MicroRNA-218 Is Deleted and Downregulated in Lung Squamous Cell Carcinoma

MicroRNAs (miRNAs) are a family of small, non-coding RNA species functioning as negative regulators of multiple target genes including tumour suppressor genes and oncogenes. Many miRNA gene loci are located within cancer-associated genomic regions. To identify potential new amplified oncogenic and/or deleted tumour suppressing miRNAs in lung cancer, we inferred miRNA gene dosage from high dimensional arrayCGH data. From miRBase v9.0 (http://microrna.sanger.ac.uk), 474 human miRNA genes were physically mapped to regions of chromosomal loss or gain identified from a high-resolution genome-wide arrayCGH study of 132 primary non-small cell lung cancers (NSCLCs) (a training set of 60 squamous cell carcinomas and 72 adenocarcinomas). MiRNAs were selected as candidates if their immediately flanking probes or host gene were deleted or amplified in at least 25% of primary tumours using both Analysis of Copy Errors algorithm and fold change (≥±1.2) analyses. Using these criteria, 97 miRNAs mapped to regions of aberrant copy number. Analysis of three independent published lung cancer arrayCGH datasets confirmed that 22 of these miRNA loci showed directionally concordant copy number variation. MiR-218, encoded on 4p15.31 and 5q35.1 within two host genes (SLIT2 and SLIT3), in a region of copy number loss, was selected as a priority candidate for follow-up as it is reported as underexpressed in lung cancer. We confirmed decreased expression of mature miR-218 and its host genes by qRT-PCR in 39 NSCLCs relative to normal lung tissue. This downregulation of miR-218 was found to be associated with a history of cigarette smoking, but not human papilloma virus. Thus, we show for the first time that putative lung cancer-associated miRNAs can be identified from genome-wide arrayCGH datasets using a bioinformatics mapping approach, and report that miR-218 is a strong candidate tumour suppressing miRNA potentially involved in lung cancer

Isoform-specific targeting of PKA to multivesicular bodies

PKA RIα subunit is localized to MVBs by the A-kinase–anchoring protein AKAP11 when disassociated from the PKA catalytic subunit

Array-CGH and breast cancer

The introduction of comparative genomic hybridization (CGH) in 1992 opened new avenues in genomic investigation; in particular, it advanced analysis of solid tumours, including breast cancer, because it obviated the need to culture cells before their chromosomes could be analyzed. The current generation of CGH analysis uses ordered arrays of genomic DNA sequences and is therefore referred to as array-CGH or matrix-CGH. It was introduced in 1998, and further increased the potential of CGH to provide insight into the fundamental processes of chromosomal instability and cancer. This review provides a critical evaluation of the data published on array-CGH and breast cancer, and discusses some of its expected future value and developments

Pharmacological Treatment of Internet Addiction

The increasing number of Internet users has resulted in an increased population percentage affected by the negative effects of problematic Internet usage. To date, the management of psychopathological Internet use is not supported by extensive empirical research. No standard clinical treatment protocols for pharmacological treatment exist, and as a result, empirical or anecdotal assessments based on case studies are mainly consulted. A relevant problem in performing clinical trials is the evolving nosology, which encompasses ambiguous definitions of Internet addiction and a diversity of diagnostic, prognostic, and therapeutic criteria. The aim of this chapter is to review the current literature, to assess the extent to which specific pharmacological interventions (e.g., using antidepressants, mood stabilizers, opioid receptor antagonists, or antipsychotics) can alleviate the symptomatic burden in patients with \u201cInternet addiction.\u201d We also explore pharmacological interventions that target patterns of comorbidity and underlying psychopathological dimensions (e.g., addiction, impulsivity, obsessive-compulsive spectrum, bipolar spectrum, dissociation, etc.) shared with other behavioral or substance addictions