PRC2 Inhibitors Overcome Glucocorticoid Resistance Driven by Mutation in Pediatric Acute Lymphoblastic Leukemia.

Mutations in epigenetic regulators are common in relapsed pediatric acute lymphoblastic leukemia (ALL). Here, we uncovered the mechanism underlying the relapse of ALL driven by an activating mutation of the histone methyltransferase (p.E1099K).

Healthcare practitioner views and experiences of patients self-monitoring blood pressure: a vignette study.

Background: Home self-monitoring of blood pressure is widely used in primary care to assist in the diagnosis of hypertension, as well as to improve clinical outcomes and support adherence to medication. The National Institute for Health and Care Excellence (NICE) care pathways for hypertension recommend specific guidelines, although they lack detail on supporting patients to self-monitor.

Aim: To elicit primary care practitioners' experiences of managing patients' home blood pressure self-monitoring, across surgeries located in different socioeconomic areas.

Negotiating the practical ethics of 'self-tracking' in intimate relationships: Looking for care in healthy living.

In this paper, we offer insights into practices of tracking as part of healthy living through talk about home blood pressure and weight from adults living in the UK. Drawing on theoretical resources from feminist ethics of care and Science and Technology Studies on care as socio-material practice, we build on interest in the relational dimensions of tracking and the potential for intimate surveillance and care using monitoring technologies. Our cases offer not only new perspectives in a field that has often focused on fitness tracking but also help go beyond a narrow focus on surveillance, showing how surveillance and care may be intertwined in the everyday negotiation of health-related tracking and other 'health practices' in family life.

A Mutation in Histone H2B Represents a New Class of Oncogenic Driver.

By examination of the cancer genomics database, we identified a new set of mutations in core histones that frequently recur in cancer patient samples and are predicted to disrupt nucleosome stability. In support of this idea, we characterized a glutamate to lysine mutation of histone H2B at amino acid 76 (H2B-E76K), found particularly in bladder and head and neck cancers, that disrupts the interaction between H2B and H4. Although H2B-E76K forms dimers with H2A, it does not form stable histone octamers with H3 and H4 and when reconstituted with DNA forms unstable nucleosomes with increased sensitivity to nuclease.

An activating mutation of the NSD2 histone methyltransferase drives oncogenic reprogramming in acute lymphocytic leukemia.

NSD2, a histone methyltransferase specific for methylation of histone 3 lysine 36 (H3K36), exhibits a glutamic acid to lysine mutation at residue 1099 (E1099K) in childhood acute lymphocytic leukemia (ALL), and cells harboring this mutation can become the predominant clone in relapsing disease. We studied the effects of this mutant enzyme in silico, in vitro, and in vivo using gene edited cell lines. The E1099K mutation altered enzyme/substrate binding and enhanced the rate of H3K36 methylation.

New General Relativistic Contribution to Mercury's Perihelion Advance.

We point out the existence of a new general relativistic contribution to the perihelion advance of Mercury that, while smaller than the contributions arising from the solar quadrupole moment and angular momentum, is 100 times larger than the second-post-Newtonian contribution. It arises in part from relativistic "crossterms" in the post-Newtonian equations of motion between Mercury's interaction with the Sun and with the other planets, and in part from an interaction between Mercury's motion and the gravitomagnetic field of the moving planets. At a few parts in 10^{6} of the leading general relativistic precession of 42.

UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition.

Loss or inactivation of the histone H3K27 demethylase UTX occurs in several malignancies, including multiple myeloma (MM). Using an isogenic cell system, we found that loss of UTX leads to deactivation of gene expression ultimately promoting the proliferation, clonogenicity, adhesion, and tumorigenicity of MM cells. Moreover, UTX mutant cells showed increased in vitro and in vivo sensitivity to inhibition of EZH2, a histone methyltransferase that generates H3K27me3.

Structure-function relationships for the selective inhibition of human 3β-hydroxysteroid dehydrogenase type 1 by a novel androgen analog.

3β-Hydroxysteroid dehydrogenase type 1 (3β-HSD1) is selectively expressed in human placenta, mammary glands and breast tumors in women. Human 3β-HSD2 is selectively expressed in adrenal glands and ovaries. Based on AutoDock 3 and 4 results, we have exploited key differences in the amino acid sequences of 3β-HSD1 (Ser194, Arg195) and 3β-HSD2 (Gly194, Pro195) by designing a selective inhibitor of 3β-HSD1.

Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape.

Unrestrained receptor tyrosine kinase (RTK) signaling and epigenetic deregulation are root causes of tumorigenesis. We establish linkage between these processes by demonstrating that aberrant RTK signaling unleashed by oncogenic HRas(G12V) or loss of negative feedback through Sprouty gene deletion remodels histone modifications associated with active typical and super-enhancers. However, although both lesions disrupt the Ras-Erk axis, the expression programs, enhancer signatures, and transcription factor networks modulated upon HRas(G12V) transformation or Sprouty deletion are largely distinct.

Histone methyltransferase MMSET/NSD2 alters EZH2 binding and reprograms the myeloma epigenome through global and focal changes in H3K36 and H3K27 methylation.

Overexpression of the histone methyltransferase MMSET in t(4;14)+ multiple myeloma patients is believed to be the driving factor in the pathogenesis of this subtype of myeloma. MMSET catalyzes dimethylation of lysine 36 on histone H3 (H3K36me2), and its overexpression causes a global increase in H3K36me2, redistributing this mark in a broad, elevated level across the genome. Here, we demonstrate that an increased level of MMSET also induces a global reduction of lysine 27 trimethylation on histone H3 (H3K27me3).

The drugs don't sell: DIY heart health and the over-the-counter statin experience.

This paper draws on a study of over-the-counter statins to provide a critical account of the figure of the 'pharmaceutical consumer' as a key actor in the pharmaceuticalisation literature. A low dose statin, promising to reduce cardiovascular risk, was reclassified to allow sale in pharmacies in the UK in 2004. We analysed professional and policy debates about the new product, promotional and sales information, and interviews with consumers and potential consumers conducted between 2008 and 2011, to consider the different consumer identities invoked by these diverse actors.

Sustained multiplicity in everyday cholesterol reduction: repertoires and practices in talk about 'healthy living'.

This article is concerned with talk about and the practices of healthy living in relation to cholesterol reduction. It draws on qualitative interviews with 89 people who are current or former users of either cholesterol-lowering functional foods or statins for cardiovascular risk reduction. Focusing on data about everyday activities including food preparation, shopping and exercise, we illustrate four repertoires that feature in talk about cholesterol reduction (health, pleasure, sociality and pragmatism).

The Confrontation between General Relativity and Experiment.

The status of experimental tests of general relativity and of theoretical frameworks for analyzing them is reviewed and updated. Einstein's equivalence principle (EEP) is well supported by experiments such as the Eötvös experiment, tests of local Lorentz invariance and clock experiments. Ongoing tests of EEP and of the inverse square law are searching for new interactions arising from unification or quantum gravity.

MMSET stimulates myeloma cell growth through microRNA-mediated modulation of c-MYC.

Multiple myeloma (MM) represents the malignant proliferation of terminally differentiated B cells, which, in many cases, is associated with the maintenance of high levels of the oncoprotein c-MYC. Overexpression of the histone methyltransferase MMSET (WHSC1/NSD2), due to t(4;14) chromosomal translocation, promotes the proliferation of MM cells along with global changes in chromatin; nevertheless, the precise mechanisms by which MMSET stimulates neoplasia remain incompletely understood. We found that MMSET enhances the proliferation of MM cells by stimulating the expression of c-MYC at the post-transcriptional level.

On the unreasonable effectiveness of the post-Newtonian approximation in gravitational physics.

The post-Newtonian approximation is a method for solving Einstein's field equations for physical systems in which motions are slow compared to the speed of light and where gravitational fields are weak. Yet it has proven to be remarkably effective in describing certain strong-field, fast-motion systems, including binary pulsars containing dense neutron stars and binary black hole systems inspiraling toward a final merger. The reasons for this effectiveness are largely unknown.

The management of enthusiasm: motives and expectations in cardiovascular medicine.

Debates about appropriate action in medicine often turn on finding the right emotional orientation to new developments. In this article enthusiasm emerges as a key term in a professional 'vocabulary of motive' around innovation, complicating current sociological interest in expectations. The negative associations that adhere to this word among clinical researchers indicate awareness with the difficulty of managing hype and public hopes, but analysis of its use by cardiologists over the past two decades also reveals tension around more specific professional dangers, including 'credulity' and inappropriate activism.

Genetic unexceptionalism: clinician accounts of genetic testing for familial hypercholesterolaemia.

This paper considers the implications of genetic testing in the case of familial hypercholesterolaemia, drawing on twenty semi-structured interviews with general practitioners (family doctors in primary care), nurses and specialists in hospital clinics (secondary care) in the UK. Though these professionals appear aware of and interested in the genetic component of the condition, and DNA testing is underway in at least some centres, their accounts suggest that the genetic test is not having a major impact on clinical work. Instead we find that professionals report that they generally rely on other information when making a diagnosis, especially cholesterol levels understood as a key risk factor, while the results of DNA tests, if used, come late in a much longer series of clinical investigations, judgements and interventions.

Carter-like constants of the motion in Newtonian gravity and electrodynamics.

For a test body orbiting an axisymmetric body in Newtonian gravitational theory with mass m and multiple moments Q_{l} (and for a charge in orbit about a charge distribution with the same multipole moments) we show that there exists, in addition to the energy and angular momentum component along the symmetry axis, a conserved quantity analogous to the Carter constant of Kerr spacetimes for rotating black holes in general relativity, if the odd-l moments vanish, and the even-l moments satisfy Q_{2l}=m(Q_{2}/m);{l}. Strangely, this is precisely the relation among mass moments enforced by the no-hair theorems of rotating black holes. By contrast, if Newtonian gravity is supplemented by a multipolar gravitomagnetic field, whose leading term represents frame dragging, we are unable to find an analogous Carter-like constant.

The Confrontation between General Relativity and Experiment.

The status of experimental tests of general relativity and of theoretical frameworks for analyzing them is reviewed. Einstein's equivalence principle (EEP) is well supported by experiments such as the Eötvös experiment, tests of special relativity, and the gravitational redshift experiment. Ongoing tests of EEP and of the inverse square law are searching for new interactions arising from unification or quantum gravity.

Arguing about the evidence: readers, writers and inscription devices in coronary heart disease risk assessment.

This paper examines the history of tools developed to assess an individual's risk of coronary heart disease. A close reading of the tools themselves is combined with an analysis of debates published in medical journals such as the British Medical Journal (BMJ) and The Lancet. These literary conversations between scientists and doctors reveal complex negotiations about the form and meaning of medical technologies that have yet to become fully 'stable'.