bluuebunny/crossref_metadata_2025 huggingface dataset:
SPECTRUM OF THE EXCITED N* AND Δ* BARYONS IN A RELATIVISTIC CHIRAL QUARK MODEL
Authors: TURSUNOV E. M. , KREWALD S.
Published: January 2014

The spectrum of the SU(2) flavor baryons is studied in the frame of a relativistic chiral quark potential model based on the one-pion and one-gluon exchange mechanisms. All the N* and Δ* resonances appearing in the πN scattering data are identified with the orbital configurations (1S1/2)2(nlj) with a single excited valence quark. The obtained selection rules allow one to construct a schematic periodic table of baryon resonances, consistent with the experimental data and yielding no "missing resonances". A new original method for the center of mass correction problem of the zero-order three-quark core energy values of the excited baryon resonances is suggested, which is based on the separation of the three-quark Dirac Hamiltonian into the parts, corresponding to the Jacobi coordinates. The numerical estimations for the energy positions of the Nucleon and Delta baryons, obtained within the field-theoretical framework, yield an overall good description of the experimental data at a level of the relativized Constituent quark model.
POSSIBLE MOLECULAR STRUCTURES IN THE HEAVY BARYON SPECTRUM
Authors: ENTEM D. R. , ORTEGA P. G. , FERNÁNDEZ F.
Published: January 2014

We use a chiral constituent quark model to study possible molecular structures in the heavy baryon spectrum. We first analyze D*N states and we find a bound state in the JP = 3/2- sector with an small binding energy. This state can be identified with the Λc(2940)+. The decays of this state are compatible with the existent experimental data. As a by product a state is predicted in the bottom baryon spectrum as a [Formula: see text] state with a mass around 6250 MeV. Moreover we also analyze other DN, D*N, DΔ and D*Δ states and their analogs in the bottom baryon sector finding several bound states.
Observation of centimetre-scale argon diffusion in alkali feldspars: implications for
40
Ar/
39
Ar thermochronology
Authors: Flude Stephanie , Halton Alison M. , Kelley Simon P. , Sherlock Sarah C. , Schwanethal James , Wilkinson Camilla M.
Published: January 2014

New data from a gem-quality feldspar from Itrongay, Madagascar, record naturally occurring
40
Ar/
39
Ar age profiles which can be numerically modelled by invoking a single diffusion mechanism and show that microtexturally simple crystals are capable of recording complex thermal histories. We present the longest directly measured, naturally produced
40
Ar*-closure profiles from a single, homogeneous orthoclase feldspar. These data appear to confirm the assumption that laboratory derived diffusion parameters are valid in nature and over geological timescales. Diffusion domains are defined by crystal faces and ancient cracks, thus in gem-quality feldspars the diffusion domain size equates to the physical grain size. The data also illustrate the potential of large, gem-quality feldspars to record detailed thermal histories over tens of millions of years and such samples should be considered for future studies on the slow cooling of continental crust.

Supplementary material:

Ar-isotope data, standards and constants used in calculations and irradiation parameters are available at
http://www.geolsoc.org.uk/SUP18720
.
Sympathetic nerve activity and peripheral vasodilator capacity in young and older men
Authors: Hart Emma C. , Wallin B. Gunnar , Barnes Jill N. , Joyner Michael J. , Charkoudian Nisha
Published: January 2014

Interindividual variability in sympathetic nerve activity (SNA) has provided insight into integrative mechanisms contributing to blood pressure (BP) regulation in humans. In young people, the influence of high SNA on BP is balanced by lower cardiac output and less adrenergic vasoconstrictor responsiveness. Older people have higher SNA and higher BP. We hypothesized that SNA has a restraining effect on peripheral vasodilator responsiveness in young and older men, such that individuals with higher tonic SNA would show less forearm vasodilatation to exogenous vasodilators. We measured muscle SNA (MSNA; microneurography) and forearm vasodilator responses to intra-arterial infusions of acetylcholine (ACh; endothelium dependent) and sodium nitroprusside (SNP; endothelium independent) in 13 young (age; 27 ± 1 yr) and 16 older (61 ± 2 yr) men. Forearm vascular conductance (FVC) responses to ACh were lower in the older men at the two highest doses (2 and 4 μg·100 ml−1·min−1; Δ395 ± 81 vs. 592 ± 87% and 412 ± 87 vs. 616 ± 132%, P < 0.05), and MSNA was higher (64 ± 4 vs. 41 ± 2 bursts/100 hb; P < 0.05). There was no difference in the FVC response to SNP between young and older men ( P > 0.05). In young men, there was an inverse relationship between resting MSNA and FVC responses (%change) to both ACh and SNP ( r = −0.83 and r = −0.83, respectively; P < 0.05). In older men, however, this relationship was not observed. Tonic SNA may act to restrain vasodilator responses in young men, whereas in older men a lack of such restraint may be protective against the pressor effects of higher SNA.
Altered reactivity of resistance vasculature contributes to hypertension in elastin insufficiency
Authors: Osei-Owusu Patrick , Knutsen Russell H. , Kozel Beth A. , Dietrich Hans H. , Blumer Kendall J. , Mecham Robert P.
Published: January 2014

Elastin ( Eln) insufficiency in mice and humans is associated with hypertension and altered structure and mechanical properties of large arteries. However, it is not known to what extent functional or structural changes in resistance arteries contribute to the elevated blood pressure that is characteristic of Eln insufficiency. Here, we investigated how Eln insufficiency affects the structure and function of the resistance vasculature. A functional profile of resistance vasculature in Eln+/− mice was generated by assessing small mesenteric artery (MA) contractile and vasodilatory responses to vasoactive agents. We found that Eln haploinsufficiency had a modest effect on phenylephrine-induced vasoconstriction, whereas ANG II-evoked vasoconstriction was markedly increased. Blockade of ANG II type 2 receptors with PD-123319 or modulation of Rho kinase activity with the inhibitor Y-27632 attenuated the augmented vasoconstriction, whereas acute Y-27632 administration normalized blood pressure in Eln+/− mice. Sodium nitroprusside- and isoproterenol-induced vasodilatation were normal, whereas ACh-induced vasodilatation was severely impaired in Eln+/− MAs. Histologically, the number of smooth muscle layers did not change in Eln+/− MAs; however, an additional discontinuous layer of Eln appeared between the smooth muscle layers that was absent in wild-type arteries. We conclude that high blood pressure arising from Eln insufficiency is due partly to permanent changes in vascular tone as a result of increased sensitivity of the resistance vasculature to circulating ANG II and to impaired vasodilatory mechanisms arising from endothelial dysfunction characterized by impaired endothelium-dependent vasodilatation. Eln insufficiency causes augmented ANG II-induced vasoconstriction in part through a novel mechanism that facilitates contraction evoked by ANG II type 2 receptors and altered G protein signaling.
Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling
Authors: Rodriguez-Menocal Luis , Faridi Mohd Hafeez , Martinez Laisel , Shehadeh Lina A. , Duque Juan C. , Wei Yuntao , Mesa Annia , Pena Angela , Gupta Vineet , Pham Si M. , Vazquez-Padron Roberto I.
Published: January 2014

Aging has been associated with pathological vascular remodeling and increased neointimal hyperplasia. The understanding of how aging exacerbates this process is fundamental to prevent cardiovascular complications in the elderly. This study proposes a mechanism by which aging sustains leukocyte adhesion, vascular inflammation, and increased neointimal thickness after injury. The effect of aging on vascular remodeling was assessed in the rat balloon injury model using microarray analysis, immunohistochemistry, and LINCOplex assays. The injured arteries in aging rats developed thicker neointimas than those in younger animals, and this significantly correlated with a higher number of tissue macrophages and increased vascular IL-18. Indeed, IL-18 was 23-fold more abundant in the injured vasculature of aged animals compared with young rats, while circulating levels were similar in both groups of animals. The depletion of macrophages in aged rats with clodronate liposomes ameliorated vascular accumulation of IL-18 and significantly decreased neointimal formation. IL-18 was found to inhibit apoptosis of vascular smooth muscle cells (VSMC) and macrophages, thus favoring both the formation and inflammation of the neointima. In addition, injured arteries of aged rats accumulated 18-fold more fibrinogen-γ than those of young animals. Incubation of rat peritoneal macrophages with immobilized IL-18 increased leukocyte adhesion to fibrinogen and suggested a proinflammatory positive feedback loop among macrophages, VSMC, and the deposition of fibrinogen during neointimal hyperplasia. In conclusion, our data reveal that concentration changes in vascular cytokine and fibrinogen following injury in aging rats contribute to local inflammation and postinjury neointima formation.
Intraventricular vortex properties in nonischemic dilated cardiomyopathy
Authors: Bermejo Javier , Benito Yolanda , Alhama Marta , Yotti Raquel , Martínez-Legazpi Pablo , del Villar Candelas Pérez , Pérez-David Esther , González-Mansilla Ana , Santa-Marta Cristina , Barrio Alicia , Fernández-Avilés Francisco , del Álamo Juan C.
Published: January 2014

Vortices may have a role in optimizing the mechanical efficiency and blood mixing of the left ventricle (LV). We aimed to characterize the size, position, circulation, and kinetic energy (KE) of LV main vortex cores in patients with nonischemic dilated cardiomyopathy (NIDCM) and analyze their physiological correlates. We used digital processing of color-Doppler images to study flow evolution in 61 patients with NIDCM and 61 age-matched control subjects. Vortex features showed a characteristic biphasic temporal course during diastole. Because late filling contributed significantly to flow entrainment, vortex KE reached its maximum at the time of the peak A wave, storing 26 ± 20% of total KE delivered by inflow (range: 1–74%). Patients with NIDCM showed larger and stronger vortices than control subjects (circulation: 0.008 ± 0.007 vs. 0.006 ± 0.005 m2/s, respectively, P = 0.02; KE: 7 ± 8 vs. 5 ± 5 mJ/m, P = 0.04), even when corrected for LV size. This helped confining the filling jet in the dilated ventricle. The vortex Reynolds number was also higher in the NIDCM group. By multivariate analysis, vortex KE was related to the KE generated by inflow and to chamber short-axis diameter. In 21 patients studied head to head, Doppler measurements of circulation and KE closely correlated with phase-contract magnetic resonance values (intraclass correlation coefficient = 0.82 and 0.76, respectively). Thus, the biphasic nature of filling determines normal vortex physiology. Vortex formation is exaggerated in patients with NIDCM due to chamber remodeling, and enlarged vortices are helpful for ameliorating convective pressure losses and facilitating transport. These findings can be accurately studied using ultrasound.
Mechanisms of cardiac conduction: a history of revisions
Authors: Veeraraghavan Rengasayee , Gourdie Robert G. , Poelzing Steven
Published: January 2014

Cardiac conduction is the process by which electrical excitation spreads through the heart, triggering individual myocytes to contract in synchrony. Defects in conduction disrupt synchronous activation and are associated with life-threatening arrhythmias in many pathologies. Therefore, it is scarcely surprising that this phenomenon continues to be the subject of active scientific inquiry. Here we provide a brief review of how the conceptual understanding of conduction has evolved over the last century and highlight recent, potentially paradigm-shifting developments.
Beneficial effects of acute inhibition of the oxidative pentose phosphate pathway in the failing heart
Authors: Vimercati Claudio , Qanud Khaled , Mitacchione Gianfranco , Sosnowska Danuta , Ungvari Zoltan , Sarnari Roberto , Mania Daniella , Patel Neel , Hintze Thomas H. , Gupte Sachin A. , Stanley William C. , Recchia Fabio A.
Published: January 2014

In vitro studies suggested that glucose metabolism through the oxidative pentose phosphate pathway (oxPPP) can paradoxically feed superoxide-generating enzymes in failing hearts. We therefore tested the hypothesis that acute inhibition of the oxPPP reduces oxidative stress and enhances function and metabolism of the failing heart, in vivo. In 10 chronically instrumented dogs, congestive heart failure (HF) was induced by high-frequency cardiac pacing. Myocardial glucose consumption was enhanced by raising arterial glycemia to levels mimicking postprandial peaks, before and after intravenous administration of the oxPPP inhibitor 6-aminonicotinamide (80 mg/kg). Myocardial energy substrate metabolism was measured with radiolabeled glucose and oleic acid, and cardiac 8-isoprostane output was used as an index of oxidative stress. A group of five chronically instrumented, normal dogs served as control. In HF, raising glycemic levels from ∼80 to ∼170 mg/dL increased cardiac isoprostane output by approximately twofold, whereas oxPPP inhibition normalized oxidative stress and enhanced cardiac oxygen consumption, glucose oxidation, and stroke work. In normal hearts glucose infusion did not induce significant changes in cardiac oxidative stress. Myocardial tissue concentration of 6P-gluconate, an intermediate metabolite of the oxPPP, was significantly reduced by ∼50% in treated versus nontreated failing hearts, supporting the inhibitory effect of 6-aminonicotinamide. Our study indicates an important contribution of the oxPPP activity to cardiac oxidative stress in HF, which is particularly pronounced during common physiological changes such as postprandial glycemic peaks.
Role of estrogen in diastolic dysfunction
Authors: Zhao Zhuo , Wang Hao , Jessup Jewell A. , Lindsey Sarah H. , Chappell Mark C. , Groban Leanne
Published: January 2014

The prevalence of left ventricular diastolic dysfunction (LVDD) sharply increases in women after menopause and may lead to heart failure. While evidence suggests that estrogens protect the premenopausal heart from hypertension and ventricular remodeling, the specific mechanisms involved remain elusive. Moreover, whether there is a protective role of estrogens against cardiovascular disease, and specifically LVDD, continues to be controversial. Clinical and basic science have implicated activation of the renin-angiotensin-aldosterone system (RAAS), linked to the loss of ovarian estrogens, in the pathogenesis of postmenopausal diastolic dysfunction. As a consequence of increased tissue ANG II and low estrogen, a maladaptive nitric oxide synthase (NOS) system produces ROS that contribute to female sex-specific hypertensive heart disease. Recent insights from rodent models that mimic the cardiac phenotype of an estrogen-insufficient or -deficient woman (e.g., premature ovarian failure or postmenopausal), including the ovariectomized congenic mRen2.Lewis female rat, provide evidence showing that estrogen modulates the tissue RAAS and NOS system and related intracellular signaling pathways, in part via the membrane G protein-coupled receptor 30 (GPR30; also called G protein-coupled estrogen receptor 1). Complementing the cardiovascular research in this field, the echocardiographic correlates of LVDD as well as inherent limitations to its use in preclinical rodent studies will be briefly presented. Understanding the roles of estrogen and GPR30, their interactions with the local RAAS and NOS system, and the relationship of each of these to LVDD is necessary to identify new therapeutic targets and alternative treatments for diastolic heart failure that achieve the cardiovascular benefits of estrogen replacement without its side effects and contraindications.
Inhibition of NADPH oxidase prevents acute lung injury in obese rats following severe trauma
Authors: Xiang Lusha , Lu Silu , Mittwede Peter N. , Clemmer John S. , Hester Robert L.
Published: January 2014

Lung capillary filtration coefficient (Kf) and impacts of oxidative stress have not been determined in the setting of severe trauma, especially in obese patients who exhibit increased lung injury. We hypothesized that severe trauma leads to a greater increase in lung Kf in obesity due to exacerbated production of and/or vulnerability to oxidative stress. Severe trauma was induced in lean and obese Zucker rats by muscle injury, fibula fracture, and bone component injection to both hindlimbs, with or without 24-h treatments of apocynin, a NADPH oxidase (NOX) inhibitor. Lung wet/dry weight ratios, lung vascular Kf, lung neutrophil counts, lung NOX and myeloperoxidase (MPO) activity, and plasma IL-6 levels were measured 24 h after trauma. In an additional study, lungs were isolated from nontrauma lean and obese rats to determine the acute effect of phenazime methosulfate, a superoxide donor, on pulmonary vascular Kf. After trauma, compared with lean rats, obese rats exhibited greater increases in lung capillary Kf, neutrophil accumulation, NOX and MPO activity, and plasma IL-6. The lung wet/dry weight ratio was increased in obese rats but not in lean rats. Apocynin treatment decreased lung Kf, neutrophil counts, NOX and MPO activities, wet/dry weight ratio, and plasma IL-6 in obese rats. Phenazime methosulfate treatment resulted in a greater increase in lung Kf in nontrauma obese rats compared with nontrauma lean rats. These results suggest that obese rats are susceptible to lung injury following severe trauma due to increased production of and responsiveness to pulmonary oxidative stress.
Skeletal muscle microvascular oxygenation dynamics in heart failure: exercise training and nitric oxide-mediated function
Authors: Hirai Daniel M. , Copp Steven W. , Holdsworth Clark T. , Ferguson Scott K. , McCullough Danielle J. , Behnke Bradley J. , Musch Timothy I. , Poole David C.
Published: January 2014

Chronic heart failure (CHF) impairs nitric oxide (NO)-mediated regulation of skeletal muscle O2 delivery-utilization matching such that microvascular oxygenation falls faster (i.e., speeds PO2 mv kinetics) during increases in metabolic demand. Conversely, exercise training improves (slows) muscle PO2 mv kinetics following contractions onset in healthy young individuals via NO-dependent mechanisms. We tested the hypothesis that exercise training would improve contracting muscle microvascular oxygenation in CHF rats partly via improved NO-mediated function. CHF rats (left ventricular end-diastolic pressure = 17 ± 2 mmHg) were assigned to sedentary (n = 11) or progressive treadmill exercise training (n = 11; 5 days/wk, 6–8 wk, final workload of 60 min/day at 35 m/min; −14% grade downhill running) groups. PO2 mv was measured via phosphorescence quenching in the spinotrapezius muscle at rest and during 1-Hz twitch contractions under control (Krebs-Henseleit solution), sodium nitroprusside (SNP; NO donor; 300 μM), and NG-nitro-l-arginine methyl ester (L-NAME, nonspecific NO synthase blockade; 1.5 mM) superfusion conditions. Exercise-trained CHF rats had greater peak oxygen uptake and spinotrapezius muscle citrate synthase activity than their sedentary counterparts ( p < 0.05 for both). The overall speed of the PO2 mv fall during contractions (mean response time; MRT) was slowed markedly in trained compared with sedentary CHF rats (sedentary: 20.8 ± 1.4, trained: 32.3 ± 3.0 s; p < 0.05), and the effect was not abolished by L-NAME (sedentary: 16.8 ± 1.5, trained: 31.0 ± 3.4 s; p > 0.05). Relative to control, SNP increased MRT in both groups such that trained CHF rats had slower kinetics (sedentary: 43.0 ± 6.8, trained: 55.5 ± 7.8 s; p < 0.05). Improved NO-mediated function is not obligatory for training-induced improvements in skeletal muscle microvascular oxygenation (slowed PO2 mv kinetics) following contractions onset in rats with CHF.
Protective effect of adenosine receptors against lipopolysaccharide-induced acute lung injury
Authors: Gonzales Joyce N. , Gorshkov Boris , Varn Matthew N. , Zemskova Marina A. , Zemskov Evgeny A. , Sridhar Supriya , Lucas Rudolf , Verin Alexander D.
Published: January 2014

Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) affect 200,000 people a year in the USA. Pulmonary vascular and specifically endothelial cell (EC) barrier compromise is a hallmark of these diseases. We have recently shown that extracellular adenosine enhances human pulmonary (EC) barrier via activation of adenosine receptors (ARs) in cell cultures. On the basis of these data, we hypothesized that activation of ARs might exert barrier-protective effects in a model of ALI/ARDS in mice. To test this hypothesis, we examined the effects of pre- and posttreatment of adenosine and 5′- N-ethylcarboxamidoadenosine (NECA), a nonselective stable AR agonist, on LPS-induced lung injury. Mice were given vehicle or LPS intratracheally followed by adenosine, NECA, or vehicle instilled via the internal jugular vein. Postexperiment cell counts, Evans Blue Dye albumin (EBDA) extravasation, levels of proteins, and inflammatory cytokines were analyzed. Harvested lungs were used for histology and myeloperoxidase studies. Mice challenged with LPS alone demonstrated an inflammatory response typical of ALI. Cell counts, EBDA extravasation, as well as levels of proteins and inflammatory cytokines were decreased in adenosine-treated mice. Histology displayed reduced infiltration of neutrophils. NECA had a similar effect on LPS-induced vascular barrier compromise. Importantly, posttreatment with adenosine or NECA recovers lung vascular barrier and reduces inflammation induced by LPS challenge. Furthermore, adenosine significantly attenuated protein degradation of A2A and A3 receptors induced by LPS. Collectively, our results demonstrate that activation of ARs protects and restores vascular barrier functions and reduces inflammation in LPS-induced ALI.
Nox2/ROS-dependent human antigen R translocation contributes to TNF-α-induced SOCS-3 expression in human tracheal smooth muscle cells
Authors: Hsu Chih-Kai , Lee I-Ta , Lin Chih-Chung , Hsiao Li-Der , Yang Chuen-Mao
Published: January 2014

Elevated levels of TNF-α have been detected in the airway fluids, which may induce upregulation of inflammatory proteins. Suppressors of cytokine signaling (SOCS)-3 proteins can be induced by various cytokines and negatively regulated inflammatory responses. Although TNF-α has been shown to induce SOCS-3 expression, the mechanisms underlying TNF-α-induced SOCS-3 expression in human tracheal smooth muscle cells (HTSMCs) remain unclear. Here, we showed that TNF-α induced SOCS-3 expression, which was inhibited by pretreatment with the inhibitor of transcription level (actinomycin D), translation level (cycloheximide), JNK1/2 (SP600125), MEK1/2 (U0126), NADPH oxidase (Nox; apocynin and diphenyleneiodonium chloride), or reactive oxygen species (ROS; N-acetyl-l-cysteine) and transfection with siRNA of JNK1, p47phox, p42, Nox2, or human antigen R (HuR). In addition, TNF-α-stimulated JNK1/2 and p42/p44 MAPK phosphorylation, Nox activation, and ROS generation were inhibited by pretreatment with U0126 or SP600125 and transfection with siRNA of JNK1 or p42. We further showed that TNF-α markedly induced HuR protein expression and translocation from the nucleus to the cytosol, which could stabilize SOCS-3 mRNA. Moreover, TNF-α-enhanced HuR translocation was reduced by transfection with siRNA of p42, JNK1, or p47phox. These results suggested that TNF-α induces SOCS-3 protein expression and mRNA stabilization via a TNFR1/JNK1/2, p42/p44 MAPK/Nox2/ROS-dependent HuR signaling in HTSMCs. Lipopolysaccharide (LPS) has been shown to play a key role in inflammation via induction of adhesion molecules and then causes airway and lung injury. Moreover, we also demonstrated that overexpression of SOCS-3 protects against LPS-induced adhesion molecules expression and airway inflammation.
Differential Regulation of Estrogen Receptor α Expression in Breast Cancer Cells by Metastasis-Associated Protein 1
Authors: Kang Hyun-Jin , Lee Min-Ho , Kang Hae-Lim , Kim Sung-Hye , Ahn Jung-Ranh , Na Hyelin , Na Tae-Young , Kim Yo Na , Seong Je Kyung , Lee Mi-Ock
Published: January 2014

Metastasis-associated protein 1 (MTA1) is a component of the nucleosome remodeling and histone deacetylase (HDAC) complex, which plays an important role in progression of breast cancer. Although MTA1 is known as a repressor of the transactivation function of estrogen receptor α (ERα), its involvement in the epigenetic control of transcription of the ERα gene ESR1 has not been studied. Here, we show that silencing of MTA1 reduced the level of expression of ERα in ERα-positive cells but increased it in ERα-negative cells. In both MCF7 and MDA-MB-231, MTA1 was recruited to the region +146 to +461 bp downstream of the transcription start site of ESR1 (ERpro315). Proteomics analysis of the MTA1 complex that was pulled down by an oligonucleotide encoding ERpro315 revealed that the transcription factor AP-2γ (TFAP2C) and the IFN-γ–inducible protein 16 (IFI16) were components of the complex. Interestingly, in MCF7, TFAP2C activated the reporter encoding ERpro315 and the level of ERα mRNA. By contrast, in MDA-MB-231, IFI16 repressed the promoter activity and silencing of MTA1 increased expression of ERα. Importantly, class II HDACs are involved in the MTA1-mediated differential regulation of ERα. Finally, an MDA-MB-231-derived cell line that stably expressed shIFI16 or shMTA1 was more susceptible to tamoxifen-induced growth inhibition in in vitro and in vivo experiments. Taken together, our findings suggest that the MTA1–TFAP2C or the MTA1–IFI16 complex may contribute to the epigenetic regulation of ESR1 expression in breast cancer and may determine the chemosensitivity of tumors to tamoxifen therapy in patients with breast cancer. Cancer Res; 74(5); 1484–94. ©2014 AACR.
Triapine Disrupts CtIP-Mediated Homologous Recombination Repair and Sensitizes Ovarian Cancer Cells to PARP and Topoisomerase Inhibitors
Authors: Lin Z. Ping , Ratner Elena S. , Whicker Margaret E. , Lee Yashang , Sartorelli Alan C.
Published: January 2014

PARP inhibitors exploit synthetic lethality to target epithelial ovarian cancer (EOC) with hereditary BRCA mutations and defects in homologous recombination repair (HRR). However, such an approach is limited to a small subset of EOC patients and compromised by restored HRR due to secondary mutations in BRCA genes. Here, it was demonstrated that triapine, a small-molecule inhibitor of ribonucleotide reductase, enhances the sensitivity of BRCA wild-type EOC cells to the PARP inhibitor olaparib and the topoisomerase II inhibitor etoposide. Triapine abolishes olaparib-induced BRCA1 and Rad51 foci, and disrupts the BRCA1 interaction with the Mre11–Rad50–Nbs1 (MRN) complex in BRCA1 wild-type EOC cells. It has been shown that phosphorylation of CtIP (RBBP8) is required for the interaction with BRCA1 and with MRN to promote DNA double-strand break (DSB) resection during S and G2 phases of the cell cycle. Mechanistic studies within reveal that triapine inhibits cyclin-dependent kinase (CDK) activity and blocks olaparib-induced CtIP phosphorylation through Chk1 activation. Furthermore, triapine abrogates etoposide-induced CtIP phosphorylation and DSB resection as evidenced by marked attenuation of RPA32 phosphorylation. Concurrently, triapine obliterates etoposide-induced BRCA1 foci and sensitizes BRCA1 wild-type EOC cells to etoposide. Using a GFP-based HRR assay, it was determined that triapine suppresses HRR activity induced by an I-SceI–generated DSB. These results suggest that triapine augments the sensitivity of BRCA wild-type EOC cells to drug-induced DSBs by disrupting CtIP-mediated HRR.

Implications: These findings provide a strong rationale for combining triapine with PARP or topoisomerase inhibitors to target HRR-proficient EOC cells. Mol Cancer Res; 12(3); 381–93. ©2014 AACR.
PD-L1 Expression in Triple-Negative Breast Cancer
Authors: Mittendorf Elizabeth A. , Philips Anne V. , Meric-Bernstam Funda , Qiao Na , Wu Yun , Harrington Susan , Su Xiaoping , Wang Ying , Gonzalez-Angulo Ana M. , Akcakanat Argun , Chawla Akhil , Curran Michael , Hwu Patrick , Sharma Padmanee , Litton Jennifer K. , Molldrem Jeffrey J. , Alatrash Gheath
Published: January 2014

Early-phase trials targeting the T-cell inhibitory molecule programmed cell death ligand 1 (PD-L1) have shown clinical efficacy in cancer. This study was undertaken to determine whether PD-L1 is overexpressed in triple-negative breast cancer (TNBC) and to investigate the loss of PTEN as a mechanism of PD-L1 regulation. The Cancer Genome Atlas (TCGA) RNA sequencing data showed significantly greater expression of the PD-L1 gene in TNBC (n = 120) compared with non-TNBC (n = 716; P < 0.001). Breast tumor tissue microarrays were evaluated for PD-L1 expression, which was present in 19% (20 of 105) of TNBC specimens. PD-L1+ tumors had greater CD8+ T-cell infiltrate than PD-L1− tumors (688 cells/mm vs. 263 cells/mm; P < 0.0001). To determine the effect of PTEN loss on PD-L1 expression, stable cell lines were generated using PTEN short hairpin RNA (shRNA). PTEN knockdown led to significantly higher cell-surface PD-L1 expression and PD-L1 transcripts, suggesting transcriptional regulation. Moreover, phosphoinositide 3-kinase (PI3K) pathway inhibition using the AKT inhibitor MK-2206 or rapamycin resulted in decreased PD-L1 expression, further linking PTEN and PI3K signaling to PD-L1 regulation. Coculture experiments were performed to determine the functional effect of altered PD-L1 expression. Increased PD-L1 cell surface expression by tumor cells induced by PTEN loss led to decreased T-cell proliferation and increased apoptosis. PD-L1 is expressed in 20% of TNBCs, suggesting PD-L1 as a therapeutic target in TNBCs. Because PTEN loss is one mechanism regulating PD-L1 expression, agents targeting the PI3K pathway may increase the antitumor adaptive immune responses. Cancer Immunol Res; 2(4); 361–70. ©2014 AACR.
Primary Synovial Sarcoma of the Thyroid Gland: Case Report and Review of the Literature
Authors: Boudin Laurys , Fakhry Nicolas , Chetaille Bruno , Perrot Delphine , Nguyen Anh Tuan , Daidj Nassima , Guiramand Jérôme , Sarran Anthony , Moureau-Zabotto Laurence , Bertucci François
Published: January 2014

Synovial sarcoma (SVS) of the thyroid gland is exceedingly rare. We report the case of a 55-year-old man with a rapidly growing 7-cm neck mass. Because of suspicion of anaplastic thyroid carcinoma, a total thyroidectomy was planned, without preoperative cytology. During surgery, the tumor ruptured, leading to fragmented and incomplete resection. The morphological and immunohistochemical aspects suggested thyroid SVS, which was confirmed by fluorescent in situ hybridization (SYT gene rearrangement). The patient experienced immediate local relapse in close contact with large vessels and the thyroid cartilage and was referred to our institution. Doxorubicin-ifosfamide chemotherapy led to a minor response that authorized secondary conservative surgery. Because of microscopically incomplete resection, adjuvant radiotherapy was chosen and is ongoing 10 months after initial surgery. The prognosis of thyroid SVS is associated with a high risk for local and metastatic relapses. Pretreatment diagnosis is fundamental and may benefit from molecular analysis. Margin-free monobloc surgical excision is the best chance for cure, but adjuvant chemotherapy and radiotherapy deserve to be discussed.
Lower Levels of Sodium Intake and Reduced Cardiovascular Risk
Authors: Cook Nancy R. , Appel Lawrence J. , Whelton Paul K.
Published: January 2014

Background—

Recent studies have raised the possibility of adverse effects of low sodium, particularly <2300 mg/d, on cardiovascular disease; however, these paradoxical findings might have resulted from suboptimal measurement of sodium and potential biases related to indication or reverse causation.

Methods and Results—

Phases 1 and 2 of the Trials of Hypertension Prevention (TOHP) collected multiple 24-hour urine specimens among prehypertensive individuals. During extended posttrial surveillance, 193 cardiovascular events or cardiovascular disease deaths occurred among 2275 participants not in a sodium reduction intervention with 10 (TOHP II) or 15 (TOHP I) years of posttrial follow-up. Median sodium excretion was 3630 mg/d, with 1.4% of the participants having intake <1500 mg/d and 10% <2300 mg/d, consistent with national levels. Compared with those with sodium excretion of 3600 to <4800 mg/d, risk for those with sodium <2300 mg/d was 32% lower after multivariable adjustment (hazard ratio, 0.68; 95% confidence interval, 0.34–1.37;
P
for trend=0.13). There was a linear 17% increase in risk per 1000 mg/d increase in sodium (
P
=0.05). Spline curves supported a linear association of sodium with cardiovascular events, which continued to decrease from 3600 to 2300 and 1500 mg/d, although the data were sparse at the lowest levels. Controlling for creatinine levels had little effect on these results.

Conclusions—

Results from the TOHP studies, which overcome the major methodological challenges of prior studies, are consistent with overall health benefits of reducing sodium intake to the 1500 to 2300 mg/d range in the majority of the population, in agreement with current dietary guidelines.
Timing and Patterns of the ENSO Signal in Africa over the Last 30 Years: Insights from Normalized Difference Vegetation Index Data
Authors: Philippon N. , Martiny N. , Camberlin P. , Hoffman M. T. , Gond V.
Published: January 2014

A more complete picture of the timing and patterns of the ENSO signal during the seasonal cycle for the whole of Africa over the three last decades is provided using the normalized difference vegetation index (NDVI). Indeed, NDVI has a higher spatial resolution and is more frequently updated than in situ climate databases, and highlights the impact of ENSO on vegetation dynamics as a combined result of ENSO on rainfall, solar radiation, and temperature.

The month-by-month NDVI–Niño-3.4 correlation patterns evolve as follows. From July to September, negative correlations are observed over the Sahel, the Gulf of Guinea coast, and regions from the northern Democratic Republic of Congo to Ethiopia. However, they are not uniform in space and are moderate (~0.3). Conversely, positive correlations are recorded over the winter rainfall region of South Africa. In October–November, negative correlations over Ethiopia, Sudan, and Uganda strengthen while positive correlations emerge in the Horn of Africa and in the southeast coast of South Africa. By December with the settlement of the ITCZ south of the equator, positive correlations over the Horn of Africa spread southward and westward while negative correlations appear over Mozambique, Zimbabwe, and South Africa. This pattern strengthens and a dipole at 18°S is well established in February–March with reduced (enhanced) greenness during ENSO years south (north) of 18°S. At the same time, at ~2°N negative correlations spread northward. Last, from April to June negative correlations south of 18°S spread to the north (to 10°S) and to the east (to the south of Tanzania).
Uncertainties, Correlations, and Optimal Blends of Drought Indices from the NLDAS Multiple Land Surface Model Ensemble
Authors: Xia Youlong , Ek Michael B. , Mocko David , Peters-Lidard Christa D. , Sheffield Justin , Dong Jiarui , Wood Eric F.
Published: January 2014

This study analyzed uncertainties and correlations over the United States among four ensemble-mean North American Land Data Assimilation System (NLDAS) percentile-based drought indices derived from monthly mean evapotranspiration ET, total runoff Q, top 1-m soil moisture SM1, and total column soil moisture SMT. The results show that the uncertainty is smallest for SM1, largest for SMT, and moderate for ET and Q. The strongest correlation is between SM1 and SMT, and the weakest correlation is between ET and Q. The correlation between ET and SM1 (SMT) is strongest in arid–semiarid regions, and the correlation between Q and SM1 (SMT) is strongest in more humid regions in the Pacific Northwest and the Southeast. Drought frequency analysis shows that SM1 has the most frequent drought occurrence, followed by SMT, Q, and ET. The study compared the NLDAS drought indices (a research product) with the U.S. Drought Monitor (USDM; an operational product) in terms of drought area percentage derived from each product. It proposes an optimal blend of NLDAS drought indices by searching for weights for each index that minimizes the RMSE between NLDAS and USDM drought area percentage for a 10-yr period (2000–09) with a cross validation. It reconstructed a 30-yr (1980–2009) Objective Blended NLDAS Drought Index (OBNDI) and monthly drought percentage. Overall, the OBNDI performs the best with the smallest RMSE, followed by SM1 and SMT. It should be noted that the contribution to OBNDI from different variables varies with region. So a single formula is probably not the best representation of a blended index. The representation of a blended index using the multiple formulas will be addressed in a future study.
Effects of Irrigation in India on the Atmospheric Water Budget
Authors: Tuinenburg O. A. , Hutjes R. W. A. , Stacke T. , Wiltshire A. , Lucas-Picher P.
Published: January 2014

The effect of large-scale irrigation in India on the moisture budget of the atmosphere was investigated using three regional climate models and one global climate model, all of which performed an irrigated run and a natural run without irrigation. Using a common irrigation map, year-round irrigation was represented by adding water to the soil moisture to keep it at 90% of the maximum soil moisture storage capacity, regardless of water availability. For two focus regions, the seasonal cycle of irrigation matched that of the reference dataset, but irrigation application varied between the models by up to 0.8 mm day−1. Because of the irrigation, evaporation increased in all models, but precipitation decreased because of a strong decrease in atmospheric moisture convergence. A moisture tracking scheme was used to track individual evaporated moisture parcels through the atmosphere to determine where these lead to precipitation. Up to 35% of the evaporation moisture from the Ganges basin is recycling within the river basin. However, because of a decreased moisture convergence into the river basin, the total amount of precipitation in the Ganges basin decreases. Although a significant fraction of the evaporation moisture recycles within the river basin, the changes in large-scale wind patterns due to irrigation shift the precipitation from the eastern parts of India and Nepal to the northern and western parts of India and Pakistan. In these areas where precipitation increases, the relative precipitation increase is larger than the relative decrease in the areas where precipitation decreases. It is concluded 1) that the direct effects of irrigation on precipitation are small and are not uniform across the models; 2) that a fraction of up to 35% of any marginal evaporation increase (for example, due to irrigation) will recycle within the river basin; and 3) that when irrigation is applied on a large scale, the dominant effect will be a change in large-scale atmospheric flow that decreases precipitation in eastern India and increases it in western and northern India.
A Procedure for Operational Use of Wave Hindcasts to Identify Landfall of Heavy Swell
Authors: Innocentini Valdir , Caetano Ernesto , Carvalho Jonas Takeo
Published: January 2014

The wave pattern on the Brazilian coastline is composed of both wind waves and swell. The wave systems (WSs), extracted from the spectra near the coast produced by numerical wave models, reveal the occasional presence of intense swells, with small significant wave height (HS) and large average period (Ta). This kind of event has nearly no effect over deep water, but its landfall can be accompanied by inundation, mainly when coupled with favorable tides and storm surge. Since these events are not clearly evident in the bulk parameters, this study proposes a methodology (i) to identify intense swells simulated by a coarse grid resolution wave modeling system (CWS) and (ii) to evaluate their importance. In this methodology, monitoring sites are defined along a 100-m isobath contouring the Brazilian coast, where the CWS hindcasts the spectra for a 31-yr period, from 1979 to 2009, obtained by the WAVEWATCH wave model. The spectra are partitioned into WSs, which are used to build cumulative distribution tables (CDTs) for each site. The variable used in the CDT is the flux of energy per unit length perpendicular to the wave propagation (PW), which contains in its definition both HS and Ta. The direction of propagation of a WS is used to compute the components of PW parallel and perpendicular to the coast. From the CDT of the perpendicular component of PW, the percentile of an incoming WS can be found and its intensity ranked. To illustrate the feasibility of this proposal, the method is used to find the 50 most powerful distantly generated swells for two sites: one on the northern and another on the southern Brazilian coast. In addition, the method is applied in two case studies, both accompanied by coastal flooding and erosion: one represents a very powerful WS arriving at the northern coast and the other a less energetic event occurring on the southeastern coast. The analysis of bulk parameters fails to identify the second case as potentially destructive, while the proposed methodology clearly gives some indication.
Individual resource contributions to voluntary organizations in the United States
Authors: Somma Nicolás M
Published: January 2014

Although social movement organizations (SMOs) are often depicted as mobilizing intensive resources from their individual members, we lack a systematic assessment of this issue. Based on the notion of ‘modern social movements’ I argue that SMOs mobilize fewer human and monetary resources from their members than other voluntary organizations do. A regression model using a survey representative of American adults shows that, when compared to other organization members, SMO members generally contribute significantly lower amounts of money and time. They are also less likely to attend, plan or chair meetings, and give speeches on behalf of the organization. The only exception to this pattern is that SMO members are more likely to write letters for the organization than other members do.
Fit for purpose? Validation of a conceptual framework for personal recovery with current mental health consumers
Authors: Bird Victoria , Leamy Mary , Tew Jerry , Le Boutillier Clair , Williams Julie , Slade Mike
Published: January 2014

Objective:

Mental health services in the UK, Australia and other Anglophone countries have moved towards supporting personal recovery as a primary orientation. To provide an empirically grounded foundation to identify and evaluate recovery-oriented interventions, we previously published a conceptual framework of personal recovery based on a systematic review and narrative synthesis of existing models. Our objective was to test the validity and relevance of this framework for people currently using mental health services.

Method:

Seven focus groups were conducted with 48 current mental health consumers in three NHS trusts across England, as part of the REFOCUS Trial. Consumers were asked about the meaning and their experience of personal recovery. Deductive and inductive thematic analysis applying a constant comparison approach was used to analyse the data. The analysis aimed to explore the validity of the categories within the conceptual framework, and to highlight any areas of difference between the conceptual framework and the themes generated from new data collected from the focus groups.

Results:

Both the inductive and deductive analysis broadly validated the conceptual framework, with the super-ordinate categories Connectedness, Hope and optimism, Identity, Meaning and purpose, and Empowerment (CHIME) evident in the analysis. Three areas of difference were, however, apparent in the inductive analysis. These included practical support; a greater emphasis on issues around diagnosis and medication; and scepticism surrounding recovery.

Conclusions:

This study suggests that the conceptual framework of personal recovery provides a defensible theoretical base for clinical and research purposes which is valid for use with current consumers. However, the three areas of difference further stress the individual nature of recovery and the need for an understanding of the population and context under investigation.
Introduction: Postimperial sovereignty games in the Nordic region
Authors: Adler-Nissen Rebecca , Gad Ulrik P
Published: January 2014

Benevolence, homogeneity and peace has never been the full story of the Nordic region. Building on a critical review of myths of ‘ Norden’ in international relations theory and beyond (international political economy, security studies, regional and European integration theory and postcolonialism), we develop the framework of postimperial sovereignty games for understanding contemporary Nordic foreign policy and regional dynamics. We shift focus from the ‘large’ Nordic countries to the remnants of Nordic empires: Iceland, Greenland, the Faroe Islands and Åland. On the one hand, these polities struggle to enhance their independence – Iceland even after becoming a sovereign state; the other polities via self-government arrangements. On the other hand, the former colonies develop close relationships to a supranational European Union in their effort to achieve independent subjectivity. Contrasting the developments towards increased independence and European integration, the article demonstrates the importance of imperial legacies. Firstly, it challenges Norden as a model security community. Secondly, it questions the image of a harmonious Nordic welfare model based on equality and consensus in light of the experiences of Iceland, Greenland, the Faroe Islands and Åland. Finally, it suggests that no theory of European integration is complete without taking imperial and postimperial processes into account.
The Faroe Islands
Authors: Adler-Nissen Rebecca
Published: January 2014

This article examines the intersection of postimperial sovereignty and European integration in the context of a disintegrating Nordic empire. More specifically, it explores the relationships between the Faroe Islands – a group of self-governing islands in the North Atlantic – Denmark and the rest of the world. While the Faroe Islands have gained increased autonomy from Denmark, Faroese separatists are now discussing whether to transfer their newly won autonomy further on to the EU. This contradictory development of separation and integration is shaped by interweaving ideas of sovereignty, nationalism, globalization and postcolonial dependency. The article shows that the Faroese–Danish relationship is being internationalized and Europeanized as the EU and UN become reference points in negotiations of political visions for an independent Faroese state and the controversial issue of pilot whaling. Notwithstanding dramatic transformations, the Faroese–Danish relationship has maintained its postcolonial character, where Denmark is awkwardly constituted as a maternalistic colonial power defending an adolescent colonized from the rest of the world. The real novelty is not the increased Faroese autonomy from Denmark, but how the EU challenges the unity of the postimperial Danish realm and hence the myth of a homogenous Danish nation-state.