SUMMARY Many genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus. We performed a systematic analysis of yeast RLS in a set of 4,698 viable single-gene deletion strains. Multiple functional gene clusters were identified, and full genome-to-genome comparison demonstrated a significant conservation in longevity pathways between yeast and C. elegans. Among the mechanisms of aging identified, deletion of tRNA exporter LOS1 robustly extended lifespan. Dietary restriction (DR) and inhibition of mechanistic Target of Rapamycin (mTOR) exclude Los1 from the nucleus in a Rad53-dependent manner. Moreover, lifespan extension from deletion of LOS1 is non-additive with DR or mTOR inhibition, and results in Gcn4 transcription factor activation. Thus, the DNA damage response and mTOR converge on Los1-mediated nuclear tRNA export to regulate Gcn4 activity and aging.

Viewing dual-energy CT images may result in the greatest subjective lesion conspicuity and measured contrast-to-noise ratio at 50 keV with equal detection of hyperenhancing liver lesions compared with viewing 77-keV images alone. In addition, the radiation doses of dual-energy CT may be similar to those of single-energy CT.

OBJECTIVE The purpose of this study is to compare three CT image reconstruction algorithms for liver lesion detection and appearance, subjective lesion conspicuity, and measured noise. MATERIALS AND METHODS Thirty-six patients with known liver lesions were scanned with a routine clinical three-phase CT protocol using a weight-based noise index of 30 or 36. Image data from each phase were reconstructed with filtered back projection (FBP), adaptive statistical iterative reconstruction (ASIR), and model-based iterative reconstruction (MBIR). Randomized images were presented to two independent blinded reviewers to detect and categorize the appearance of lesions and to score lesion conspicuity. Lesion size, lesion density (in Hounsfield units), adjacent liver density (in Hounsfield units), and image noise were measured. Two different unblinded truth readers established the number, appearance, and location of lesions. RESULTS Fifty-one focal lesions were detected by truth readers. For blinded reviewers compared with truth readers, there was no difference for lesion detection among the reconstruction algorithms. Lesion appearance was statistically the same among the three reconstructions. Although one reviewer scored lesions as being more conspicuous with MBIR, the other scored them the same. There was significantly less background noise in air with MBIR (mean [± SD], 2.1 ± 1.4 HU) than with ASIR (8.9 ± 1.9 HU; p < 0.001) or FBP (10.6 ± 2.6 HU; p < 0.001). Mean lesion contrast-to-noise ratio was statistically significantly higher for MBIR (34.4 ± 29.1) than for ASIR (6.5 ± 4.9; p < 0.001) or FBP (6.3 ± 6.0; p < 0.001). CONCLUSION In routine-dose clinical CT of the liver, MBIR resulted in comparable lesion detection, lesion characterization, and subjective lesion conspicuity, but significantly lower background noise and higher contrast-to-noise ratio compared with ASIR or FBP. This finding suggests that further investigation of the use of MBIR to enable dose reduction in liver CT is warranted.

Context.— Immunomarkers with diagnostic, therapeutic, or prognostic values have been increasingly used to maximize the benefits of clinical management of patients with neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. Objectives.— To review the characteristics of immunomarkers that are commonly used in surgical pathology practice for neoplasms of the gastrointestinal tract, liver, biliary tract, and pancreas, and to summarize the clinical usefulness of immunomarkers that have been discovered in recent years in these fields. Data Sources.— Data sources include literature review, authors' research data, and personal practice experience. Conclusions.— Immunohistochemistry is an indispensable tool for the accurate diagnosis of neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. Useful immunomarkers are available to help distinguish malignant neoplasms from benign conditions, determine organ origins, and subclassify neoplasms that are morphologically and biologically heterogeneous. Specific immunomarkers are also available to help guide patient treatment and assess disease aggressiveness, which are keys to the success of personalized medicine. Pathologists will continue to play a critical role in the discovery, validation, and application of new biomarkers, which will ultimately improve patient care.

SUMMARY Activation of Sir2-orthologs is proposed to increase lifespan downstream of dietary restriction (DR). Here we describe an examination of the effect of 32 different lifespan-extending mutations and four methods of dietary restriction on replicative lifespan (RLS) in the short-lived sir2Δ yeast strain. In every case, deletion of SIR2 prevented RLS extension; however, RLS extension was restored when both SIR2 and FOB1 were deleted in several cases, demonstrating that SIR2 is not directly required for RLS extension. These findings indicate that suppression of the sir2Δ lifespan defect is a rare phenotype among longevity interventions and suggest that sir2Δ cells senesce rapidly by a mechanism distinct from that of wild-type cells. They also demonstrate that failure to observe life span extension in a short-lived background, such as cells or animals lacking sirtuins, should be interpreted with caution.