Multiple comparisons model-based clustering and ternary pattern tree numerical display of gene response to treatment: procedure and application to the preclinical evaluation of chemopreventive agents

Microarray technology has greatly aided the identification of genes that are expressed differentially. Statistical analysis of such data by multiple comparisons procedures has been slow to develop, in part, because methods to cluster the results of such comparisons in biologically meaningful ways have not been available. We isolated and analyzed, by Northern blot and GeneChip, replicate liver RNA samples (n = 4/group) from rats fed with control diet or diet containing one of three chemopreventive compounds, selected because their pharmacological activities, including RNA expression response, are relatively well understood. We report on a classification tree, based on the results of nonparametric multiple comparisons, which results in the bipolar hierarchical clustering of genes in relation to their response to treatment. In addition to identifying treatment-responsive genes, application of this procedure to our test study identified the known pharmacological relationships among the treatment groups without supervision. Also, small treatment-specific subsets of genes were identified that may be indicative of additional pharmacophores present in the test compounds.     

The brain's master circadian clock: implications and opportunities for therapy of sleep disorders

The suprachiasmatic nuclei (SCN) residing in the anterior hypothalamus maintains a near-24-h rhythm of electrical activity, even in the absence of environmental cues. This circadian rhythm is generated by intrinsic molecular mechanisms in the neurons of the SCN; however, the circadian clock is modulated by a wide variety of influences, including glutamate and pituitary adenylate cyclase-activating peptide (PACAP) from the retinohypothalamic tract, melatonin from the pineal gland, and neuropeptide Y from the intergeniculate leaflet. By virtue of these and other inputs, the SCN responds to environmental cues such as light, social and physical activities. In turn, the SCN controls or influences a wide variety of physiologic and behavioral functions, including attention, endocrine cycles, body temperature, melatonin secretion, and the sleep-wake cycle. Regulation of the sleep-wake cycle by the SCN has important implications for development of therapies for sleep disorders, including those involving desynchronization of circadian rhythms and insomnia.     

Clinicopathologic Features and Long-Term Outcomes of 293 Phyllodes Tumors of the Breast

BACKGROUND: Phyllodes tumors (PT) are rare fibroepithelial neoplasms of the breast with unpredictable behavior. We reviewed our single institution experience with PT over 51 years to identify factors predictive of local recurrence (LR) and metastasis. METHODS: From 1954 to 2005, a total of 352 cases of PT were identified; 293 had follow-up. All available pathology slides (90%) were rereviewed for margins, borders, fibroproliferation in the surrounding breast tissue, stromal pattern, stromal cellularity, frequency of mitoses, and necrosis. RESULTS: All cases occurred in women, with a median age of 42, with 203 originally categorized as benign and 90 as malignant. Median follow-up was 7.9 years. A total of 35 patients developed LR at a median of 2 years. In univariate analyses, a higher actuarial LR rate was associated with positive margins (P = .04), fibroproliferation (P = .001), and necrosis (P = .006). PT classified as malignant did not have a higher risk of LR (P = .79). Five patients developed distant disease at a median of 1.2 years. These patients constituted 71% of the seven patients who had uniformly aggressive pathologic features, including large tumor size (>or=7.0 cm), infiltrative borders, marked stromal overgrowth, marked stromal cellularity, high mitotic count, and necrosis. CONCLUSIONS: Positive margins, fibroproliferation in the surrounding breast tissue, and necrosis are associated with a marked increase in LR rates. Efforts should be made to achieve negative surgical margins to reduce risk of LR. Death from PT is rare (2%), and only PT that demonstrate uniformly aggressive pathologic features seem to be associated with mortality.