Chromosomal aberrations and gene expression profiles in non-small cell lung cancer.

Alterations in genomic content and changes in gene expression levels are central characteristics of tumors and pivotal to the tumorigenic process. We analyzed 23 non-small cell lung cancer (NSCLC) tumors by array comparative genomic hybridization (array CGH). Aberrant regions identified included well-characterized chromosomal aberrations such as amplifications of 3q and 8q and deletions of 3p21.31. Less frequently identified aberrations such as amplifications of 7q22.3-31.31 and 12p11.23-13.2, and previously unidentified aberrations such as deletion of 11q12.3-13.3 were also detected. To enhance our ability to identify key acting genes residing in these regions, we combined array CGH results with gene expression profiling performed on the same tumor samples. We identified a set of genes with concordant changes in DNA copy number and expression levels, i.e. overexpressed genes located in amplified regions and underexpressed genes located in deleted regions. This set included members of the Wnt/beta-catenin pathway, genes involved in DNA replication, and matrix metalloproteases (MMPs). Functional enrichment analysis of the genes both overexpressed and amplified revealed a significant enrichment for DNA replication and repair, and extracellular matrix component gene ontology annotations. We verified the changes in expressions of MCM2, MCM6, RUVBL1, MMP1, MMP12 by real-time quantitative PCR. Our results provide a high resolution map of copy number changes in non-small cell lung cancer. The joint analysis of array CGH and gene expression analysis highlights genes with concordant changes in expression and copy number that may be critical to lung cancer development and progression.

Comparative genomic hybridization analysis of radiation-associated and sporadic meningiomas.

Ionizing irradiation to the skull is a known risk factor for meningioma development. To gain insight into the molecular mechanisms that underlie radiation-associated meningioma (RAM), we characterized the somatic genetic alterations in 16 RAMs by using comparative genomic hybridization and compared the pattern of alterations with 17 nonradiation-associated meningiomas (non-RAM). Most tumors (29/33;87.9%) displayed at least one DNA copy number alteration, and 11 out of 33 (33%) exhibited four or more changes. The mean number of DNA copy number changes was similar in RAMs (2.4+/-1.9) and in non-RAMs (2.5+/-1.9). The most common DNA losses were noted in chromosome 22 (56.2% in RAM, and 47% in non-RAM) and chromosome 1 (37.5% in RAM and 35.3% in non-RAM), with no significant differences between the two groups. Noteworthy, gain in DNA copy number of chromosomes 8 and 12 was detected in two RAM tumors only. In conclusion, no significant differences were noted between RAMs and non-RAMs regarding the number of genetic changes and the extent and frequency of chromosomes 1 and 22 losses. These preliminary data suggest that the tumorogenic pathways of meningioma formation are similar, regardless of previous skull irradiation.

Caudal dysplasia sequence with penile enlargement: case report and a potential pathogenic hypothesis.

The clinical spectrum of caudal dysplasia sequence (CDS) is noted for its diversity. The origin of CDS remains unknown, though poorly controlled gestational diabetes has been implicated in some cases. Here we describe the case of a newborn with CDS associated with penile enlargement (PE). The main anomalies included anal atresia, agenesis of the kidneys and of the sacrococcygeal vertebrae, dysgenesis of lumbar vertebrae, and bilateral cryptorchidism. Penile enlargement (7 cm), a rather unusual finding, has so far not been reported in association with CDS. Chromosomal analysis failed, and the neonate died 30 min after birth. Comparative genomic hybridization analysis using stored DNA showed a balanced normal male DNA content, which negates chromosomal losses or gains as a cause of CDS and/or PE. PE due to virilizing-type adrenal hyperplasia, caused by common mutations in the genes encoding for the adrenal enzymes 21-hydroxylase and 11-hydroxylase, was ruled out. We report on a previously unpublished case of the coexistence of PE and severe CDS and propose a possible pathogenetic hypothesis of this association.

Time dependency of hematopoietic growth factor coupled to chronotoxicity of carboplatin.

A growing body of data suggests that cancer therapy may be improved and toxicity reduced by administration of antineoplastic agents and cytokines at carefully selected times of the day. The time-dependent effects of each of the drugs have been documented, but not their mutual time dependencies. In the present studies we sought to determine the best time for granulocyte colony-stimulating factor (G-CSF) administration after carboplatin treatment. Carboplatin was injected in different groups of ICR mice at four different circadian stages for 5 consecutive days. Mice were synchronized with an alternation of 12 h of light (from 6:00 a.m. to 6:00 p.m.) and 12 h of darkness. After the last injection, peripheral WBCs of three mice from each group were counted every 4 h over a 24-h period. Bone marrow toxicity was estimated with the mean 24-h WBC count. The most severe leukopenia occurred in the group injected at 3:00 p.m. - 9 h after light onset. The second set of experiments evaluated the time-dependent effect of G-CSF when singly injected or given after carboplatin injections for 5 days only at 3:00 p.m. G-CSF was injected into various groups on days 8 and 9 at the same four different circadian stages. On the 10th day after the first injection, peripheral WBCs of three mice from each group were counted every 4 h over a 24-h period. Time-dependent effects were observed when G-CSF was injected as a single agent. When G-CSF was given at various times to the group with the most severe carboplatin-induced leukopenia, peripheral WBC count recovery was monitored at all injection times; it reached its highest level (exceeding even that of the control) when G-CSF was injected at 3:00 a.m. Dosing times of both chemotherapy and growth factor are relevant for optimization of carboplatin's hematologic tolerability.

Daily rhythms in male mice meiosis.

Various processes associated with mammalian reproduction exhibit circadian rhythms, yet no information is available concerning the presence of rhythmicity in meiosis-the crucial process of the production of sex cells. Following meiosis in cells derived from male mice exposed in vivo to daily light-dark cycles (LD), we were able to demonstrate the existence of a clear 24h rhythmic pattern in the overall meiotic process, as well as in the production of spermatids, the immediate products of male meiosis and the precursors of male sex cells. On the other hand, cells of free-running male mice exposed to constant external conditions (light-light, LL) revealed a 12h rhythmic pattern in the overall meiotic process, indicating the endogenous nature of this rhythm. The existence of a 24h rhythm component in a long-lasting (approximately 12 days) process like meiosis suggests a time-dependent gating mechanism that controls the dynamics of miocyte arrest and release. The 12h rhythms observed in LL may indicate the presence of either a 12h rhythm component or of two 24h endogenous components, phased 12h from each other, that are coupled in daily LD cycles and split up in the free-running condition (LL). The rhythmic pattern observed in the course of male meiosis might have significant implications for male reproduction.