bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimates of yet-to-find impact crater population on Earth
Authors: Stewart S.A. 
Published: January 2011

Abstract:

One hundred and seventy-six craters on Earth are currently accepted as resulting from bolide impact; this list is growing at a rate of approximately two craters per year because of new discoveries and revised interpretations. Here we take the subset of craters most relevant to sedimentary basin exploration and utilization (Phanerozoic kilometre-scale craters) and tackle the question of how many remain to be found in Phanerozoic strata on Earth. A surprising range in predictions of crater numbers is obtained from published crater population functions, reaching two orders of magnitude variation for craters in the range 1–5 km diameter. This range in predictions is largely due to variations in treatment of impactor breakup in the atmosphere. Also required is quantification of the total area and timespan of Phanerozoic sediment currently preserved on Earth; an estimate of 8.87 × 10
15
km
2
a is derived here. Together with a relatively conservative crater population function this yields a prediction of 845 craters; subtracting the 131 known Phanerozoic craters larger than 1 km leaves a predicted population yet to find of 714, of which 228 are larger than 2.5 km. Uncertainties, subsets of this population, and spatial distribution are also considered.
Phase equilibrium constraints on conditions of granulite-facies metamorphism at Scourie, NW Scotland
Authors: Johnson T.E. , White R.W. 
Published: January 2011

Abstract:

The metamorphic evolution of a metapyroxenite and metagabbro from Scourie, NW Scotland, is investigated using phase equilibria modelled in the NCFMASHTO (Na
2
O–CaO–FeO–MgO–Al
2
O
3
–SiO
2
–H
2
O–TiO
2
–O) system. The calculated stability fields for the observed assemblages in each rock overlap and imply conditions of 8.5–11.5 kbar and 875–975 °C for the peak of granulite-facies (Badcallian) metamorphism. The lack of any evidence for the former presence of garnet in the metapyroxenite suggests that the rocks cannot have reached pressures much in excess of those recorded at the metamorphic peak. The growth of coronas of plagioclase, orthopyroxene and magnetite replacing garnet in the metagabbro is consistent with near-isothermal retrograde decompression from the metamorphic peak to pressures of 7–9 kbar. The constraints on the pressure–temperature evolution imposed by the modelled phase equilibria are more consistent with a process of crustal growth dominated by magmatic accretion rather than by significant tectonic thickening during the early Scourian.

Supplementary material:

Mineral chemical data are available at
http://www.geolsoc.org.uk/SUP18436
.
Design as learning---or "knowledge creation"---the SECI model
Authors: Dubberly Hugh , Evenson Shelley 
Published: January 2011

Models help bridge the gap between observing and making---especially when systems are involved (as in designing for interaction, service, and evolution). This forum introduces new models, links them to existing models, and describes their history and why they matter.

Hugh Dubberly, Editor | hugh@dubberly.com
Mast Cell 5-Lipoxygenase Activity Promotes Intestinal Polyposis in APCΔ468 Mice
Authors: Cheon Eric C. , Khazaie Khashayarsha , Khan Mohammad W. , Strouch Matthew J. , Krantz Seth B. , Phillips Joseph , Blatner Nichole R. , Hix Laura M. , Zhang Ming , Dennis Kristen L. , Salabat Mohammed R. , Heiferman Michael , Grippo Paul J. , Munshi Hidayatullah G. , Gounaris Elias , Bentrem David J. 
Published: January 2011

AbstractArachidonic acid metabolism has been implicated in colon carcinogenesis, but the role of hematopoietic 5-lipoxygenase (5LO) that may impact tumor immunity in development of colon cancer has not been explored. Here we show that tissue-specific deletion of the 5LO gene in hematopoietic cells profoundly attenuates polyp development in the APCΔ468 murine model of colon polyposis. In vitro analyses indicated that mast cells in particular utilized 5LO to limit proliferation of intestinal epithelial cells and to mobilize myeloid-derived suppressor cells (MDSCs). Mice lacking hemapoietic expression of 5LO exhibited reduced recruitment of MDSCs to the spleen, mesenteric lymph nodes, and primary tumor site. 5LO deficiency also reduced the activity in MDSCs of arginase-1, which is thought to be critical for MDSC function. Together, our results establish a pro-tumorigenic role of hematopoietic 5LO in the immune microenvironment and suggest 5LO inhibition as an avenue for future investigation in treatment of colorectal polyposis and cancer. Cancer Res; 71(5); 1627–36. ©2011 AACR.
Antagonism of VEGF by Genetically Engineered Dendritic Cells Is Essential to Induce Antitumor Immunity against Malignant Ascites
Authors: Sugiyama Masahiko , Kakeji Yoshihiro , Tsujitani Shunichi , Harada Yui , Onimaru Mitsuho , Yoshida Kumi , Tanaka Sakura , Emi Yasunori , Morita Masaru , Morodomi Yosuke , Hasegawa Mamoru , Maehara Yoshihiko , Yonemitsu Yoshikazu 
Published: January 2011

AbstractMalignant ascitis (MA) is a highly intractable and immunotherapy-resistant state of advanced gastrointestinal and ovarian cancers. Using a murine model of MA with CT26 colon cancer cells, we here determined that the imbalance between the VEGF-A/vascular permeability factor and its decoy receptor, soluble fms-like tryrosine kinase receptor-1 (sFLT-1), was a major cause of MA resistance to dendritic cell (DC)-based immunotherapy. We found that the ratio of VEGF-A/sFLT-1 was increased not only in murine but also in human MA, and F-gene–deleted recombinant Sendai virus (rSeV/dF)-mediated secretion of human sFLT-1 by DCs augmented not only the activity of DCs themselves, but also dramatically improved the survival of tumor-bearing animals associated with enhanced CTL activity and its infiltration to peritoneal tumors. These findings were not seen in immunodeficient mice, indicating that a VEGF-A/sFLT-1 imbalance is critical for determining the antitumor immune response by DC-vaccination therapy against MA. Mol Cancer Ther; 10(3); 540–9. ©2011 AACR.
Anticancer Activity of a Combination of Cisplatin and Fisetin in Embryonal Carcinoma Cells and Xenograft Tumors
Authors: Tripathi Rakshamani , Samadder Tanmoy , Gupta Sarika , Surolia Avadhesha , Shaha Chandrima 
Published: January 2011

Abstract
Use of chemotherapeutic drug cisplatin is limited because of its toxicity. Therefore, efforts continue for the discovery of novel combination therapies with cisplatin to reduce its effective treatment dose. This study evaluates the potential of fisetin, a flavonoid, to increase cisplatin cytotoxicity in human embryonal carcinoma NT2/D1 cells. Addition of fisetin to cisplatin enhanced cisplatin cytoxicity in vitro at four times lower dose than that required by cisplatin monotherapy for similar cytotoxic effects. Cisplatin, fisetin monotherapy, and addition of fisetin to cisplatin in a combination increased FasL expression. Cisplatin and fisetin as single agents activated caspases-8 and -3 and caspases-9 and -7, respectively, whereas combination treatment activated all 4 caspases. Increases in p53 and p21 and decreases in cyclin B1 and survivin occurred, all effects being more exaggerated with the combination. Fisetin, with or without cisplatin, increased expression of proapoptotic protein Bak and induced its mitochondrial oligomerization. Bid truncation and mitochondrial translocation of Bid and p53 was induced by fisetin in the presence or absence of cisplatin. Downregulation of p53 by short hairpin RNA during drug treatment decreased p21 levels but caused survivin increase, thus reducing cell death. Upstream to p53, inhibition of p38 phosphorylation reduced p53 phosphorylation and cell death. In a NT2/D1 mouse xenograft model, combination therapy was most effective in reducing tumor size. In summary, findings of this study suggest that addition of fisetin to cisplatin activates both the mitochondrial and the cell death receptor pathway and could be a promising regimen for the elimination of embryonal carcinoma cells. Mol Cancer Ther; 10(2); 255–68. ©2011 AACR.
Low-Dose Fractionated Radiation Potentiates the Effects of Cisplatin Independent of the Hyper-Radiation Sensitivity in Human Lung Cancer Cells
Authors: Gupta Seema , Koru-Sengul Tulay , Arnold Susanne M. , Devi Gayathri R. , Mohiuddin Mohammed , Ahmed Mansoor M. 
Published: January 2011

AbstractIn this study, the role of hyper-radiation sensitivity (HRS) in potentiating the effects of cisplatin by low-dose fractionated radiation (LDFRT) was evaluated in four human non–small cell lung cancer cell lines. Presence of HRS and cisplatin enhancement ratio (CER) by LDFRT/2 Gy was assessed using colony-forming and apoptotic assays. Cell-cycle disturbances were studied by flow cytometry. Expression of genes involved in apoptosis was assessed using real-time reverse transcriptase PCR arrays. H-157 cells showed a distinct HRS region, followed by UKY-29 and A549 cells, whereas it was absent in H460 cells, which when lack HRS showed maximum CER with LDFRT (4 × 0.5 Gy) both by clonogenic inhibition and by apoptosis compared with single fraction of 2 Gy whereas the most radioresistant A549 cells had the least CER, with no significant differences between LDFRT or 2 Gy. Interestingly, in H-157 cells, a more pronounced CER was observed with LDFRT when assessed by apoptosis but clonogenic inhibition-CER was higher with 2 Gy than with LDFRT. Excluding H-157 cells, the CER by LDFRT was inversely proportional to radioresistance [(determined by D0, the dose to reduce survival by 67% from any point on the linear portion of the survival curve or surviving fraction (SF) at 2 Gy (SF2)] of the cells. LDFRT alone or in combination with cisplatin induced larger number of proapoptotic genes than 2 Gy or cisplatin + 2 Gy in cells showing HRS when compared to H460 cells that lack HRS. These findings indicate that chemopotentiation by LDFRT is correlated more with the intrinsic radiation sensitivity of the non–small lung cancer cells than the HRS phenomenon whereas the mode of cell killing is both through apoptosis and clonogenic inhibition. Mol Cancer Ther; 10(2); 292–302. ©2011 AACR.
A Robust High-Content Imaging Approach for Probing the Mechanism of Action and Phenotypic Outcomes of Cell-Cycle Modulators
Authors: Sutherland Jeffrey J. , Low Jonathan , Blosser Wayne , Dowless Michele , Engler Thomas A. , Stancato Louis F. 
Published: January 2011

Abstract
High-content screening is increasingly used to elucidate changes in cellular biology arising from treatment with small molecules and biological probes. We describe a cell classifier for automated analysis of multiparametric data from immunofluorescence microscopy and characterize the phenotypes of 41 cell-cycle modulators, including several protein kinase inhibitors in preclinical and clinical development. This method produces a consistent assessment of treatment-induced phenotypes across experiments done by different biologists and highlights the prevalence of nonuniform and concentration-dependent cellular response to treatment. Contrasting cell phenotypes from high-content screening to kinase selectivity profiles from cell-free assays highlights the limited utility of enzyme potency ratios in understanding the mechanism of action for cell-cycle kinase inhibitors. Our cell-level approach for assessing phenotypic outcomes is reliable, reproducible and capable of supporting medium throughput analyses of a wide range of cellular perturbations. Mol Cancer Ther; 10(2); 242–54. ©2011 AACR.
Chromatin Structure Predicts Epigenetic Therapy Responsiveness in Sarcoma
Authors: Mills Joslyn , Hricik Todd , Siddiqi Sara , Matushansky Igor 
Published: January 2011

Abstract
To formally explore the potential therapeutic effect of histone deacetylase inhibitors (HDACI) and DNA-methyltransferase inhibitors (DNA-MI) on sarcomas, we treated a large sarcoma cell line panel with five different HDACIs in the absence and presence of the DNA-MI decitabine. We observed that the IC50 value of each HDACI was consistent for all cell lines whereas decitabine as a single agent showed no growth inhibition at standard doses. Combination HDACI/DNA-MI therapy showed a preferential synergism for specific sarcoma cell lines. Subsequently, we identified and validated (in vitro and in vivo) a two-gene set signature (high CUGBP2; low RHOJ) that associated with the synergistic phenotype. We further uncover that the epigenetic synergism leading to specific upregulation of CDKI p21 in specific cell lines is a function of the differences in the degree of baseline chromatin modification. Finally, we show that these chromatin and gene expression patterns are similarly present in the majority of high-grade primary sarcomas. Our results provide the first demonstration of a gene set that can predict responsiveness to HDACI/DNA-MI and links this responsiveness mechanistically to the baseline chromatin structure. Mol Cancer Ther; 10(2); 313–24. ©2011 AACR.
Transcription Factor Stat5 Knockdown Enhances Androgen Receptor Degradation and Delays Castration-Resistant Prostate Cancer Progression In vivo
Authors: Thomas Christian , Zoubeidi Amina , Kuruma Hidetoshi , Fazli Ladan , Lamoureux Francois , Beraldi Eliana , Monia Brett P. , MacLeod A. Robert , Thüroff Joachim W. , Gleave Martin E. 
Published: January 2011

Abstract
Signal transducer and activator of transcription 5 (Stat5) plays an important role in the transition of prostate cancer (PCa) to its castrate-resistant state. Pharmacologic targeting of Stat5 is a rational approach to delay castrate-resistant progression, in part, because Stat5 cooperates with the androgen receptor (AR) to promote PCa progression. Immunostaining of tissue microarrays was used to correlate Stat5 expression with Gleason grade and to characterize changes in treatment-naive and androgen-deprived human PCa. Potency of a Stat5 antisense oligonucleotide (ASO) on Stat5 knockdown, cell growth, and apoptosis was assessed in LNCaP, C4-2, and DU145 cells. Effects of Stat5 knockdown on AR activity and stability was assessed using a PSA transactivation-luciferase assay and cyclohexamide plus MG132 treatment, respectively. LNCaP tumor-bearing mice were castrated and randomly assigned to treatment with Stat5-ASO or controls. Here, we show that the frequency of Stat5 expression is significantly increased in high Gleason grade as well as in hormone-treated PCa. Also, specific knockdown of Stat5 with ASO abrogates androgen-induced AR nuclear translocation and PSA transactivation despite R1881 stimulation. Moreover, Stat5 knockdown destabilizes AR, which leads to AR degradation via the proteasome. Shown for the first time as a preclinical proof-of-principle, Stat5 knockdown with Stat5-ASO significantly delays CRPC tumor progression in vivo. Thereby, we are able to recapitulate our in vitro results by reducing serum PSA and expression levels of target proteins in the xenograft tumors. Mol Cancer Ther; 10(2); 347–59. ©2011 AACR.
PIK3CA Mutations in Patients with Advanced Cancers Treated with PI3K/AKT/mTOR Axis Inhibitors
Authors: Janku Filip , Tsimberidou Apostolia M. , Garrido-Laguna Ignacio , Wang Xuemei , Luthra Rajyalakshmi , Hong David S. , Naing Aung , Falchook Gerald S. , Moroney John W. , Piha-Paul Sarina A. , Wheler Jennifer J. , Moulder Stacy L. , Fu Siqing , Kurzrock Razelle 
Published: January 2011

Abstract
Preclinical data suggest that PIK3CA mutations predict response to PI3K/AKT/mTOR inhibitors. Concomitant KRAS or BRAF mutations may mediate resistance. Therefore, tumors from patients referred to the phase I program for targeted therapy starting in October 2008 were analyzed for PIK3CA mutations using PCR-based DNA sequencing of exons 9 and 20. Consecutive patients with diverse tumor types and PIK3CA mutation were treated whenever possible with agents targeting the PI3K/AKT/mTOR pathway. Overall, PIK3CA mutations were detected in 25 of 217 patients (11.5%; exon 9, n = 11; exon 20, n = 14). In tumor types with more than 10 patients tested, PIK3CA mutations were most frequent in endometrial (3 of 14, 21%), ovarian (5 of 30, 17%), colorectal (9 of 54, 17%), breast (2 of 14, 14%), cervical (2 of 15, 13%), and squamous cell cancer of the head and neck (1 of 11, 9%). Of the 25 patients with PIK3CA mutations, 17 (68%) were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor, and 6 (35%) achieved a partial response. In contrast, only 15 of 241 patients (6%) without documented PIK3CA mutations treated on the same protocols responded (P = 0.001). Of the 17 patients with PIK3CA mutations, 6 (35%) had simultaneous KRAS or BRAF mutations (colorectal, n = 4; ovarian, n = 2). Colorectal cancer patients with PIK3CA and KRAS mutations did not respond to therapy, whereas both ovarian cancer patients with PIK3CA and KRAS or BRAF mutations did. In conclusion, PIK3CA mutations were detected in 11.5% of patients with diverse solid tumors. The response rate was significantly higher for patients with PIK3CA mutations treated with PI3K/AKT/mTOR pathway inhibitors than for those without documented mutations. Mol Cancer Ther; 10(3); 558–65. ©2011 AACR.
Cholesterol Regulates VEGFR-1 (FLT-1) Expression and Signaling in Acute Leukemia Cells
Authors: Casalou Cristina , Costa Ana , Carvalho Tânia , Gomes Ana L. , Zhu Zhenping , Wu Yan , Dias Sérgio 
Published: January 2011

Abstract
VEGF receptors 1 (FLT-1) and 2 (KDR) are expressed on subsets of acute myeloid leukemia (AML) and acute lymphoid leukemia cells, in which they induce cell survival, proliferation, and migration. However, little is known about possible cofactors that regulate VEGF receptor expression and activation on leukemia cells. Here we show that cholesterol accumulates in leukemia-rich sites within bone marrow of xenotransplanted severe combined immunodeficient (SCID) mice. Therefore, we hypothesized that cholesterol-rich domains might regulate FLT-1 signaling and chemotaxis of acute leukemias. We then showed that FLT-1 accumulates in discrete cholesterol-rich membrane domains where it associates with caveolin-1 and that placenta growth factor (PlGF)/VEGF stimulation promotes FLT-1 localization in such cholesterol-rich domains. Accordingly, FLT-1 localization and its phosphorylation are abrogated by methyl-β-cyclodextrin (MβCD), which removes cellular cholesterol, and by nystatin, an inhibitor of lipid-raft endocytosis. Mechanistically, cholesterol increases FLT-1 expression and promotes PlGF/VEGF-induced leukemia cells viability and also induces VEGF production by the leukemia cells in vitro. Taken together, we conclude that cholesterol regulates VEGF:VEGFR-1 signaling on subsets of acute leukemias, modulating cell migration, and viability, which may be crucial for disease progression. Finally, we provide evidence obtained from human AML samples that primary leukemia cells accumulate significantly more cholesterol than do normal cells and that cholesterol accumulation correlates with disease aggressiveness. Mol Cancer Res; 9(2); 215–24. ©2011 AACR.
Randomized Phase II Trial of Sulindac, Atorvastatin, and Prebiotic Dietary Fiber for Colorectal Cancer Chemoprevention
Authors: Limburg Paul J. , Mahoney Michelle R. , Ziegler Katie L. Allen , Sontag Stephen J. , Schoen Robert E. , Benya Richard , Lawson Michael J. , Weinberg David S. , Stoffel Elena , Chiorean Michael , Heigh Russell , Levine Joel , Della'Zanna Gary , Rodriguez Luz , Richmond Ellen , Gostout Christopher , Mandrekar Sumithra J. , Smyrk Thomas C. 
Published: January 2011

Abstract
Sulindac, atorvastatin, or prebiotic dietary fiber may reduce colorectal cancer (CRC) risk. However, clinical trial data are currently limited. We conducted a randomized, phase II chemoprevention trial involving subjects 40 years or older, with previously resected colon cancer or multiple/advanced colorectal adenomas. Magnification chromoendoscopy (MCE) was performed to identify and characterize rectal aberrant crypt foci (ACF); eligibility criteria required five or more rectal ACFs at baseline. Intervention assignments were as follows: (a) atorvastatin 20 mg qd; (b) sulindac 150 mg bid; (c) oligofructose-enriched inulin (as ORAFTI®Synergy1) 6 gm bid; or (d) control (maltodextrin) 6 gm bid, for 6 months. Percent change in rectal ACF number (%ΔACF) within arm was the primary endpoint. Secondary endpoints included changes in proliferation (Ki67) and apoptosis (caspase-3), as measured from normal mucosa biopsy samples. Among 85 eligible randomized subjects, 76 (86%) completed the trial per protocol. The median (range) of rectal ACF was 9 (5–34) and 8 (0–37) at baseline and postintervention, respectively. The median (SD) for %ΔACF was 5.6 (−69% to 143%), −18.6 (−83% to 160%), −3.6 (−88% to 83%), and −10.0 (−100% to 117%) in the atorvastatin, sulindac, ORAFTI®Synergy1 and control arms, respectively. Neither within-arm (P = 0.12–0.59) nor between-arm (P = 0.30–0.92) comparisons of %ΔACF were statistically significant. The active and control interventions also seemed to have similar effects on mucosal proliferation and apoptosis (P &gt; 0.05 for each comparison). Data from this multicenter, phase II trial do not provide convincing evidence of CRC risk reduction from 6-month interventions with atorvastatin, sulindac, or ORAFTI®Synergy1, although statistical power was limited by the relatively small sample size. Cancer Prev Res; 4(2); 259–69. ©2011 AACR.
Decompensated Heart Failure Is Associated With Reduced Corin Levels and Decreased Cleavage of Pro–Atrial Natriuretic Peptide
Authors: Ibebuogu Uzoma N. , Gladysheva Inna P. , Houng Aiilyan K. , Reed Guy L. 
Published: January 2011

Background—
By promoting salt and water excretion, the corin and the atrial natriuretic peptide (ANP) system should help to maintain fluid balance in heart failure. Yet, the development of fluid retention despite high levels of ANP-related peptides suggests that this compensatory system is limited.

Methods and Results—

Levels of circulating corin (the pro–ANP-converting enzyme) and pro-ANP were measured in hospitalized patients with heart failure, using novel immunoassays. Patients (n=14) had severe heart failure (New York Heart Association class III-IV) with a median ejection fraction of 18% and median brain natriuretic peptide levels of 1940 pg/mL. In heart failure, median plasma corin levels were 7.6-fold lower than measured in plasma from 16 normal control subjects (180 versus 1368 pg/mL,
P
<0.01). In contrast, in patients with heart failure, levels of plasma N-terminal ANP peptides (N-ANP and pro-ANP) levels were markedly elevated (42.0 versus 7.5 ng/mL,
P
<0.01). Levels of uncleaved pro-ANP, measured by novel immunoassays, were significantly higher in patients with heart failure (
P
<0.01), suggesting that corin cleavage of pro-ANP was impaired. Median plasma levels of cyclic guanosine monophosphate were elevated in patients with heart failure (150.0 versus 7.6 pmol/mL,
P
<0.01), and plasma cyclic guanosine monophosphate levels positively correlated with the fractional amount of cleaved pro-ANP (
r
s
=0.59,
P
<0.03) but not with levels of uncleaved pro-ANP, implying that the cellular response to ANP remained intact.

Conclusions—
Taken together, these data suggest that there may be patients for whom low corin levels and impaired pro-ANP cleavage contribute to acute decompensation.