bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small RNA Sequencing and Functional Characterization Reveals MicroRNA-143 Tumor Suppressor Activity in Liposarcoma
Authors: Ugras Stacy , Brill Elliott , Jacobsen Anders , Hafner Markus , Socci Nicholas D. , DeCarolis Penelope L. , Khanin Raya , O'Connor Rachael , Mihailovic Aleksandra , Taylor Barry S. , Sheridan Robert , Gimble Jeffrey M. , Viale Agnes , Crago Aimee , Antonescu Cristina R. , Sander Chris , Tuschl Thomas , Singer Samuel 
Published: June 2011

Abstract
Liposarcoma remains the most common mesenchymal cancer, with a mortality rate of 60% among patients with this disease. To address the present lack of therapeutic options, we embarked upon a study of microRNA (miRNA) expression alterations associated with liposarcomagenesis with the goal of exploiting differentially expressed miRNAs and the gene products they regulate as potential therapeutic targets. MicroRNA expression was profiled in samples of normal adipose tissue, well-differentiated liposarcoma, and dedifferentiated liposarcoma by both deep sequencing of small RNA libraries and hybridization-based Agilent microarrays. The expression profiles discriminated liposarcoma from normal adipose tissue and well differentiated from dedifferentiated disease. We defined over 40 miRNAs that were dysregulated in dedifferentiated liposarcomas in both the sequencing and the microarray analysis. The upregulated miRNAs included two cancer-associated species (miR-21 and miR-26a), and the downregulated miRNAs included two species that were highly abundant in adipose tissue (miR-143 and miR-145). Restoring miR-143 expression in dedifferentiated liposarcoma cells inhibited proliferation, induced apoptosis, and decreased expression of BCL2, topoisomerase 2A, protein regulator of cytokinesis 1 (PRC1), and polo-like kinase 1 (PLK1). The downregulation of PRC1 and its docking partner PLK1 suggests that miR-143 inhibits cytokinesis in these cells. In support of this idea, treatment with a PLK1 inhibitor potently induced G2–M growth arrest and apoptosis in liposarcoma cells. Taken together, our findings suggest that miR-143 re-expression vectors or selective agents directed at miR-143 or its targets may have therapeutic value in dedifferentiated liposarcoma. Cancer Res; 71(17); 5659–69. ©2011 AACR.
BARD1 Expression Predicts Outcome in Colon Cancer
Authors: Sporn Judith C. , Hothorn Torsten , Jung Barbara 
Published: June 2011

Abstract
Purpose: BARD1 is a BRCA1-binding partner with tumor suppressive properties. Aberrant splice variants of BARD1 have been detected in various cancers, and it has been postulated that the presence of some splice variants is cancer specific. This is the first study assessing BARD1 expression patterns and correlation with clinical outcome in colon cancer.
Experimental Design: We analyzed colon cancer samples for the occurrence of BARD1 splice variants, characterized novel BARD1 splice variants, and quantified the mRNA expression levels of these isoforms in primary colon cancers and their corresponding normal tissue. We tested the correlation of full-length BARD1 protein expression and clinical outcome in primary colon cancer samples.
Results: In addition to the full-length BARD1 mRNA, we now find 19 distinct BARD1 splice variants in colon cancer. Contrary to previous assumptions, these splice variants also occur in the adjacent normal colon tissue. Although BARD1 splice variants account for a considerable amount of BARD1 mRNA in both cancer and normal colon samples, distinct variants show a cancer-specific regulation pattern. Consistent with its role as tumor suppressor, we further find that the expression of the full-length BARD1 protein predicts outcome in colon cancer and that loss of full-length BARD1 protein is associated with a poor prognosis (P = 0.0002).
Conclusion: Taken together, this is the first report to suggest that BARD1 regulation is an important pathway in colon cancer and that the BARD1 full-length protein may be a useful marker to improve risk stratification in colon cancer patients. Clin Cancer Res; 17(16); 5451–62. ©2011 AACR.
c-MYC Oncoprotein Dictates Transcriptional Profiles of ATP-Binding Cassette Transporter Genes in Chronic Myelogenous Leukemia CD34+ Hematopoietic Progenitor Cells
Authors: Porro Antonio , Iraci Nunzio , Soverini Simona , Diolaiti Daniel , Gherardi Samuele , Terragna Carolina , Durante Sandra , Valli Emanuele , Kalebic Thea , Bernardoni Roberto , Perrod Chiara , Haber Michelle , Norris Murray D. , Baccarani Michele , Martinelli Giovanni , Perini Giovanni 
Published: June 2011

Abstract
Resistance to chemotherapeutic agents remains one of the major impediments to a successful treatment of chronic myeloid leukemia (CML). Misregulation of the activity of a specific group of ATP-binding cassette transporters (ABC) is responsible for reducing the intracellular concentration of drugs in leukemic cells. Moreover, a consistent body of evidence also suggests that ABC transporters play a role in cancer progression beyond the efflux of cytotoxic drugs. Despite a large number of studies that investigated the function of the ABC transporters, little is known about the transcriptional regulation of the ABC genes. Here, we present data showing that the oncoprotein c-MYC is a direct transcriptional regulator of a large set of ABC transporters in CML. Furthermore, molecular analysis carried out in CD34+ hematopoietic cell precursors of 21 CML patients reveals that the overexpression of ABC transporters driven by c-MYC is a peculiar characteristic of the CD34+ population in CML and was not found either in the population of mononuclear cells from which they had been purified nor in CD34+ cells isolated from healthy donors. Finally, we describe how the methylation state of CpG islands may regulate the access of c-MYC to ABCG2 gene promoter, a well-studied gene associated with multidrug resistance in CML, hence, affecting its expression. Taken together, our findings support a model in which c-MYC–driven transcriptional events, combined with epigenetic mechanisms, direct and regulate the expression of ABC genes with possible implications in tumor malignancy and drug efflux in CML. Mol Cancer Res; 9(8); 1054–66. ©2011 AACR.
MicroRNA-138 Modulates DNA Damage Response by Repressing Histone H2AX Expression
Authors: Wang Yemin , Huang Jen-Wei , Li Ming , Cavenee Webster K. , Mitchell Patrick S. , Zhou Xiaofeng , Tewari Muneesh , Furnari Frank B. , Taniguchi Toshiyasu 
Published: June 2011

Abstract
Precise regulation of DNA damage response is crucial for cellular survival after DNA damage, and its abrogation often results in genomic instability in cancer. Phosphorylated histone H2AX (γH2AX) forms nuclear foci at sites of DNA damage and facilitates DNA damage response and repair. MicroRNAs (miRNA) are short, nonprotein-encoding RNA molecules, which posttranscriptionally regulate gene expression by repressing translation of and/or degrading mRNA. How miRNAs modulate DNA damage response is largely unknown. In this study, we developed a cell-based screening assay using ionizing radiation (IR)-induced γH2AX foci formation in a human osteosarcoma cell line, U2OS, as the readout. By screening a library of human miRNA mimics, we identified several miRNAs that inhibited γH2AX foci formation. Among them, miR-138 directly targeted the histone H2AX 3′-untranslated region, reduced histone H2AX expression, and induced chromosomal instability after DNA damage. Overexpression of miR-138 inhibited homologous recombination and enhanced cellular sensitivity to multiple DNA-damaging agents (cisplatin, camptothecin, and IR). Reintroduction of histone H2AX in miR-138 overexpressing cells attenuated miR-138–mediated sensitization to cisplatin and camptothecin. Our study suggests that miR-138 is an important regulator of genomic stability and a potential therapeutic agent to improve the efficacy of radiotherapy and chemotherapy with DNA-damaging agents. Mol Cancer Res; 9(8); 1100–11. ©2011 AACR.
Methyl-Binding Domain Protein 2–Dependent Proliferation and Survival of Breast Cancer Cells
Authors: Mian Omar Y. , Wang Shou Zhen , Zhu Sheng Zu , Gnanapragasam Merlin N. , Graham Laura , Bear Harry D. , Ginder Gordon D. 
Published: June 2011

Abstract
Methyl cytosine binding domain protein 2 (MBD2) has been shown to bind to and mediate repression of methylated tumor suppressor genes in cancer cells, where repatterning of CpG methylation and associated gene silencing is common. We have investigated the role of MBD2 in breast cancer cell growth and tumor suppressor gene expression. We show that stable short hairpin RNA (shRNA)-mediated knockdown of MBD2 leads to growth suppression of cultured human mammary epithelial cancer lines, SK-BR-3, MDA-MB-231, and MDA-MB-435. The peak antiproliferative occurs only after sustained, stable MBD2 knockdown. Once established, the growth inhibition persists over time and leads to a markedly decreased propensity for aggressive breast cancer cell lines to form in vivo xenograft tumors in Bagg Albino (BALB)/C nu/nu mice. The growth effects of MBD2 knockdown are accompanied by derepression of tumor suppressor genes, including DAPK1 and KLK10. Chromatin immunoprecipitation assays and bisulfite sequencing show MBD2 binding directly to the hyper methylated and CpG-rich promoters of both DAPK1 and KLK10. Remarkably, the promoter CpG island–associated methylation of these genes remained stable despite robust transcriptional activation in MBD2 knockdown cells. Expression of a shRNA-resistant MBD2 protein resulted in restoration of growth and resilencing of the MBD2-dependent tumor suppressor genes. Our data suggest that uncoupling CpG methylation from repressive chromatin remodeling and histone modifications by removing MBD2 is sufficient to initiate and maintain tumor suppressor gene transcription and suppress neoplastic cell growth. These results show a role for MBD2 in cancer progression and provide support for the prospect of targeting MBD2 therapeutically in aggressive breast cancers. Mol Cancer Res; 9(8); 1152–62. ©2011 AACR.
Identifying Patients Hospitalized With Heart Failure at Risk for Unfavorable Future Quality of Life
Authors: Allen Larry A. , Gheorghiade Mihai , Reid Kimberly J. , Dunlay Shannon M. , Chan Paul S. , Hauptman Paul J. , Zannad Faiez , Konstam Marvin A. , Spertus John A. 
Published: June 2011

Background—
Communicating prognosis to enable shared decision-making is strongly endorsed by heart failure (HF) guidelines. Patients are concerned with both their quantity and quality of life (QoL). To facilitate the recognition of patients at high risk for unfavorable future QoL or death, we created a simple prognostic tool to estimate this combined outcome.

Methods and Results—

We identified factors associated with 6-month mortality or persistently unfavorable QoL, defined by Kansas City Cardiomyopathy Questionnaire (KCCQ) scores <45 at 1 and 24 weeks after hospital discharge, among 1458 patients from the Efficacy of Vasopressin Antagonism in HF Outcome Study with Tolvaptan (EVEREST). Within 24 weeks of discharge, 478 (32.8%) patients had died and 192 (13.2%) patients had serial KCCQ scores <45. After adjusting for 23 predischarge covariates, independent predictors of the combined end point included low admission KCCQ score, high B-type natriuretic peptide, hyponatremia, tachycardia, hypotension, absence of β-blocker therapy, and history of diabetes mellitus and arrhythmia. A simplified predischarge HF score for subsequent death or unfavorable QoL had moderate discrimination (
c
-statistic 0.72). Predischarge clinical covariates were substantially different in predicting the QoL end point as compared with traditional death or rehospitalization end points.

Conclusions—
At the time of hospital discharge, readily available clinical characteristics are associated with HF patients at high risk for persistently unfavorable QoL or death over the next 6 months. Such information can target patients for whom aggressive treatment options (eg, devices or transplantation) and/or end-of-life discussions should be strongly considered before hospital discharge.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00071331.
Prevalence of Inadequate Blood Pressure Control Among Veterans After Acute Ischemic Stroke Hospitalization
Authors: Roumie Christianne L. , Ofner Susan , Ross Joseph S. , Arling Greg , Williams Linda S. , Ordin Diana L. , Bravata Dawn M. 
Published: June 2011

Background—
Reducing blood pressure (BP) after stroke reduces risk for recurrent events. Our aim was to describe hypertension care among veterans with ischemic stroke including BP control by discharge and over the 6 months after the stroke event.

Methods and Results—
The Office of Quality and Performance Stroke Special Study included a systematic sample of veterans hospitalized for ischemic stroke in 2007. We examined BP control (<140/90 mm Hg) at discharge excluding those who died, enrolled in hospice, or had unknown discharge disposition (n=3640, n=3382 adjusted analysis). The second outcome was BP control (<140/90 mm Hg) within 6-months after stroke, excluding patients who died/readmitted within 30 days, were lost to follow-up, or did not have a BP recorded (n=2054, n=1915 adjusted analysis). The population was 62.7% white and 97.7% men; 46.9% were <65 years of age; and 29% and 37% had a history of cerebrovascular or cardiovascular disease, respectively. Among the 3640 stroke patients, 1573 (43%) had their last documented BP before discharge as >140/90 mm Hg. Black race (adjusted odds ratio, 0.77; 95% confidence interval, 0.65 to 0.91), diabetes (odds ratio, 0.73; 95% confidence interval, 0.62 to 0.86), and hypertension history (odds ratio, 0.51; 95% confidence interval, 0.42 to 0.63) were associated with lower odds for controlled BP at discharge. Of the 2054 stroke patients seen within 6 months from their index event, 673 (32.8%) remained uncontrolled. By 6 months after the event, neither race nor diabetes was associated with BP control, whereas history of hypertension continued to have lower odds of BP control. For each 10-point increase in systolic BP >140 mm Hg at discharge, odds of BP control within 6 months after discharge decreased by 12% (95% confidence interval [8%, 18%]).

Conclusions—
BP values in excess of national guidelines are common after stroke. Forty-three percent of patients were discharged with an elevated BP, and 33% remained uncontrolled by 6 months.
A Comparison of Southern Ocean Air–Sea Buoyancy Flux from an Ocean State Estimate with Five Other Products
Authors: Cerovečki Ivana , Talley Lynne D. , Mazloff Matthew R. 
Published: June 2011

Abstract
The authors have intercompared the following six surface buoyancy flux estimates, averaged over the years 2005–07: two reanalyses [the recent ECMWF reanalysis (ERA-Interim; hereafter ERA), and the National Centers for Environmental Prediction (NCEP)–NCAR reanalysis 1 (hereafter NCEP1)], two recent flux products developed as an improvement of NCEP1 [the flux product by Large and Yeager and the Southern Ocean State Estimate (SOSE)], and two ad hoc air–sea flux estimates that are obtained by combining the NCEP1 or ERA net radiative fluxes with turbulent flux estimates using the Coupled Ocean–Atmosphere Response Experiment (COARE) 3.0 bulk formulas with NCEP1 or ERA input variables.
The accuracy of SOSE adjustments of NCEP1 atmospheric fields (which SOSE uses as an initial guess and a constraint) was assessed by verification that SOSE reduces the biases in the NCEP1 fluxes as diagnosed by the Working Group on Air–Sea Fluxes (Taylor), suggesting that oceanic observations may be a valuable constraint to improve atmospheric variables.
Compared with NCEP1, both SOSE and Large and Yeager increase the net ocean heat loss in high latitudes, decrease ocean heat loss in the subtropical Indian Ocean, decrease net evaporation in the subtropics, and decrease net precipitation in polar latitudes. The large-scale pattern of SOSE and Large and Yeager turbulent heat flux adjustment is similar, but the magnitude of SOSE adjustments is significantly larger. Their radiative heat flux adjustments patterns differ. Turbulent heat fluxes determined by combining COARE bulk formulas with NCEP1 or ERA should not be combined with unmodified NCEP1 or ERA radiative fluxes as the net ocean heat gain poleward of 25°S becomes unrealistically large. The other surface flux products (i.e., NCEP1, ERA, Large and Yeager, and SOSE) balance more closely.
Overall, the statistical estimates of the differences between the various air–sea heat flux products tend to be largest in regions with strong ocean mesoscale activity such as the Antarctic Circumpolar Current and the western boundary currents.
Seasonal and Diurnal Variations in Aerosol Concentration on Whistler Mountain: Boundary Layer Influence and Synoptic-Scale Controls
Authors: Gallagher John P. , McKendry Ian G. , Macdonald Anne Marie , Leaitch W. Richard 
Published: June 2011

AbstractA mountain air chemistry observatory has been operational on the summit of Whistler Mountain in British Columbia, Canada, since 2002. A 1-yr dataset of condensation nuclei (CN) concentration from this site has been analyzed along with corresponding meteorological data to assess the frequency and patterns of influence from the planetary boundary layer (PBL). Characterization of air masses sampled from the site as either PBL influenced or representative of the free troposphere (FT) is important to subsequent analysis of the chemistry data. Median CN concentrations and seasonal trends were found to be comparable to other midlatitude mountain sites. Monthly median number concentrations ranged from 120 cm−3in January to 1601 cm−3in July. Using well-defined diurnal cycles in CN concentration as an indicator of air arriving from nearby valleys, PBL influence was found to occur on a majority of days during spring and summer and less frequently in late autumn and winter. Days with PBL influence were usually associated with synoptic-scale weather patterns that were conducive to convective mixing processes. Although more common in the warm season, vertical mixing capable of transporting valley air to the mountaintop also occurred in February during a period of high pressure aloft. In contrast, an August case study indicated that the more stable character of marine air masses can at times keep the PBL below the summit on summer days. Considerable variability in the synoptic-scale weather conditions at Whistler means that careful analysis of available datasets must be made to discriminate FT from PBL periods at the observatory.
Nonlinear Dynamics and Regional Variations in the MJO Skeleton
Authors: Majda Andrew J. , Stechmann Samuel N. 
Published: June 2011

Abstract
A minimal, nonlinear oscillator model is analyzed for the Madden–Julian oscillation (MJO) “skeleton” (i.e., its fundamental features on intraseasonal/planetary scales), which includes the following: (i) a slow eastward phase speed of roughly 5 m s−1, (ii) a peculiar dispersion relation with dω/dk ≈ 0, and (iii) a horizontal quadrupole vortex structure. Originally proposed in recent work by the authors, the fundamental mechanism involves neutrally stable interactions between (i) planetary-scale, lower-tropospheric moisture anomalies and (ii) the envelope of subplanetary-scale, convection/wave activity. Here, the model’s nonlinear dynamics are analyzed in a series of numerical experiments, using either a uniform sea surface temperature (SST) or a warm-pool SST. With a uniform SST, the results show significant variations in the number, strength, and/or locations of MJO events, including, for example, cases of a strong MJO event followed by a weaker MJO event, similar to the Tropical Ocean and Global Atmosphere Coupled Ocean–Atmosphere Response Experiment (TOGA COARE). With a warm-pool SST, MJO events often begin as standing oscillations and then propagate slowly eastward across the warm pool, a behavior imitating MJOs in nature. While displaying the fundamental features of the MJO skeleton, these MJO events had significant variations in their lifetimes and regional extents, and they displayed intense, irregular fluctuations in their amplitudes. The model reproduces all of these features of the MJO skeleton without including mechanisms for the MJO’s “muscle,” such as refined vertical structure and upscale convective momentum transport from subplanetary-scale convection/waves. Besides these numerical experiments, it is also shown that the nonlinear model conserves a total energy that includes a contribution from the convective activity.
Stratospheric Sudden Warmings as Self-Tuning Resonances. Part I: Vortex Splitting Events
Authors: Matthewman N. Joss , Esler J. G. 
Published: June 2011

Abstract
The fundamental dynamics of “vortex splitting” stratospheric sudden warmings (SSWs), which are known to be predominantly barotropic in nature, are reexamined using an idealized single-layer f-plane model of the polar vortex. The aim is to elucidate the conditions under which a stationary topographic forcing causes the model vortex to split, and to express the splitting condition as a function of the model parameters determining the topography and circulation.
For a specified topographic forcing profile the model behavior is governed by two nondimensional parameters: the topographic forcing height M and a surf-zone potential vorticity parameter Ω. For relatively low M, vortex splits similar to observed SSWs occur only for a narrow range of Ω values. Further, a bifurcation in parameter space is observed: a small change in Ω (or M) beyond a critical value can lead to an abrupt transition between a state with low-amplitude vortex Rossby waves and a sudden vortex split. The model behavior can be fully understood using two nonlinear analytical reductions: the Kida model of elliptical vortex motion in a uniform strain flow and a forced nonlinear oscillator equation. The abrupt transition in behavior is a feature of both reductions and corresponds to the onset of a nonlinear (self-tuning) resonance. The results add an important new aspect to the “resonant excitation” theory of SSWs. Under this paradigm, it is not necessary to invoke an anomalous tropospheric planetary wave source, or unusually favorable conditions for upward wave propagation, in order to explain the occurrence of SSWs.
Initial Studies with the Lightning Detector on the C/NOFS Satellite, and Cross Validation with WWLLN
Authors: Jacobson Abram R. , Holzworth Robert H. , McCarthy Michael P. , Pfaff Robert F. 
Published: June 2011

Abstract
The lightning detector (LD) on the Communications/Navigation Outage Forecast System (C/NOFS) satellite uses a pair of silicon photodiodes, viewing each flank at right angles to the satellite track over an extended field of view. The data product is a report every ½ s of the number of digitizer cycles (125 μs each) for which the detected power was in predefined ranges. The performance of this system over the first 2.5 years of the C/NOFS mission is discussed, statistics of its lightning observations are presented, and a statistical cross validation using the World-Wide Lightning Location Network (WWLLN) as a ground truth is provided. It is found that the LD reports of lightning, despite their blunt timing (½ s), show correlation with strokes detected and located by WWLLN. The irradiance of these strokes lies on the high-power flank of the irradiance distribution seen earlier by the FORTE satellite. Thus, the LD thresholds favor high-power lightning; it is shown that the closest portion of the field of view is more likely to provide WWLLN coincidences than is the furthest portion of the field of view. Statistics of lightning incidence are examined at low latitudes, versus longitude, and distributions that are consistent with those established earlier by the OTD and LIS instruments are retrieved. Finally, the longitude dependence of the irradiance per stroke is examined and the ways in which it differs between the three major lightning “hot spots” is explored. It is observed that the radiance per stroke over the Congo Basin is lower than that over the other two hot spots (Maritime Continent/South Asia and the Americas), consistent with earlier observations by the OTD imager.