Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion

Endocrine therapies target the activation of the oestrogen receptor alpha (ERα) via distinct mechanisms, but it is not clear whether breast cancer cells can adapt to treatment using drug-specific mechanisms. Here we demonstrate that resistance emerges via drug-specific epigenetic reprogramming. Resistant cells display a spectrum of phenotypical changes with invasive phenotypes evolving in lines resistant to the aromatase inhibitor (AI). Orthogonal genomics analysis of reprogrammed regulatory regions identifies individual drug-induced epigenetic states involving large topologically associating domains (TADs) and the activation of super-enhancers. AI-resistant cells activate endogenous cholesterol biosynthesis (CB) through stable epigenetic activation in vitro and in vivo. Mechanistically, CB sparks the constitutive activation of oestrogen receptors alpha (ERα) in AI-resistant cells, partly via the biosynthesis of 27-hydroxycholesterol. By targeting CB using statins, ERα binding is reduced and cell invasion is prevented. Epigenomic-led stratification can predict resistance to AI in a subset of ERα-positive patients

The impact of trained patient educators on musculoskeletal clinical skills attainment in pre-clerkship medical students

<p>Abstract</p> <p>Background</p> <p>Despite the high burden of musculoskeletal (MSK) diseases, few generalists are comfortable teaching MSK physical examination (PE) skills. Patient Partners^®in Arthritis (PP^®IA) is a standardized patient educator program that could potentially supplement current MSK PE teaching. This study aims to determine if differences exist in MSK PE skills between non-MSK specialist physician and PP^®IA taught students.</p> <p>Methods</p> <p>Pre-clerkship medical students attended 2-hour small group MSK PE teaching by either non-MSK specialist physician tutors or by PP^®IA. All students underwent an MSK OSCE and completed retrospective pre-post questionnaires regarding comfort with MSK PE and interest in MSK.</p> <p>Results</p> <p>83 students completed the OSCE (42 PP^®IA, 41 physician taught) and 82 completed the questionnaire (42 PP^®IA, 40 physician taught). There were no significant differences between groups in OSCE scores. For all questionnaire items, post-session ratings were significantly higher than pre-session ratings for both groups. In exploratory analysis PP^®IA students showed significantly greater improvement in 12 of 22 questions including three of five patient-centred learning questions.</p> <p>Conclusions</p> <p>PP^®IA MSK PE teaching is as good as non-MSK specialist physician tutor teaching when measured by a five station OSCE and provide an excellent complementary resource to address current deficits in MSK PE teaching.</p

Effects of American ginseng (Panax quinquefolius) on neurocognitive function: an acute, randomised, double-blind, placebo-controlled, crossover study

Over the last decade, Asian ginseng (Panax ginseng) has been shown to improve aspects of human cognitive function. American ginseng (Panax quinquefolius) has a distinct ginsenoside profile from P. ginseng, promising cognitive enhancing properties in preclinical studies and benefits processes linked to human cognition. The availability of a highly standardised extract of P. quinquefolius (Cereboost (TM)) led us to evaluate its neurocognitive properties in humans for the first time. This randomised, double-blind, placebo-controlled, crossover trial (N = 32, healthy young adults) assessed the acute mood, neurocognitive and glycaemic effects of three doses (100, 200 400 mg) of Cereboost (TM) (P. quinquefolius standardised to 10.65% ginsenosides). Participants' mood, cognitive function and blood glucose were measured 1, 3 and 6 h following administration. There was a significant improvement of working memory (WM) performance associated with P. quinquefolius. Corsi block performance was improved by all doses at all testing times. There were differential effects of all doses on other WM tasks which were maintained across the testing day. Choice reaction time accuracy and 'calmness' were significantly improved by 100 mg. There were no changes in blood glucose levels. This preliminary study has identified robust working memory enhancement following administration of American ginseng. These effects are distinct from those of Asian ginseng and suggest that psychopharmacological properties depend critically on ginsenoside profiles. These results have ramifications for the psychopharmacology of herbal extracts and merit further study using different dosing regimens and in populations where cognition is fragile

Measurement of the branching fraction for B−→D0K∗−B^- \to D^0 K^{*-}

We present a measurement of the branching fraction for the decay B- --> D0 K*- using a sample of approximately 86 million BBbar pairs collected by the BaBar detector from e+e- collisions near the Y(4S) resonance. The D0 is detected through its decays to K- pi+, K- pi+ pi0 and K- pi+ pi- pi+, and the K*- through its decay to K0S pi-. We measure the branching fraction to be B.F.(B- --> D0 K*-)= (6.3 +/- 0.7(stat.) +/- 0.5(syst.)) x 10^{-4}

Observation of a significant excess of π0π0\pi^{0}\pi^{0} events in B meson decays

We present an observation of the decay $B^{0} \to \pi^{0} \pi^{0}$ based on a sample of 124 million $B\bar{B}$ pairs recorded by the BABAR detector at the PEP-II asymmetric-energy $B$ Factory at SLAC. We observe $46 \pm 13 \pm 3$ events, where the first error is statistical and the second is systematic, corresponding to a significance of 4.2 standard deviations including systematic uncertainties. We measure the branching fraction \BR(B^{0} \to \pi^{0} \pi^{0}) = (2.1 \pm 0.6 \pm 0.3) \times 10^{-6}, averaged over $B^{0}$ and $\bar{B}^{0}$ decays

Measurements of branching fractions and CP-violating asymmetries in B meson decays to charmless two-body states containing a K-0

We present measurements of branching fractions and CP-violating asymmetries in decays of B mesons to two-body final states containing a K-0. The results are based on a data sample of approximately 88x10(6) Y(4S)-->B (B) over bar decays collected with the BABAR detector at the PEP-II asymmetric-energy B Factory at SLAC. We measure B(B+-->K(0)pi(+))=(22.3+/-1.7+/-1.1)x10(-6), B(B-0-->K(0)pi(0))=(11.4+/-1.7+/-0.8)x10(-6), B(B+-->(K) over bar K-0(+))K-0(K) over bar (0))K(0)pi(+))=-0.05+/-0.08+/-0.01 and A(CP)(B-0-->K(0)pi(0))=0.03+/-0.36+/-0.11

Measurement of the branching fraction for B±→χc0K±

We present preliminary results for the measurement of the branching fraction of the decay B+- -> chi_c0 K+- from a sample of 75 million BB pairs collected by the BABAR detector at the PEP-II asymmetric-energy B Factory at SLAC. The chi_c0 meson is reconstructed through its two-body decays to pi+ pi- and K+ K-. We measure BR(B+- -> chi_c0 K+-) * BR(chi_c0 -> pi+ pi-) = (1.08 +- 0.35 (stat) +- 0.10 (syst))*10^-6 and BR(B+- -> chi_c0 K+-) * BR(chi_c0 -> K+ K-) = (1.48 +- 0.44 (stat) +- 0.17 (syst)) * 10^-6. Using the known values for the chi_c0 decays branching fractions, we combined these results to obtain BR(B+- -> chi_c0 K+-) = (2.4 +- 0.7) * 10^-4

Measurement of the branching fractions and CP asymmetry of B- -> (D(CP)K-)-K-0 decays with the BaBar detector

We present a study of B--->(DCPK-)-K-0 decays, where D-CP(0) is reconstructed in CP-even channels, based on a sample of 88.8x10(6) Y(4S)-->B (B) over bar decays collected with the BABAR detector at the PEP-II e(+)e(-) storage ring. We measure the ratio of Cabibbo-suppressed to Cabibbo-favored branching fractions B(B--->(DCPK-)-K-0)/B(B--->D(CP)(0)pi(-))=[8.8+/-1.6(stat)+/-0.5(syst)]x10(-2) and the CP asymmetry A(CP)=0.07+/-0.17(stat)+/-0.06(syst). We also measure B(B--->(DK-)-K-0)/B(B--->D(0)pi(-))=[8.31+/-0.35(stat)+/-0.20(syst)]x10(-2) using a sample of 61.0x10(6) B (B) over bar pairs

Measurement of the branching fractions and CP asymmetry of B- -> (D(CP)K-)-K-0 decays with the BaBar detector

We present a study of B--->(DCPK-)-K-0 decays, where D-CP(0) is reconstructed in CP-even channels, based on a sample of 88.8x10(6) Y(4S)-->B (B) over bar decays collected with the BABAR detector at the PEP-II e(+)e(-) storage ring. We measure the ratio of Cabibbo-suppressed to Cabibbo-favored branching fractions B(B--->(DCPK-)-K-0)/B(B--->D(CP)(0)pi(-))=[8.8+/-1.6(stat)+/-0.5(syst)]x10(-2) and the CP asymmetry A(CP)=0.07+/-0.17(stat)+/-0.06(syst). We also measure B(B--->(DK-)-K-0)/B(B--->D(0)pi(-))=[8.31+/-0.35(stat)+/-0.20(syst)]x10(-2) using a sample of 61.0x10(6) B (B) over bar pairs.The Particle Physics and Astronomy Research Council (United Kingdom); A. P. Sloan Foundation; the Research Corporation; and the Alexander von Humboldt Foundation