bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deletion of
mtrC
in Haemophilus ducreyi Increases Sensitivity to Human Antimicrobial Peptides and Activates the CpxRA Regulon
Authors: Rinker Sherri D. , Trombley Michael P. , Gu Xiaoping , Fortney Kate R. , Bauer Margaret E. 
Published: March 2011

ABSTRACT

Haemophilus ducreyi
resists killing by antimicrobial peptides encountered during human infection, including cathelicidin LL-37, α-defensins, and β-defensins. In this study, we examined the role of the proton motive force-dependent multiple transferable resistance (MTR) transporter in antimicrobial peptide resistance in
H. ducreyi
. We found a proton motive force-dependent effect on
H. ducreyi
's resistance to LL-37 and β-defensin HBD-3, but not α-defensin HNP-2. Deletion of the membrane fusion protein MtrC rendered
H. ducreyi
more sensitive to LL-37 and human β-defensins but had relatively little effect on α-defensin resistance. The
mtrC
mutant 35000HP
mtrC
exhibited phenotypic changes in outer membrane protein profiles, colony morphology, and serum sensitivity, which were restored to wild type by
trans
-complementation with
mtrC
. Similar phenotypes were reported in a
cpxA
mutant; activation of the two-component CpxRA regulator was confirmed by showing transcriptional effects on CpxRA-regulated genes in 35000HP
mtrC
. A
cpxR
mutant had wild-type levels of antimicrobial peptide resistance; a
cpxA
mutation had little effect on defensin resistance but led to increased sensitivity to LL-37. 35000HP
mtrC
was more sensitive than the
cpxA
mutant to LL-37, indicating that MTR contributed to LL-37 resistance independent of the CpxRA regulon. The CpxRA regulon did not affect proton motive force-dependent antimicrobial peptide resistance; however, 35000HP
mtrC
had lost proton motive force-dependent peptide resistance, suggesting that the MTR transporter promotes proton motive force-dependent resistance to LL-37 and human β-defensins. This is the first report of a β-defensin resistance mechanism in
H. ducreyi
and shows that LL-37 resistance in
H. ducreyi
is multifactorial.
LipA, a Tyrosine and Lipid Phosphatase Involved in the Virulence of Listeria monocytogenes
Authors: Kastner Renate , Dussurget Olivier , Archambaud Cristel , Kernbauer Elisabeth , Soulat Didier , Cossart Pascale , Decker Thomas 
Published: March 2011

ABSTRACTIntracellular bacterial pathogens manipulate host cell functions by producing enzymes that stimulate or antagonize signal transduction. TheListeria monocytogenesgenome contains a gene,lmo1800, encoding a protein with a conserved motif of conventional tyrosine phosphatases. Here, we report that thelmo1800-encoded protein LipA is secreted byListeriaand displays tyrosine as well as lipid phosphatase activityin vitro. Bacteria lacking LipA are severely attenuated in virulencein vivo, thus revealing a so-far-undescribed enzymatic activity involved inListeriainfection.
miR-125b Is Methylated and Functions as a Tumor Suppressor by Regulating the ETS1 Proto-oncogene in Human Invasive Breast Cancer
Authors: Zhang Yan , Yan Li-Xu , Wu Qi-Nian , Du Zi-Ming , Chen Jing , Liao Ding-Zhun , Huang Ma-Yan , Hou Jing-Hui , Wu Qiu-Liang , Zeng Mu-Sheng , Huang Wen-Lin , Zeng Yi-Xin , Shao Jian-Yong 
Published: March 2011

Abstract
The microRNA miR-125b is dysregulated in various human cancers but its underlying mechanisms of action are poorly understood. Here, we report that miR-125b is downregulated in invasive breast cancers where it predicts poor patient survival. Hypermethylation of the miR-125b promoter partially accounted for reduction of miR-125b expression in human breast cancer. Ectopic restoration of miR-125b expression in breast cancer cells suppressed proliferation, induced G1 cell-cycle arrest in vitro, and inhibited tumorigenesis in vivo. We identified the ETS1 gene as a novel direct target of miR-125b. siRNA-mediated ETS1 knockdown phenocopied the effect of miR-125b in breast cell lines and ETS1 overexpression in invasive breast cancer tissues also correlated with poor patient prognosis. Taken together, our findings point to an important role for miR-125b in the molecular etiology of invasive breast cancer, and they suggest miR-125b as a potential theranostic tool in this disease. Cancer Res; 71(10); 3552–62. ©2011 AACR.
Endoglin Regulates Cancer–Stromal Cell Interactions in Prostate Tumors
Authors: Romero Diana , O'Neill Christine , Terzic Aleksandra , Contois Liangru , Young Kira , Conley Barbara A. , Bergan Raymond C. , Brooks Peter C. , Vary Calvin P.H. 
Published: March 2011

Abstract
Endoglin is an accessory receptor for TGF-β that has been implicated in prostate cancer cell detachment, migration, and invasiveness. However, the pathophysiologic significance of endoglin with respect to prostate tumorigenesis has yet to be fully established. In this study, we addressed this question by investigation of endoglin-dependent prostate cancer progression in a TRAMP (transgenic adenocarcinoma mouse prostate) mouse model where endoglin was genetically deleted. In this model, endoglin was haploinsufficient such that its allelic deletion slightly increased the frequency of tumorigenesis, yet produced smaller, less vascularized, and less metastatic tumors than TRAMP control tumors. Most strikingly, TRAMP:eng+/−-derived tumors lacked the pronounced infiltration of carcinoma-associated fibroblasts (CAF) that characterize TRAMP prostate tumors. Studies in human primary prostate-derived stromal cells (PrSC) confirmed that suppressing endoglin expression decreased cell proliferation, the ability to recruit endothelial cells, and the ability to migrate in response to tumor cell–conditioned medium. We found increased levels of secreted insulin-like growth factor–binding proteins (IGFBP) in the conditioned medium from endoglin-deficient PrSCs and that endoglin-dependent regulation of IGFBP-4 secretion was crucial for stromal cell–conditioned media to stimulate prostate tumor cell growth. Together, our results firmly establish the pathophysiologic involvement of endoglin in prostate cancer progression; furthermore, they show how endoglin acts to support the viability of tumor-infiltrating CAFs in the tumor microenvironment to promote neovascularization and growth. Cancer Res; 71(10); 3482–93. ©2011 AACR.
Unraveling Cancer Chemoimmunotherapy Mechanisms by Gene and Protein Expression Profiling of Responses to Cyclophosphamide
Authors: Moschella Federica , Valentini Mara , Aricò Eleonora , Macchia Iole , Sestili Paola , D'Urso Maria Teresa , Alessandri Cristiano , Belardelli Filippo , Proietti Enrico 
Published: March 2011

Abstract
Certain chemotherapeutic drugs, such as cyclophosphamide (CTX), can enhance the antitumor efficacy of immunotherapy because of their capacity to modulate innate and adaptive immunity. Indeed, it has been argued that this capacity may be more significant to chemotherapeutic efficacy in general than is currently appreciated. To gain insights into the core mechanisms of chemoimmunotherapy, we methodically profiled the effects of CTX on gene expression in bone marrow, spleen, and peripheral blood, and on cytokine expression in plasma and bone marrow of tumor-bearing mice. Gene and protein expression were modulated early and transiently by CTX, leading to upregulation of a variety of immunomodulatory factors, including danger signals, pattern recognition receptors, inflammatory mediators, growth factors, cytokines, chemokines, and chemokine receptors. These factors are involved in sensing CTX myelotoxicity and activating repair mechanisms, which, in turn, stimulate immunoactivation events that promote efficacy. In particular, CTX induced a T-helper 17 (Th17)-related gene signature associated with an increase in Th17, Th1, and activated CD25+CD4+Foxp3− T lymphocytes and a slight recovery of regulatory T cells. By analyzing gene and protein expression kinetics and their relationship to the antitumor efficacy of different therapeutic schedules of combination, we determined that optimal timing for performing adoptive immunotherapy is approximately 1 day after CTX treatment. Together, our findings highlight factors that may propel the efficacy of chemoimmunotherapy, offering a mechanistic glimpse of the important immune modulatory effects of CTX. Cancer Res; 71(10); 3528–39. ©2011 AACR.
Therapeutic Implications of the Emerging Molecular Biology of Uveal Melanoma
Authors: Patel Mrinali , Smyth Elizabeth , Chapman Paul B. , Wolchok Jedd D. , Schwartz Gary K. , Abramson David H. , Carvajal Richard D. 
Published: March 2011

Abstract
Uveal melanoma represents the most common primary intraocular malignancy in adults. Although uveal and cutaneous melanomas both arise from melanocytes, uveal melanoma is clinically and biologically distinct from its more common cutaneous counterpart. Metastasis occurs frequently in this disease, and once distant spread occurs, outcomes are poor. No effective systemic therapies are currently available; however, recent advances in our understanding of the biology of this rare and devastating disease, combined with the growing availability of targeted agents, which can be used to rationally exploit these findings, hold the promise for novel and effective therapies in the foreseeable future. Herein, we review our rapidly growing understanding of the molecular biology of uveal melanoma, including the pathogenic roles of GNAQ (guanine nucleotide binding protein q polypeptide)/11, PTEN (phosphatase and tensin homolog), IGF (insulin-like growth factor)/IGF-1 receptor, MET (hepatocyte growth factor), BAP1 [breast cancer 1, early onset (BRCA1)-associated protein-1], and other key molecules, potential therapeutic strategies derived from this emerging biology, and the next generation of recently initiated clinical trials for the treatment of advanced uveal melanoma. Clin Cancer Res; 17(8); 2087–100. ©2011 AACR.
Incremental Prognostic Significance of Combined Cardiac Magnetic Resonance Imaging, Adenosine Stress Perfusion, Delayed Enhancement, and Left Ventricular Function Over Preimaging Information for the Prediction of Adverse Events
Authors: Bingham Scott E. , Hachamovitch Rory 
Published: March 2011

Background—
Although cardiac magnetic resonance imaging (CMR) is capable of yielding extensive data in routine practice, the relative incremental prognostic value of adenosine stress perfusion, myocardial delayed enhancement (DE), and left ventricular volumes and function is unclear.

Methods and Results—

We followed up 908 consecutive patients who underwent combined CMR for suspicion of coronary stenosis and/or ischemia at 2.6±1.2 years, during which 101 total cardiac events occurred (all-cause death, myocardial infarction, or late revascularization). Increase in Cox proportional-hazards model global χ
2
(χ
2
) with the addition of CMR data after adjustment for clinical data defined incremental prognostic value. Cardiac magnetic resonance imaging without abnormalities had a 2.4% event rate per year (<1% cardiac death or myocardial infarction). Abnormal CMR was associated with event rates of 5.6% to 7.0% per year, varying with which and how many components were abnormal. After adjusting for the pre-CMR data (age, dyspnea, prior coronary artery disease, resting heart rate, renal disease, and diabetes mellitus, χ
2
:43.6,
P
<0.0001; C index 0.695), the addition of left ventricular ejection fraction, aortic flow, delayed enhancement, and stress perfusion data all incrementally increased χ
2
(55.2, 63.3, 68.0, and 68.9, respectively; all
P
<0.00001; C indices 0.717, 0.722, 0.747, and 0.736). The number of abnormal CMR domains both added incremental prognostic value and risk stratified patients with respect to risk of events.

Conclusions—
CMR analysis of ventricular volume, aortic flow, myocardial viability, and stress perfusion all add incremental value for prediction of adverse events over pre-CMR data and can be combined to further enhance prognostication. Normal combined CMR confers a low risk of subsequent cardiac events.
On T2* Magnetic Resonance and Cardiac Iron
Authors: Carpenter John-Paul , He Taigang , Kirk Paul , Roughton Michael , Anderson Lisa J. , de Noronha Sofia V. , Sheppard Mary N. , Porter John B. , Walker J. Malcolm , Wood John C. , Galanello Renzo , Forni Gianluca , Catani Gualtiero , Matta Gildo , Fucharoen Suthat , Fleming Adam , House Michael J. , Black Greg , Firmin David N. , St. Pierre Timothy G. , Pennell Dudley J. 
Published: March 2011

Background—
Measurement of myocardial iron is key to the clinical management of patients at risk of siderotic cardiomyopathy. The cardiovascular magnetic resonance relaxation parameter R2* (assessed clinically via its reciprocal, T2*) measured in the ventricular septum is used to assess cardiac iron, but iron calibration and distribution data in humans are limited.

Methods and Results—

Twelve human hearts were studied from transfusion-dependent patients after either death (heart failure, n=7; stroke, n=1) or transplantation for end-stage heart failure (n=4). After cardiovascular magnetic resonance R2* measurement, tissue iron concentration was measured in multiple samples of each heart with inductively coupled plasma atomic emission spectroscopy. Iron distribution throughout the heart showed no systematic variation between segments, but epicardial iron concentration was higher than in the endocardium. The mean±SD global myocardial iron causing severe heart failure in 10 patients was 5.98±2.42 mg/g dry weight (range, 3.19 to 9.50 mg/g), but in 1 outlier case of heart failure was 25.9 mg/g dry weight. Myocardial ln[R2*] was strongly linearly correlated with ln[Fe] (
R
2
=0.910,
P
<0.001), leading to [Fe]=45.0×(T2*)
−1.22
for the clinical calibration equation with [Fe] in milligrams per gram dry weight and T2* in milliseconds. Midventricular septal iron concentration and R2* were both highly representative of mean global myocardial iron.

Conclusions—
These data detail the iron distribution throughout the heart in iron overload and provide calibration in humans for cardiovascular magnetic resonance R2* against myocardial iron concentration. The iron values are of considerable interest in terms of the level of cardiac iron associated with iron-related death and indicate that the heart is more sensitive to iron loading than the liver. The results also validate the current clinical practice of monitoring cardiac iron in vivo by cardiovascular magnetic resonance of the midseptum.
Absolute and Attributable Risks of Atrial Fibrillation in Relation to Optimal and Borderline Risk Factors
Authors: Huxley Rachel R. , Lopez Faye L. , Folsom Aaron R. , Agarwal Sunil K. , Loehr Laura R. , Soliman Elsayed Z. , Maclehose Rich , Konety Suma , Alonso Alvaro 
Published: March 2011

Background—
Atrial fibrillation (AF) is an important risk factor for stroke and overall mortality, but information about the preventable burden of AF is lacking. The aim of this study was to determine what proportion of the burden of AF in blacks and whites could theoretically be avoided by the maintenance of an optimal risk profile.

Methods and Results—
This study included 14 598 middle-aged Atherosclerosis Risk in Communities (ARIC) Study cohort members. Previously established AF risk factors, namely high blood pressure, elevated body mass index, diabetes mellitus, cigarette smoking, and prior cardiac disease, were categorized into optimal, borderline, and elevated levels. On the basis of their risk factor levels, individuals were classified into 1 of these 3 groups. The population-attributable fraction of AF resulting from having a nonoptimal risk profile was estimated separately for black and white men and women. During a mean follow-up of 17.1 years, 1520 cases of incident AF were identified. The age-adjusted incidence rates were highest in white men and lowest in black women (7.45 and 3.67 per 1000 person-years, respectively). The overall prevalence of an optimal risk profile was 5.4% but varied according to race and gender: 10% in white women versus 1.6% in black men. Overall, 56.5% of AF cases could be explained by having ≥1 borderline or elevated risk factors, of which elevated blood pressure was the most important contributor.

Conclusion—
As with other forms of cardiovascular disease, more than half of the AF burden is potentially avoidable through the optimization of cardiovascular risk factors levels.
Impact of Remote Telemedical Management on Mortality and Hospitalizations in Ambulatory Patients With Chronic Heart Failure
Authors: Koehler Friedrich , Winkler Sebastian , Schieber Michael , Sechtem Udo , Stangl Karl , Böhm Michael , Boll Herbert , Baumann Gert , Honold Marcus , Koehler Kerstin , Gelbrich Goetz , Kirwan Bridget-Anne , Anker Stefan D. 
Published: March 2011

Background—
This study was designed to determine whether physician-led remote telemedical management (RTM) compared with usual care would result in reduced mortality in ambulatory patients with chronic heart failure (HF).

Methods and Results—

We enrolled 710 stable chronic HF patients in New York Heart Association functional class II or III with a left ventricular ejection fraction ≤35% and a history of HF decompensation within the previous 2 years or with a left ventricular ejection fraction ≤25%. Patients were randomly assigned (1:1) to RTM or usual care. Remote telemedical management used portable devices for ECG, blood pressure, and body weight measurements connected to a personal digital assistant that sent automated encrypted transmission via cell phones to the telemedical centers. The primary end point was death from any cause. The first secondary end point was a composite of cardiovascular death and hospitalization for HF. Baseline characteristics were similar between the RTM (n=354) and control (n=356) groups. Of the patients assigned to RTM, 287 (81%) were at least 70% compliant with daily data transfers and no break for >30 days (except during hospitalizations). The median follow-up was 26 months (minimum 12), and was 99.9% complete. Compared with usual care, RTM had no significant effect on all-cause mortality (hazard ratio, 0.97; 95% confidence interval, 0.67 to 1.41;
P
=0.87) or on cardiovascular death or HF hospitalization (hazard ratio, 0.89; 95% confidence interval, 0.67 to 1.19;
P
=0.44).

Conclusions—
In ambulatory patients with chronic HF, RTM compared with usual care was not associated with a reduction in all-cause mortality.

Clinical Trial Registration:—

URL:
http://www.ClinicalTrials.gov
. Unique identifier: NCT00543881.
Application of Cluster Analysis to Climate Model Performance Metrics
Authors: Yokoi Satoru , Takayabu Yukari N. , Nishii Kazuaki , Nakamura Hisashi , Endo Hirokazu , Ichikawa Hiroki , Inoue Tomoshige , Kimoto Masahide , Kosaka Yu , Miyasaka Takafumi , Oshima Kazuhiro , Sato Naoki , Tsushima Yoko , Watanabe Masahiro 
Published: March 2011

AbstractThe overall performance of general circulation models is often investigated on the basis of the synthesis of a number of scalar performance metrics of individual models that measure the reproducibility of diverse aspects of the climate. Because of physical and dynamic constraints governing the climate, a model’s performance in simulating a certain aspect of the climate is sometimes related closely to that in simulating another aspect, which results in significant intermodel correlation between performance metrics. Numerous metrics and intermodel correlations may cause a problem in understanding the evaluation and synthesizing the metrics. One possible way to alleviate this problem is to group the correlated metrics beforehand. This study attempts to use simple cluster analysis to group 43 performance metrics. Two clustering methods, the K-means and the Ward methods, yield considerably similar clustering results, and several aspects of the results are found to be physically and dynamically reasonable. Furthermore, the intermodel correlation between the cluster averages is considerably lower than that between the metrics. These results suggest that the cluster analysis is helpful in obtaining the appropriate grouping. Applications of the clustering results are also discussed.
Interannual Changes of Stratospheric Temperature and Ozone: Forcing by Anomalous Wave Driving and the QBO
Authors: Salby Murry L. 
Published: March 2011

Abstract
A 3D model of dynamics and photochemistry is used to investigate interannual changes of stratospheric dynamical and chemical structure through their dependence on tropospheric planetary waves and on the quasi-biennial oscillation (QBO). The integrations reproduce the salient features of the climate sensitivities of temperature and ozone, which have been composited from the observed records of ECMWF and the Total Ozone Mapping Spectrometer (TOMS). Characterized by a strong anomaly of one sign at polar latitudes and a comparatively weak anomaly of opposite sign at subpolar latitudes, each bears the signature of the residual mean circulation. The structure is very similar to that associated with the Arctic Oscillation.
The integrations imply that, jointly, anomalous Eliassen–Palm (EP) flux transmitted from the troposphere by planetary waves and the QBO are the major mechanisms behind interannual changes in the stratosphere. An analogous conclusion follows from the observational record. During early winter, anomalous temperature and ozone are accounted for almost entirely by anomalous EP flux from the troposphere, as they are in the observational record. During late winter, both mechanisms are required to reproduce observed anomalies. Although the QBO forces anomalous structure equatorward of 40°N, the strong anomaly over the Arctic follows principally from anomalous upward EP flux. Reflecting anomalous wave driving of residual mean motion, the change of EP flux leads to anomalous downwelling of ozone-rich air. In concert with isentropic mixing by planetary waves, the anomalous enrichment that ensues at extratropical latitudes sharply modifies total ozone over the Arctic. Integrations distinguished by the omission of heterogeneous processes indicate that chemical destruction accounts for approximately 20% of the anomaly in Arctic ozone between warm and cold winters. Analogous to estimates derived from the observed record of the Solar Backscatter Ultraviolet, version 8 (SBUV-V8) instrument, the remaining approximately 80% follows from anomalous transport.
The climate sensitivities of temperature and ozone describe random changes between years, introduced by anomalous EP flux and the QBO. Those interannual changes evolve with a particular seasonality. Like their structure, the seasonal dependence of anomalous temperature and ozone bears the signature of the residual mean circulation. Systematic changes in the observed record, which comprise stratospheric trends, have similar structure and seasonality.