Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice

Insulin resistance is a defining feature of metabolic syndrome and type 2 diabetes mellitus but also may occur independently of these conditions. Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of these disorders, increases the risk of hepatocellular carcinoma (HCC). However, mechanisms linking hyperinsulinemia to NAFLD and HCC require clarification. We describe a novel model of primary insulin resistance and HCC with strong parent-of-origin effects. Male AB6F1 (A/JCr dam × C57BL/6 sire) but not B6AF1 (B6 dam × A/J sire) mice developed spontaneous insulin resistance, NAFLD, and HCC without obesity or diabetes. A survey of mitochondrial, imprinted, and sex-linked traits revealed modest associations with X-linked genes. However, a diet-induced obesity study, including B6.A chromosome substitution–strain (consomic) mice, showed no segregation by sex chromosome. Thus, parent-of-origin effects were specified within the autosomal genome. Next, we interrogated mechanisms of insulin-associated hepatocarcinogenesis. Steatotic hepatocytes exhibited adipogenic transition characterized by vacuolar metaplasia and up-regulation of vimentin, adipsin, fatty acid translocase (CD36), peroxisome proliferator–activated receptor-γ, and related products. This profile was largely recapitulated in insulin-supplemented primary mouse hepatocyte cultures. Importantly, pyruvate kinase M2, a fetal anabolic enzyme implicated in the Warburg effect, was activated by insulin in vivo and in vitro. Thus, our study reveals parent-of-origin effects in heritable insulin resistance, implicating adipogenic transition with acquired anabolic metabolism in the progression from NAFLD to HCC.National Institutes of Health (U.S.) (NIH grant AA016563)National Institutes of Health (U.S.) (NIH grant CA067529)National Institutes of Health (U.S.) (NIH grant P01CA0267)National Institutes of Health (U.S.) (NIH grant P30ES02109)National Institutes of Health (U.S.) (NIH grant RR007036)National Institutes of Health (U.S.) (NIH grant CA158661)National Institutes of Health (U.S.) (NIH grant CA016086

Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases

Bone metastases occur in approximately 70% of metastatic breast cancer patients, often leading to skeletal injuries. Current treatments are mainly palliative and underscore the unmet clinical need for improved therapies. In this study, we provide preclinical evidence for an antimetastatic therapy based on targeting integrin β3 (β3), which is selectively induced on breast cancer cells in bone by the local bone microenvironment. In a preclinical model of breast cancer, β3 was strongly expressed on bone metastatic cancer cells, but not primary mammary tumors or visceral metastases. In tumor tissue from breast cancer patients, β3 was significantly elevated on bone metastases relative to primary tumors from the same patient (n = 42). Mechanistic investigations revealed that TGFβ signaling through SMAD2/SMAD3 was necessary for breast cancer induction of β3 within the bone. Using a micelle-based nanoparticle therapy that recognizes integrin αvβ3 (αvβ3-MPs of ∼12.5 nm), we demonstrated specific localization to breast cancer bone metastases in mice. Using this system for targeted delivery of the chemotherapeutic docetaxel, we showed that bone tumor burden could be reduced significantly with less bone destruction and less hepatotoxicity compared with equimolar doses of free docetaxel. Furthermore, mice treated with αvβ3-MP-docetaxel exhibited a significant decrease in bone-residing tumor cell proliferation compared with free docetaxel. Taken together, our results offer preclinical proof of concept for a method to enhance delivery of chemotherapeutics to breast cancer cells within the bone by exploiting their selective expression of integrin αvβ3 at that metastatic site

Regional Systems of Care Demonstration Project: American Heart Association Mission: Lifeline STEMI Systems Accelerator.

BACKGROUND: Up to 50% of patients fail to meet ST-segment-elevation myocardial infarction (STEMI) guideline goals recommending a first medical contact-to-device time of <90 minutes for patients directly presenting to percutaneous coronary intervention-capable hospitals and <120 minutes for transferred patients. We sought to increase the proportion of patients treated within guideline goals by organizing coordinated regional reperfusion plans. METHODS: We established leadership teams, coordinated protocols, and provided regular feedback for 484 hospitals and 1253 emergency medical services (EMS) agencies in 16 regions across the United States. RESULTS: Between July 2012 and December 2013, 23 809 patients presented with acute STEMI (direct to percutaneous coronary intervention hospital: 11 765 EMS transported and 6502 self-transported; 5542 transferred). EMS-transported patients differed from self-transported patients in symptom onset to first medical contact time (median, 47 versus 114 minutes), incidence of cardiac arrest (10% versus 3%), shock on admission (11% versus 3%), and in-hospital mortality (8% versus 3%; P<0.001 for all comparisons). There was a significant increase in the proportion of patients meeting guideline goals of first medical contact-to-device time, including those directly presenting via EMS (50% to 55%; P<0.001) and transferred patients (44%-48%; P=0.002). Despite regional variability, the greatest gains occurred among patients in the 5 most improved regions, increasing from 45% to 57% (direct EMS; P<0.001) and 38% to 50% (transfers; P<0.001). CONCLUSIONS: This Mission: Lifeline STEMI Systems Accelerator demonstration project represents the largest national effort to organize regional STEMI care. By focusing on first medical contact-to-device time, coordinated treatment protocols, and regional data collection and reporting, we were able to increase significantly the proportion of patients treated within guideline goals

A New Rhesus Macaque Assembly and Annotation for Next-Generation Sequencing Analyses

BACKGROUND: The rhesus macaque (Macaca mulatta) is a key species for advancing biomedical research. Like all draft mammalian genomes, the draft rhesus assembly (rheMac2) has gaps, sequencing errors and misassemblies that have prevented automated annotation pipelines from functioning correctly. Another rhesus macaque assembly, CR_1.0, is also available but is substantially more fragmented than rheMac2 with smaller contigs and scaffolds. Annotations for these two assemblies are limited in completeness and accuracy. High quality assembly and annotation files are required for a wide range of studies including expression, genetic and evolutionary analyses. RESULTS: We report a new de novo assembly of the rhesus macaque genome (MacaM) that incorporates both the original Sanger sequences used to assemble rheMac2 and new Illumina sequences from the same animal. MacaM has a weighted average (N50) contig size of 64 kilobases, more than twice the size of the rheMac2 assembly and almost five times the size of the CR_1.0 assembly. The MacaM chromosome assembly incorporates information from previously unutilized mapping data and preliminary annotation of scaffolds. Independent assessment of the assemblies using Ion Torrent read alignments indicates that MacaM is more complete and accurate than rheMac2 and CR_1.0. We assembled messenger RNA sequences from several rhesus tissues into transcripts which allowed us to identify a total of 11,712 complete proteins representing 9,524 distinct genes. Using a combination of our assembled rhesus macaque transcripts and human transcripts, we annotated 18,757 transcripts and 16,050 genes with complete coding sequences in the MacaM assembly. Further, we demonstrate that the new annotations provide greatly improved accuracy as compared to the current annotations of rheMac2. Finally, we show that the MacaM genome provides an accurate resource for alignment of reads produced by RNA sequence expression studies. CONCLUSIONS: The MacaM assembly and annotation files provide a substantially more complete and accurate representation of the rhesus macaque genome than rheMac2 or CR_1.0 and will serve as an important resource for investigators conducting next-generation sequencing studies with nonhuman primates. REVIEWERS: This article was reviewed by Dr. Lutz Walter, Dr. Soojin Yi and Dr. Kateryna Makova

Coordinate Gene Regulation during Hematopoiesis Is Related to Genomic Organization

Gene loci are found in nuclear subcompartments that are related to their expression status. For instance, silent genes are often localized to heterochromatin and the nuclear periphery, whereas active genes tend to be found in the nuclear center. Evidence also suggests that chromosomes may be specifically positioned within the nucleus; however, the nature of this organization and how it is achieved are not yet fully understood. To examine whether gene regulation is related to a discernible pattern of genomic organization, we analyzed the linear arrangement of co-regulated genes along chromosomes and determined the organization of chromosomes during the differentiation of a hematopoietic progenitor to erythroid and neutrophil cell types. Our analysis reveals that there is a significant tendency for co-regulated genes to be proximal, which is related to the association of homologous chromosomes and the spatial juxtaposition of lineage-specific gene domains. We suggest that proximity in the form of chromosomal gene distribution and homolog association may be the basis for organizing the genome for coordinate gene regulation during cellular differentiation

LSST Science Book, Version 2.0

A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo

Correcting Mortality for Loss to Follow-Up: A Nomogram Applied to Antiretroviral Treatment Programmes in Sub-Saharan Africa

Matthias Egger and colleagues present a nomogram and a web-based calculator to correct estimates of program-level mortality for loss to follow-up, for use in antiretroviral treatment programs

OMIP contribution to CMIP6: experimental and diagnostic protocol for the physical component of the Ocean Model Intercomparison Project

The Ocean Model Intercomparison Project (OMIP) is an endorsed project in the Coupled Model Intercomparison Project Phase 6 (CMIP6). OMIP addresses CMIP6 science questions, investigating the origins and consequences of systematic model biases. It does so by providing a framework for evaluating (including assessment of systematic biases), understanding, and improving ocean, sea-ice, tracer, and biogeochemical components of climate and earth system models contributing to CMIP6. Among the WCRP Grand Challenges in climate science (GCs), OMIP primarily contributes to the regional sea level change and near-term (climate/decadal) prediction GCs. OMIP provides (a) an experimental protocol for global ocean/sea-ice models run with a prescribed atmospheric forcing; and (b) a protocol for ocean diagnostics to be saved as part of CMIP6. We focus here on the physical component of OMIP, with a companion paper (Orr et al., 2016) detailing methods for the inert chemistry and interactive biogeochemistry. The physical portion of the OMIP experimental protocol follows the interannual Coordinated Ocean-ice Reference Experiments (CORE-II). Since 2009, CORE-I (Normal Year Forcing) and CORE-II (Interannual Forcing) have become the standard methods to evaluate global ocean/sea-ice simulations and to examine mechanisms for forced ocean climate variability. The OMIP diagnostic protocol is relevant for any ocean model component of CMIP6, including the DECK (Diagnostic, Evaluation and Characterization of Klima experiments), historical simulations, FAFMIP (Flux Anomaly Forced MIP), C4MIP (Coupled Carbon Cycle Climate MIP), DAMIP (Detection and Attribution MIP), DCPP (Decadal Climate Prediction Project), ScenarioMIP, HighResMIP (High Resolution MIP), as well as the ocean/sea-ice OMIP simulations

Avoid or Embrace? Practice Effects in Alzheimer's Disease Prevention Trials

Demonstrating a slowing in the rate of cognitive decline is a common outcome measure in clinical trials in Alzheimer’s disease (AD). Selection of cognitive endpoints typically includes modeling candidate outcome measures in the many, richly phenotyped observational cohort studies available. An important part of choosing cognitive endpoints is a consideration of improvements in performance due to repeated cognitive testing (termed “practice effects”). As primary and secondary AD prevention trials are comprised predominantly of cognitively unimpaired participants, practice effects may be substantial and may have considerable impact on detecting cognitive change. The extent to which practice effects in AD prevention trials are similar to those from observational studies and how these potential differences impact trials is unknown. In the current study, we analyzed data from the recently completed DIAN-TU-001 clinical trial (TU) and the associated DIAN-Observational (OBS) study. Results indicated that asymptomatic mutation carriers in the TU exhibited persistent practice effects on several key outcomes spanning the entire trial duration. Critically, these practice related improvements were larger on certain tests in the TU relative to matched participants from the OBS study. Our results suggest that the magnitude of practice effects may not be captured by modeling potential endpoints in observational studies where assessments are typically less frequent and drug expectancy effects are absent. Using alternate instrument forms (represented in our study by computerized tasks) may partly mitigate practice effects in clinical trials but incorporating practice effects as outcomes may also be viable. Thus, investigators must carefully consider practice effects (either by minimizing them or modeling them directly) when designing cognitive endpoint AD prevention trials by utilizing trial data with similar assessment frequencies

J Womens Health (Larchmt)

BackgroundIdentifying and treating chronic diseases, their precursors, and other cardiovascular disease (CVD) risk factors during family planning visits may improve long-term health and reproductive outcomes among low-income women. A cross-sectional study design was used to describe the prevalence of chronic diseases (hypertension, high cholesterol, and diabetes), their precursors (pre-hypertension, borderline high cholesterol, and pre-diabetes), and related CVD risk factors (such as obesity, smoking, and physical inactivity) among low-income women of reproductive age.MethodsPrevalence of chronic diseases, their precursors, and related CVD risk factors were assessed for 462 out of 859 (53.8%) female family planning patients, ages 18\u201344 years, who attended a Title X clinic in eastern North Carolina during 2011 and 2012 and consented to participate. Data were obtained from clinical measurements, blood test results, and questionnaire. Differences in distribution of demographic and health care characteristics and CVD risk factors by presence of prehypertension and pre-diabetes were assessed by Pearson chi-square tests.ResultsThe prevalence of hypertension was 12%, high cholesterol 16%, and diabetes 3%. Nearly two-thirds of women with hypertension were newly diagnosed (62%) as were 75% of women with diabetes. The prevalence of pre-hypertension was 35%, pre-diabetes 31%, obesity 41%, smoking 32%, and physical inactivity 42%. The majority of participants (87%) had one or more chronic disease or related cardiovascular disease risk factor.ConclusionsCVD screening during family planning visits can identify significant numbers of women at risk for poor pregnancy outcomes and future chronic disease and can provide prevention opportunities if effective interventions are available and acceptable to this population.20132015-04-06T00:00:00ZCC999999/Intramural CDC HHS/United States5U48DP001944/DP/NCCDPHP CDC HHS/United States23531099PMC4386647673