Citations

Abstract The Sleeping Beauty (SB) transposon system has been used as a somatic mutagen to identify candidate cancer genes. In previous studies, efficient leukemia/lymphoma formation on an otherwise wild-type genetic background occurred in mice undergoing whole-body mobilization of transposons, but was accompanied by high levels of embryonic lethality. To explore the utility of SB for large-scale cancer gene discovery projects, we have generated mice that carry combinations of different transposon and transposase transgenes. We have identified a transposon/transposase combination that promotes highly penetrant leukemia/lymphoma formation on an otherwise wild-type genetic background, yet does not cause embryonic lethality. Infiltrating gliomas also occurred at lower penetrance in these mice. SB-induced or accelerated tumors do not harbor large numbers of chromosomal amplifications or deletions, indicating that transposon mobilization likely promotes tumor formation by insertional mutagenesis of cancer genes, and not by promoting wide-scale genomic instability. Cloning of transposon insertions from lymphomas/leukemias identified common insertion sites at known and candidate novel cancer genes. These data indicate that a high mutagenesis rate can be achieved using SB without high levels of embryonic lethality or genomic instability. Furthermore, the SB system could be used to identify new genes involved in lymphomagenesis/leukemogenesis. [Cancer Res 2009;69(21):8429–37]

Abstract We have a long-term interest in the connectivity between autoimmunity and tumor rejection. However, outside of the melanocyte/melanoma paradigm, little is known about whether autoimmune responses to normal tissue can induce rejection of tumors of the same histologic type. Here, we induced direct, pathogen-like cytotoxicity to the normal pancreas in association with the immune adjuvant heat shock protein 70. In sharp contrast to our studies with a similar approach for the treatment of prostate cancer, inflammatory killing of the normal pancreas induced a Th1-like, anti-self-response to pancreatic antigens, which was rapidly suppressed by a concomitant suppressive regulatory T cell (Treg) response. Interestingly, even when Treg cells were depleted, the Th1-like response was insufficient to induce significant ongoing autoimmunity. However, the Th1-like response to antigens expressed in the pancreas at the time of damage was sufficient to induce rejection of tumors expressing either a foreign (ova) antigen or fully syngeneic tumor antigens (on Panc02 tumor cells), provided that Treg were depleted before inflammatory killing of the normal pancreas. Taken together, these data indicate that profound differences exist between the immunoprotective mechanisms in place between different tissues (pancreas and prostate) in their response to pathogen-like damage. Moreover, they also show that, although multiple layers of immunologic safeguards are in place to prevent the development of severe autoimmune consequences in the pancreas (in contrast to the prostate), tumor rejection responses can still be decoupled from pathologic autoimmune responses in vivo, which may provide novel insights into the immunotherapeutic treatment of pancreatic cancer. [Cancer Res 2009;69(19):7767–74]

In this study, 65% (132/195) of level B/C obstetric recommendations are amenable to randomized clinical trials (RCTs) and seven were identified as most needed. The purpose of the survey was to evaluate levels B and C recommendations in obstetric practice bulletins (PBs) regarding the feasibility of performing RCT to elevate each subject to level A evidence. Eleven geographically dispersed physicians with experience in research reviewed levels B and C recommendations for the ethical and logistical feasibility of performing an RCT. In the 35 obstetric PBs, 195 level B/C recommendations were reviewed. The majority considered 47 (24%) topics unethical for an RCT and thought 16 (11%) did not need an RCT, thus leaving 132 (67%) levels B and C recommendations available for an RCT. Two-thirds of levels B and C recommendations in obstetric PB are amenable to RCTs and potentially becoming level A evidence.

Background. Laparoscopic ventral hernia repair (LVHR) can be challenging in patients with large abdominal wall defects and loss of domain (LOD). When hernia contents are reduced, the pneumoperitoneum preferentially fills the sac, leaving no space for mesh manipulation. This study presents a modification for LVHR in LOD patients, as well as outcomes for a series of patients. Methods. Between September 2002 and August 2004, 10 patients with large ventral hernias and LOD underwent attempts at LVHR. The technique is modified by placing additional trocars to allow for fixation from above the mesh. Patient data were harvested from a prospective database and analyzed. Results. All hernias were recurrent in nature. Mean defect size was 626 cm 2 , requiring 1 to 4 pieces of sutured Gore Dualmesh for a tension-free repair. Three patients' procedures were aborted after adhesiolysis, with concerns about missed enterotomies. All 3 underwent delayed mesh placement within the same hospitalization. Only 2 were successful. The third patient had significant bowel edema precluding mesh placement. Two patients were converted to open repairs (Rives—Stoppa and component separation). There were no mortalities, but there were 2 major complications: inferior vena cava thrombosis and transient abdominal compartment syndrome. In follow-up (7.7 months) there were 2 recurrences secondary to excision of infected mesh. Conclusion. It is possible to obtain a successful LVHR in patients with large defects and LOD. The technique is complex and is modified to allow for mesh fixation from above the mesh. Frequent change in patient positioning allows for visualization below the fascial defect.

OBJECTIVE. In this study, we investigated the accuracy of measuring walking steps with commercially available pedometers and an accelerometer-based step-counter in normal and overweight children. Our primary hypothesis was that commercially available pedometers are not an accurate measure of walking steps in normal and overweight children while walking. Our secondary hypothesis was that the accelerometer-based step-counter provides an accurate measure of walking steps in normal and overweight children. METHODS. Thirteen boys (11 ± 1 years) and 14 girls (11 ± 1 years) who ranged in BMI from 15 to 27 kg/m2 (16 normal and 11 overweight or obese) were recruited. Each child wore 4 pedometers at the waist and 1 accelerometer-based step-counter on each ankle. Steps were manually counted and energy expenditure was measured while the child walked on the treadmill at 0.5, 1.0, 1.5, and 2.0 mph, each for 5 minutes. The step-counting devices were also validated while children walked on level ground at a self-selected pace. RESULTS. For the commercially available pedometers at the lowest speed of 0.5 mph, the percentage error approximated 100% for both of the pedometers. At the fastest speed of 2.0 mph, the percentage error approximated 60%. Conversely the accelerometer-based step-counter showed a percentage error of 24% ± 22% (mean ± SD) at 0.5 mph; however, as walking speed increased, the error declined to 5% ± 8% at 1.0 mph, 4% ± 5% at 1.5 mph, and 2% ± 2% at 2.0 mph. The relationship between steps counted and walking energy expenditure showed good linear correlation. CONCLUSIONS. Commercially available pedometers are less accurate for measuring walking and require discretion in their use for children. The accuracy of the accelerometer-based step-counter enables it to be used as a tool to assess and potentially promote physical activity in normal and overweight children.

Abstract Previous work has demonstrated that a subset of macrophages expresses a folate receptor (FR) that can mediate internalization of folate-linked molecules, including imaging and therapeutic agents. To characterize this subset, macrophages were collected from peritoneal cavities of mice injected with saline, thioglycolate, zymosan, heat-killed or live bacteria, and cell-surface markers that coexpress with FR were identified. Virtually no F4/80+ peritoneal macrophages from saline-injected mice expressed FR, whereas numerous macrophages from mice injected with each inflammatory stimulus expressed FR. Examination of cell differentiation antigens that are up-regulated in FR+ macrophages revealed markers characteristic of an activated state (CD80, CD86, Ly-6C/G), whereas macrophages lacking these activation markers expressed few or no FR. FR+ macrophages also produced tumor necrosis factor-α (TNF-α) and reactive oxygen species, and production of reactive oxygen species correlated linearly with expression of FR. Synovial macrophages collected from arthritic patients were found to bind and internalize folate-linked dyes. Moreover, a folate-linked radioimaging agent was shown to image inflamed joints of rheumatoid arthritic patients. These results suggest that FR constitutes a marker for macrophage activation and that FR+ macrophages can be targeted with folate-linked drugs without promoting drug uptake by nonactivated macrophages. This trial was registered at www.clinicaltrials.gov as #NCT00588393.