bluuebunny/crossref_metadata_2025 huggingface dataset:
Zambian Peer Educators for HIV Self-Testing (ZEST) study: rationale and design of a cluster randomised trial of HIV self-testing among female sex workers in Zambia
Authors: Oldenburg Catherine E , Ortblad Katrina F , Chanda Michael M , Mwanda Kalasa , Nicodemus Wendy , Sikaundi Rebecca , Fullem Andrew , Barresi Leah G , Harling Guy , Bärnighausen Till
Published: April 2017

Background

HIV testing and knowledge of status are starting points for HIV treatment and prevention interventions. Among female sex workers (FSWs), HIV testing and status knowledge remain far from universal. HIV self-testing (HIVST) is an alternative to existing testing services for FSWs, but little evidence exists how it can be effectively and safely implemented. Here, we describe the rationale and design of a cluster randomised trial designed to inform implementation and scale-up of HIVST programmes for FSWs in Zambia.

Methods

The Zambian Peer Educators for HIV Self-Testing (ZEST) study is a 3-arm cluster randomised trial taking place in 3 towns in Zambia. Participants (N=900) are eligible if they are women who have exchanged sex for money or goods in the previous 1 month, are HIV negative or status unknown, have not tested for HIV in the previous 3 months, and are at least 18 years old. Participants are recruited by peer educators working in their communities. Participants are randomised to 1 of 3 arms: (1) direct distribution (in which they receive an HIVST from the peer educator directly); (2) fixed distribution (in which they receive a coupon with which to collect the HIVST from a drug store or health post) or (3) standard of care (referral to existing HIV testing services only, without any offer of HIVST). Participants are followed at 1 and 4 months following distribution of the first HIVST. The primary end point is HIV testing in the past month measured at the 1-month and 4-month visits.

Ethics and dissemination

This study was approved by the Institutional Review Boards at the Harvard T.H. Chan School of Public Health in Boston, USA and ERES Converge in Lusaka, Zambia. The findings of this trial will be presented at local, regional and international meetings and submitted to peer-reviewed journals for publication.

Trial registration number

Pre-results;NCT02827240.
Thematic analysis of US stakeholder views on the influence of labour nurses’ care on birth outcomes
Authors: Lyndon Audrey , Simpson Kathleen Rice , Spetz Joanne
Published: April 2017

Background

Childbirth is a leading reason for hospital admission in the USA, and most labour care is provided by registered nurses under physician or midwife supervision in a nurse-managed care model. Yet, there are no validated nurse-sensitive quality measures for maternity care. We aimed to engage primary stakeholders of maternity care in identifying the aspects of nursing care during labour and birth they believe influence birth outcomes, and how these aspects of care might be measured.

Methods

This qualitative study used 15 focus groups to explore perceptions of 73 nurses, 23 new mothers and 9 physicians regarding important aspects of care. Transcripts were analysed thematically. Participants in the final six focus groups were also asked whether or not they thought each of five existing perinatal quality measures were nurse-sensitive.

Results

Nurses, new mothers and physicians identified nurses' support of and advocacy for women as important to birth outcomes. Support and advocacy actions included keeping women and their family members informed, being present with women, setting the emotional tone, knowing and advocating for women's wishes and avoiding caesarean birth. Mothers and nurses took technical aspects of care for granted, whereas physicians discussed this more explicitly, noting that nurses were their ‘eyes and ears’ during labour. Participants endorsed caesarean rates and breastfeeding rates as likely to be nurse-sensitive.

Conclusions

Stakeholder values support inclusion of maternity nursing care quality measures related to emotional support and providing information in addition to physical support and clinical aspects of care. Care models that ensure labour nurses have sufficient time and resources to engage in the supportive relationships that women value might contribute to better health outcomes and improved patient experience.
Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner
Authors: Trivedi Palak J , Tickle Joseph , Vesterhus Mette Nåmdal , Eddowes Peter J , Bruns Tony , Vainio Jani , Parker Richard , Smith David , Liaskou Evaggelia , Thorbjørnsen Liv Wenche , Hirschfield Gideon M , Auvinen Kaisa , Hubscher Stefan G , Salmi Marko , Adams David H , Weston Chris J
Published: April 2017

Objective

Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of IBD. This clinical association is linked pathologically to the recruitment of mucosal T cells to the liver, via vascular adhesion protein (VAP)-1-dependent enzyme activity. Our aim was to examine the expression, function and enzymatic activation of the ectoenzyme VAP-1 in patients with PSC.

Design

We examined VAP-1 expression in patients with PSC, correlated levels with clinical characteristics and determined the functional consequences of enzyme activation by specific enzyme substrates on hepatic endothelium.

Results

The intrahepatic enzyme activity of VAP-1 was elevated in PSC versus immune-mediated disease controls and non-diseased liver (p<0.001). The adhesion of gut-tropic α4β7+lymphocytes to hepatic endothelial cells in vitro under flow was attenuated by 50% following administration of the VAP-1 inhibitor semicarbazide (p<0.01). Of a number of natural VAP-1 substrates tested, cysteamine—which can be secreted by inflamed colonic epithelium and gut bacteria—was the most efficient (yielded the highest enzymatic rate) and efficacious in its ability to induce expression of functional mucosal addressin cell adhesion molecule-1 on hepatic endothelium. In a prospectively evaluated patient cohort with PSC, elevated serum soluble (s)VAP-1 levels predicted poorer transplant-free survival for patients, independently (HR: 3.85, p=0.003) and additively (HR: 2.02, p=0.012) of the presence of liver cirrhosis.

Conclusions

VAP-1 expression is increased in PSC, facilitates adhesion of gut-tropic lymphocytes to liver endothelium in a substrate-dependent manner, and elevated levels of its circulating form predict clinical outcome in patients.
Characterisation of GATA3 expression in invasive breast cancer: differences in histological subtypes and immunohistochemically defined molecular subtypes
Authors: Shaoxian Tang , Baohua Yu , Xiaoli Xu , Yufan Cheng , Xiaoyu Tu , Hongfen Lu , Rui Bi , Xiangjie Sun , Ruohong Shui , Wentao Yang
Published: April 2017

Aims

GATA-binding protein 3 (GATA3) is a sensitive and relatively specific marker in breast and urothelial carcinomas. Its diagnostic utility in primary and metastatic breast cancers has been explored and confirmed. However, the relationship between GATA3 expression and different breast carcinoma intrinsic subtypes has not been specifically defined in the literature despite a few reports with a small number of cases. The aim of the current investigation is to clarify GATA3 expression among different histological subtypes and surrogate molecular breast carcinoma subtypes in a large series of cases.

Methods

Immunohistochemical staining of GATA3, GCDFP15 and mammaglobin was performed in a cohort of 1637 cases of primary invasive breast carcinoma. The association of GATA3 expression with different histological and surrogate intrinsic subtypes was assessed and compared with the expression of GCDFP15 and mammaglobin.

Results

The overall positivity of GATA3 across the various immunohistochemistry-based surrogate intrinsic subtypes was 99.51% for luminal A-like, 97.70% for luminal B-like, 68.50% for HER2 overexpression and 20.16% for triple negative breast cancers. GATA3 expression was positively correlated with estrogen receptor (ER)-positive (luminal subtypes) breast carcinomas. For luminal-like and HER2 overexpression subtypes, GATA3 was much more sensitive than GCDFP15 and mammaglobin. For triple negative tumours, GATA3 was less sensitive than GCDFP15.

Conclusions

GATA3 exhibits a relatively high sensitivity for breast carcinomas. It is more sensitive than GCDFP15 and mammaglobin in luminal-like and HER2 overexpression subtypes. GATA3 expression is associated with breast carcinomas of luminal subtype and low histological grade.
Factual text and emotional pictures: overcoming a false dichotomy of cigarette warning labels
Authors: Popova Lucy , Owusu Daniel , Jenson Desmond , Neilands Torsten B
Published: April 2017

Background

In reviewing the first set of pictorial warning labels in the USA, the courts equated textual labels with facts and information, and images with emotion. This study tested the differences in perceived informativeness and emotion between textual and pictorial cigarette warning labels.

Methods

An online study with 1838 US adults who were non-smokers (n=764), transitioning smokers (quit smoking in the past 2 years or currently trying to quit, n=505) or current smokers (n=569). Each participant evaluated 9 out of 81 text and pictorial cigarette warning labels. Participants reported to what extent they perceived the label as informative and factual and the negative emotions they felt while looking at each label. We used linear mixed models to account for the nesting of multiple observations within each participant.

Results

There were no significant differences in perceived informativeness between textual (mean 6.15 on a 9-point scale) and pictorial labels (6.14, p=0.80, Cohen’s d=0.003). Textual labels evoked slightly less emotion (4.21 on a 9-point scale) than pictorial labels (4.42, p<0.001, Cohen’s d=0.08). Perceived informativeness and emotion were strongly correlated (Pearson r=0.53, p<0.001).

Conclusion

Our findings contradict courts’ conclusions that pictorial messages are emotional and not factual. Pictorial labels are rated as informative and factual, textual labels evoke emotion, and emotionality and informativeness are strongly correlated. These findings serve as evidence for the Food and Drug Administration (FDA) to counteract the claim that pictorial warning labels, by definition, are not ‘purely factual and uncontroversial’.
Career‐long support that starts with new graduates
Authors: Mackintosh Darren
Published: April 2017

Armed with the knowledge that newly qualified vets want a clinical mentor and surgical support in their first job, Independent Vetcare set up its two‐year Graduate Academy. Operations manager Darren Mackintosh describes how it works
Exact solutions of a two-dimensional Duffin–Kemmer–Petiau oscillator subject to a Coulomb potential in the gravitational field of cosmic string
Authors: Boumali Abdelmalek , Messai Nadjette
Published: April 2017

In this paper, the problem of a two-dimensional Duffin–Kemmer–Petiau (DKP) oscillator in the presence of a Coulomb potential in the cosmic string background is solved. The eigensolutions of the problem in question have been found, and the influence of the Coulomb potential in the presence of the gravitational field of cosmic string has been analyzed.
K-semistable Fano manifolds with the smallest alpha invariant
Authors: Jiang Chen
Published: April 2017

In this paper, we show that K-semistable Fano manifolds with the smallest alpha invariant are projective spaces. Singular cases are also investigated.
The birational geometry of unramified irregular Higgs bundles on curves
Authors: Szabó Szilárd
Published: April 2017

We give a variant of the Beauville–Narasimhan–Ramanan correspondence for irregular parabolic Higgs bundles on smooth projective curves with fixed semi-simple irregular part and show that it defines a Poisson isomorphism between certain irregular Dolbeault moduli spaces and relative Picard bundles of families of ruled surfaces over the curve.
Generating luminous and dark matter during inflation
Authors: Barrie Neil D. , Kobakhidze Archil
Published: April 2017

We propose a new mechanism for generating both luminous and dark matter during cosmic inflation. According to this mechanism, ordinary and dark matter carry common charge which is associated with an anomalous U(1)[Formula: see text] group. Anomaly terms source [Formula: see text] and U(1)[Formula: see text] charge violating processes during inflation, producing corresponding nonzero Chern–Simons numbers which are subsequently reprocessed into baryon and dark matter densities. The general framework developed is then applied to two possible extensions of the Standard Model with anomalous gauged [Formula: see text] and [Formula: see text], each with an additional dark matter candidate. In each scenario, we consider the parameter choices that predict the correct dark matter to baryonic matter density ratio and baryon asymmetry. Interestingly, under these conditions, for the U(1)[Formula: see text] extension we obtain a prediction for the mass of the dark matter candidate which is independent of the other choice of parameters, when assuming an [Formula: see text] and [Formula: see text].
Thermodynamics and emergent universe
Authors: Ghosh Saumya , Gangopadhyay Sunandan
Published: April 2017

We show that in the isentropic scenario, the first-order thermodynamical particle creation model gives an emergent universe solution even when the chemical potential is nonzero. However, there exists no emergent universe scenario in the second-order non-equilibrium theory for the particle creation model. We then point out a correspondence between the particle creation model with barotropic equation of state and the equation of state giving rise to an emergent universe without particle creation in spatially flat FRW cosmology.
Finite-difference method applied for eight-band kp model for Hg1−xCdxTe/HgTe quantum well
Authors: Marchewka Michał
Published: April 2017

In this work the finite-difference method (FDM) is presented for the undoped Hg[Formula: see text]CdxTe/HgTe quantum well (QW) which allows to calculate the band structures based on Kane’s 8 × 8 kp model including all second-order terms representing the remote-band contributions. In particular the common central-difference form is employed in the discretization procedure. The FDM is applied in the envelope function approach (EFA) for the [001]-oriented system for two cases: without a magnetic field ([Formula: see text] = 0) and with a magnetic field perpendicular to the layer ([Formula: see text]). A proposed presented method can solve all the states simultaneously and can be used for a wide range of temperatures and widths of QW for different values of [Formula: see text] for Hg[Formula: see text]CdxTe/HgTe QW as well as for more complex structures, e.g., asymmetric QW, double quantum wells (DQWs), multiple quantum wells (MQWs) and for the so-called 3D topological insulator with a strained HgTe layer. The results obtained by this method are in a complete agreement with the previous ones. Based on that it is shown that the different [Formula: see text]–Cd compounds in the barrier as well as in the QW make the critical width different than 6.4 nm for HgTe QW. What is also very interesting from the application point of view of the strained mixed HgCdTe QW is that for a different width and a different mismatch lattice it is possible to observe the influence of the upper and lower parts of the Dirac cone in, e.g., a magneto-transport experiment.
Incoherently coupled photorefractive spatial solitons supported by pyroelectric effects
Authors: Katti Aavishkar , Yadav R. A.
Published: April 2017

A theory for predicting the existence of incoherently coupled spatial soliton pairs due to solely the pyroelectric effect in nonphotovoltaic–photorefractive crystals with an appreciable pyroelectric coefficient is presented. The bright–bright, dark–dark, gray–gray, and bright–dark soliton pairs are shown to exist. These soliton pairs are established if the incident beams propagate collinearly and have the same polarization and wavelength but are mutually incoherent. The magnitude of temperature change of the crystal and the incident beams’ intensity profoundly affect these soliton pairs.
Studies on growth and characterization of nicotinium tartrate single crystal: An efficient organic nonlinear optical material
Authors: Alexandar A. , Lakshmanan A. , Sakthy Priya S. , Surendran P. , Rameshkumar P. , Antony Arockiaraj M.
Published: April 2017

Organic single crystal of nicotinium tartrate (NT), an efficient nonlinear optical (NLO) material for frequency conversion, has been grown at a constant temperature at 40[Formula: see text]C within a period of 20 days by slow evaporation solution technique (SEST). Structural information and lattice dimensions were determined using powder X-ray diffractometer (PXRD) analysis. The functional groups and vibrational frequencies were identified using FTIR spectrum analysis with the range of 4000–450[Formula: see text]cm[Formula: see text]. Mechanical properties of the grown crystal were studied using Vickers microhardness tester. The optical properties of grown crystal were investigated using UV–Vis NIR spectrum analysis and it is confirmed that the crystal has very low absorption in the entire visible region. The dislocations and defects were studied by photoluminescence spectrum. The crystal has single stage melting, which was observed at 180[Formula: see text]C and there was no decomposition before its melting point. Piezoelectric, photoconductivity and chemical etching analysis have also been performed on the grown NT single crystals and the observed results were discussed. Nonlinear optical property of the material was measured using the powder Kurtz–Perry technique.
Optical properties of one-dimensional defective photonic crystal containing nanocomposite material
Authors: Aly Arafa H. , Elsayed Hussein A. , Malek Christina
Published: April 2017

We have obtained the optical properties of one-dimensional defective photonic crystals containing nanocomposite materials of Ag as a defect layer in UV region; the permittivity of nanocomposite materials depends on plasmon frequency of metal nanoparticles. Our analysis is based on the fundamentals of the transfer matrix method. We have investigated the effect of many parameters such as metal thickness, volume fraction, and defected dielectric materials on the intensity of a defect layer.
Charge transport in LiNbO3-based heterostructures
Authors: Sumets M.
Published: April 2017

Successful application of the LiNbO3-based heterostructures in the integrated electronics and optoelectronics is mostly determined by the charge transport phenomenon in the LiNbO3 since this affects their basic parameters. Depending on the particular conditions (temperature, applied field, properties of LiNbO3/substrate heterojunction, etc.), various conduction mechanisms occur simultaneously and primarily, they can be divided into two major groups: contact-limited and bulk-limited. Identification and study of the charge transport mechanisms allow deriving the vital physical properties such as the barrier height at LiNbO3 film/substrate interface, charged defect concentration, traps spacing as well as type and drift mobility of the carriers in the LiNbO3 films. In this paper, the conduction mechanisms in LiNbO3-based heterostructures are discussed in detail and electrical parameters are derived.
e-Symmetric rings
Authors: Meng Fanyun , Wei Junchao
Published: April 2017

Let [Formula: see text] be a ring and [Formula: see text] an idempotent of [Formula: see text], [Formula: see text] is called an [Formula: see text]-symmetric ring if [Formula: see text] implies [Formula: see text] for all [Formula: see text]. Obviously, [Formula: see text] is a symmetric ring if and only if [Formula: see text] is a [Formula: see text]-symmetric ring. In this paper, we show that a ring [Formula: see text] is [Formula: see text]-symmetric if and only if [Formula: see text] is left semicentral and [Formula: see text] is symmetric. As an application, we show that a ring [Formula: see text] is left min-abel if and only if [Formula: see text] is [Formula: see text]-symmetric for each left minimal idempotent [Formula: see text] of [Formula: see text]. We also introduce the definition of strongly [Formula: see text]-symmetric ring and prove that [Formula: see text] is a strongly [Formula: see text]-symmetric ring if and only if [Formula: see text] and [Formula: see text] is a symmetric ring. Finally, we introduce [Formula: see text]-reduced ring and study some properties of it.
Chernoff approximation of subordinate semigroups
Authors: Butko Yana A.
Published: April 2017

This note is devoted to the approximation of evolution semigroups generated by some Markov processes and hence to the approximation of transition probabilities of these processes. The considered semigroups correspond to processes obtained by subordination (i.e. by a time-change) of some original (parent) Markov processes with respect to some subordinators, i.e. Lévy processes with a.s. increasing paths (they play the role of the new time). If the semigroup, corresponding to a parent Markov process, is not known explicitly then neither the subordinate semigroup, nor even the generator of the subordinate semigroup are known explicitly too. In this note, some (Chernoff) approximations are constructed for subordinate semigroups (in the case when subordinators have either known transitional probabilities, or known and bounded Lévy measure) under the condition that the parent semigroups are not known but are already Chernoff-approximated. As it has been shown in the recent literature, this condition is fulfilled for several important classes of Markov processes. This fact allows, in particular, to use the constructed Chernoff approximations of subordinate semigroups, in order to approximate semigroups corresponding to subordination of Feller processes and (Feller type) diffusions in Euclidean spaces, star graphs and Riemannian manifolds. Such approximations can be used for direct calculations and simulation of stochastic processes. The method of Chernoff approximation is based on the Chernoff theorem and can be interpreted also as a construction of Markov chains approximating a given Markov process and as the numerical path integration method of solving the corresponding PDE/SDE.
Wide subcategories of finitely generated Λ-modules
Authors: Marcos Eduardo N. , Mendoza Octavio , Sáenz Corina , Santiago Valente
Published: April 2017

We explore some properties of wide subcategories of the category [Formula: see text] of finitely generated left [Formula: see text]-modules, for some artin algebra [Formula: see text] In particular we look at wide finitely generated subcategories and give a connection with the class of standard modules and standardly stratified algebras. Furthermore, for a wide class [Formula: see text] in [Formula: see text] we give necessary and sufficient conditions to see that [Formula: see text] for some projective [Formula: see text]-module [Formula: see text] and finally, a connection with ring epimorphisms is given.
Highly Solar-Reflective Litchis-Like Core-Shell HGM/TiO2 Microspheres Synthesized by Controllable Heterogeneous Precipitation Method
Authors: Jin Hu , Xu Dehua , Li Jingling , Wang Kelai , Bi Zhuoneng , Xu Gang , Xu Xueqing
Published: April 2017

Hollow glass microsphere (HGM)/TiO2 core-shell structural composites have promising applications in the field of energy efficient solar-reflective paints. In this work, after pretreated with saturated Ca(OH)2 solutions, litchis-like TiO2 shells have been successfully synthesized on HGMs via a controllably heterogeneous precipitation method with Titanium (IV) sulfate (Ti(SO[Formula: see text] and urea as reaction precursors. It is emphasized that the use of urea as the precipitating agent is essential for the heterogeneous nucleation and growth of Ti(OH)4 on HGMs, while the Ca(OH)2 pretreatment provides the heterogeneous nucleation sites on HGMs which promotes the nucleation and growth of Ti(OH)4, and gives rise to large secondary Ti(OH)4 particles, leading to the formation of litchis-like TiO2 shells. The resulted core-shell structural HGM/TiO2 microspheres exhibited highest solar reflectance of [Formula: see text]83%.
SSAGA
Authors: Saha Shamik , Basu Prabal , Rajamanikkam Chidhambaranathan , Bal Aatreyi , Chakraborty Koushik , Roy Sanghamitra
Published: April 2017

The emergence of GPGPU applications, bolstered by flexible GPU programming platforms, has created a tremendous challenge in maintaining high energy efficiency in modern GPUs. In this article, we demonstrate that customizing a Streaming Multiprocessor (SM) of a GPU at a lower frequency is significantly more energy efficient compared to employing DVFS on an SM designed for a high-frequency operation. Using a system-level CAD technique, we propose
SSAGA—Streaming Multiprocessors Synthesized for Asymmetric GPGPU Applications
—an energy-efficient GPU design paradigm. SSAGA creates architecturally identical SM cores, customized for different voltage-frequency domains. Our rigorous cross-layer methodology demonstrates an average of 20% improvement in energy efficiency over a spatially multitasking GPU across a range of GPGPU applications.
Imaging and modeling of acute pressure-induced changes of collagen and elastin microarchitectures in pig and human resistance arteries
Authors: Bloksgaard Maria , Leurgans Thomas M. , Spronck Bart , Heusinkveld Maarten H. G. , Thorsted Bjarne , Rosenstand Kristoffer , Nissen Inger , Hansen Ulla M. , Brewer Jonathan R. , Bagatolli Luis A. , Rasmussen Lars M. , Irmukhamedov Akhmadjon , Reesink Koen D. , De Mey Jo G. R.
Published: April 2017

The impact of disease-related changes in the extracellular matrix (ECM) on the mechanical properties of human resistance arteries largely remains to be established. Resistance arteries from both pig and human parietal pericardium (PRA) display a different ECM microarchitecture compared with frequently used rodent mesenteric arteries. We hypothesized that the biaxial mechanics of PRA mirror pressure-induced changes in the ECM microarchitecture. This was tested using isolated pig PRA as a model system, integrating vital imaging, pressure myography, and mathematical modeling. Collagenase and elastase digestions were applied to evaluate the load-bearing roles of collagen and elastin, respectively. The incremental elastic modulus linearly related to the straightness of adventitial collagen fibers circumferentially and longitudinally (both R2 ≥ 0.99), whereas there was a nonlinear relationship to the internal elastic lamina elastin fiber branching angles. Mathematical modeling suggested a collagen recruitment strain (means ± SE) of 1.1 ± 0.2 circumferentially and 0.20 ± 0.01 longitudinally, corresponding to a pressure of ~40 mmHg, a finding supported by the vital imaging. The integrated method was tested on human PRA to confirm its validity. These showed limited circumferential distensibility and elongation and a collagen recruitment strain of 0.8 ± 0.1 circumferentially and 0.06 ± 0.02 longitudinally, reached at a distending pressure below 20 mmHg. This was confirmed by vital imaging showing negligible microarchitectural changes of elastin and collagen upon pressurization. In conclusion, we show here, for the first time in resistance arteries, a quantitative relationship between pressure-induced changes in the extracellular matrix and the arterial wall mechanics. The strength of the integrated methods invites for future detailed studies of microvascular pathologies.

NEW & NOTEWORTHY This is the first study to quantitatively relate pressure-induced microstructural changes in resistance arteries to the mechanics of their wall. Principal findings using a pig model system were confirmed in human arteries. The combined methods provide a strong tool for future hypothesis-driven studies of microvascular pathologies.
MK5 haplodeficiency attenuates hypertrophy and preserves diastolic function during remodeling induced by chronic pressure overload in the mouse heart
Authors: Nawaito Sherin Ali , Dingar Dharmendra , Sahadevan Pramod , Hussein Bahira , Sahmi Fatiha , Shi Yanfen , Gillis Marc-Antoine , Gaestel Matthias , Tardif Jean-Claude , Allen Bruce G.
Published: April 2017

MAPK-activated protein kinase-5 (MK5) is a protein serine/threonine kinase that is activated by p38 MAPK and the atypical MAPKs ERK3 and ERK4. The physiological function(s) of MK5 remains unknown. Here, we examined the effect of MK5 haplodeficiency on cardiac function and myocardial remodeling. At 12 wk of age, MK5 haplodeficient mice (MK5+/−) were smaller than age-matched wild-type littermates (MK5+/+), with similar diastolic function but reduced systolic function. Transverse aortic constriction (TAC) was used to induce chronic pressure overload in 12-wk-old male MK5+/− and MK5+/+ mice. Two weeks post-TAC, heart weight-to-tibia length ratios were similarly increased in MK5+/− and MK5+/+ hearts, as was the abundance of B-type natriuretic peptide and β-myosin heavy chain mRNA. Left ventricular ejection fraction was reduced in both MK5+/+ and MK5+/− mice, whereas regional peak systolic tissue velocities were reduced and isovolumetric relaxation time was prolonged in MK5+/+ hearts but not in MK5+/− hearts. The TAC-induced increase in collagen type 1-α1 mRNA observed in MK5+/+ hearts was markedly attenuated in MK5+/− hearts. Eight weeks post-TAC, systolic function was equally impaired in MK5+/+ and MK5+/− mice. In contrast, the increase in E wave deceleration rate and progression of hypertrophy observed in TAC MK5+/+ mice were attenuated in TAC MK5+/− mice. MK5 immunoreactivity was detected in adult fibroblasts but not in myocytes. MK5+/+, MK5+/−, and MK5−/− fibroblasts all expressed α-smooth muscle actin in culture. Hence, reduced MK5 expression in cardiac fibroblasts was associated with the attenuation of both hypertrophy and development of a restrictive filling pattern during myocardial remodeling in response to chronic pressure overload.

NEW & NOTEWORTHY MAPK-activated protein kinase-5 (MK5)/p38-regulated/activated protein kinase is a protein serine/threonine kinase activated by p38 MAPK and/or the atypical MAPKs ERK3 and ERK4. MK5 immunoreactivity was detected in adult ventricular fibroblasts but not in myocytes. MK5 haplodeficiency attenuated the progression of hypertrophy, reduced collagen type 1 mRNA, and protected diastolic function in response to chronic pressure overload.
Increased amplitude of inward rectifier K+ currents with advanced age in smooth muscle cells of murine superior epigastric arteries
Authors: Hayoz Sebastien , Pettis Jessica , Bradley Vanessa , Segal Steven S. , Jackson William F.
Published: April 2017

Inward rectifier K+ channels (KIR) may contribute to skeletal muscle blood flow regulation and adapt to advanced age. Using mouse abdominal wall superior epigastric arteries (SEAs) from either young (3–6 mo) or old (24–26 mo) male C57BL/6 mice, we investigated whether SEA smooth muscle cells (SMCs) express functional KIR channels and how aging may affect KIR function. Freshly dissected SEAs were either enzymatically dissociated to isolate SMCs for electrophysiological recording (perforated patch) and mRNA expression or used intact for pressure myography. With 5 mM extracellular K+ concentration ([K+]o), exposure of SMCs to the KIR blocker Ba2+ (100 μM) had no significant effect ( P > 0.05) on whole cell currents elicited by membrane potentials spanning −120 to −30 mV. Raising [K+]o to 15 mM activated Ba2+-sensitive KIR currents between −120 and −30 mV, which were greater in SMCs from old mice than in SMCs from young mice ( P < 0.05). Pressure myography of SEAs revealed that while aging decreased maximum vessel diameter by ~8% ( P < 0.05), it had no significant effect on resting diameter, myogenic tone, dilation to 15 mM [K+]o, Ba2+-induced constriction in 5 mM [K+]o, or constriction induced by 15 mM [K+]o in the presence of Ba2+ ( P > 0.05). Quantitative RT-PCR revealed SMC expression of KIR2.1 and KIR2.2 mRNA that was not affected by age. Barium-induced constriction of SEAs from young and old mice suggests an integral role for KIR in regulating resting membrane potential and vasomotor tone. Increased functional expression of KIR channels during advanced age may compensate for other age-related changes in SEA function.

NEW & NOTEWORTHY Ion channels are integral to blood flow regulation. We found greater functional expression of inward rectifying K+ channels in smooth muscle cells of resistance arteries of mouse skeletal muscle with advanced age. This adaptation to aging may contribute to the maintenance of vasomotor tone and blood flow regulation during exercise.
Functional roles of globin proteins in hypoxia-tolerant ectothermic vertebrates
Authors: Fago Angela
Published: April 2017

Globins are heme-containing proteins ubiquitously expressed in vertebrates, where they serve a broad range of biological functions, directly or indirectly related to the tight control of oxygen levels and its toxic products in vivo. Perhaps the most investigated of all proteins, hemoglobin and myoglobin are primarily involved in oxygen transport and storage, but also in facilitating arterial vasodilation, suppressing mitochondrial respiration, and preventing tissue oxidative damage via accessory redox enzymatic activities during hypoxia. By contrast, the more recently discovered neuroglobin and cytoglobin do not seem to function as reversible oxygen carriers and are instead involved in redox activities, although their exact biological roles remain to be clarified. In this context, hypoxia-tolerant ectotherms, such as freshwater turtles and members of the carp family that survive winter in extreme hypoxia, have proven as excellent models to appreciate the diversity of biological functions of globin proteins. Unraveling physiological roles of globin proteins in these extreme animals will clarify an important part of the adaptive mechanisms for surviving extreme fluctuations of oxygen availability that are prohibitive to mammals.
Low-frequency blood pressure oscillations and inotrope treatment failure in premature infants
Authors: Vesoulis Zachary A. , Hao Jessica , McPherson Christopher , El Ters Nathalie M. , Mathur Amit M.
Published: April 2017

The underlying mechanism as to why some hypotensive preterm infants do not respond to inotropic medications remains unclear. For these infants, we hypothesize that impaired vasomotor function is a significant factor and is manifested through a decrease in low-frequency blood pressure variability across regulatory components of vascular tone. Infants born ≤28 wk estimated gestational age underwent prospective recording of mean arterial blood pressure for 72 h after birth. After error correction, root-mean-square spectral power was calculated for each valid 10-min data frame across each of four frequency bands ( B1, 0.005–0.0095 Hz; B2, 0.0095–0.02 Hz; B3, 0.02–0.06 Hz; and B4, 0.06–0.16) corresponding to different components of vasomotion control. Forty infants (twenty-nine normotensive control and eleven inotrope-exposed) were included with a mean ± SD estimated gestational age of 25.2 ± 1.6 wk and birth weight 790 ± 211 g. 9.7/11.8 Million (82%) data points were error-free and used for analysis. Spectral power across all frequency bands increased with time, although the magnitude was 20% less in the inotrope-exposed infants. A statistically significant increase in spectral power in response to inotrope initiation was noted across all frequency bands. Infants with robust blood pressure response to inotropes had a greater increase compared with those who had limited or no blood pressure response. In this study, hypotensive infants who require inotropes have decreased low-frequency variability at baseline compared with normotensive infants, which increases after inotrope initiation. Low-frequency spectral power does not change for those with inotrope treatment failure, suggesting dysfunctional regulation of vascular tone as a potential mechanism of treatment failure.

NEW & NOTEWORTHY In this study, we examine patterns of low-frequency oscillations in blood pressure variability across regulatory components of vascular tone in normotensive and hypotensive infants exposed to inotropic medications. We found that hypotensive infants who require inotropes have decreased low-frequency variability at baseline, which increases after inotrope initiation. Low-frequency spectral power does not change for those with inotrope treatment failure, suggesting dysfunctional regulation of vascular tone as a potential mechanism of treatment failure.
Interaction between Tumor Cell Surface Receptor RAGE and Proteinase 3 Mediates Prostate Cancer Metastasis to Bone
Authors: Kolonin Mikhail G. , Sergeeva Anna , Staquicini Daniela I. , Smith Tracey L. , Tarleton Christy A. , Molldrem Jeffrey J. , Sidman Richard L. , Marchiò Serena , Pasqualini Renata , Arap Wadih
Published: April 2017

Human prostate cancer often metastasizes to bone, but the biological basis for such site-specific tropism remains largely unresolved. Recent work led us to hypothesize that this tropism may reflect pathogenic interactions between RAGE, a cell surface receptor expressed on malignant cells in advanced prostate cancer, and proteinase 3 (PR3), a serine protease present in inflammatory neutrophils and hematopoietic cells within the bone marrow microenvironment. In this study, we establish that RAGE–PR3 interaction mediates homing of prostate cancer cells to the bone marrow. PR3 bound to RAGE on the surface of prostate cancer cells in vitro, inducing tumor cell motility through a nonproteolytic signal transduction cascade involving activation and phosphorylation of ERK1/2 and JNK1. In preclinical models of experimental metastasis, ectopic expression of RAGE on human prostate cancer cells was sufficient to promote bone marrow homing within a short timeframe. Our findings demonstrate how RAGE–PR3 interactions between human prostate cancer cells and the bone marrow microenvironment mediate bone metastasis during prostate cancer progression, with potential implications for prognosis and therapeutic intervention. Cancer Res; 77(12); 3144–50. ©2017 AACR.
Master Transcriptional Regulators in Cancer: Discovery via Reverse Engineering Approaches and Subsequent Validation
Authors: Moran Bruce , Rahman Arman , Palonen Katja , Lanigan Fiona T. , Gallagher William M.
Published: April 2017

Reverse engineering of transcriptional networks using gene expression data enables identification of genes that underpin the development and progression of different cancers. Methods to this end have been available for over a decade and, with a critical mass of transcriptomic data in the oncology arena having been reached, they are ever more applicable. Extensive and complex networks can be distilled into a small set of key master transcriptional regulators (MTR), genes that are very highly connected and have been shown to be involved in processes of known importance in disease. Interpreting and validating the results of standardized bioinformatic methods is of crucial importance in determining the inherent value of MTRs. In this review, we briefly describe how MTRs are identified and focus on providing an overview of how MTRs can and have been validated for use in clinical decision making in malignant diseases, along with serving as tractable therapeutic targets. Cancer Res; 77(9); 2186–90. ©2017 AACR.
Assessing Prostate Cancer Aggressiveness with Hyperpolarized Dual-Agent 3D Dynamic Imaging of Metabolism and Perfusion
Authors: Chen Hsin-Yu , Larson Peder E.Z. , Bok Robert A. , von Morze Cornelius , Sriram Renuka , Delos Santos Romelyn , Delos Santos Justin , Gordon Jeremy W. , Bahrami Naeim , Ferrone Marcus , Kurhanewicz John , Vigneron Daniel B.
Published: April 2017

New magnetic resonance (MR) molecular imaging techniques offer the potential for noninvasive, simultaneous quantification of metabolic and perfusion parameters in tumors. This study applied a three-dimensional dynamic dual-agent hyperpolarized 13C magnetic resonance spectroscopic imaging approach with 13C-pyruvate and 13C-urea to investigate differences in perfusion and metabolism between low- and high-grade tumors in the transgenic adenocarcinoma of mouse prostate (TRAMP) transgenic mouse model of prostate cancer. Dynamic MR data were corrected for T1 relaxation and RF excitation and modeled to provide quantitative measures of pyruvate to lactate flux (kPL) and urea perfusion (urea AUC) that correlated with TRAMP tumor histologic grade. kPL values were relatively higher for high-grade TRAMP tumors. The increase in kPL flux correlated significantly with higher lactate dehydrogenase activity and mRNA expression of Ldha, Mct1, and Mct4 as well as with more proliferative disease. There was a significant reduction in perfusion in high-grade tumors that associated with increased hypoxia and mRNA expression of Hif1α and Vegf and increased ktrans, attributed to increased blood vessel permeability. In 90% of the high-grade TRAMP tumors, a mismatch in perfusion and metabolism measurements was observed, with low perfusion being associated with increased kPL. This perfusion-metabolism mismatch was also associated with metastasis. The molecular imaging approach we developed could be translated to investigate these imaging biomarkers for their diagnostic and prognostic power in future prostate cancer clinical trials. Cancer Res; 77(12); 3207–16. ©2017 AACR.
PD-L1 Expression in Melanoma: A Quantitative Immunohistochemical Antibody Comparison
Authors: Sunshine Joel C. , Nguyen Peter L. , Kaunitz Genevieve J. , Cottrell Tricia R. , Berry Sneha , Esandrio Jessica , Xu Haiying , Ogurtsova Aleksandra , Bleich Karen B. , Cornish Toby C. , Lipson Evan J. , Anders Robert A. , Taube Janis M.
Published: April 2017

Purpose: PD-L1 expression in the pretreatment tumor microenvironment enriches for response to anti-PD-1/PD-L1 therapies. The purpose of this study was to quantitatively compare the performance of five monoclonal anti-PD-L1 antibodies used in recent landmark publications.

Experimental Design: PD-L1 IHC was performed on 34 formalin-fixed paraffin-embedded archival melanoma samples using the 5H1, SP142, 28-8, 22C3, and SP263 clones. The percentage of total cells (including melanocytes and immune cells) demonstrating cell surface PD-L1 staining, as well as intensity measurements/H-scores, were assessed for each melanoma specimen using a computer-assisted platform. Staining properties were compared between antibodies.

Results: Strong correlations were observed between the percentage of PD-L1(+) cells across all clones studied (R2 = 0.81–0.96). When present, discordant results were attributable to geographic heterogeneity of the melanoma tissue section rather than differences in PD-L1 antibody staining characteristics. PD-L1 intensity/H-scores strongly correlated with percentage of PD-L1(+) cells (R2 > 0.78, all clones).

Conclusions: The 5H1, SP142, 28-8, 22C3, and SP263 clones all demonstrated similar performance characteristics when used in a standardized IHC assay on melanoma specimens. Reported differences in PD-L1 IHC assays using these antibodies are thus most likely due to assay characteristics beyond the antibody itself. Our findings also argue against the inclusion of an intensity/H-score in chromogenic PD-L1 IHC assays. Clin Cancer Res; 23(16); 4938–44. ©2017 AACR.
Selective Glucocorticoid Receptor Modulators (SGRMs) Delay Castrate-Resistant Prostate Cancer Growth
Authors: Kach Jacob , Long Tiha M. , Selman Phillip , Tonsing-Carter Eva Y. , Bacalao Maria A. , Lastra Ricardo R. , de Wet Larischa , Comiskey Shane , Gillard Marc , VanOpstall Calvin , West Diana C. , Chan Wen-Ching , Griend Donald Vander , Conzen Suzanne D. , Szmulewitz Russell Z.
Published: April 2017

Increased glucocorticoid receptor (GR) expression and activity following androgen blockade can contribute to castration-resistant prostate cancer (CRPC) progression. Therefore, we hypothesized that GR antagonism will have therapeutic benefit in CRPC. However, the FDA-approved nonselective, steroidal GR antagonist, mifepristone, lacks GR specificity, reducing its therapeutic potential. Here, we report that two novel nonsteroidal and highly selective GR modulators (SGRM), CORT118335 and CORT108297, have the ability to block GR activity in prostate cancer and slow CRPC progression. In contrast to mifepristone, these novel SGRMs did not affect androgen receptor (AR) signaling, but potently inhibited GR transcriptional activity. Importantly, SGRMs decreased GR-mediated tumor cell viability following AR blockade. In vivo, SGRMs significantly inhibited CRPC progression in high GR–expressing, but not in low GR–expressing xenograft models. Transcriptome analysis following AR blockade and GR activation revealed that these SGRMs block GR-mediated proliferative gene expression pathways. Furthermore, GR-regulated proliferation-associated genes AKAP12, FKBP5, SGK1, CEBPD, and ZBTB16 are inhibited by CORT108297 treatment in vivo. Together, these data suggest that GR-selective nonsteroidal SGRMs potently inhibit GR activity and prostate cancer growth despite AR pathway inhibition, demonstrating the therapeutic potential of SGRMs in GR-expressing CRPC. Mol Cancer Ther; 16(8); 1680–92. ©2017 AACR.
Oral Contraceptives after Bariatric Surgery
Authors: Schlatter Joël
Published: April 2017

Objective: Bariatric surgery offers a highly effective mode of treatment for obese patients. Some procedures such as bypass cause an alteration in normal gastrointestinal tract with possible consequences for the uptake of orally administered drugs. Methods: We assessed the literature to ascertain whether the use of oral drugs and especially oral contraceptives is effective and adequate after bariatric surgery. Results: The bioavailability of drugs could be affected by the solubility and pH of the modified medium after bariatric surgery and by the loss of gastrointestinal transporters. Bariatric surgery could potentially result in a transient change in the absorption of drugs such as analgesics, antibiotics, antiarrhythmics, anticoagulants, psychotropic, and oral contraceptive drugs. Effective contraception is especially critical in the postoperative period, and implants might be representing a safe contraceptive method in women undergoing bariatric surgery. Conclusion: Each drug will have to be evaluated with respect to its site of absorption and its mechanism of absorption, with special attention on parameters influencing the effectiveness of the absorption processes.
In situ Hearing Tests for the Purpose of a Self-Fit Hearing Aid
Authors: Boymans Monique , Dreschler Wouter A.
Published: April 2017

This study investigated the potential and limitations of a self-fit hearing aid. This can be used in the “developing” world or in countries with large distances between the hearing-impaired subjects and the professional. It contains an on-board tone generator for in situ user-controlled, automated audiometry, and other tests for hearing aid fitting. Twenty subjects with mild hearing losses were involved. In situ audiometry showed a test-retest reliability (SD <3.7 dB) that compared well with the precision of diagnostic audiometry using headphones. There was good correspondence (SD <5.2 dB) with traditional pure-tone audiometry. In situ loudness scaling yielded important information about suprathreshold perception, which will have an added value for the selection of compression and the selection of maximum power output to be allowed in hearing aids.