bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase II and Biomarker Study of Ramucirumab, a Human Monoclonal Antibody Targeting the VEGF Receptor-2, as First-Line Monotherapy in Patients with Advanced Hepatocellular Cancer
Authors: Zhu Andrew X. , Finn Richard S. , Mulcahy Mary , Gurtler Jayne , Sun Weijing , Schwartz Jonathan D. , Dalal Rita P. , Joshi Adarsh , Hozak Rebecca R. , Xu Yihuan , Ancukiewicz Marek , Jain Rakesh K. , Nugent Francis W. , Duda Dan G. , Stuart Keith 
Published: October 2013

Abstract
Purpose: To assess the efficacy and safety of the anti-VEGF receptor-2 (VEGFR-2) antibody ramucirumab as first-line therapy in patients with advanced hepatocellular carcinoma and explore potential circulating biomarkers.
Experimental Design: Adults with advanced hepatocellular carcinoma and no prior systemic treatment received ramucirumab 8 mg/kg every two weeks until disease progression or limiting toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR) and overall survival (OS). Circulating biomarkers were evaluated before and after ramucirumab treatment in a subset of patients.
Results: Forty-two patients received ramucirumab. Median PFS was 4.0 months [95% confidence interval (CI), 2.6–5.7], ORR was 9.5% (95% CI, 2.7–22.6; 4/42 patients had a partial response), and median OS was 12.0 months (95% CI, 6.1–19.7). For patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease, median OS was 4.4 months (95% CI, 0.5–9.0) for patients with Child-Pugh B cirrhosis versus 18.0 months (95% CI, 6.1–23.5) for patients with Child-Pugh A cirrhosis. Treatment-related grade ≥3 toxicities included hypertension (14%), gastrointestinal hemorrhage and infusion-related reactions (7% each), and fatigue (5%). There was one treatment-related death (gastrointestinal hemorrhage). After treatment with ramucirumab, there was an increase in serum VEGF and placental growth factor (PlGF) and a transient decrease in soluble VEGFR-2.
Conclusion: Ramucirumab monotherapy may confer anticancer activity in advanced hepatocellular carcinoma with an acceptable safety profile. Exploratory biomarker studies showed changes in circulating VEGF, PlGF, and sVEGFR-2 that are consistent with those seen with other anti-VEGF agents. Clin Cancer Res; 19(23); 6614–23. ©2013 AACR.
Systematic Screen Identifies miRNAs That Target RAD51 and RAD51D to Enhance Chemosensitivity
Authors: Huang Jen-Wei , Wang Yemin , Dhillon Kiranjit K. , Calses Philamer , Villegas Emily , Mitchell Patrick S. , Tewari Muneesh , Kemp Christopher J. , Taniguchi Toshiyasu 
Published: October 2013

Abstract
Homologous recombination mediates error-free repair of DNA double-strand breaks (DSB). RAD51 is an essential protein for catalyzing homologous recombination and its recruitment to DSBs is mediated by many factors including RAD51, its paralogs, and breast/ovarian cancer susceptibility gene products BRCA1/2. Deregulation of these factors leads to impaired DNA repair, genomic instability, and cellular sensitivity to chemotherapeutics such as cisplatin and PARP inhibitors. microRNAs (miRNA) are short, noncoding RNAs that posttranscriptionally regulate gene expression; however, the contribution of miRNAs in the regulation of homologous recombination is not well understood. To address this, a library of human miRNA mimics was systematically screened to pinpoint several miRNAs that significantly reduce RAD51 foci formation in response to ionizing radiation in human osteosarcoma cells. Subsequent study focused on two of the strongest candidates, miR-103 and miR-107, as they are frequently deregulated in cancer. Consistent with the inhibition of RAD51 foci formation, miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA-damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107–mediated chemosensitization. Furthermore, endogenous regulation of RAD51D by miR-103/107 was observed in several tumor subtypes. Taken together, these data show that miR-103 and miR-107 overexpression promotes genomic instability and may be used therapeutically to chemosensitize tumors.
Implications: These findings demonstrate a role for miR-103 and -107 in regulating DNA damage repair, thereby identifying new players in the progression of cancer and response to chemotherapy. Mol Cancer Res; 11(12); 1564–73. ©2013 AACR.
Activation of the Wnt Pathway through AR79, a GSK3β Inhibitor, Promotes Prostate Cancer Growth in Soft Tissue and Bone
Authors: Jiang Yuan , Dai Jinlu , Zhang Honglai , Sottnik Joe L. , Keller Jill M. , Escott Katherine J. , Sanganee Hitesh J. , Yao Zhi , McCauley Laurie K. , Keller Evan T. 
Published: October 2013

Abstract
Due to its bone anabolic activity, methods to increase Wnt activity, such as inhibitors of dickkopf-1 and sclerostin, are being clinically explored. Glycogen synthase kinase (GSK3β) inhibits Wnt signaling by inducing β-catenin degradation, and a GSK3β inhibitor, AR79, is being evaluated as an osteoanabolic agent. However, Wnt activation has the potential to promote tumor growth; therefore, the goal of this study was to determine if AR79 has an impact on the progression of prostate cancer. Prostate cancer tumors were established in subcutaneous and bone sites of mice followed by AR79 administration, and tumor growth, β-catenin activation, proliferation, and apoptosis were assessed. Additionally, prostate cancer and osteoblast cell lines were treated with AR79, and β-catenin status, proliferation (with β-catenin knockdown in some cases), and proportion of ALDH+CD133+ stem-like cells were determined. AR79 promoted prostate cancer tumor growth, decreased phospho-β-catenin, increased total and nuclear β-catenin, and increased tumor-induced bone remodeling. Additionally, AR79 treatment decreased caspase-3 and increased Ki67 expression in tumors and increased bone formation in normal mouse tibiae. Similarly, AR79 inhibited β-catenin phosphorylation, increased nuclear β-catenin accumulation in prostate cancer and osteoblast cell lines, and increased proliferation of prostate cancer cells in vitro through β-catenin. Furthermore, AR79 increased the ALDH+CD133+ cancer stem cell–like proportion of the prostate cancer cell lines. In conclusion, AR79, while being bone anabolic, promotes prostate cancer cell growth through Wnt pathway activation.
Implications: These data suggest that clinical application of pharmaceuticals that promote Wnt pathway activation should be used with caution as they may enhance tumor growth. Mol Cancer Res; 11(12); 1597–610. ©2013 AACR.
Aberrant DNA Methylation at Genes Associated with a Stem Cell-like Phenotype in Cholangiocarcinoma Tumors
Authors: Sriraksa Ruethairat , Zeller Constanze , Dai Wei , Siddiq Afshan , Walley Andrew J. , Limpaiboon Temduang , Brown Robert 
Published: October 2013

Abstract
Genetic abnormalities of cholangiocarcinoma have been widely studied; however, epigenomic changes related to cholangiocarcinogenesis have been less well characterized. We have profiled the DNA methylomes of 28 primary cholangiocarcinoma and six matched adjacent normal tissues using Infinium's HumanMethylation27 BeadChips with the aim of identifying gene sets aberrantly and epigenetically regulated in this tumor type. Using a linear model for microarray data, we identified 1610 differentially methylated autosomal CpG sites, with 809 hypermethylated (representing 603 genes) and 801 hypomethylated (representing 712 genes) in cholangiocarcinoma versus adjacent normal tissues (false-discovery rate ≤ 0.05). Gene ontology and gene set enrichment analyses identified gene sets significantly associated with hypermethylation at linked CpG sites in cholangiocarcinoma including homeobox genes and target genes of PRC2, EED, SUZ12, and histone H3 trimethylation at lysine 27. We confirmed frequent hypermethylation at the homeobox genes HOXA9 and HOXD9 by bisulfite pyrosequencing in a larger cohort of cholangiocarcinoma (n = 102). Our findings indicate a key role for hypermethylation of multiple CpG sites at genes associated with a stem cell-like phenotype as a common molecular aberration in cholangiocarcinoma. These data have implications for cholangiocarcinogenesis, as well as possible novel treatment options using histone methyltransferase inhibitors. Cancer Prev Res; 6(12); 1348–55. ©2013 AACR.
A Chimeric RNA Characteristic of Rhabdomyosarcoma in Normal Myogenesis Process
Authors: Yuan Huiling , Qin Fujun , Movassagh Mercedeh , Park Hong , Golden Wendy , Xie Zhongqiu , Zhang Peng , Sklar Jeffrey , Li Hui 
Published: October 2013

Abstract
Gene fusions and their chimeric products are common features of neoplasia. Given that many cancers arise by the dysregulated recapitulation of processes in normal development, we hypothesized that comparable chimeric gene products may exist in normal cells. Here, we show that a chimeric RNA, PAX3–FOXO1, identical to that found in alveolar rhabdomyosarcoma, is transiently present in cells undergoing differentiation from pluripotent cells into skeletal muscle. Unlike cells of rhabdomyosarcoma, these cells do not seem to harbor the t(2;13) chromosomal translocation. Importantly, both PAX3–FOXO1 RNA and protein could be detected in the samples of normal fetal muscle. Overexpression of the chimera led to continuous expression of MYOD and MYOG—two myogenic markers that are overexpressed in rhabdomyosarcoma cells. Our results are consistent with a developmental role of a specific chimeric RNA generated in normal cells without the corresponding chromosomal rearrangement at the DNA level seen in neoplastic cells presumably of the same lineage.
Significance: A chimeric fusion RNA, PAX3–FOXO1, associated with alveolar rhabdomyosarcoma, is also present in normal non-cancer cells and tissues. Its transient expression nature and the absence of t(2;13) chromosomal translocation are consistent with a posttranscriptional mechanism. When constantly expressed, PAX3–FOXO1 interfered with the muscle differentiation process, which presumably contributes to tumorigenesis. Cancer Discov; 3(12); 1394–1403. ©2013 AACR.
This article is highlighted in the In This Issue feature, p. 1317
Interplay Between Mitral Regurgitation and Transcatheter Aortic Valve Replacement With the CoreValve Revalving System
Authors: Bedogni Francesco , Latib Azeem , De Marco Federico , Agnifili Mauro , Oreglia Jacopo , Pizzocri Samuele , Latini Roberto A. , Lanotte Stefania , Petronio Anna Sonia , De Carlo Marco , Ettori Federica , Fiorina Claudia , Poli Arnaldo , Cirri Silvia , De Servi Stefano , Ramondo Angelo , Tarantini Giuseppe , Marzocchi Antonio , Fiorilli Rosario , Klugmann Silvio , Ussia Gian Paolo , Tamburino Corrado , Maisano Francesco , Brambilla Nedy , Colombo Antonio , Testa Luca 
Published: October 2013

Background—
Little is known of the prognostic significance of mitral regurgitation (MR) on transcatheter aortic valve replacement (TAVR), the impact of TAVR on MR severity, and the variables associated with possible post-TAVR improvement in MR. We evaluated these issues in a multicenter registry of patients undergoing CoreValve Revalving System–TAVR.

Methods and Results—

Among 1007 consecutive patients, 670 (66.5%), 243 (24.1%), and 94 (9.3%) presented with no/mild, moderate, and severe MR, respectively. At 1 month after TAVR, patients with severe or moderate MR showed comparable mortality rates (odds ratio, 1.1; 95% confidence interval [95% CI], 0.7–1.55;
P
=0.2), but both were significantly higher compared with patients with mild/no MR (odds ratio, 2.2; 95% CI, 1.78–3.28;
P
<0.001; and odds ratio, 1.9; 95% CI, 1.1–3.3;
P
=0.02, respectively).

One-year mortality was also similar between patients with severe and those with moderate MR (hazard ratio, 1.4; 95% CI, 0.94–2.4;
P
=0.06) and still significantly higher compared with patients with mild/no MR (hazard ratio, 1.7; 95% CI, 1.2–3.41;
P
<0.001; and hazard ratio, 1.4; 95% CI, 1.2–2.2;
P
=0.03, respectively). Severe pulmonary hypertension, atrial fibrillation, and MR more than mild, but not an improvement of ≥1 grade in MR severity, were independent predictors of mortality at 1 year. At 1 year, an improved MR was observed in 47% and 35% of patients with severe and moderate MR, respectively. The rate of low implantation was consistent across groups with improved, unchanged, or worsened MR. A functional type of MR and the absence of severe pulmonary hypertension and atrial fibrillation independently predicted the improvement in MR severity.

Conclusions—
Baseline MR greater than mild is associated with higher mortality after CoreValve Revalving System–TAVR. A significant improvement in MR was more likely in patients with functional MR and without severe pulmonary hypertension or atrial fibrillation. The improvement in MR did not independently predict mortality.
Chronic Heart Failure Is Associated With Transforming Growth Factor Beta‐Dependent Yield and Functional Decline in Atrial Explant‐Derived c‐Kit+ Cells
Authors: Zakharova Liudmila , Nural‐Guvener Hikmet , Nimlos James , Popovic Snjezana , Gaballa Mohamed A. 
Published: October 2013

Background

Cardiac c‐Kit+ cells isolated from cardiac explant‐derived cells modestly improve cardiac functions after myocardial infarction; however, their full potential has not yet been realized. For instance, the majority of potential candidates for cell therapy suffer from chronic heart failure (
CHF
), and it is unclear how this disease affects the explant‐derived progenitor cells. Therefore, the objective of this study was to determine the effect of
CHF
on the number and phenotype of cardiac explant c‐Kit+ progenitors and elucidate mechanisms of their regulation.

Methods and Results

Myocardial infarction was created by left anterior descending coronary artery occlusion. Sham‐operated animals were used as a control group.
CHF
‐developed infarcted animals were selected on the basis of left ventricle end‐diastolic pressure ≥20 mm Hg and scar size ≥30%. Here, we found that
CHF
atrial explants produced less c‐Kit+ cells than sham explants.
CHF
‐derived c‐Kit+ cells exhibited upregulated transforming growth factor–β (
TGF
‐β) signaling, increased level of epithelial to mesenchymal transition markers, and diminished expression of pluripotency markers compared with shams. We show that intervention with
TGF
‐β signaling by inhibiting
TGF
‐β receptor type I or Smad 2/3 using small‐molecule inhibitors improved c‐Kit+ cell yield, attenuated epithelial to mesenchymal transition markers, stimulated the pluripotency marker Nanog, and improved efficiency of c‐Kit+ cell differentiation toward cardiomyocyte‐like cells in vitro.

Conclusions

Taken together, our findings suggest that
TGF
‐β inhibition positively modulates c‐Kit+ cell phenotype and function in vitro, and this strategy may be considered in optimizing cardiac progenitor function and cell expansion protocols for clinical application.
Twenty‐Two‐Year Population Trends in Sodium and Potassium Consumption: The Minnesota Heart Survey
Authors: Meyer Katie A. , Harnack Lisa J. , Luepker Russell V. , Zhou Xia , Jacobs David R. , Steffen Lyn M. 
Published: October 2013

Background
Limiting dietary sodium consumption is a core lifestyle recommendation for the prevention of hypertension. There is increasing evidence that low potassium consumption also increases hypertension risk. We estimated sex‐specific 22‐year trends in sodium and potassium consumption.

Methods and Results

We used data from the
M
innesota
H
eart
S
urvey, which performs surveillance of risk factors for cardiovascular disease in the
M
inneapolis–
S
t.
P
aul metropolitan area. The
M
innesota
H
eart
S
urvey is a random population‐based sample of free‐living adults aged 25 to 74. Surveys were conducted in 1985–1987 (n=2273), 1990–1992 (n=2487), 1995–1997 (n=1842), 2000–2002 (n=2759), and 2007–2009 (n=1502). Dietary intake of sodium and potassium was estimated from one 24‐hour dietary recall. Over 22 years, age‐adjusted sodium and potassium intake among men remained relatively stable in 1985–1987 and 2007–2009 (
P
trend
=0.41 and 0.29, respectively); sodium ranged from 3820 mg/day (1995–1997) to 3968 mg/day (2007–2009) and potassium from 3111 mg/day (2000–2002) to 3249 mg/day (1995–1997). Sodium and potassium intake increased among women, from 2531 mg/day in 1985–1987 to 2854 mg/day in 2007–2009 (
P
trend
=0.001) for sodium and from 2285 to 2533 mg/day (
P
trend
<0.0001) for potassium. We observed stable or increasing sodium and potassium intake within some strata of age, education, and body mass index.

Conclusions
Despite long‐standing public health recommendations to limit sodium intake to <2300 mg/day, high sodium intake levels have persisted over the past 22 years. Furthermore, although potassium consumption increased in some subgroups over the study period, mean consumption remained significantly lower than the recommended 4700 mg/day in all groups.
On the correct name of Icterus bullockii (Passeriformes: Icteridae)
Authors: CHESSER R. TERRY 
Published: October 2013

William Bullock was an Englishman who owned the Egyptian Hall (also known as the London Museum or Bullock’s Museum) at Piccadilly in London, a museum opened in 1812 to display his collection of antiquities, artifacts, and natural history specimens. Following the sale of Bullock’s collection in 1819, the Egyptian Hall served as an exhibition space. Bullock and his son, William Bullock, Jr., both enthusiastic naturalists, travelled in Mexico in 1822–1823, spending some six months together collecting natural history specimens and other artifacts for exhibition and investigating mining and other business opportunities (Costeloe 2006). The elder Bullock returned to London with the collections in 1823, but his son, while ostensibly managing the silver mine his father had purchased in Temascaltepec, outside of Mexico City, continued to travel in Mexico and collect specimens, often in the company of German naturalist Ferdinand Deppe (Costeloe 2006). William Bullock, Sr., meanwhile prepared the Mexican collection for exhibition at the Egyptian Hall. Twin exhibitions on ancient and modern Mexico opened, with much fanfare, in April 1824, and were a great success, remaining open until September 1825 (Costeloe 2006). Afterwards, the contents of the exhibitions were dispersed via auction, but not before Bullock had made the bird specimens available to English naturalist William Swainson for “recording this portion of his discoveries” (Swainson 1827: 365).
The Fast Longwave and Shortwave Flux (FLASHFlux) Data Product: Single-Scanner Footprint Fluxes
Authors: Kratz David P. , Stackhouse Paul W. , Gupta Shashi K. , Wilber Anne C. , Sawaengphokhai Parnchai , McGarragh Greg R. 
Published: October 2013

AbstractThe Clouds and the Earth’s Radiant Energy Systems (CERES) project utilizes radiometric measurements taken aboard the Terra and Aqua spacecrafts to derive the world-class data products needed for climate research. Achieving the exceptional fidelity of the CERES data products, however, requires a considerable amount of processing to assure quality and to verify accuracy and precision, which results in the CERES data being released more than 6 months after the satellite observations. For most climate studies such delays are of little consequence; however, there are a significant number of near–real time uses for CERES data products. The Fast Longwave and Shortwave Radiative Flux (FLASHFlux) data product was therefore developed to provide a rapid release version of the CERES results, which could be made available to the research and applications communities within 1 week of the satellite observations by exchanging some accuracy for speed. FLASHFlux has both achieved this 1-week processing objective and demonstrated the ability to provide remarkably good agreement when compared with the CERES data products for both the instantaneous single-scanner footprint (SSF) fluxes and the time- and space-averaged (TISA) fluxes. This paper describes the methods used to expedite the production of the FLASHFlux SSF fluxes by utilizing data from the CERES and Moderate Resolution Imaging Spectroradiometer instruments, as well as other meteorological sources. This paper also reports on the validation of the FLASHFlux SSF results against ground-truth measurements and the intercomparison of FLASHFlux and CERES SSF results. A complementary paper will discuss the production and validation of the FLASHFlux TISA fluxes.
Introducing an Irrigation Scheme to a Regional Climate Model: A Case Study over West Africa
Authors: Marcella Marc P. , Eltahir Elfatih A. B. 
Published: October 2013

Abstract
This article presents a new irrigation scheme and biome to the dynamic vegetation model, Integrated Biosphere Simulator (IBIS), coupled to version 3 of the Regional Climate Model (RegCM3-IBIS). The new land cover allows for only the plant functional type (crop) to exist in an irrigated grid cell. Irrigation water (i.e., negative runoff) is applied until the soil root zone reaches relative field capacity. The new scheme allows for irrigation scheduling (i.e., when to apply water) and for the user to determine the crop to be grown. Initial simulations show a large sensitivity of the scheme to soil texture types, how the water is applied, and the climatic conditions over the region. Application of the new scheme is tested over West Africa, specifically Mali and Niger, to simulate the potential irrigation of the Niger River. A realistic representation of irrigation of the Niger River is performed by constraining the land irrigated by the annual flow of the Niger River and the amount of arable land in the region as reported by the Food and Agriculture Organization of the United Nations (FAO). A 30-yr simulation including irrigated cropland is compared to a 30-yr simulation that is identical but with no irrigation of the Niger. Results indicate a significant greening of the irrigated land as evapotranspiration over the crop fields largely increases—mostly via increases in transpiration from plant growth. The increase in the evapotranspiration, or latent heat flux (by 65–150 W m−2), causes a significant decrease in the sensible heat flux while surface temperatures cool on average by nearly 5°C. This cooling is felt downwind, where average daily temperatures outside the irrigation are reduced by 0.5°–1.0°C. Likewise, large increases in 2-m specific humidity are experienced across the irrigated cropland (on the order of 5 g kg−1) but also extend farther north and east, reflecting the prevailing surface southwesterlies. Changes (decreases) in rainfall are found only over the irrigated lands of west Mali. The decrease in rainfall can be explained by the large surface cooling and collapse of the boundary layer (by approximately 500 m). Both lead to a reduction in the triggering of convection as the convective inhibition, or negative buoyant energy, is never breached. Nevertheless, the new scheme and land cover allows for a novel line of research that can accurately reflect the effects of irrigation on climate and the surrounding environment using a dynamic vegetation model coupled to a regional climate model.