bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immediate Antioxidant and Antiplatelet Effect of Atorvastatin via Inhibition of Nox2
Authors: Pignatelli Pasquale , Carnevale Roberto , Pastori Daniele , Cangemi Roberto , Napoleone Laura , Bartimoccia Simona , Nocella Cristina , Basili Stefania , Violi Francesco 
Published: May 2012

Background—
Statins exert an antithrombotic effect in patients at risk of or with acute thrombosis, but no study has investigated whether this effect is immediate and whether there is an underline mechanism.

Methods and Results—

Patients with hypercholesterolemia were randomly allocated to a Mediterranean diet with low cholesterol intake (<300 mg/d; n=15) or atorvastatin (40 mg/d; n=15). Oxidative stress, as assessed by serum Nox2 and urinary isoprostanes, and platelet activation, as assessed by platelet recruitment, platelet isoprostanes, and thromboxane A
2
, platelet Nox2, Rac1, p47
phox
, protein kinase C, vasodilator-stimulated phosphoprotein, nitric oxide, and phospholipase A
2
, were determined at baseline and after 2, 24, and 72 hours and 7 days of follow-up. An in vitro study was also performed to see whether atorvastatin affects platelet oxidative stress and activation. The atorvastatin-assigned group showed a significant and progressive reduction of urinary isoprostanes and serum Nox2, along with inhibition of platelet recruitment, platelet isoprostanes, Nox2, Rac1, p47
phox
, and protein kinase C, starting 2 hours after administration. Platelet phospholipase A
2
and thromboxane A
2
significantly decreased and vasodilator-stimulated phosphoprotein and nitric oxide increased after 24 hours. Low-density lipoprotein cholesterol decreased significantly after 72 hours and further declined after 7 days. No changes were observed in the Mediterranean diet group. In vitro experiments demonstrated that atorvastatin dose-dependently inhibited platelet Nox2 and phospholipase A
2
activation, along with inhibition of platelet recruitment, platelet isoprostanes, and thromboxane A
2
, and increased vasodilator-stimulated phosphoprotein and nitric oxide.

Conclusions—

The study provides the first evidence that atorvastatin acutely and simultaneously decreases oxidative stress and platelet activation by directly inhibiting platelet Nox2 and ultimately platelet isoprostanes and thromboxane A
2
. These findings provide a rationale for the use of statins to prevent or modulate coronary thrombosis.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01322711.
A Theory of the Interhemispheric Meridional Overturning Circulation and Associated Stratification
Authors: Nikurashin Maxim , Vallis Geoffrey 
Published: May 2012

AbstractA quantitative theoretical model of the meridional overturning circulation and associated deep stratification in an interhemispheric, single-basin ocean with a circumpolar channel is presented. The theory includes the effects of wind, eddies, and diapycnal mixing and predicts the deep stratification and overturning streamfunction in terms of the surface forcing and other parameters of the problem. It relies on a matching among three regions: the circumpolar channel at high southern latitudes, a region of isopycnal outcrop at high northern latitudes, and the ocean basin between.The theory describes both the middepth and abyssal cells of a circulation representing North Atlantic Deep Water and Antarctic Bottom Water. It suggests that, although the strength of the middepth overturning cell is primarily set by the wind stress in the circumpolar channel, middepth stratification results from a balance between the wind-driven upwelling in the channel and deep-water formation at high northern latitudes. Diapycnal mixing in the ocean interior can lead to warming and upwelling of deep waters. However, for parameters most representative of the present ocean mixing seems to play a minor role for the middepth cell. In contrast, the abyssal cell is intrinsically diabatic and controlled by a balance between the deep mixing-driven upwelling and the residual of the wind-driven and eddy-induced circulations in the Southern Ocean.The theory makes explicit predictions about how the stratification and overturning circulation vary with the wind strength, diapycnal diffusivity, and mesoscale eddy effects. The predictions compare well with numerical results from a coarse-resolution general circulation model.
The Wavy Ekman Layer: Langmuir Circulations, Breaking Waves, and Reynolds Stress
Authors: McWilliams James C. , Huckle Edward , Liang Jun-Hong , Sullivan Peter P. 
Published: May 2012

Abstract
Large-eddy simulations are made for the canonical Ekman layer problem of a steady wind above a uniformly rotating, constant-density ocean. The focus is on the influence of surface gravity waves: namely, the wave-averaged Stokes-Coriolis and Stokes-vortex forces and parameterized wave breaking for momentum and energy injection. The wave effects are substantial: the boundary layer is deeper, the turbulence is stronger, and eddy momentum flux is dominated by breakers and Langmuir circulations with a vertical structure inconsistent with both the conventional logarithmic layer and eddy viscosity relations. The surface particle mean drift is dominated by Stokes velocity with Langmuir circulations playing a minor role. Implications are assessed for parameterization of the mean velocity profile in the Ekman layer with wave effects by exploring several parameterization ideas. The authors find that the K-profile parameterization (KPP) eddy viscosity is skillful for the interior of the Ekman layer with wave-enhanced magnitude and depth scales. Furthermore, this parameterization form is also apt in the breaker and Stokes layers near the surface when it is expressed as a Lagrangian eddy viscosity (i.e., turbulent Reynolds stress proportional to vertical shear of the Lagrangian mean flow, inclusive of Stokes drift) with a derived eddy-viscosity shape and with a diagnosed vertical profile of a misalignment angle between Reynolds stress and Lagrangian mean shear.
Tropical Cyclone Contribution to Rainfall over Australia
Authors: Dare Richard A. , Davidson Noel E. , McBride John L. 
Published: May 2012

Abstract
Tropical cyclone (TC) rainfall over the Australian continent is studied using observations from 41 TC seasons 1969/70 to 2009/10. A total of 318 storms, whose centers either crossed the coastline or were located within 500 km of the coast, are considered in this study. Mean seasonal (November/April) contributions by TCs to the total rainfall are largest along the northern coastline from 120°–150°E. However, the percentage contributions by TCs are greatest west of 125°E, with mean coastal values of 20%–40% and inland values of approximately 20%. Farther east, percentages near the coast are only around 10%, and even lower inland. Inland penetration by TC rainfall is generally greatest over western portions of the continent, associated with greater inland penetration of TC tracks. During the peak of the TC season (January–March), TCs contribute around 40% to the rainfall total of coastal regions west of 120°E, while during December, TCs contribute approximately 60%–70% to the total rainfall west of 115°E. Rain from TCs varies sharply between TC seasons, with some longitude bands receiving no TC rain during some seasons. For the 110°–115°E longitude band the TC rain contribution is quite inconsistent, varying interannually from 0%–86%. This has an impact on water supplies, with storage dams falling to low levels during some years, while filling to capacity during TC-related flood events in other years. These large interannual variations and their impacts underline why it is important to understand TC rainfall characteristics over the Australian continent.
SAP expression in invariant NKT cells is required for cognate help to support B-cell responses
Authors: Detre Cynthia , Keszei Marton , Garrido-Mesa Natividad , Kis-Toth Katalin , Castro Wilson , Agyemang Amma F. , Veerapen Natacha , Besra Gurdyal S. , Carroll Michael C. , Tsokos George C. , Wang Ninghai , Leadbetter Elizabeth A. , Terhorst Cox 
Published: May 2012

Abstract
One of the manifestations of X-linked lymphoproliferative disease (XLP) is progressive agammaglobulinemia, caused by the absence of a functional signaling lymphocyte activation molecule (SLAM)–associated protein (SAP) in T, invariant natural killer T (NKT) cells and NK cells. Here we report that α-galactosylceramide (αGalCer) activated NKT cells positively regulate antibody responses to haptenated protein antigens at multiple checkpoints, including germinal center formation and affinity maturation. Whereas NKT cell–dependent B cell responses were absent in SAP−/−.B6 mice that completely lack NKT cells, the small number of SAP-deficient NKT cells in SAP−/−.BALB/c mice adjuvated antibody production, but not the germinal center reaction. To test the hypothesis that SAP-deficient NKT cells can facilitate humoral immunity, SAP was deleted after development in SAPfl/fl.tgCreERT2.B6 mice. We find that NKT cell intrinsic expression of SAP is dispensable for noncognate helper functions, but is critical for providing cognate help to antigen-specific B cells. These results demonstrate that SLAM-family receptor-regulated cell-cell interactions are not limited to T-B cell conjugates. We conclude that in the absence of SAP, several routes of NKT cell–mediated antibody production are still accessible. The latter suggests that residual NKT cells in XLP patients might contribute to variations in dysgammaglobulinemia.
Epitope targeting and viral inoculum are determinants of Nef-mediated immune evasion of HIV-1 from cytotoxic T lymphocytes
Authors: Chen Diana Y. , Balamurugan Arumugam , Ng Hwee L. , Cumberland William G. , Yang Otto O. 
Published: May 2012

AbstractThe impact of HIV-1 Nef-mediated HLA-I down-regulation on CD8+ cytotoxic T lymphocytes (CTLs) varies by epitope, but the determining factors have not been elucidated. In the present study, we investigated the impact of Nef on the antiviral efficiency of HIV-1–specific CTLs targeting 17 different epitopes to define properties that determine susceptibility to Nef. The impact of Nef was not correlated with the presenting HLA-I type or functional avidity of CTLs, but instead was related directly to the kinetics of infected cell clearance. Whereas Gag-specific CTLs generally were less susceptible to Nef than those targeting other proteins, this was determined by the ability to eliminate infected cells before de novo synthesis of viral proteins, which was also observed for CTLs targeting a Nef epitope. This very early clearance of infected cells depended on virus inoculum, and the required inoculum varied by epitope. These results suggest that whereas Gag-specific CTLs are more likely to recognize infected cells before Nef-mediated HLA-I down-regulation, this varies depending on the specific epitope and virus inoculum. Reduced susceptibility to Nef therefore may contribute to the overall association of Gag-specific CTL responses to better immune control if a sufficient multiplicity of infection is attained in vivo, but this property is not unique to Gag.
How I treat newly diagnosed chronic phase CML
Authors: Cortes Jorge , Kantarjian Hagop 
Published: May 2012

AbstractThe progress made in the understanding of chronic myeloid leukemia (CML) since the recognition of a common chromosomal abnormality to the introduction of ever more effective tyrosine kinase inhibitors is unprecedented in cancer. The expected survival for patients diagnosed with CML today, if properly managed, is probably similar to that of the general population. When managing patients with CML the goal is to achieve the best long-term outcome and we should base the treatment decisions on the data available. The results from cytogenetic and molecular analyses have to be interpreted judiciously and all available treatment options integrated into the treatment plan properly. The availability of several treatment options in CML is an asset, but the temptation of rapid succession of treatment changes because of perceived suboptimal response or for adverse events that could be managed needs to be avoided. Any decision to change therapy needs to weigh the expected long-term outcome with the current option versus the true expectations with any new option, particularly as it relates to irre-versible outcomes, such as transformation to blast phase and death. In this manuscript, we discuss the treatment approach that has helped us manage successfully a large CML population.
Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution
Authors: Zeng Ming , Paiardini Mirko , Engram Jessica C. , Beilman Greg J. , Chipman Jeffrey G. , Schacker Timothy W. , Silvestri Guido , Haase Ashley T. 
Published: May 2012

Abstract
Loss of the fibroblastic reticular cell (FRC) network in lymphoid tissues during HIV-1 infection has been shown to impair the survival of naive T cells and limit immune reconstitution after antiretroviral therapy. What causes this FRC loss is unknown. Because FRC loss correlates with loss of both naive CD4 and CD8 T-cell subsets and decreased lymphotoxin-β, a key factor for maintenance of FRC network, we hypothesized that loss of naive T cells is responsible for loss of the FRC network. To test this hypothesis, we assessed the consequences of antibody-mediated depletion of CD4 and CD8 T cells in rhesus macaques and sooty mangabeys. We found that only CD4 T-cell depletion resulted in FRC loss in both species and that this loss was caused by decreased lymphotoxin-β mainly produced by the CD4 T cells. We further found the same dependence of the FRC network on CD4 T cells in HIV-1–infected patients before and after antiretroviral therapy and in other immunodeficiency conditions, such as CD4 depletion in cancer patients induced by chemotherapy and irradiation. CD4 T cells thus play a central role in the maintenance of lymphoid tissue structure necessary for their own homeostasis and reconstitution.
Overrepresentation of transcription factor families in the genesets underlying breast cancer subtypes
Authors: Joshi Himanshu , Nord Silje H , Frigessi Arnoldo , Børresen-Dale Anne-Lise , Kristensen Vessela N 
Published: May 2012

Abstract

Background
The human genome contains a large amount of cis-regulatory DNA elements responsible for directing both spatial and temporal gene-expression patterns. Previous studies have shown that based on their mRNA expression breast tumors could be divided into five subgroups (Luminal A, Luminal B, Basal, ErbB2+ and Normal-like), each with a distinct molecular portrait. Whole genome gene expression analysis of independent sets of breast tumors reveals repeatedly the robustness of this classification. Furthermore, breast tumors carrying a TP53 mutation show a distinct gene expression profile, which is in strong association to the distinct molecular portraits. The mRNA expression of 552 genes, which varied considerably among the different tumors, but little between two samples of the same tumor, has been shown to be sufficient to separate these tumor subgroups.

Results
We analyzed in silico the transcriptional regulation of genes defining the subgroups at 3 different levels: 1. We studied the pathways in which the genes distinguishing the subgroups of breast cancer may be jointly involved including upstream regulators (1st and 2nd level of regulation) as well as downstream targets of these genes. 2. Then we analyzed the promoter areas of these genes (−500 bp to +100 bp relative to the transcription start site) for canonical transcription binding sites using Genomatix. 3. We looked for the actual expression levels of the identified TF and how they correlate with the overrepresentation of their TF binding sites in the separate groups. We report that promoter composition of the genes that most strongly predict the patient subgroups is distinct. The class-predictive genes showed a clearly different degree of overrepresentation of transcription factor families in their promoter sequences.

Conclusion
The study suggests that transcription factors responsible for the observed expression pattern in breast cancers may lead us to important biological pathways.
Programmed cell death in Saccharomyces cerevisiae is hampered by the deletion of GUP1 gene
Authors: Tulha Joana , Faria-Oliveira Fábio , Lucas Cândida , Ferreira Célia 
Published: May 2012

Abstract

Background
During the past years, yeast has been successfully established as a model to study mechanisms of programmed cell death regulation. Saccharomyces cerevisiae commits to cell death showing typical hallmarks of metazoan apoptosis, in response to different stimuli. Gup1p, an O-acyltransferase, is required for several cellular processes that are related to apoptosis development, such as rafts integrity and stability, lipid metabolism including GPI anchor correct remodeling, proper mitochondrial and vacuole function, bud site selection and actin dynamics. Therefore, we hypothesize that apoptotic process would be affected by GUP1 deletion.

Results
In the present work we used two known apoptosis inducing conditions, chronological aging and acetic acid, to assess several apoptotic markers in gup1∆ mutant strain. We found that this mutant presents a significantly reduced chronological lifespan as compared to Wt and it is also highly sensitive to acetic acid treatment. In addition, it presents extremely high levels of ROS. There were notorious differences on apoptotic markers between Wt and gup1∆ mutant strains, namely on the maintenance of plasma membrane integrity, on the phosphatidylserine externalization, on the depolarization of mitochondrial membrane and on the chromatin condensation. Those suggested that the mutant, under either condition, probably dies of necrosis and not from apoptosis.

Conclusions
To Gup1p has been assigned an important function on lipid rafts assembly/integrity, lipid metabolism and GPI anchor remodeling. Our results provide, for the first time, the connection of the integrity of yeast lipid rafts and apoptosis induction and/or signaling, giving new insights into the molecular mechanisms underlying this process in yeast.
Reduced-Calorie Dietary Weight Loss, Exercise, and Sex Hormones in Postmenopausal Women: Randomized Controlled Trial
Authors: Campbell Kristin L. , Foster-Schubert Karen E. , Alfano Catherine M. , Wang Chia-Chi , Wang Ching-Yun , Duggan Catherine R. , Mason Caitlin , Imayama Ikuyo , Kong Angela , Xiao Liren , Bain Carolyn E. , Blackburn George L. , Stanczyk Frank Z. , McTiernan Anne 
Published: May 2012

Purpose Estrogens and androgens are elevated in obesity and associated with increased postmenopausal breast cancer risk, but the effect of weight loss on these biomarkers is unknown. We evaluated the individual and combined effects of a reduced-calorie weight loss diet and exercise on serum sex hormones in overweight and obese postmenopausal women. Patients and Methods We conducted a single-blind, 12-month, randomized controlled trial from 2005 to 2009. Participants (age 50 to 75 years; body mass index > 25.0 kg/m2, exercising < 100 minutes/wk) were randomly assigned using a computer-generated sequence to (1) reduced-calorie weight loss diet (“diet”; n = 118), (2) moderate- to vigorous-intensity aerobic exercise (“exercise”; n = 117), (3) combined reduced-calorie weight loss diet and moderate- to vigorous-intensity aerobic exercise (“diet + exercise”; n = 117), or (4) control (n = 87). Outcomes were estrone concentration (primary) and estradiol, free estradiol, total testosterone, free testosterone, androstenedione, and sex hormone–binding globulin (SHBG) concentrations (secondary). Results Mean age and body mass index were 58 years and 30.9 kg/m2, respectively. Compared with controls, estrone decreased 9.6% (P = .001) with diet, 5.5% (P = .01) with exercise, and 11.1% (P < .001) with diet + exercise. Estradiol decreased 16.2% (P < .001) with diet, 4.9% (P = .10) with exercise, and 20.3% (P < .001) with diet + exercise. SHBG increased 22.4% (P < .001) with diet and 25.8% (P < .001) with diet + exercise. Free estradiol decreased 21.4% (P < .001) with diet and 26.0% (P < .001) with diet + exercise. Free testosterone decreased 10.0% (P < .001) with diet and 15.6% (P < .001) with diet + exercise. Greater weight loss produced stronger effects on estrogens and SHBG. Conclusion Weight loss significantly lowered serum estrogens and free testosterone, supporting weight loss for risk reduction through lowering exposure to breast cancer biomarkers.
Early- and Long-Term Outcome Data of Patients With Pseudomyxoma Peritonei From Appendiceal Origin Treated by a Strategy of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy
Authors: Chua Terence C. , Moran Brendan J. , Sugarbaker Paul H. , Levine Edward A. , Glehen Olivier , Gilly François N. , Baratti Dario , Deraco Marcello , Elias Dominique , Sardi Armando , Liauw Winston , Yan Tristan D. , Barrios Pedro , Gómez Portilla Alberto , de Hingh Ignace H.J.T. , Ceelen Wim P. , Pelz Joerg O. , Piso Pompiliu , González-Moreno Santiago , Van Der Speeten Kurt , Morris David L. 
Published: May 2012

Purpose Pseudomyxoma peritonei (PMP) originating from an appendiceal mucinous neoplasm remains a biologically heterogeneous disease. The purpose of our study was to evaluate outcome and long-term survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) consolidated through an international registry study. Patients and Methods A retrospective multi-institutional registry was established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group International. Results Two thousand two hundred ninety-eight patients from 16 specialized units underwent CRS for PMP. Treatment-related mortality was 2% and major operative complications occurred in 24% of patients. The median survival rate was 196 months (16.3 years) and the median progression-free survival rate was 98 months (8.2 years), with 10- and 15-year survival rates of 63% and 59%, respectively. Multivariate analysis identified prior chemotherapy treatment (P < .001), peritoneal mucinous carcinomatosis (PMCA) histopathologic subtype (P < .001), major postoperative complications (P = .008), high peritoneal cancer index (P = .013), debulking surgery (completeness of cytoreduction [CCR], 2 or 3; P < .001), and not using HIPEC (P = .030) as independent predictors for a poorer progression-free survival. Older age (P = .006), major postoperative complications (P < .001), debulking surgery (CCR 2 or 3; P < .001), prior chemotherapy treatment (P = .001), and PMCA histopathologic subtype (P < .001) were independent predictors of a poorer overall survival. Conclusion The combined modality strategy for PMP may be performed safely with acceptable morbidity and mortality in a specialized unit setting with 63% of patients surviving beyond 10 years. Minimizing nondefinitive operative and systemic chemotherapy treatments before definitive cytoreduction may facilitate the feasibility and improve the outcome of this therapy to achieve long-term survival. Optimal cytoreduction achieves the best outcomes.