Classifying the precancers: A metadata approach

BACKGROUND: During carcinogenesis, precancers are the morphologically identifiable lesions that precede invasive cancers. In theory, the successful treatment of precancers would result in the eradication of most human cancers. Despite the importance of these lesions, there has been no effort to list and classify all of the precancers. The purpose of this study is to describe the first comprehensive taxonomy and classification of the precancers. As a novel approach to disease classification, terms and classes were annotated with metadata (data that describes the data) so that the classification could be used to link precancer terms to data elements in other biological databases. METHODS: Terms in the UMLS (Unified Medical Language System) related to precancers were extracted. Extracted terms were reviewed and additional terms added. Each precancer was assigned one of six general classes. The entire classification was assembled as an XML (eXtensible Mark-up Language) file. A Perl script converted the XML file into a browser-viewable HTML (HyperText Mark-up Language) file. RESULTS: The classification contained 4700 precancer terms, 568 distinct precancer concepts and six precancer classes: 1) Acquired microscopic precancers; 2) acquired large lesions with microscopic atypia; 3) Precursor lesions occurring with inherited hyperplastic syndromes that progress to cancer; 4) Acquired diffuse hyperplasias and diffuse metaplasias; 5) Currently unclassified entities; and 6) Superclass and modifiers. CONCLUSION: This work represents the first attempt to create a comprehensive listing of the precancers, the first attempt to classify precancers by their biological properties and the first attempt to create a pathologic classification of precancers using standard metadata (XML). The classification is placed in the public domain, and comment is invited by the authors, who are prepared to curate and modify the classification

Fast Optimal Transport Averaging of Neuroimaging Data

Knowing how the Human brain is anatomically and functionally organized at the level of a group of healthy individuals or patients is the primary goal of neuroimaging research. Yet computing an average of brain imaging data defined over a voxel grid or a triangulation remains a challenge. Data are large, the geometry of the brain is complex and the between subjects variability leads to spatially or temporally non-overlapping effects of interest. To address the problem of variability, data are commonly smoothed before group linear averaging. In this work we build on ideas originally introduced by Kantorovich to propose a new algorithm that can average efficiently non-normalized data defined over arbitrary discrete domains using transportation metrics. We show how Kantorovich means can be linked to Wasserstein barycenters in order to take advantage of an entropic smoothing approach. It leads to a smooth convex optimization problem and an algorithm with strong convergence guarantees. We illustrate the versatility of this tool and its empirical behavior on functional neuroimaging data, functional MRI and magnetoencephalography (MEG) source estimates, defined on voxel grids and triangulations of the folded cortical surface.Comment: Information Processing in Medical Imaging (IPMI), Jun 2015, Isle of Skye, United Kingdom. Springer, 201

Associations of sitting accumulation patterns with cardio-metabolic risk biomarkers in Australian adults

Backgroun

Effects of Low-Energy Diet or Exercise on Cardiovascular Function in Working-Age Adults With Type 2 Diabetes: A Prospective, Randomized, Open-Label, Blinded End Point Trial

OBJECTIVE To confirm the presence of subclinical cardiovascular dysfunction in working-age adults with type 2 diabetes (T2D) and determine whether this is improved by a low-energy meal replacement diet (MRP) or exercise training. RESEARCH DESIGN AND METHODS This article reports on a prospective, randomized, open-label, blinded end point trial with nested case-control study. Asymptomatic younger adults with T2D were randomized 1:1:1 to a 12-week intervention of 1) routine care, 2) supervised aerobic exercise training, or 3) a low-energy (∼810 kcal/day) MRP. Participants underwent echocardiography, cardiopulmonary exercise testing, and cardiac magnetic resonance (CMR) at baseline and 12 weeks. The primary outcome was change in left ventricular (LV) peak early diastolic strain rate (PEDSR) as measured by CMR. Healthy volunteers were enrolled for baseline case-control comparison. RESULTS Eighty-seven participants with T2D (age 51 ± 7 years, HbA1c 7.3 ± 1.1%) and 36 matched control participants were included. At baseline, those with T2D had evidence of diastolic dysfunction (PEDSR 1.01 ± 0.19 vs. 1.10 ± 0.16 s−1, P = 0.02) compared with control participants. Seventy-six participants with T2D completed the trial (30 routine care, 22 exercise, and 24 MRP). The MRP arm lost 13 kg in weight and had improved blood pressure, glycemia, LV mass/volume, and aortic stiffness. The exercise arm had negligible weight loss but increased exercise capacity. PEDSR increased in the exercise arm versus routine care (β = 0.132, P = 0.002) but did not improve with the MRP (β = 0.016, P = 0.731). CONCLUSIONS In asymptomatic working-age adults with T2D, exercise training improved diastolic function. Despite beneficial effects of weight loss on glycemic control, concentric LV remodeling, and aortic stiffness, a low-energy MRP did not improve diastolic function

The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells

We thank S.S. Marelli for discussions. Supported by the Medical Research Council (A.L.), the Biotechnology and Biological Science Research Council (BB/J006750/1 to A.N.A. and S.M.H.) and the Instituto de Salud Carlos III, Spain (D.E.)

Relationships between heavy metal concentrations in three different body fluids and male reproductive parameters: a pilot study

<p>Abstract</p> <p>Background</p> <p>Animal studies have shown the reproductive toxicity of a number of heavy metals. Very few human observational studies have analyzed the relationship between male reproductive function and heavy metal concentrations in diverse biological fluids.</p> <p>Methods</p> <p>The current study assessed the associations between seminal and hormonal parameters and the concentration of the 3 most frequent heavy metal toxicants (lead, cadmium and mercury) in three different body fluids. Sixty one men attending infertility clinics that participated in a case-control study to explore the role of environmental toxins and lifestyles on male infertility were analyzed. Concentration of lead, cadmium and mercury were measured in blood and seminal plasma and whole blood using anodic stripping voltammetry and atomic absorption spectrophotometry. Serum samples were analyzed for follicle-stimulating hormone, luteinizing hormone and testosterone. Semen analyses were performed according to World Health Organization criteria. Mann-Whitney test and Spearman's rank correlations were used for unadjusted analyses. Multiple linear regression models were performed controlling for age, body mass index and number of cigarettes per day.</p> <p>Results</p> <p>There were no significant differences between cases and controls in the concentrations of heavy metals in any of the three body fluids. In multivariate analyses using all subjects no significant associations were found between serum hormone levels and metal concentrations. However there was a significant positive association between the percentage of immotile sperms and seminal plasma levels of lead and cadmium.</p> <p>Conclusions</p> <p>Our results suggest that the presence of lead and cadmium in the reproductive tract of men may be related to a moderate alteration of their seminal parameters.</p

Interactions between Naïve and Infected Macrophages Reduce Mycobacterium tuberculosis Viability

A high intracellular bacillary load of Mycobacterium tuberculosis in macrophages induces an atypical lysosomal cell death with early features of apoptosis that progress to necrosis within hours. Unlike classical apoptosis, this cell death mode does not appear to diminish M. tuberculosis viability. We previously reported that culturing heavily infected macrophages with naïve macrophages produced an antimicrobial effect, but only if naïve macrophages were added during the pre-necrotic phase of M. tuberculosis-induced cell death. In the present study we investigated the mechanism of antimicrobial activity in co-cultures, anticipating that efferocytosis of bacilli in apoptotic bodies would be required. Confocal microscopy revealed frustrated phagocytosis of M. tuberculosis-infected macrophages with no evidence that significant numbers of bacilli were transferred to the naïve macrophages. The antimicrobial effect of naïve macrophages was retained when they were separated from infected macrophages in transwells, and conditioned co-culture supernatants transferred antimicrobial activity to cultures of infected macrophages alone. Antimicrobial activity in macrophage co-cultures was abrogated when the naïve population was deficient in IL-1 receptor or when the infected population was deficient in inducible nitric oxide synthase. The participation of nitric oxide suggested a conventional antimicrobial mechanism requiring delivery of bacilli to a late endosomal compartment. Using macrophages expressing GFP-LC3 we observed the induction of autophagy specifically by a high intracellular load of M. tuberculosis. Bacilli were identified in LC3-positive compartments and LC3-positive compartments were confirmed to be acidified and LAMP1 positive. Thus, the antimicrobial effect of naïve macrophages acting on M. tuberculosis in heavily-infected macrophages is contact-independent. Interleukin-1 provides an afferent signal that induces an as yet unidentified small molecule which promotes nitric oxide-dependent antimicrobial activity against bacilli in autolysosomes of heavily infected macrophages. This cooperative, innate antimicrobial interaction may limit the maximal growth rate of M. tuberculosis prior to the expression of adaptive immunity in pulmonary tuberculosis

Chk2 and p53 Are Haploinsufficient with Dependent and Independent Functions to Eliminate Cells after Telomere Loss

The mechanisms that cells use to monitor telomere integrity, and the array of responses that may be induced, are not fully defined. To date there have been no studies in animals describing the ability of cells to survive and contribute to adult organs following telomere loss. We developed assays to monitor the ability of somatic cells to proliferate and differentiate after telomere loss. Here we show that p53 and Chk2 limit the growth and differentiation of cells that lose a telomere. Furthermore, our results show that two copies of the genes encoding p53 and Chk2 are required for the cell to mount a rapid wildtype response to a missing telomere. Finally, our results show that, while Chk2 functions by activating the p53-dependent apoptotic cascade, Chk2 also functions independently of p53 to limit survival. In spite of these mechanisms to eliminate cells that have lost a telomere, we find that such cells can make a substantial contribution to differentiated adult tissues