Role of lipocalin 2 and its complex with matrix metalloproteinase-9 in oral cancer.

OBJECTIVES: Recent evidence demonstrated that lipocalin (LCN)2 is induced in many types of human cancer, while the detection of its complex with matrix metalloproteinase (MMP)-9 is correlated with the cancer disease status. We attempted to evaluate plasma expressions of LCN2, MMP-9, and their complex (LCN2/MMP-9) during the diagnostic work-up of patients with oral squamous cell carcinoma (OSCC) and investigated their correlations with disease progression. METHODS: In total, 195 patients with OSCC and 81 healthy controls were recruited. Expression levels of LCN2, MMP-9, and LCN2/MMP-9 were determined with immunoenzymatic assays. RESULTS: Patients with OSCC exhibited significantly higher levels of LCN2, MMP-9, and LCN2/MMP-9 compared with healthy controls (LCN2: P < 0.001; MMP-9: P < 0.001; LCN2/MMP-9: P < 0.01). Plasma levels of LCN2, MMP-9, and LCN2/MMP-9 in patients with OSCC were significantly correlated with each other and were associated with more-advanced clinical stages (P < 0.05) and/or a larger tumor size (P < 0.05), but were not associated with positive lymph-node metastasis or distal metastasis. CONCLUSION: Our results suggest that plasma levels of LCN2 and the LCN2/MMP-9 complex may be useful in non-invasively monitoring OSCC progression, while supporting their potential role as biomarkers of oral cancer disease status.

Topoisomerase 2alpha plays a pivotal role in the tumor biology of stage IV thymic neoplasia.

BACKGROUND: Microsatellite studies in histologic types B3 and C thymic neoplasia detected gains on chromosome 17q, which contains the Her-2/neu and its juxtaposed topoisomerase 2alpha (T2alpha) genes. The study aimed to evaluate their impact on tumor biology and survival of advanced thymic neoplasia patients. METHODS: From 1991 to 2005, 36 consecutive stage IV thymic carcinoma patients were treated, 18 men and 18 women, aged 11 to 84 years. There were 22 thymic carcinoma, 13 type B3, and 1 type B2 thymoma. Patients received treatment consisting of surgical resection, combination chemotherapy with the CAP (cyclophosphamide, Adriamycin, cisplatin) regimen, or radiation therapy potentiated by high-dose weekly 5-fluorouracil infusion. Permutations of these 3 treatment modalities were prescribed as necessary. RESULTS: T2alpha gene amplification was detected in 4 of 14 thymic carcinoma and 1 of 15 type B3 thymoma. Three thymic carcinoma patients had Her-2/neu coamplification and these 3 patients had rapidly growing tumor and extensive disease at initial diagnosis. CAP was prescribed in 28 patients and 20 patients responded (response rate, 71.4%, 95% confidence interval [CI]: 52.8% to 85%); all responders overexpressed (> or = 10% nuclei positive) the T2alpha protein, whereas 4 nonresponders had very low expression. T2alpha overexpression predicts CAP response, and its absence predicts resistance (P = .001). Overall survival was significantly prolonged if the tumor was resectable (P = .001), of type B3 histology (P = .0039), and had no Her-2 gene amplification (P = .0081). CONCLUSION: T2alpha and Her-2/neu genes play a pivotal role in the tumor biology, CAP response, and survival of advanced thymic neoplasia patients.

Chromosomal integration dependent induction of junB by growth factors requires multiple flanking evolutionarily conserved sequences.

The junB locus contains nine flanking evolutionarily conserved sequences (FECS) that share 72% to 91% sequence identity between human and mouse. These FECS encompass the same regions of flanking DNA necessary for maximal mitogenic induction of junB. Most of the cis elements reported to date that affect junB regulation also reside within FECS. These observations suggest that the persistence of FECS through evolution reflects a necessary role in junB transcriptional regulation. In this report, we identify specific regulatory cis elements within junB FECS II and III and provide a quantitative analysis of the contribution made by these sequences to junB induction. These cis elements include a Serum Response Element (SRE), two Ets sites previously unrecognized as contributing to junB expression, and two novel Ets-linked motifs (ELMs). In general, mutating any single element significantly impairs junB induction. Moreover, the same mutations alter the structure of junB 5' flanking DNA within chromatin. Collectively, these results suggest that multiple proteins bound within FECS confederate to form a functional promoter complex, the activity of which is dependent upon a specific chromatin architecture.

The structure of the transitional and aganglionic zones of Auerbach's plexus in patients with Hirschsprung's disease: a computer-assisted three-dimensional reconstruction study.

Intestines resected from two patients with Hirschsprung's disease, both aged 6 months, were submitted to serial sectioning and three-dimensional reconstruction to visualize the overall structure of Auerbach's plexus and correlate its changes with functional abnormalities. Reconstruction was made possible by using a graphics computer system. In normal intestines taken from an autopsy case, both large and small, the plexus was shown extending along the intermuscular septum as a regular network. But in the large intestine, the density of the network was apparently higher and the individual bundles thicker than in the small intestines. This neural network was absent in the aganglionic zone in Hirschsprung's disease, as expected, where only hypertrophic extrinsic nerves were running in the septum. The "transitional zone" of Hirschsprung's disease was clearly definable as an area extending over a certain length, where the network meshes grow more irregular and the bundles taper more, toward the aganglionic zone. This finding was considered to be of profound significance in the design of a surgical strategy to prevent postoperative bowel dysfunction. In determining the range of resection, one must consider not only the presence or absence of nerve cells but also the grade of plexus hypoplasia.

Complex genetic organization of junB: multiple blocks of flanking evolutionarily conserved sequence at the murine and human junB loci.

A comparison of the murine and human junB loci reveals nine regions of distal 5'- and 3'-flanking DNA that exhibit greater than 72% sequence identity. A large fraction (over 50%) of the junB locus is contained in these flanking evolutionarily conserved sequences (FECS), which may be required for effecting the proper transcriptional regulation of this gene. Comparative sequence analyses involving kilobases of distal flanking DNAs have been performed for only a small number of vertebrate genes. The available data and the results presented here suggest that FECS may emerge as common yet important functional components of genes, a hypothesis with significant implications for characterizing genes involved in human disease.

Two-point rectal mucosal biopsy for selection of surgical treatment of Hirschsprung's disease.

A two-point rectal mucosal biopsy (utilizing a histochemical study), namely biopsies at sites 5 to 10 mm and 30 to 50 mm oral to the dentate line, was developed to differentiate patients who can be treated adequately by rectal myectomy without colostomy and those who require other definitive surgery for Hirschsprung's disease. The examinations were performed in 28 patients suspected having a short aganglionic rectum. Ganglion cells were demonstrated by upper biopsy in four of 13 neonates, six of nine infants, and three of six children. These cases were successfully treated by rectal myectomy. The two-point rectal mucosal biopsy is useful not only for making definitive diagnosis but also for the selection of the surgical treatment for patients with Hirschsprung's disease.