bluuebunny/crossref_metadata_2025_split huggingface dataset:
COX-2 Blockade Suppresses Gliomagenesis by Inhibiting Myeloid-Derived Suppressor Cells
Authors: Fujita Mitsugu , Kohanbash Gary , Fellows-Mayle Wendy , Hamilton Ronald L. , Komohara Yoshihiro , Decker Stacy A. , Ohlfest John R. , Okada Hideho 
Published: February 2011

AbstractEpidemiologic studies have highlighted associations between the regular use of nonsteroidal anti-inflammatory drugs (NSAID) and reduced glioma risks in humans. Most NSAIDs function as COX-2 inhibitors that prevent production of prostaglandin E2 (PGE2). Because PGE2 induces expansion of myeloid-derived suppressor cells (MDSC), we hypothesized that COX-2 blockade would suppress gliomagenesis by inhibiting MDSC development and accumulation in the tumor microenvironment (TME). In mouse models of glioma, treatment with the COX-2 inhibitors acetylsalicylic acid (ASA) or celecoxib inhibited systemic PGE2 production and delayed glioma development. ASA treatment also reduced the MDSC-attracting chemokine CCL2 (C-C motif ligand 2) in the TME along with numbers of CD11b+Ly6GhiLy6Clo granulocytic MDSCs in both the bone marrow and the TME. In support of this evidence that COX-2 blockade blocked systemic development of MDSCs and their CCL2-mediated accumulation in the TME, there were defects in these processes in glioma-bearing Cox2-deficient and Ccl2-deficient mice. Conversely, these mice or ASA-treated wild-type mice displayed enhanced expression of CXCL10 (C-X-C motif chemokine 10) and infiltration of cytotoxic T lymphocytes (CTL) in the TME, consistent with a relief of MDSC-mediated immunosuppression. Antibody-mediated depletion of MDSCs delayed glioma growth in association with an increase in CXCL10 and CTLs in the TME, underscoring a critical role for MDSCs in glioma development. Finally, Cxcl10-deficient mice exhibited reduced CTL infiltration of tumors, establishing that CXCL10 limited this pathway of immunosuppression. Taken together, our findings show that the COX-2 pathway promotes gliomagenesis by directly supporting systemic development of MDSCs and their accumulation in the TME, where they limit CTL infiltration. Cancer Res; 71(7); 2664–74. ©2011 AACR.
Serum Biomarker Panels for the Detection of Pancreatic Cancer
Authors: Brand Randall E. , Nolen Brian M. , Zeh Herbert J. , Allen Peter J. , Eloubeidi Mohamad A. , Goldberg Michael , Elton Eric , Arnoletti Juan P. , Christein John D. , Vickers Selwyn M. , Langmead Christopher J. , Landsittel Douglas P. , Whitcomb David C. , Grizzle William E. , Lokshin Anna E. 
Published: February 2011

Abstract
Purpose: Serum–biomarker based screening for pancreatic cancer could greatly improve survival in appropriately targeted high-risk populations.
Experimental Design: Eighty-three circulating proteins were analyzed in sera of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC, n = 333), benign pancreatic conditions (n = 144), and healthy control individuals (n = 227). Samples from each group were split randomly into training and blinded validation sets prior to analysis. A Metropolis algorithm with Monte Carlo simulation (MMC) was used to identify discriminatory biomarker panels in the training set. Identified panels were evaluated in the validation set and in patients diagnosed with colon (n = 33), lung (n = 62), and breast (n = 108) cancers.
Results: Several robust profiles of protein alterations were present in sera of PDAC patients compared to the Healthy and Benign groups. In the training set (n = 160 PDAC, 74 Benign, 107 Healthy), the panel of CA 19–9, ICAM-1, and OPG discriminated PDAC patients from Healthy controls with a sensitivity/specificity (SN/SP) of 88/90%, while the panel of CA 19–9, CEA, and TIMP-1 discriminated PDAC patients from Benign subjects with an SN/SP of 76/90%. In an independent validation set (n = 173 PDAC, 70 Benign, 120 Healthy), the panel of CA 19–9, ICAM-1 and OPG demonstrated an SN/SP of 78/94% while the panel of CA19–9, CEA, and TIMP-1 demonstrated an SN/SP of 71/89%. The CA19–9, ICAM-1, OPG panel is selective for PDAC and does not recognize breast (SP = 100%), lung (SP = 97%), or colon (SP = 97%) cancer.
Conclusions: The PDAC-specific biomarker panels identified in this investigation warrant additional clinical validation to determine their role in screening targeted high-risk populations. Clin Cancer Res; 17(4); 805–16. ©2010 AACR.
Riluzole Enhances Ionizing Radiation–Induced Cytotoxicity in Human Melanoma Cells that Ectopically Express Metabotropic Glutamate Receptor 1 In Vitro and In Vivo
Authors: Khan Atif J. , Wall Brian , Ahlawat Stuti , Green Camille , Schiff Devora , Mehnert Janice M. , Goydos James S. , Chen Suzie , Haffty Bruce G. 
Published: February 2011

Abstract
Purpose: Brain metastases are a common preterminal event in patients with metastatic melanoma and require radiation therapy. Our group has previously shown that human GRM1 (hGRM1) expressing melanoma cells release excess extracellular glutamate and are growth inhibited by riluzole, an inhibitor of glutamate release. Riluzole-treated cells accumulate in G2/M phase of the cell cycle at 24 hours, and then undergo apoptotic cell death. We evaluated whether riluzole enhanced radiosensitivity in melanoma cells.
Experimental Design: Clonogenic assays were performed to evaluate clonogenic survival after treatment in hGRM1 expressing and nonexpressing melanoma cells. Western immunoblots were performed to confirm apoptotic cell death. A xenograft mouse model was used to validate the in vitro experiments. Tumors harvested from the xenografts were fixed and stained for apoptosis and DNA damage markers.
Results: In the hGRM1-positive cell lines C8161 and UACC903, riluzole enhanced the lethal effects of ionizing radiation; no difference was seen in the hGRM1-negative UACC930 cell line. C8161 cells treated with riluzole plus irradiation also showed the highest levels of the cleaved forms of PARP and caspase-3; excised C8161 xenografts showed the greatest number of apoptotic cells by immunohistochemistry (P &lt; 0.001). On cell cycle analysis, a sequence-dependent enrichment in the G2/M phase was shown with the combination of riluzole and irradiation. Xenografts treated with riluzole and weekly radiation fractions showed significant growth inhibition and revealed markedly increased DNA damage.
Conclusions: We have shown, in vitro and in vivo, that the combination of riluzole and ionizing radiation leads to greater cytotoxicity. These results have clinical implications for patients with brain metastases receiving whole brain radiation therapy. Clin Cancer Res; 17(7); 1807–14. ©2011 AACR.
Close and Stable Relationship between Proliferation and a Hypoxia Metagene in Aromatase Inhibitor–Treated ER-Positive Breast Cancer
Authors: Ghazoui Zara , Buffa Francesca M. , Dunbier Anita K. , Anderson Helen , Dexter Tim , Detre Simone , Salter Janine , Smith Ian E. , Harris Adrian L. , Dowsett Mitchell 
Published: February 2011

Abstract
Purpose: The majority of breast cancer patients who have estrogen receptor positive (ER+) tumors whose proliferation is reduced after estrogen deprivation by aromatase inhibitors (AI). This study investigates any link between proliferation and hypoxia, a major determinant of tumor biology, and defines the effect of estrogen deprivation on hypoxia-associated genes.
Methods: Genome-wide expression profiles were obtained from tumor biopsies from 81 ER+ postmenopausal patients, before and after 2 weeks' anastrozole treatment. A hypoxia metagene was developed by identifying genes clustered with classical hypoxia-regulated genes, excluding those associated with proliferation. Proliferation was measured by Ki67 and a proliferation metagene derived from two published breast cancer data sets.
Results: Hypoxia and proliferation metagenes were associated at baseline (Pearson correlation coefficient, r = 0.67, P &lt; 10−4) and after 2 weeks (r = 0.71, P &lt; 10−4). Hypoxia metagene at baseline was associated with 2-week Ki67 (r = 0.43, P = 0.0002) and more weakly with poor 2-week Ki67 change consistent with a weak association with AI resistance. Hypoxia metagene was significantly downregulated with AI. This downregulation was significantly associated with change in the proliferation metagene and with Ki67 but, importantly, not with the substantial change in expression of classical estrogen-dependent genes.
Conclusions: Hypoxia metagene is closely associated with proliferation before and after AI treatment. The downregulation of hypoxia metagene after AI therapy is most likely the result of changes in proliferation. There may be a weak effect of hypoxia metagene on de novo resistance to AIs. These findings are important to consider in coapplication of antiproliferative agents with antiangiogenic or antihypoxia agents. Clin Cancer Res; 17(9); 3005–12. ©2011 AACR.
Androgen Receptor Expression and Breast Cancer Survival in Postmenopausal Women
Authors: Hu Rong , Dawood Shaheenah , Holmes Michelle D. , Collins Laura C. , Schnitt Stuart J. , Cole Kimberley , Marotti Jonathan D. , Hankinson Susan E. , Colditz Graham A. , Tamimi Rulla M. 
Published: February 2011

Abstract
Purpose: Androgen receptor (AR) is commonly expressed in breast cancers. However, the association between tumor AR status and breast cancer survival is uncertain. Hence, we examined the association between AR status and breast cancer survival in the Nurses' Health Study (NHS).
Experimental Design: It was a prospective study of postmenopausal women enrolled in the Nurses' Health Study with stage I to III breast cancer diagnosed between 1976 and 1997 and followed from the date of diagnosis until January 1, 2008 or death. Analyses were conducted using Kaplan–Meier methods and Cox proportional hazard models, to determine the association of AR status with survival outcomes adjusting for covariates.
Results: Among 1467 breast cancers, 78.7% were AR-positive (AR+). Among 1,164 estrogen receptor (ER)-positive cases, 88.0% were AR+. AR positivity was associated with a significant reduction in breast cancer mortality (HR, 0.68; 95% CI, 0.47–0.99) and overall mortality (HR, 0.70; 95% CI, 0.53–0.91) after adjustment for covariates. In contrast, among women with ER-negative tumors (303 cases), 42.9% were AR+. There was a nonsignificant association between AR status and breast cancer death (HR, 1.59; 95% CI, 0.94–2.68).
Conclusions: The association of AR status and breast cancer survival is dependent on ER status. In particular, AR expression was associated with a more favorable prognosis among women with ER-positive tumors. Thus, determination of AR status may provide additional information on prognosis for postmenopausal women with breast cancer, and provide novel opportunities for targeted therapy. Clin Cancer Res; 17(7); 1867–74. ©2011 AACR.
Natural Killer Cells are Scarce in Colorectal Carcinoma Tissue Despite High Levels of Chemokines and Cytokines
Authors: Halama Niels , Braun Monika , Kahlert Christoph , Spille Anna , Quack Christian , Rahbari Nuh , Koch Moritz , Weitz Jürgen , Kloor Matthias , Zoernig Inka , Schirmacher Peter , Brand Karsten , Grabe Niels , Falk Christine S. 
Published: February 2011

Abstract
Purpose: Tumor infiltrating T lymphocytes in colorectal cancer (CRC) have prognostic impact, but the role of natural killer (NK) cells in CRC tissue is unclear. The contribution of intratumoral cytokines and chemokines in shaping the composition of the inflammatory lymphocytic infiltrate is also unclear.
Experimental Design: In this study, localization and densities of NK and T cells within primary CRC, CRC liver metastases, adenomas, and normal tissues were analyzed on whole tissue sections from 112 patients. In a subset of these patients, the most important 50 cytokines and chemokines were quantified in paired serum, primary CRC and adjacent mucosa samples and in CRC liver metastases and correlated with NK and T-cell infiltration, respectively.
Results: The various compartments displayed characteristic differences like significantly higher chemokine concentrations in CRC tissue. Most importantly, despite high local chemokine levels, NK cells were generally scarce within CRC tumor tissues, independent of human leukocyte antigen (HLA) class I expression. Adjacent normal mucosa contained normal levels of NK cells. In contrast, corresponding T-cell numbers varied substantially and were positively correlated with higher chemokine levels.
Conclusions: Our findings indicate a distinct regulation of NK cells versus T cells in the CRC tumor microenvironment. NK-cell migration into CRC tumor tissue is obviously impaired early during tumor development by mechanisms that do not affect T-cell infiltration. Clin Cancer Res; 17(4); 678–89. ©2011 AACR.
Identification of Loss of p16 Expression and Upregulation of MDR-1 as Genetic Events Resulting from Two Novel Chromosomal Translocations Found in a Plasmablastic Lymphoma of the Uterus
Authors: Matsuki Eri , Miyakawa Yoshitaka , Asakawa Shuichi , Tsukada Yuiko , Yamada Taketo , Yokoyama Kenji , Kudoh Jun , Ikeda Yasuo , Okamoto Shinichiro 
Published: February 2011

Abstract
Purpose: To establish cell lines from the patient with plasmablastic lymphoma, who was immunologically competent including negative human immunodeficiency virus (HIV) serology, and analyze the unique chromosomal translocations seen in the cell lines in order to unveil the pathogenesis of this tumor, which had no evidence of Epstein-Barr virus involvement.
Experimental Design: Establishment of the cell lines was attempted by inoculating the patient's lymph node biopsy specimen subcutaneously to immunodeficient mice. Comparative genomic hybridization (CGH) array and FISH analysis were performed to identify breakpoints of the two chromosomal translocations. Of the 4 candidate genes identified by FISH analysis to be involved in the translocations, reverse transcription-PCR, Western blot, flow cytometry, and proliferation assay were performed to identify the exact genes involved.
Results: Analysis of the cell lines identified loss of p16 at the protein level by chromosomal translocation of t(9;13) and upregulation of MDR-1 by t(4;7). The cell lines expressing MDR-1 acquired resistance to chemotherapeutic agents such as cisplatin and doxorubicin, but not bortezomib. Expression of B lymphoid lineage marker genes of these cell lines was negative for paired box 5 (Pax5) or PR domain containing 1, with ZNF domain (PRDM1), but was positive for X-box binding protein 1 (Xbp1).
Conclusions: We established three novel cell lines of plasmablastic lymphoma. Characterization of the unique chromosomal translocation identified loss of p16 and upregulation of MDR-1 at protein level. Expression of Xbp1(s), which is involved in the maturation of plasma cells, corresponded to the plasmablastic appearance of the tumor. These cell lines may be a useful tool to understand the pathophysiology of the disease and to develop novel treatment strategies. Clin Cancer Res; 17(8); 2101–9. ©2011 AACR.
CTCF and BORIS Regulate Rb2/p130 Gene Transcription: A Novel Mechanism and a New Paradigm for Understanding the Biology of Lung Cancer
Authors: Fiorentino Francesco Paolo , Macaluso Marcella , Miranda Fabrizio , Montanari Micaela , Russo Antonio , Bagella Luigi , Giordano Antonio 
Published: February 2011

Abstract
Although innumerable investigations regarding the biology of lung cancer have been carried out, many aspects thereof remain to be addressed, including the role played by the retinoblastoma-related protein Rb2/p130 during the evolution of this disease. Here we report novel findings on the mechanisms that control Rb2/p130 gene expression in lung fibroblasts and characterize the effects of Rb2/p130 deregulation on the proliferative features of lung cancer cells. We revealed for the first time that in lung fibroblasts the expression of Rb2/p130 gene is directly controlled by the chromatin insulator CCCTC-binding factor, CTCF, which by binding to the Rb2/p130 gene promoter induces, and/or maintains, a specific local chromatin organization that in turn governs the transcriptional activity of Rb2/p130 gene. However, in lung cancer cells the activity of CTCF in controlling Rb2/p130 gene expression is impaired by BORIS, a CTCF-paralogue, which by binding to the Rb2/p130 gene could trigger changes in the chromatin asset established by CTCF, thereby affecting CTCF regulatory activity on Rb2/p130 transcription. These studies not only provide essential basic insights into the molecular mechanisms that control Rb2/p130 gene expression in lung cancer, but also offer a potential paradigm for the actions of other activators and/or corepressors, such as CTCF and BORIS, that could be crucial in explaining how alterations in the mechanism regulating Rb2/p130 gene expression may accelerate the progression of lung tumors, or favor the onset of recurrence after cancer treatment. Mol Cancer Res; 9(2); 225–33. ©2011 AACR.
Genetic Variations in the α
2A
-Adrenoreceptor Are Associated With Blood Pressure Response to the Agonist Dexmedetomidine
Authors: Kurnik Daniel , Muszkat Mordechai , Li Chun , Sofowora Gbenga G. , Friedman Eitan A. , Scheinin Mika , Wood Alastair J.J. , Stein C. Michael 
Published: February 2011

Background—

α
2A
-Adrenoceptors (α
2A
-ARs) have important roles in sympathetic cardiovascular regulation. Variants of
ADRA2A
affect gene transcription and expression and are associated with insulin release and risk for type 2 diabetes. We examined whether
ADRA2A
variants are also associated with cardiovascular responses to the selective α
2
-AR-agonist dexmedetomidine.

Methods and Results—

Seventy-three healthy subjects participated in a placebo-controlled, single-blind study. After 3 infusions of placebo, subjects received 3 incremental infusions of dexmedetomidine (cumulative dose, 0.4 μg/kg). Primary outcomes were changes in systolic blood pressure (SBP) and plasma norepinephrine concentrations, measured as difference of the area-under-the-curve during placebo and dexmedetomidine infusions (ΔAUC). We used multiple linear regression analysis to examine the associations between 9
ADRA2A
tagging variants and 5 inferred haplotypes and ΔAUC after adjustment for covariates. Homozygous carriers of rs553668 and the corresponding haplotype 4, previously associated with increased α
2A
-AR expression, had a 2.2-fold greater decrease in AUC
SBP
after dexmedetomidine (adjusted
P
=0.006); similarly, the maximum decrease in SBP was 24.7±8.1 mm Hg compared with 13.6±5.9 mm Hg in carriers of the wild-type allele (
P
=0.007). Carriers of haplotype 3, previously associated with reduced α
2A
-AR expression, had a 44% smaller decrease in AUC
SBP
(
P
=0.013). Haplotype information significantly improved the model predicting the decrease in SBP (
P
<0.001). There were similar but nonsignificant trends for diastolic blood pressure and heart rate. Genotypes were not significantly associated with norepinephrine responses.

Conclusions—
Common ADRA2A variants are associated with the hypotensive response to dexmedetomidine. Effects of specific variants/haplotypes in vivo are compatible with their known effects on gene expression in vitro.
SCN5A Variation Is Associated With Electrocardiographic Traits in the Jackson Heart Study
Authors: Jeff Janina M. , Brown-Gentry Kristin , Buxbaum Sarah G. , Sarpong Daniel F. , Taylor Herman A. , George Alfred L. , Roden Dan M. , Crawford Dana C. 
Published: February 2011

Background—
Understanding variation in the normal electric activity of the heart, assessed by the ECG, may provide a starting point for studies of susceptibility to serious arrhythmias such as sudden cardiac death during myocardial infarction or drug therapy. Recent genetic association studies of one ECG trait, the QT interval, have identified common variation in European-descent populations, but little is known about the genetic determinants of ECG traits in populations of African descent.

Methods and Results—

To identify genetic risk factors, we have undertaken a candidate gene study of ECG traits in collaboration with the Jackson Heart Study, a longitudinal study of 5301 blacks ascertained from the Jackson, Mississippi, area. Nine quantitative ECG traits were evaluated: P, PR, QRS, QT, and QTc durations, heart rate, and P, QRS, and T axes. We genotyped 72 variations in the predominant sodium channel gene expressed in heart,
SCN5A
, encoding the Na
v
1.5 voltage-gated sodium channel in 4558 subjects. Both rare and common variants in this gene have previously been associated with inherited arrhythmia syndromes and variable conduction. Adjusting for age, sex, and European ancestry, we performed tests of association in 3054 unrelated participants and identified 14 significant associations (
P
<1.0×10
−4
), of which 13 are independent, based on linkage disequilibrium. These variants explain up to 2% of the variation in ECG traits in the Jackson Heart Study.

Conclusions—

These results suggest that
SCN5A
variation contributes to ECG trait distributions in blacks, and these same variations may be risk or protective factors associated with susceptibility to arrhythmias.
Observed Increase of TTL Temperature and Water Vapor in Polluted Clouds over Asia
Authors: Su Hui , Jiang Jonathan H. , Liu Xiaohong , Penner Joyce E. , Read William G. , Massie Steven , Schoeberl Mark R. , Colarco Peter , Livesey Nathaniel J. , Santee Michelle L. 
Published: February 2011

Abstract
Satellite observations are analyzed to examine the correlations between aerosols and the tropical tropopause layer (TTL) temperature and water vapor. This study focuses on two regions, both of which are important pathways for the mass transport from the troposphere to the stratosphere and over which Asian pollution prevails: South and East Asia during boreal summer and the Maritime Continent during boreal winter. Using the upper-tropospheric carbon monoxide measurements from the Aura Microwave Limb Sounder as a proxy of aerosols to classify ice clouds as polluted or clean, the authors find that polluted clouds have a smaller ice effective radius and a higher temperature and specific humidity near the tropopause than clean clouds. The increase in water vapor appears to be related to the increase in temperature, as a result of increased aerosols. Meteorological differences between the clouds cannot explain the differences in temperature and water vapor for the polluted and clean clouds. The authors hypothesize that aerosol semidirect radiative heating and/or changes in cirrus radiative heating, resulting from aerosol microphysical effects on clouds, may contribute to the increased TTL temperature and thus increased water vapor in the polluted clouds.