A common mutant epidermal growth factor receptor confers enhanced tumorigenicity on human glioblastoma cells by increasing proliferation and reducing apoptosis.

Alterations of the EGFR gene occur frequently in human gliomas where the most common is an in-frame deletion of exons 2-7 from the extracellular domain, resulting in a truncated mutant receptor (deltaEGFR or de 2-7 EGFR). We previously demonstrated that introduction of deltaEGFR into human U87MG glioblastoma cells (U87MG.deltaEGFR) conferred remarkably enhanced tumorigenicity in vivo. Here, we show by cell-mixing experiments that the enhanced tumorigenicity conferred by deltaEGFR is attributable to a growth advantage intrinsic to cells expressing the mutant receptor. We analyzed the labeling index of the proliferation markers Ki-67 and bromodeoxyuridine and found that tumors derived from U87MG.deltaEGFR cells had significantly higher labeling indexes than those of tumors derived from U87MG cells that were either naive, expressed kinase-deficient mutants of deltaEGFR, or overexpressed exogenous wild-type EGFR. We also utilized terminal deoxynucleotidyl transferase-mediated nick end-labeling assays and showed that the apoptotic index of U87MG.deltaEGFR tumors was more than 4-fold lower than that of parental U87MG tumors. This decrease in cell death was inversely correlated with the expression level of Bcl-X(L), a negative regulator of apoptosis, which was more than 3-fold higher in U87MG.deltaEGFR-derived tumors than in those derived from parental cells. Similar observations were obtained in vitro in serum-free conditions. These results suggest that deltaEGFR exerts its pronounced enhancement of glioblastoma tumorigenicity by stimulating proliferation and inhibiting apoptosis and that the effects are directly attributable to its constitutively active signal.

Perioperative nutrition and postoperative complications in patients undergoing spinal surgery.

STUDY DESIGN: The authors undertook a three-part study to better understand the impact of perioperative nutritional status on postoperative complications in patients undergoing spinal surgery. In preliminary Parts I and II, the authors targeted two groups of patients who are particularly nutritionally challenged. In Part III, they studied a large group of consecutive patients undergoing routine lumbar spinal fusion. OBJECTIVES: To determine whether preoperative nutritional status was a significant predictor of postoperative complications in patients undergoing elective lumbar spinal fusion. SUMMARY OF BACKGROUND DATA: In Part I, 27 patients treated surgically for vertebral osteomyelitis were divided into two groups based on their preoperative nutritional status. Twenty-four of the 26 postoperative complications were in the malnourished group (P < 0.001). In Part II, 15 (75%) of 20 patients treated surgically for spinal cord injury were found to become malnourished in the postoperative period. Seventeen complications were noted, all in the malnourished group (P = 0.001). METHODS: One hundred fourteen consecutive patients undergoing selective lumbar decompression and fusion were identified and their records reviewed. In addition to preoperative nutritional status, data gathered included age, sex, height, weight, past medical history, steroid use, alcohol use, tobacco use, type of bone graft (allograft vs. autograft), history of previous lumbar surgery, number of levels fused, and use of spinal instrumentation. RESULTS: Eleven of 13 postoperative infectious complications (10 deep wound infections) were noted in the malnourished group (P < 0.001). By stepwise logistic regression analysis, preoperative nutritional status was an extremely significant independent predictor of postoperative complications in patients undergoing elective lumbar spinal fusion (P = 0.0018). CONCLUSIONS: The prevalence data in our study population suggest that a large number (25%) of patients undergoing elective lumbar spine surgery are nourished inadequately at surgery. This number is higher (42%) in older patients. The authors recommend that close attention be paid to the perioperative nutritional status of patients undergoing lumbar spinal surgery. Patients with suboptimal nutritional parameters should be supplemented and replenished before elective surgery.

Suprasellar germinoma associated with Cushing's disease and diabetes insipidus in a child.

Cushing's disease is described in a child with a suprasellar germinoma. The patient presented with all of the classic stigmata of Cushing's disease as well as diabetes insipidus, but after surgical resection of the lesion was found to have pathology incompatible with an ACTH-secreting tumor. We believe that this is the first reported incidence of Cushing's disease associated with a suprasellar germinoma. The implications of this unusual association are discussed.

Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques.

Three transgenic mouse lines designated Tg 69, 71, and 81 were produced harboring a Syrian hamster (Ha) prion protein (PrP) gene; all expressed the cellular HaPrP isoform in their brains. Inoculation of Tg 81 mice or hamsters with Ha prions caused scrapie in integral of 75 days; nontransgenic control mice failed to develop scrapie after greater than 500 days. Tg 71 mice inoculated with Ha prions developed scrapie in integral of 170 days. Both Tg 71 and Tg 81 mice exhibited spongiform degeneration and reactive astrocytic gliosis, and they produced the scrapie HaPrP isoform in their brains. Tg 81 brains also showed HaPrP amyloid plaques characteristic of Ha scrapie and contained integral of 10(9) ID50 units of Ha prions based on Ha bioassays. Our findings argue that the PrP gene modulates scrapie susceptibility, incubation times, and neuropathology; furthermore, they demonstrate synthesis of infectious scrapie prions programmed by a recombinant DNA molecule.