Lung cancer is the leading cause of cancer mortality worldwide, yet there exists a limited view of the genetic lesions driving this disease. In this study, an integrated high-resolution survey of regional amplifications and deletions, coupled with gene-expression profiling of non-small-cell lung cancer subtypes, adenocarcinoma and squamous-cell carcinoma (SCC), identified 93 focal copynumber alterations, of which 21 span <0.5 megabases and contain a median of five genes. Whereas all known lung cancer genes͞loci are contained in the dataset, most of these recurrent copy-number alterations are previously uncharacterized and include high-amplitude amplifications and homozygous deletions. Notably, despite their distinct histopathological phenotypes, adenocarcinoma and SCC genomic profiles showed a nearly complete overlap, with only one clear SCC-specific amplicon. Among the few genes residing within this amplicon and showing consistent overexpression in SCC is p63, a known regulator of squamous-cell differentiation. Furthermore, intersection with the published pancreatic cancer comparative genomic hybridization dataset yielded, among others, two focal amplicons on 8p12 and 20q11 common to both cancer types. Integrated DNA-RNA analyses identified WHSC1L1 and TPX2 as two candidates likely targeted for amplification in both pancreatic ductal adenocarcinoma and non-small-cell lung cancer.array comparative genomic hybridization ͉ expression profiling ͉ lung adenocarcinoma ͉ squamous-cell lung carcinoma ͉ TP73L L ung cancer is the leading cause of cancer-related mortality in the United States, accounting for more than one-fourth of all cancer fatalities in 2004. Lung cancer is classified into two major subtypes, small-cell and non-small-cell lung cancer (NSCLC). NSCLC constitutes 75% of lung cancer cases and is subdivided further into three major histological subtypes: adenocarcinoma (AC), squamous-cell carcinoma (SCC), and large-cell carcinoma. The AC and SCC subtypes represent Ͼ85% of NSCLC cases. Although these NSCLC subtypes exhibit distinct pathological characteristics, the treatment approaches have remained generic and largely ineffective, despite advances in cytotoxic drugs, radiotherapy, and clinical management. For all stages of NSCLC, the 5-year survival rate has remained fixed at 15% for the last 15 years. The recent success of molecularly targeted therapies for a limited subset of cancer genotypes (1) has solidified the view that a more detailed knowledge of the spectrum of genetic lesions in lung cancer will, in turn, lead to meaningful therapeutic progress.To date, the majority of lung cancer genetic studies have cataloged mutations or the promoter methylation status of known cancer genes, performed genome-wide loss-of-heterozygosity surveys, and applied comparative genomic hybridization (CGH) to audit regional copy-number alterations (CNAs) on metaphase chromosomes or small-scale bacterial artificial chromosome (BAC) arrays. These concerted efforts have identified a core set of lesions, including activating...

Growing evidence suggests that lactoferrin (Lf), an iron-binding glycoprotein, is a pleiotropic functional nutrient. In addition, Lf was recently implicated as a neuroprotective agent. These properties make Lf a valuable therapeutic candidate for the treatment of Alzheimer's disease (AD). However, the mechanisms regulating the physiological roles of Lf in the pathologic condition of AD remain unknown. In the present study, an APPswe/PS1DE9 transgenic mouse model of AD was used. We explored whether intranasal human Lf (hLf) administration could reduce β-amyloid (Aβ) deposition and ameliorate cognitive decline in this AD model. We found that hLf promoted the non-amyloidogenic metabolism of amyloid precursor protein (APP) processing through activation of α-secretase a-disintegrin and metalloprotease10 (ADAM10), resulting in enhanced cleavage of the α-COOH-terminal fragment of APP and the corresponding elevation of the NH2-terminal APP product, soluble APP-α (sAPPα), which consequently reduced Aβ generation and improved spatial cognitive learning ability in AD mice. To gain insight into the molecular mechanism by which Lf modulates APP processing, we evaluated the involvement of the critical molecules for APP cleavage and the signaling pathways in N2a cells stably transfected with Swedish mutant human APP (APPsw N2a cells). The results show that the ERK1/2-CREB and HIF-1α signaling pathways were activated by hLf treatment, which is responsible for the expression of induced ADAM10. Additional tests were performed before suggesting the potential use of hLf as an antioxidant and anti-inflammatory. These findings provide new insights into the sources and mechanisms by which hLf inhibits the cognitive decline that occurs in AD via activation of ADAM10 expression in an ERK1/2-CREB and HIF-1α-dependent manner.