues from lethally irradiated wild-type inbred Fischer 344 (F344) rats transplanted (BMT) with unfractionated BM from ALPP-transgenic F344 rats ubiquitously expressing the marker. Histochemical, immunohistochemical and immunoelectron microscopic analysis showed that the proportion of ALPP(+) capillary endothelial cells (EC) profoundly increased from 1 until 6 months after BMT in all organs except brain and adrenal medulla.

Identification of susceptibility loci in a mouse model of KRASG12D-driven pancreatic cancer.

Genetic background affects susceptibility to pancreatic ductal adenocarcinoma in the Ela-KRAS(G12D) mouse model. In this model, KRAS oncogene expression is driven by an elastase promoter in acinar cells of the pancreas on an FVB/NTac (FVB) background [FVB-Tg(Ela-KRAS(G12D))] with the transgene carried on the Y chromosome. Through linkage analysis of crosses between the C57BL/6J (B6), BALB/cJ (BALB), and DBA/2J (D2) inbred strains of mice and resistant FVB-Tg(Ela-KRAS(G12D)), we have identified six susceptibility loci that affect mean preinvasive lesion multiplicity.

Quantifying growth and transformation frequency of oncogene-expressing mouse hepatocytes in vivo.

Unlabelled: Gene changes can affect cancer cells in many ways, but changes that increase disease severity--by allowing cells to proliferate when they should be quiescent, by enhancing their rate of growth under growth permissive conditions, or by increasing the risk that they will accumulate additional carcinogenic alterations--must be identified so that strategies to counter their effects can be developed. We describe a novel in vivo assay system based on hepatocyte transplantation that permits us to accomplish this objective for genetically modified hepatocytes. We find that the oncogenes c-myc and transforming growth factor alpha, but not simian virus 40 T-antigen, increase the rate of hepatocyte growth under growth permissive conditions.

Role of endogenous bone marrow cells in long-term repair mechanisms after myocardial infarction.

Homing and regenerative potential of endogenous bone marrow cells (BMC) in myocardial infarction (MI) is a controversial issue. Using human placental alkaline phosphatase (hPLAP) as genetic marker for cell tracking, we examined the influx of bone marrow-derived cells during tissue repair after the induction of MI over a study period of 17 weeks in wild-type inbred Fischer 344 rats, lethally irradiated and reconstituted with bone marrow (BM) from transgenic F344 rats expressing hPLAP under the control of the ubiquitous R26 promoter. During the early phases of tissue repair, hPLAP-positive macrophages, endothelial cells, fibroblasts and also myofibroblast-like cells were recruited from BM.

Regulation of pancreas plasticity and malignant transformation by Akt signaling.

Background & Aims: Extensive evidence suggests that Akt signaling plays an important role in beta-cell mass and function, although its function in the regulation of the different pancreatic fates has not been adequately investigated. The goal of these studies was to assess the role of Akt signaling in the pancreatic differentiation programs.

Methods: For these experiments, we have generated a double reporter mouse model that provides activation of Akt signaling in a cell type-specific manner.

A tool for semiannual review of the institutional animal care and use program.

To ensure compliance with animal welfare laws and regulations, many research institutions review their animal care and use programs on a semiannual basis. In many cases, however, review committees fail to make the most of this process, basing their evaluations on general and sometimes outdated guidelines that do not address their specific needs. The authors present a worksheet that they developed and successfully implemented at their institution, aimed at inspiring an efficient and fruitful discussion of animal care and use.

Marker tolerant, immunocompetent animals as a new tool for regenerative medicine and long-term cell tracking.

Background: Immune-mediated rejection of labeled cells is a general problem in transplantation studies using cells labeled with any immunogenic marker, and also in gene therapy protocols. The aim of this study was to establish a syngeneic model for long-term histological cell tracking in the absence of immune-mediated rejection of labeled cells in immunocompetent animals. We used inbred transgenic Fischer 344 rats expressing human placental alkaline phosphatase (hPLAP) under the control of the ubiquitous R26 promoter for this study.

Utility of human placental alkaline phosphatase as a genetic marker for cell tracking in bone and cartilage.

It was the aim of the current study to evaluate the utility of human placental alkaline phosphatase (hPLAP) as a genetic marker for cell tracking in bone and cartilage, using transgenic Fischer 344 rats expressing hPLAP under the control of the ubiquitous R26 promoter [F344-Tg(R26-hPLAP)]. hPLAP enzyme activity was retained during paraffin and methylmethacrylate (MMA) embedding, and was best preserved using 40% ethanol as fixative. Endogenous alkaline phosphatase activity could be completely blocked by heat inactivation in paraffin and MMA sections, allowing histochemical detection of hPLAP in the complete absence of background staining.

Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice.

Pancreatic ductal adenocarcinoma (PDA), one of the deadliest human cancers, often involves somatic activation of K-Ras oncogenes. We report that selective expression of an endogenous K-Ras(G12V) oncogene in embryonic cells of acinar/centroacinar lineage results in pancreatic intraepithelial neoplasias (PanINs) and invasive PDA, suggesting that PDA originates by differentiation of acinar/centroacinar cells or their precursors into ductal-like cells. Surprisingly, adult mice become refractory to K-Ras(G12V)-induced PanINs and PDA.

Mammary carcinogenesis is preceded by altered epithelial cell turnover in transforming growth factor-alpha and c-myc transgenic mice.

Identification of biomarkers that indicate an increased risk of breast cancer or that can be used as surrogates for evaluating treatment efficacy is paramount to successful disease prevention and intervention. An ideal biomarker would be identifiable before lesion development. To test the hypothesis that changes in cell turnover precede mammary carcinogenesis, we evaluated epithelial cell proliferation and apoptosis in mammary glands from transgenic mice engineered to develop mammary cancer due to expression in mammary epithelia of transforming growth factor alpha (TGF-alpha) or c-myc.

Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation.

The transcription factor pancreatic and duodenal homeobox factor 1 (PDX-1) is expressed in pancreatic progenitor cells. In exocrine pancreas, PDX-1 is down-regulated during late development, while re-up-regulation of PDX-1 has been reported in pancreatic cancer and pancreatitis. To determine whether sustained expression of PDX-1 could affect pancreas development, PDX-1 was constitutively expressed in all pancreatic lineages by transgenic approaches.

Prolactin potentiates transforming growth factor alpha induction of mammary neoplasia in transgenic mice.

Prolactin influences mammary development and carcinogenesis through endocrine and autocrine/paracrine mechanisms. In virgin female mice, pro-lactin overexpression under control of a mammary selective nonhormonally responsive promoter, neu-related lipocalin, results in estrogen receptor alpha (ERalpha)-positive and ERalpha-negative adenocarcinomas. However, disease in vivo occurs in the context of dysregulation of multiple pathways.

Defining the Animal Care and Use Program.

An effective Animal Care and Use Program is critical to an institution's ability to ensure that animal research is conducted humanely and follows all applicable regulations and guidelines; however, no straightforward definition of the fundamentals of such a Program now exists. The author provides a global view of the key programmatic components, which can be used to improve existing programs or implement new programs.

Modeling pancreatic cancer in animals to address specific hypotheses.

Multiple experimental approaches have been employed to study exocrine pancreatic cancer, including the use of animals as surrogates for the human disease. Animals have the advantage that they can be manipulated to address specific hypotheses regarding mechanisms underlying this disease. Implicit in this opportunity is the necessity to match the question being asked with an appropriate animal model.