Loss of heterozygosity at chromosome 1p in different solid human tumours: association with survival

The distal half of chromosome 1p was analysed with 15 polymorphic microsatellite markers in 683 human solid tumours at different locations. Loss of heterozygosity (LOH) was observed at least at one site in 369 cases or 54% of the tumours. LOHs detected ranged from 30–64%, depending on tumour location. The major results regarding LOH at different tumour locations were as follows: stomach, 20/38 (53%); colon and rectum, 60/109 (55%); lung, 38/63 (60%); breast, 145/238 (61%); endometrium, 18/25 (72%); ovary, 17/31 (55%); testis, 11/30 (37%); kidney, 22/73 (30%); thyroid, 4/14 (29%); and sarcomas, 9/14 (64%). High percentages of LOH were seen in the 1p36.3, 1p36.1, 1p35–p34.3, 1p32 and 1p31 regions, suggesting the presence of tumour-suppressor genes. All these regions on chromosome 1p show high LOH in more than one tumour type. However, distinct patterns of LOH were detected at different tumour locations. There was a significant separation of survival curves, with and without LOH at chromosome 1p, in the breast cancer patients. Multivariate analysis showed that LOH at 1p in breast tumours is a better indicator for prognosis than the other variables tested in our model, including nodal metastasis. © 1999 Cancer Research Campaig

Preclinical Models for Neuroblastoma: Establishing a Baseline for Treatment

Preclinical models of pediatric cancers are essential for testing new chemotherapeutic combinations for clinical trials. The most widely used genetic model for preclinical testing of neuroblastoma is the TH-MYCN mouse. This neuroblastoma-prone mouse recapitulates many of the features of human neuroblastoma. Limitations of this model include the low frequency of bone marrow metastasis, the lack of information on whether the gene expression patterns in this system parallels human neuroblastomas, the relatively slow rate of tumor formation and variability in tumor penetrance on different genetic backgrounds. As an alternative, preclinical studies are frequently performed using human cell lines xenografted into immunocompromised mice, either as flank implant or orthtotopically. Drawbacks of this system include the use of cell lines that have been in culture for years, the inappropriate microenvironment of the flank or difficult, time consuming surgery for orthotopic transplants and the absence of an intact immune system.Here we characterize and optimize both systems to increase their utility for preclinical studies. We show that TH-MYCN mice develop tumors in the paraspinal ganglia, but not in the adrenal, with cellular and gene expression patterns similar to human NB. In addition, we present a new ultrasound guided, minimally invasive orthotopic xenograft method. This injection technique is rapid, provides accurate targeting of the injected cells and leads to efficient engraftment. We also demonstrate that tumors can be detected, monitored and quantified prior to visualization using ultrasound, MRI and bioluminescence. Finally we develop and test a "standard of care" chemotherapy regimen. This protocol, which is based on current treatments for neuroblastoma, provides a baseline for comparison of new therapeutic agents.The studies suggest that use of both the TH-NMYC model of neuroblastoma and the orthotopic xenograft model provide the optimal combination for testing new chemotherapies for this devastating childhood cancer

A juvenile sheep model for the long-term evaluation of stentless bioprostheses implanted as aortic root replacements

Background and aim of the study: Orthotopic valve replacement in large animals is an important component of the preclinical assessment of bioprosthetic valves. To provide the most useful preclinical information, the development of models that parallel clinical practice patterns is essential. Therefore, we sought to develop a technically feasible and reproducible model for chronic evaluation of stentless bioprosthetic aortic valves implanted as aortic root replacements in juvenile sheep.Methods: Juvenile domestic sheep (mean age 21 2.28 weeks; range: 17-26 weeks) underwent aortic root replacement using standard cardiopulmonary bypass (CPB) and surgical techniques. Animals were implanted with 19 mm (n = 21), 21 mm (n = 18) or 23 mm (n = 4) bioprostheses from two different manufacturers, and followed for 150 days. Animals surviving at least 150 days were considered long-term survivors; those which died prior to postoperative day (POD) 31 were considered operative deaths.Results: Forty-three animals underwent aortic root replacement. The mean CPB time was 91 +/- 20 min (range: 62-149 min); mean cross-clamp time was 63 +/- 13 min (range: 39-95 min). Thirty-five animals (81%) survived the first 30 days of the study period. Five deaths occurred at POD 0 due to anastomotic complications. One death occurred each on POD 3, 6, and 26 as a result of prosthesis size mismatching, thromboembolic complications, and endocarditis, respectively. There were five late deaths. Twenty animals survived the minimum 150-day study period, and 12 were sacrificed at 183 +/- 17 days. Six animals remain alive at 151 +/- 0.98 days, and one animal died each on POD 184 and 190. The remaining 10 animals are not yet 150 days from their operation. Currently, all are well at 102 +/- 34 days (range: 33-140) days.Conclusion: These data suggest that long-term evaluation of stentless aortic bioprostheses implanted as aortic root replacements can be accomplished using juvenile sheep.Univ Minnesota, Dept Surg, Div Expt Surg, Minneapolis, MN 55455 USAUniv Minnesota, Div Thorac & Cardiovasc Surg, Minneapolis, MN 55455 USAEscola Paulista Med, Dept Cardiovasc & Thorac Surg, BR-04023 Sao Paulo, BrazilLabcor Labs Ltda, Belo Horizonte, MG, BrazilEscola Paulista Med, Dept Cardiovasc & Thorac Surg, BR-04023 Sao Paulo, BrazilWeb of Scienc

Imaging the neural circuitry and chemical control of aggressive motivation

<p>Abstract</p> <p>Background</p> <p>With the advent of functional magnetic resonance imaging (fMRI) in awake animals it is possible to resolve patterns of neuronal activity across the entire brain with high spatial and temporal resolution. Synchronized changes in neuronal activity across multiple brain areas can be viewed as functional neuroanatomical circuits coordinating the thoughts, memories and emotions for particular behaviors. To this end, fMRI in conscious rats combined with 3D computational analysis was used to identifying the putative distributed neural circuit involved in aggressive motivation and how this circuit is affected by drugs that block aggressive behavior.</p> <p>Results</p> <p>To trigger aggressive motivation, male rats were presented with their female cage mate plus a novel male intruder in the bore of the magnet during image acquisition. As expected, brain areas previously identified as critical in the organization and expression of aggressive behavior were activated, e.g., lateral hypothalamus, medial basal amygdala. Unexpected was the intense activation of the forebrain cortex and anterior thalamic nuclei. Oral administration of a selective vasopressin V_1areceptor antagonist SRX251 or the selective serotonin reuptake inhibitor fluoxetine, drugs that block aggressive behavior, both caused a general suppression of the distributed neural circuit involved in aggressive motivation. However, the effect of SRX251, but not fluoxetine, was specific to aggression as brain activation in response to a novel sexually receptive female was unaffected.</p> <p>Conclusion</p> <p>The putative neural circuit of aggressive motivation identified with fMRI includes neural substrates contributing to emotional expression (i.e. cortical and medial amygdala, BNST, lateral hypothalamus), emotional experience (i.e. hippocampus, forebrain cortex, anterior cingulate, retrosplenial cortex) and the anterior thalamic nuclei that bridge the motor and cognitive components of aggressive responding. Drugs that block vasopressin neurotransmission or enhance serotonin activity suppress activity in this putative neural circuit of aggressive motivation, particularly the anterior thalamic nuclei.</p