Melanocortin-1 Receptor, Skin Cancer and Phenotypic Characteristics (M-SKIP) Project: Study Design and Methods for Pooling Results of Genetic Epidemiological Studies

Background: For complex diseases like cancer, pooled-analysis of individual data represents a powerful tool to investigate the joint contribution of genetic, phenotypic and environmental factors to the development of a disease. Pooled-analysis of epidemiological studies has many advantages over meta-analysis, and preliminary results may be obtained faster and with lower costs than with prospective consortia. Design and methods: Based on our experience with the study design of the Melanocortin-1 receptor (MC1R) gene, SKin cancer and Phenotypic characteristics (M-SKIP) project, we describe the most important steps in planning and conducting a pooled-analysis of genetic epidemiological studies. We then present the statistical analysis plan that we are going to apply, giving particular attention to methods of analysis recently proposed to account for between-study heterogeneity and to explore the joint contribution of genetic, phenotypic and environmental factors in the development of a disease. Within the M-SKIP project, data on 10,959 skin cancer cases and 14,785 controls from 31 international investigators were checked for quality and recoded for standardization. We first proposed to fit the aggregated data with random-effects logistic regression models. However, for the M-SKIP project, a two-stage analysis will be preferred to overcome the problem regarding the availability of different study covariates. The joint contribution of MC1R variants and phenotypic characteristics to skin cancer development will be studied via logic regression modeling. Discussion: Methodological guidelines to correctly design and conduct pooled-analyses are needed to facilitate application of such methods, thus providing a better summary of the actual findings on specific fields

On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver

Iron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal1. In various pathophysiological conditions, however, erythrocyte life span is severely compromised, which threatens the organism with anemia and iron toxicity2,3. Here we identify an on-demand mechanism that clears erythrocytes and recycles iron. We show that Ly-6Chigh monocytes ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate to ferroportin 1 (FPN1)-expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1+ Tim-4neg macrophages are transient, reside alongside embryonically-derived Tim-4high Kupffer cells, and depend on Csf1 and Nrf2. The spleen likewise recruits iron-loaded Ly-6Chigh monocytes, but these do not differentiate into iron-recycling macrophages due to the suppressive action of Csf2. Inhibiting monocyte recruitment to the liver leads to kidney and liver damage. These observations identify the liver as the primary organ supporting rapid erythrocyte removal and iron recycling and uncover a mechanism by which the body adapts to fluctuations in erythrocyte integrity

Vascular invasion predicts the subgroup of lung adenocarcinomas ≤2.0 cm at risk of poor outcome treated by wedge resection compared to lobectomyCentral MessagePerspective

Background: Recent randomized control trials (JCOG0802 and CALGB140503) have shown sublobar resection to be noninferior to lobectomy for non–small cell lung cancer (NSCLC) ≤2.0 cm. We have previously proposed histologic criteria stratifying lung adenocarcinoma into indolent low malignant potential (LMP) and aggressive angioinvasive adenocarcinomas, resulting in better prognostication than provided by World Health Organization grade. Here we determine whether pathologic classification is reproducible and whether subsets of adenocarcinomas predict worse outcomes when treated by wedge resection compared to lobectomy. Methods: A retrospective cohort of 108 recipients of wedge resection and 187 recipients of lobectomy for stage I/0 lung adenocarcinomas ≤2.0 cm was assembled from 2 institutions. All tumors were classified by a single pathologist, and interobserver reproducibility was assessed in a subset (n = 92) by 5 pathologists. Results: Angioinvasive adenocarcinoma (21%-27% of cases) was associated with worse outcomes when treated with wedge resection compared to lobectomy (5-year recurrence-free survival, 57% vs 85% [P = .007]; 5-year disease-free survival [DSS], 70% vs 90% [P = .043]; 7-year overall survival, 37% vs 58% [P = .143]). Adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and LMP exhibited 100% 5-year DSS regardless of the surgical approach. Multivariable analysis showed that angioinvasion, tumor size, margin status, and extent of nodal sampling were significantly associated with recurrence but not with surgical procedure. There was substantial interobserver reproducibility among the pathologists for the diagnosis of angioinvasive adenocarcinoma (κ = 0.71) and the combined indolent AIS/MIA/LMP group (κ = 0.74). Conclusions: The majority (∼75%) of lung adenocarcinomas ≤2 cm are adequately managed with wedge resection; however, angioinvasive adenocarcinomas (∼25%) treated by wedge resection with suboptimal nodal sampling exhibit poor outcomes, with a 40% to 45% rate of recurrence within 5 years and 60% to 65% overall mortality at 7 years

Do the sunk cost effect and cognitive dissonance increase risk perception? An empirical study in the context of city smog

City smog is an increasingly severe environmental hazard in China. People are eager for ways to protect themselves from city smog. By utilizing two laboratory experiments based on real context of city smog, this paper investigates the impacts of sunk cost and cognitive dissonance on individuals’ risk perception of city smog. In Experiment 1, the results show that the risk perception of individuals with a sunk cost is significantly higher than those without. Moreover, cognitive dissonance has a significant influence on risk perception. In Experiment 2, the results suggest that: (1) the risk perception of a consumer with a prevention focus is significantly greater than that of those with a promotion focus; (2) the risk perception of a prevention-oriented consumer with no sunk cost is similar to that of a promotion-oriented consumer with sunk cost. The study concludes with policy implications

Intricate tunnels in garnets from soils and river sediments in Thailand - Possible endolithic microborings

Garnets from disparate geographical environments and origins such as oxidized soils and river sediments in Thailand host intricate systems of microsized tunnels that significantly decrease the quality and value of the garnets as gems. The origin of such tunneling has previously been attributed to abiotic processes. Here we present physical and chemical remains of endolithic microorganisms within the tunnels and discuss a probable biological origin of the tunnels. Extensive investigations with synchrotron-radiation X-ray tomographic microscopy (SRXTM) reveal morphological indications of biogenicity that further support a euendolithic interpretation. We suggest that the production of the tunnels was initiated by a combination of abiotic and biological processes, and that at later stages biological processes came to dominate. In environments such as river sediments and oxidized soils garnets are among the few remaining sources of bio-available Fe2+, thus it is likely that microbially mediated boring of the garnets has trophic reasons. Whatever the reason for garnet boring, the tunnel system represents a new endolithic habitat in a hard silicate mineral otherwise known to be resistant to abrasion and chemical attack. The authors acknowledge funding from the Swedish Research Council (Contracts No. 2007-4483 (SB), 2010-3929 (HS), 2012-4364 (MI), and 2013-4290 (SB), 2015-04129 (SS)), Danish National Research Foundation (DNRF53), and Paul Scherrer Institute (20130185) (MI) as well as Swedish National Space Board (Contract No. 83/10 (MI), 121/11 and 198/15 (SS)).</p