Colorectal cancer is the second cause of cancer-related death in the western world, and although the genetic and molecular mechanisms involved in the initiation and progression of these tumors are among the best characterized, there are significant gaps in our understanding of this disease. The role of EPHB signaling in colorectal cancer has only recently been realized. Here, we use animal models to investigate the role of EphB4 in intestinal tumorigenesis. Modulation of EPHB4 levels in colon cancer cell lines resulted in significant differences in tumor growth in a xenograft model, with low levels of EPHB4 associated with faster growth. In addition, using a genetic model of intestinal tumorigenesis where adenomatous polyposis coli (Apc) mutations lead to initiation of the tumorigenic process (Apc min mice), we show that inactivation of a single allele of EphB4 results in higher proliferation in both the normal epithelium and intestinal tumors, significantly larger tumors in the small intestine, and a 10-fold increase in the number of tumors in the large intestine. This was associated with a 25% reduction in the lifespan of Apc min mice (P < 0.0001). Gene expression analysis showed that EphB4 mutations result in a profound transcriptional reprogramming, affecting genes involved in cell proliferation, remodeling of the extracellular matrix, and cell attachment to the basement membrane among other functional groups of genes. Importantly, in agreement with the expression profiling experiments, using an in vitro assay, we show that loss of EPHB4 in colon cancer cells results in a significantly increased potential to invade through a complex extracellular matrix. Collectively, these results indicate that EphB4 has tumor suppressor activities and that regulation of cell proliferation, extracellular matrix remodeling, and invasive potential are important mechanisms of tumor suppression. [Cancer Res 2009;69(18):7430-8]

BackgroundSmall and large preclinical animal models have shown that antagomir‐92a‐based therapy reduces early postischemic loss of function, but its effect on postinfarction remodeling is not known. In addition, the reported remote miR‐92a inhibition in noncardiac organs prevents the translation of nonvectorized miR‐targeted therapy to the clinical setting. We investigated whether a single intracoronary administration of antagomir‐92a encapsulated in microspheres could prevent deleterious remodeling of myocardium 1 month after acute myocardial infarction AUTHOR: Should “acute” be added before “myocardial infarction” (since abbreviation is AMI)? Also check at first mention in main text (AMI) without adverse effects.Methods and ResultsIn a percutaneous pig model of reperfused AMI, a single intracoronary administration of antagomir‐92a encapsulated in specific microspheres (9 μm poly‐d,‐lactide‐co‐glycolide [PLGA]) inhibited miR‐92a in a local, selective, and sustained manner (n=3 pigs euthanized 1, 3, and 10 days after treatment; 8×, 2×, and 5×‐fold inhibition at 1, 3, and 10 days). Downregulation of miR‐92a resulted in significant vessel growth (n=27 adult minipigs randomly allocated to blind receive encapsulated antagomir‐92a, encapsulated placebo, or saline [n=8, 9, 9]; P=0.001), reduced regional wall‐motion dysfunction (P=0.03), and prevented adverse remodeling in the infarct area 1 month after injury (P=0.03). Intracoronary injection of microspheres had no significant adverse effect in downstream myocardium in healthy pigs (n=2), and fluorescein isothiocyanate albumin‐PLGA microspheres were not found in myocardium outside the left anterior descending coronary artery territory (n=4) or in other organs (n=2).ConclusionsEarly single intracoronary administration of encapsulated antagomir‐92a in an adult pig model of reperfused AMI prevents left ventricular remodeling with no local or distant adverse effects, emerging as a promising therapeutic approach to translate to patients who suffer a large AMI.

The SAFE patch and glue coverage of surgically created fetal MMC is feasible and effective in restoring gross neurologic function in the fetal lamb model.

Regional anesthesia techniques, such as nerve blocks, are routinely used in humans and can contribute to multimodal approaches to pain management in research animals. Ultrasound guidance is an emerging aspect of regional anesthesia that has the potential to optimize local delivery and distribution of anesthetic agents, thereby reducing the amounts of these agents that must be administered. The authors developed an ultrasound-guided technique for effective block of the axillary brachial plexus in rabbits. They used this technique to carry out nerve block in 14 rabbits. The procedure was accomplished in a relatively short amount of time and achieved successful nerve block in all rabbits with no adverse effects. Sonographic visualization of the distribution of the local anesthetic ropivacaine led to administration of smaller anesthetic doses in eight of the rabbits without affecting the duration of nerve block. The authors conclude that their technique is feasible and safe and provides effective analgesia of the thoracic limb in rabbits. They recommend that this technique be integrated into multimodal approaches to pain management in rabbits undergoing thoracic limb surgery.

Background and purposeInterspecies variability and poor clinical translation from rodent studies indicate that large gyrencephalic animal stroke models are urgently needed. We present a proof-of-principle study describing an alternative animal model of malignant infarction of the middle cerebral artery (MCA) in the common pig and illustrate some of its potential applications. We report on metabolic patterns, ionic profile, brain partial pressure of oxygen (PtiO2), expression of sulfonylurea receptor 1 (SUR1), and the transient receptor potential melastatin 4 (TRPM4).MethodsA 5-hour ischemic infarct of the MCA territory was performed in 5 2.5-to-3-month-old female hybrid pigs (Large White x Landrace) using a frontotemporal approach. The core and penumbra areas were intraoperatively monitored to determine the metabolic and ionic profiles. To determine the infarct volume, 2,3,5-triphenyltetrazolium chloride staining and immunohistochemistry analysis was performed to determine SUR1 and TRPM4 expression.ResultsPtiO2 monitoring showed an abrupt reduction in values close to 0 mmHg after MCA occlusion in the core area. Hourly cerebral microdialysis showed that the infarcted tissue was characterized by reduced concentrations of glucose (0.03 mM) and pyruvate (0.003 mM) and increases in lactate levels (8.87mM), lactate-pyruvate ratio (4202), glycerol levels (588 μM), and potassium concentration (27.9 mmol/L). Immunohistochemical analysis showed increased expression of SUR1-TRPM4 channels.ConclusionsThe aim of the present proof-of-principle study was to document the feasibility of a large animal model of malignant MCA infarction by performing transcranial occlusion of the MCA in the common pig, as an alternative to lisencephalic animals. This model may be useful for detailed studies of cerebral ischemia mechanisms and the development of neuroprotective strategies.