Pharmacologic inhibition of epigenetic modifications, coupled with gene expression profiling, reveals novel targets of aberrant DNA methylation and histone deacetylation in lung cancer.

Lung cancer is the leading cause of cancer-related deaths in the United States due, in large part, to the lack of early detection methods. Lung cancer arises from a complex series of genetic and epigenetic changes leading to uncontrolled cell growth and metastasis. Unlike genetic changes, epigenetic changes, such as DNA methylation and histone acetylation, are reversible with currently available pharmaceuticals and are early events in lung tumorigenesis detectable by non-invasive methods. In order to better understand how epigenetic changes contribute to lung cancer, and to identify new disease biomarkers, we combined pharmacologic inhibition of DNA methylation and histone deacetylation in non-small cell lung cancer (NSCLC) cell lines, with genome-wide expression profiling. Of the more than 200 genes upregulated by these treatments, three of these, neuronatin, metallothionein 3 and cystatin E/M, were frequently hypermethylated and transcriptionally downregulated in NSCLC cell lines and tumors. Interestingly, four other genes, cylindromatosis, CD9, activating transcription factor 3 and oxytocin receptor, were dominantly regulated by histone deacetylation and were also frequently downregulated in lung tumors. The majority of these genes also suppressed NSCLC growth in culture when ectopically expressed. This study therefore reveals new putative NSCLC growth regulatory genes and epigenetic disease biomarkers that may enhance early detection strategies and serve as therapeutic targets.

Review of Horner's syndrome and a case report.

Sympathetic denervation of the eye [Horner's Syndrome (HS)] usually presents as ptosis, miosis, and facial anhydrosis. HS presents a challenge to the clinician because the causative lesion may involve a first, second, or third-order neuron. This paper reviews the literature regarding HS, the anatomy of the sympathetic pathway to the eye, the diagnosis, and the localization of the lesion. Our patient developed reversible HS after a migrainous episode which presumably caused "bruising" of the sympathetic plexus within the carotid canal.

Effect of corneal edema upon the smoothness of excimer laser ablation.

We studied the effect of corneal hydration upon ablation rate in excimer laser photorefractive keratectomy (PRK). This variable may alter the subepithelial smoothness and the resulting clarity of the result. The eyes of freshly slaughtered pigs (N = 5) and the eyes of Dutch-belted rabbits (N = 4) (in vivo) were de-epithelialized and central ablation zones 3.0 to 4.5 mm in diameter were produced in the subepithelial corneal layers using a 193 nm argon fluoride (ArF) ophthalmic excimer laser. Ablation was performed immediately or after a 15-min incubation period in distilled water as a means of inducing corneal edema. Smoothness was evaluated using specular reflection microscopy and showed the water-treated surface to be increasingly less regular than the nonwater-treated samples. Water treatment may affect the final outcome of the PRK procedure and indicates the need to monitor the preoperative cornea for the development of any edema, especially after the epithelium is removed.

Effect of depth upon the smoothness of excimer laser corneal ablation.

The Argon Fluoride (ArF) Excimer laser is currently used for experimental reshaping of the front surface of the cornea for the correction of myopic refractive error (photorefractive keratectomy, PRK) and for smoothing corneal irregularities (phototherapeutic keratectomy, PTK). Both PRK and PTK are in FDA clinical trials, but are more readily available outside the U.S.A. These techniques have achieved reasonable success in spite of early reports that deeper ablation procedures can cause reduced corneal clarity (haze) or a result which is less accurate or tends to regress. We studied how different depths of excimer tissue removal affect the smoothness of the ablation zone of the rabbit cornea. Dutch belted rabbits were immediately sacrificed by pentobarbital overdose. Their corneas were de-epithelialized with a knife or by the excimer laser and then were photoablated. A 4.5-mm circular ablation beam was delivered to each denuded area, but the beam was masked by positioning a steel blade to partially block the laser beam, thus creating variable ablation depths corresponding to 0.0, 12.5, 37.5, and 62.5 microns. The eyes were fixed in situ by topical and anterior chamber application of glutaraldehyde and the corneas were excised after 5 min and placed in glutaraldehyde for tissue processing. The corneas were whole-mounted and examined by scanning electron microscopy (SEM). The resultant micrographs show increasing irregularity of the ablated surface as a function of depth. The irregularity appeared to be due largely to the inhomogeneities of the anterior stroma, which is known to be layered by alternately directed collagen fibrils.(ABSTRACT TRUNCATED AT 250 WORDS)