Characterizing the cancer genome in lung adenocarcinoma.

Somatic alterations in cellular DNA underlie almost all human cancers. The prospect of targeted therapies and the development of high-resolution, genome-wide approaches are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in approximately 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.

A Matter of Choice: Opportunities and Obstacles Facing People with ESRD.

Kidney failure is an overwhelming, life-shattering event, but patients with ESRD do not see themselves as being at the end stage of their lives. On the contrary, patients opting for kidney dialysis are choosing to live. Ideally, then, public policy would support patients' choices about how to live-specifically, the choice to continue working. Many patients with ESRD faced with the limitations of their health status and the demands of their treatment understandably choose to leave their jobs, a choice that is facilitated by the availability of public disability and health insurance. However, other patients who have the desire and opportunity to continue working may not get the guidance and support that can actually make their employment possible. Specifically, current disability and health insurance may fail to provide timely treatment and employment counseling to help patients with ESRD remain in their jobs. We, therefore, propose that the Center for Medicare and Medicaid Services support ESRD Networks to initiate more timely employment and treatment counseling in both the ESRD and the late-stage pre-ESRD setting. Although it is too late to require such counseling in the new network scope of work for 2016-2020, active experimentation in the next few years can lay the groundwork for a subsequent contract.

Heart health: volume and revenue growth through clinically integrated medical fitness centers.

The number of hospital sponsored medical fitness centers has grown from fewer than 100 in the early 1980's to nearly 700 today. The reasons for this growth are: They are recognized as part of the continuum of care; They are a powerful vehicle for increasing clinical volumes, revenues, and overall market share; They can generate substantial new revenue, both clinical and retail; and, They boldly proclaim a hospital's commitment to improving the health status of the community. With proper planning and an intense focus on clinical integration, medical fitness centers can assist hospitals in achieving numerous objectives. From a cardiology standpoint, imagine being able to show the community that you have been willing to spend millions of dollars to keep people's hearts healthy. That's market differentiation.

A single-molecule method for the quantitation of microRNA gene expression.

MicroRNAs (miRNA) are short endogenous noncoding RNA molecules that regulate fundamental cellular processes such as cell differentiation, cell proliferation and apoptosis through modulation of gene expression. Critical to understanding the role of miRNAs in this regulation is a method to rapidly and accurately quantitate miRNA gene expression. Existing methods lack sensitivity, specificity and typically require upfront enrichment, ligation and/or amplification steps. The Direct miRNA assay hybridizes two spectrally distinguishable fluorescent locked nucleic acid (LNA)-DNA oligonucleotide probes to the miRNA of interest, and then tagged molecules are directly counted on a single-molecule detection instrument. In this study, we show the assay is sensitive to femtomolar concentrations of miRNA (500 fM), has a three-log linear dynamic range and is capable of distinguishing among miRNA family members. Using this technology, we quantified expression of 45 human miRNAs within 16 different tissues, yielding a quantitative differential expression profile that correlates and expands upon published results.

Rapid quantitative analysis using a single molecule counting approach.

Single molecule detection of target molecules specifically bound by paired fluorescently labeled probes has shown great potential for sensitive quantitation of biomolecules. To date, no reports have rigorously evaluated the analytical capabilities of a single molecule detection platform employing this dual-probe approach or the performance of its data analysis methodology. In this paper, we describe a rapid, automated, and sensitive multicolor single molecule detection apparatus and a novel extension of coincident event counting based on detection of fluorescent probes. The approach estimates the number of dual-labeled molecules of interest from the total number of coincident fluorescent events observed by correcting for unbound probes that randomly pass through the interrogation zone simultaneously. Event counting was evaluated on three combinations of distinct fluorescence channels and was demonstrated to outperform conventional spatial cross-correlation in generating a wider linear dynamic response to target molecules. Furthermore, this approach succeeded in detecting subpicomolar concentrations of a model RNA target to which fluorescently labeled oligonucleotide probes were hybridized in a complex background of RNA. These results illustrate that the fluorescent event counting approach described represents a general tool for rapid sensitive quantitative analysis of any sample analyte, including nucleic acids and proteins, for which pairs of specific probes can be developed.