Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: a randomized trial.

BackgroundRetinoids enhance differentiation of most epithelial tissues. Epidemiologic studies have shown an inverse relationship between dietary intake or serum levels of vitamin A and the development of cervical dysplasia and/or cervical cancer. Pilot and phase I investigations demonstrated the feasibility of the local delivery of all-trans-retinoic acid (RA) to the cervix using a collagen sponge insert and cervical cap. A phase II trial produced a clinical complete response rate of 50%.PurposeThis randomized phase III trial was designed to determine whether topically applied RA reversed moderate cervical intraepithelial neoplasia (CIN) II or severe CIN.MethodsAnalyses were based on 301 women with CIN (moderate dysplasia, 151 women; severe dysplasia, 150 women), evaluated by serial colposcopy, Papanicolaou cytology, and cervical biopsy. Cervical caps with sponges containing either 1.0 mL of 0.372% beta-trans-RA or a placebo were inserted daily for 4 days when women entered the trial, and for 2 days at months 3 and 6. Patients receiving treatment and those receiving placebo were similar with respect to age, ethnicity, birth-control methods, histologic features of the endocervical biopsy specimen and koilocytotic atypia, and percentage of involvement of the cervix at study. Treatment effects were compared using Fisher's exact test and logistic regression methods. Side effects were recorded, and differences were compared using Fisher's exact test.ResultsRA increased the complete histologic regression rate of CIN II from 27% in the placebo group to 43% in the retinoic acid treatment group (P = .041). No treatment difference between the two arms was evident in the severe dysplasia group. More vaginal and vulvar side effects were seen in the patients receiving RA, but these effects were mild and reversible.ConclusionsA short course of locally applied RA can reverse CIN II, but not more advanced dysplasia, with acceptable local side effects.ImplicationsA derivative of vitamin A can reverse or suppress an epithelial preneoplasia, lending further support to the notion that chemoprevention of human cancer is feasible

Maternal corticotropin-releasing hormone is associated with LEP DNA methylation at birth and in childhood: an epigenome-wide study in Project Viva

BackgroundCorticotropin-releasing hormone (CRH) plays a central role in regulating the secretion of cortisol which controls a wide range of biological processes. Fetuses overexposed to cortisol have increased risks of disease in later life. DNA methylation may be the underlying association between prenatal cortisol exposure and health effects. We investigated associations between maternal CRH levels and epigenome-wide DNA methylation of cord blood in offsprings and evaluated whether these associations persisted into mid-childhood.MethodsWe investigated mother-child pairs enrolled in the prospective Project Viva pre-birth cohort. We measured DNA methylation in 257 umbilical cord blood samples using the HumanMethylation450 Bead Chip. We tested associations of maternal CRH concentration with cord blood cells DNA methylation, adjusting the model for maternal age at enrollment, education, maternal race/ethnicity, maternal smoking status, pre-pregnancy body mass index, parity, gestational age at delivery, child sex, and cell-type composition in cord blood. We further examined the persistence of associations between maternal CRH levels and DNA methylation in children's blood cells collected at mid-childhood (n = 239, age: 6.7-10.3 years) additionally adjusting for the children's age at blood drawn.ResultsMaternal CRH levels are associated with DNA methylation variability in cord blood cells at 96 individual CpG sites (False Discovery Rate <0.05). Among the 96 CpG sites, we identified 3 CpGs located near the LEP gene. Regional analyses confirmed the association between maternal CRH and DNA methylation near LEP. Moreover, higher maternal CRH levels were associated with higher blood-cell DNA methylation of the promoter region of LEP in mid-childhood (P < 0.05, β = 0.64, SE = 0.30).ConclusionIn our cohort, maternal CRH was associated with DNA methylation levels in newborns at multiple loci, notably in the LEP gene promoter. The association between maternal CRH and LEP DNA methylation levels persisted into mid-childhood

The HY5-PIF regulatory module coordinates light and temperature control of photosynthetic gene transcription

The ability to interpret daily and seasonal alterations in light and temperature signals is essential for plant survival. This is particularly important during seedling establishment when the phytochrome photoreceptors activate photosynthetic pigment production for photoautotrophic growth. Phytochromes accomplish this partly through the suppression of phytochrome interacting factors (PIFs), negative regulators of chlorophyll and carotenoid biosynthesis. While the bZIP transcription factor long hypocotyl 5 (HY5), a potent PIF antagonist, promotes photosynthetic pigment accumulation in response to light. Here we demonstrate that by directly targeting a common promoter cis-element (G-box), HY5 and PIFs form a dynamic activation-suppression transcriptional module responsive to light and temperature cues. This antagonistic regulatory module provides a simple, direct mechanism through which environmental change can redirect transcriptional control of genes required for photosynthesis and photoprotection. In the regulation of photopigment biosynthesis genes, HY5 and PIFs do not operate alone, but with the circadian clock. However, sudden changes in light or temperature conditions can trigger changes in HY5 and PIFs abundance that adjust the expression of common target genes to optimise photosynthetic performance and growth

Measurement of CP-violation asymmetries in D0 to Ks pi+ pi-

We report a measurement of time-integrated CP-violation asymmetries in the resonant substructure of the three-body decay D0 to Ks pi+ pi- using CDF II data corresponding to 6.0 invfb of integrated luminosity from Tevatron ppbar collisions at sqrt(s) = 1.96 TeV. The charm mesons used in this analysis come from D*+(2010) to D0 pi+ and D*-(2010) to D0bar pi-, where the production flavor of the charm meson is determined by the charge of the accompanying pion. We apply a Dalitz-amplitude analysis for the description of the dynamic decay structure and use two complementary approaches, namely a full Dalitz-plot fit employing the isobar model for the contributing resonances and a model-independent bin-by-bin comparison of the D0 and D0bar Dalitz plots. We find no CP-violation effects and measure an asymmetry of ACP = (-0.05 +- 0.57 (stat) +- 0.54 (syst))% for the overall integrated CP-violation asymmetry, consistent with the standard model prediction.Comment: 15 page

Observation of the Baryonic Flavor-Changing Neutral Current Decay Lambda_b -> Lambda mu+ mu-

We report the first observation of the baryonic flavor-changing neutral current decay Lambda_b -> Lambda mu+ mu- with 24 signal events and a statistical significance of 5.8 Gaussian standard deviations. This measurement uses ppbar collisions data sample corresponding to 6.8fb-1 at sqrt{s}=1.96TeV collected by the CDF II detector at the Tevatron collider. The total and differential branching ratios for Lambda_b -> Lambda mu+ mu- are measured. We find B(Lambda_b -> Lambda mu+ mu-) = [1.73+-0.42(stat)+-0.55(syst)] x 10^{-6}. We also report the first measurement of the differential branching ratio of B_s -> phi mu+ mu- using 49 signal events. In addition, we report branching ratios for B+ -> K+ mu+ mu-, B0 -> K0 mu+ mu-, and B -> K*(892) mu+ mu- decays.Comment: 8 pages, 2 figures, 4 tables. Submitted to Phys. Rev. Let

Human and murine clonal CD8+ T cell expansions arise during tuberculosis because of TCR selection

The immune system can recognize virtually any antigen, yet T cell responses against several pathogens, including Mycobacterium tuberculosis, are restricted to a limited number of immunodominant epitopes. The host factors that affect immunodominance are incompletely understood. Whether immunodominant epitopes elicit protective CD8+ T cell responses or instead act as decoys to subvert immunity and allow pathogens to establish chronic infection is unknown. Here we show that anatomically distinct human granulomas contain clonally expanded CD8+ T cells with overlapping T cell receptor (TCR) repertoires. Similarly, the murine CD8+ T cell response against M. tuberculosis is dominated by TB10.44-11-specific T cells with extreme TCRß bias. Using a retro genic model of TB10.44-11-specific CD8+ Tcells, we show that TCR dominance can arise because of competition between clonotypes driven by differences in affinity. Finally, we demonstrate that TB10.4-specific CD8+ T cells mediate protection against tuberculosis, which requires interferon-? production and TAP1-dependent antigen presentation in vivo. Our study of how immunodominance, biased TCR repertoires, and protection are inter-related, provides a new way to measure the quality of T cell immunity, which if applied to vaccine evaluation, could enhance our understanding of how to elicit protective T cell immunity.This work was supported by the Portuguese Foundation for Science and Technology individual fellowship (CNA) www.fct.pt, a National Institutes of Health Grant R01 AI106725 (SMB) www.nih.gov, and a Center for AIDS Research Grant P30 AI 060354 (SMB) www.nih.gov. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Minimal Holocene retreat of large tidewater glaciers in Køge Bugt, southeast Greenland

Abstract Køge Bugt, in southeast Greenland, hosts three of the largest glaciers of the Greenland Ice Sheet; these have been major contributors to ice loss in the last two decades. Despite its importance, the Holocene history of this area has not been investigated. We present a 9100 year sediment core record of glaciological and oceanographic changes from analysis of foraminiferal assemblages, the abundance of ice-rafted debris, and sortable silt grain size data. Results show that ice-rafted debris accumulated constantly throughout the core; this demonstrates that glaciers in Køge Bugt remained in tidewater settings throughout the last 9100 years. This observation constrains maximum Holocene glacier retreat here to less than 6 km from present-day positions. Retreat was minimal despite oceanic and climatic conditions during the early-Holocene that were at least as warm as the present-day. The limited Holocene retreat of glaciers in Køge Bugt was controlled by the subglacial topography of the area; the steeply sloping bed allowed glaciers here to stabilise during retreat. These findings underscore the need to account for individual glacier geometry when predicting future behaviour. We anticipate that glaciers in Køge Bugt will remain in stable configurations in the near-future, despite the predicted continuation of atmospheric and oceanic warming

Design of Experiments for Screening

The aim of this paper is to review methods of designing screening experiments, ranging from designs originally developed for physical experiments to those especially tailored to experiments on numerical models. The strengths and weaknesses of the various designs for screening variables in numerical models are discussed. First, classes of factorial designs for experiments to estimate main effects and interactions through a linear statistical model are described, specifically regular and nonregular fractional factorial designs, supersaturated designs and systematic fractional replicate designs. Generic issues of aliasing, bias and cancellation of factorial effects are discussed. Second, group screening experiments are considered including factorial group screening and sequential bifurcation. Third, random sampling plans are discussed including Latin hypercube sampling and sampling plans to estimate elementary effects. Fourth, a variety of modelling methods commonly employed with screening designs are briefly described. Finally, a novel study demonstrates six screening methods on two frequently-used exemplars, and their performances are compared

Isomer Spectroscopy of Neutron-rich 165,167Tb

Open Access JournalWe present information on the excited states in the prolate-deformed, neutron-rich nuclei 165;167Tb100;102. The nuclei of interest were synthesized following in-flight fission of a 345 MeV per nucleon 238U primary beam on a 2 mm 9Be target at the Radioactive Ion-Beam Factory (RIBF), RIKEN, Japan. The exotic nuclei were separated and identified event-by-event using the BigRIPS separator, with discrete energy gamma-ray decays from isomeric states with half-lives in the _s regime measured using the EURICA gamma-ray spectrometer. Metastable-state decays are identified in 165Tb and 167Tb and interpreted as arising from hindered E1 decay from the 7/2-[523] single quasi-proton Nilsson configuration to rotational states built on the 3/2-[411] single quasi-proton ground state. These data correspond to the first spectroscopic information in the heaviest, odd-A terbium isotopes reported to date and provide information on proton Nilsson configurations which reside close to the Fermi surface as the 170Dy doubly-midshell nucleus is approached.postprin

Regulators of genetic risk of breast cancer identified by integrative network analysis.

Genetic risk for breast cancer is conferred by a combination of multiple variants of small effect. To better understand how risk loci might combine, we examined whether risk-associated genes share regulatory mechanisms. We created a breast cancer gene regulatory network comprising transcription factors and groups of putative target genes (regulons) and asked whether specific regulons are enriched for genes associated with risk loci via expression quantitative trait loci (eQTLs). We identified 36 overlapping regulons that were enriched for risk loci and formed a distinct cluster within the network, suggesting shared biology. The risk transcription factors driving these regulons are frequently mutated in cancer and lie in two opposing subgroups, which relate to estrogen receptor (ER)(+) luminal A or luminal B and ER(-) basal-like cancers and to different luminal epithelial cell populations in the adult mammary gland. Our network approach provides a foundation for determining the regulatory circuits governing breast cancer, to identify targets for intervention, and is transferable to other disease settings.This work was funded by Cancer Research UK and the Breast Cancer Research Foundation. MAAC is funded by the National Research Council (CNPq) of Brazil. TEH held a fellowship from the US DOD Breast Cancer Research Program (W81XWH-11-1-0592) and is currently supported by an RAH Career Development Fellowship (Australia). TEH and WDT are funded by the NHMRC of Australia (NHMRC) (ID: 1008349 WDT; 1084416 WDT, TEH) and Cancer Australia/National Breast Cancer Foundation (ID 627229; WDT, TEH). BAJP is a Gibb Fellow of Cancer Research UK. We would like to acknowledge the support of The University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.345