bluuebunny/crossref_metadata_2025_split huggingface dataset:
PIK3CA Mutations in In situ and Invasive Breast Carcinomas
Authors: Miron Alexander , Varadi Maria , Carrasco Daniel , Li Hailun , Luongo Lauren , Kim Hee Jung , Park So Yeon , Cho Eun Yoon , Lewis Gretchen , Kehoe Sarah , Iglehart J. Dirk , Dillon Deborah , Allred D. Craig , Macconaill Laura , Gelman Rebecca , Polyak Kornelia 
Published: June 2010

Abstract
The PIK3 signaling pathway has been identified as one of the most important and most frequently mutated pathways in breast cancer. Somatic mutations in the catalytic subunit of PIK3CA have been found in a significant fraction of breast carcinomas, and it has been proposed that mutant PIK3CA plays a role in tumor initiation. However, the majority of primary human tumors analyzed for genetic alterations in PIK3CA have been invasive breast carcinomas and the frequency of PIK3CA mutations in preinvasive lesions has not been explored. To investigate this, we sequenced exons 9 and 20 of PIK3CA in pure ductal carcinoma in situ (DCIS), DCIS adjacent to invasive carcinoma, and invasive ductal breast carcinomas. In a subset of cases, both in situ and invasive areas were analyzed from the same tumor. We found that the frequency of PIK3CA mutations was essentially the same (∼30%) in all three histologic groups. In some cases, in situ and invasive areas of the same tumor were discordant for PIK3CA status, and in two cases in which multiple invasive and adjacent in situ areas within the same tumor were analyzed independently, we detected intratumor heterogeneity for PIK3CA mutations. Our results suggest that mutation of PIK3CA is an early event in breast cancer that is more likely to play a role in breast tumor initiation than in invasive progression, although a potential role for exon 9 mutations in the progression of a subset of DCIS cases cannot be excluded. Cancer Res; 70(14); 5674–8. ©2010 AACR.
Hypoxic Conversion of SMAD7 Function from an Inhibitor into a Promoter of Cell Invasion
Authors: Heikkinen Pekka T. , Nummela Marika , Jokilehto Terhi , Grenman Reidar , Kähäri Veli-Matti , Jaakkola Panu M. 
Published: June 2010

Abstract
Smad7 is an inhibitor of the transforming growth factor-β–activated signaling pathway. Under well-oxygenated conditions, Smad7 is a potent inhibitor of carcinoma cell invasion. Paradoxically, however, the expression of Smad7 is upregulated across several cancers and may promote cancer progression. Hypoxia, which is frequently met in solid tumors, is an enhancer of carcinoma cell invasion and cancer progression. Here, we report that hypoxia activates the expression of Smad7 in a hypoxia-inducible factor– and von Hippel-Lindau protein–dependent manner. As expected, in normoxia, the forced expression of Smad7 inhibited carcinoma cell invasion. In contrast with the normoxic condition, the inhibitory effect of Smad7 was lost under hypoxia. The block in carcinoma cell invasion by forced expression of Smad7 was released by hypoxia in two invasive carcinoma cell lines. Moreover, the noninvasive HaCaT keratinocytes become invasive upon simultaneous hypoxia and transforming growth factor-β stimulus. The hypoxia-activated invasion was attenuated by inhibiting Smad7 expression by short interfering RNA. Finally, the increased Smad7 expression in human carcinomas correlated with hypoxic gene expression. The data provide evidence that hypoxia could convert Smad7 function from an invasion inhibitor into an activator of invasion. Furthermore, they might shed light as to why increased Smad7 expression is detected in cancers. Cancer Res; 70(14); 5984–93. ©2010 AACR.
Phosphorylation and Activation of Cell Division Cycle Associated 5 by Mitogen-Activated Protein Kinase Play a Crucial Role in Human Lung Carcinogenesis
Authors: Nguyen Minh-Hue , Koinuma Junkichi , Ueda Koji , Ito Tomoo , Tsuchiya Eiju , Nakamura Yusuke , Daigo Yataro 
Published: June 2010

AbstractWe analyzed the gene expression profiles of clinical lung carcinomas using a cDNA microarray containing 27,648 genes or expressed sequence tags, and identified CDCA5 (cell division cycle associated 5) to be upregulated in the majority of lung cancers. Tumor tissue microarray analysis of 262 non–small cell lung cancer patients revealed that CDCA5 positivity was an independent prognostic factor for lung cancer patients. Suppression of CDCA5 expression with siRNAs inhibited the growth of lung cancer cells; concordantly, induction of exogenous expression of CDCA5 conferred growth-promoting activity in mammalian cells. We also found that extracellular signal-regulated kinase (ERK) kinase phosphorylated CDCA5 at Ser79 and Ser209 in vivo. Exogenous expression of phospho-mimicking CDCA5 protein whose Ser209 residue was replaced with glutamine acid further enhanced the growth of cancer cells. In addition, functional inhibition of the interaction between CDCA5 and ERK kinase by a cell-permeable peptide corresponding to a 20-amino-acid sequence part of CDCA5, which included the Ser209 phosphorylation site by ERK, significantly reduced phosphorylation of CDCA5 and resulted in growth suppression of lung cancer cells. Our data suggest that transactivation of CDCA5 and its phosphorylation at Ser209 by ERK play an important role in lung cancer proliferation, and that the selective suppression of the ERK-CDCA5 pathway could be a promising strategy for cancer therapy. Cancer Res; 70(13); 5337–47. ©2010 AACR.
The Phosphoinositide 3-Kinase Inhibitor PI-103 Downregulates Choline Kinase α Leading to Phosphocholine and Total Choline Decrease Detected by Magnetic Resonance Spectroscopy
Authors: Al-Saffar Nada M.S. , Jackson L. Elizabeth , Raynaud Florence I. , Clarke Paul A. , Ramírez de Molina Ana , Lacal Juan C. , Workman Paul , Leach Martin O. 
Published: June 2010

Abstract
The phosphoinositide 3-kinase (PI3K) pathway is a major target for cancer drug development. PI-103 is an isoform-selective class I PI3K and mammalian target of rapamycin inhibitor. The aims of this work were as follows: first, to use magnetic resonance spectroscopy (MRS) to identify and develop a robust pharmacodynamic (PD) biomarker for target inhibition and potentially tumor response following PI3K inhibition; second, to evaluate mechanisms underlying the MRS-detected changes. Treatment of human PTEN null PC3 prostate and PIK3CA mutant HCT116 colon carcinoma cells with PI-103 resulted in a concentration- and time-dependent decrease in phosphocholine (PC) and total choline (tCho) levels (P &lt; 0.05) detected by phosphorus (31P)- and proton (1H)-MRS. In contrast, the cytotoxic microtubule inhibitor docetaxel increased glycerophosphocholine and tCho levels in PC3 cells. PI-103–induced MRS changes were associated with alterations in the protein expression levels of regulatory enzymes involved in lipid metabolism, including choline kinase α (ChoKα), fatty acid synthase (FAS), and phosphorylated ATP-citrate lyase (pACL). However, a strong correlation (r2 = 0.9, P = 0.009) was found only between PC concentrations and ChoKα expression but not with FAS or pACL. This study identified inhibition of ChoKα as a major cause of the observed change in PC levels following PI-103 treatment. We also showed the capacity of 1H-MRS, a clinically well-established technique with higher sensitivity and wider applicability compared with 31P-MRS, to assess response to PI-103. Our results show that monitoring the effects of PI3K inhibitors by MRS may provide a noninvasive PD biomarker for PI3K inhibition and potentially of tumor response during early-stage clinical trials with PI3K inhibitors. Cancer Res; 70(13); 5507–17. ©2010 AACR.
Selective BRAFV600E Inhibition Enhances T-Cell Recognition of Melanoma without Affecting Lymphocyte Function
Authors: Boni Andrea , Cogdill Alexandria P. , Dang Ping , Udayakumar Durga , Njauw Ching-Ni Jenny , Sloss Callum M. , Ferrone Cristina R. , Flaherty Keith T. , Lawrence Donald P. , Fisher David E. , Tsao Hensin , Wargo Jennifer A. 
Published: June 2010

Abstract
Targeted therapy against the BRAF/mitogen-activated protein kinase (MAPK) pathway is a promising new therapeutic approach for the treatment of melanoma. Treatment with selective BRAF inhibitors results in a high initial response rate but limited duration of response. To counter this, investigators propose combining this therapy with other targeted agents, addressing the issue of redundancy and signaling through different oncogenic pathways. An alternative approach is combining BRAF/MAPK-targeted agents with immunotherapy. Preliminary evidence suggests that oncogenic BRAF (BRAFV600E) contributes to immune escape and that blocking its activity via MAPK pathway inhibition leads to increased expression of melanocyte differentiation antigens (MDA). Recognition of MDAs is a critical component of the immunologic response to melanoma, and several forms of immunotherapy capitalize on this recognition. Among the various approaches to inhibiting BRAF/MAPK, broad MAPK pathway inhibition may have deleterious effects on T lymphocyte function. Here, we corroborate the role of oncogenic BRAF in immune evasion by melanoma cells through suppression of MDAs. We show that inhibition of the MAPK pathway with MAPK/extracellular signal-regulated kinase kinase (MEK) inhibitors or a specific inhibitor of BRAFV600E in melanoma cell lines and tumor digests results in increased levels of MDAs, which is associated with improved recognition by antigen-specific T lymphocytes. However, treatment with MEK inhibitors impairs T lymphocyte function, whereas T-cell function is preserved after treatment with a specific inhibitor of BRAFV600E. These findings suggest that immune evasion of melanomas mediated by oncogenic BRAF may be reversed by targeted BRAF inhibition without compromising T-cell function. These findings have important implications for combined kinase-targeted therapy plus immunotherapy for melanoma. Cancer Res; 70(13); 5213–9. ©2010 AACR.
Confirmation of Linkage to and Localization of Familial Colon Cancer Risk Haplotype on Chromosome 9q22
Authors: Gray-McGuire Courtney , Guda Kishore , Adrianto Indra , Lin Chee Paul , Natale Leanna , Potter John D. , Newcomb Polly , Poole Elizabeth M. , Ulrich Cornelia M. , Lindor Noralane , Goode Ellen L. , Fridley Brooke L. , Jenkins Robert , Le Marchand Loic , Casey Graham , Haile Robert , Hopper John , Jenkins Mark , Young Joanne , Buchanan Daniel , Gallinger Steve , Adams Mark , Lewis Susan , Willis Joseph , Elston Robert , Markowitz Sanford D. , Wiesner Georgia L. 
Published: June 2010

AbstractGenetic risk factors are important contributors to the development of colorectal cancer. Following the definition of a linkage signal at 9q22-31, we fine mapped this region in an independent collection of colon cancer families. We used a custom array of single-nucleotide polymorphisms (SNP) densely spaced across the candidate region, performing both single-SNP and moving-window association analyses to identify a colon neoplasia risk haplotype. Through this approach, we isolated the association effect to a five-SNP haplotype centered at 98.15 Mb on chromosome 9q. This haplotype is in strong linkage disequilibrium with the haplotype block containing HABP4 and may be a surrogate for the effect of this CD30 Ki-1 antigen. It is also in close proximity to GALNT12, also recently shown to be altered in colon tumors. We used a predictive modeling algorithm to show the contribution of this risk haplotype and surrounding candidate genes in distinguishing between colon cancer cases and healthy controls. The ability to replicate this finding, the strength of the haplotype association (odds ratio, 3.68), and the accuracy of our prediction model (∼60%) all strongly support the presence of a locus for familial colon cancer on chromosome 9q. Cancer Res; 70(13); 5409–18. ©2010 AACR.
Nuclear Alternate Estrogen Receptor GPR30 Mediates 17β-Estradiol–Induced Gene Expression and Migration in Breast Cancer–Associated Fibroblasts
Authors: Madeo Antonio , Maggiolini Marcello 
Published: June 2010

Abstract
Fibroblasts are the principal cellular component of connective tissue and are associated with cancer cells at all stages of tumor progression. Structural and functional contributions of fibroblasts to the growth, survival, and invasive capacity of cancer cells are beginning to emerge. In breast carcinoma, ∼80% of stromal fibroblasts termed cancer-associated fibroblasts (CAF) are thought to manifest an activated phenotype that promotes cancer cell proliferation tumor growth at metastatic sites similar to the primary tumor. In this report, we show that CAFs respond to physiologic concentrations of 17β-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1. Notably, the E2 response is mediated by the alternate estrogen receptor GPR30, which interfaces with the epidermal growth factor receptor (EGFR) signaling pathway. In particular, E2 stimulates a physical interaction between GPR30 and phosphorylated EGFR, recruiting them to the cyclin D1 gene promoter. Nuclear localization induced by E2 was confirmed by cellular immunofluorescence methods. GPR30 was required for CAF proliferation and migration induced by E2. Our results provide important new mechanistic insights into how CAFs are stimulated by estrogen through a GPR30-mediated nuclear signaling pathway. More generally, they define estrogenic GPR30 signaling as a functionally important component of the tumor microenvironment. Cancer Res; 70(14); 6036–46. ©2010 AACR.
RG7204 (PLX4032), a Selective BRAFV600E Inhibitor, Displays Potent Antitumor Activity in Preclinical Melanoma Models
Authors: Yang Hong , Higgins Brian , Kolinsky Kenneth , Packman Kathryn , Go Zenaida , Iyer Raman , Kolis Stanley , Zhao Sylvia , Lee Richard , Grippo Joseph F. , Schostack Kathleen , Simcox Mary Ellen , Heimbrook David , Bollag Gideon , Su Fei 
Published: June 2010

Abstract
The BRAFV600E mutation is common in several human cancers, especially melanoma. RG7204 (PLX4032) is a small-molecule inhibitor of BRAFV600E kinase activity that is in phase II and phase III clinical testing. Here, we report a preclinical characterization of the antitumor activity of RG7204 using established in vitro and in vivo models of malignant melanoma. RG7204 potently inhibited proliferation and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase and ERK phosphorylation in a panel of tumor cell lines, including melanoma cell lines expressing BRAFV600E or other mutant BRAF proteins altered at codon 600. In contrast, RG7204 lacked activity in cell lines that express wild-type BRAF or non-V600 mutations. In several tumor xenograft models of BRAFV600E-expressing melanoma, we found that RG7204 treatment caused partial or complete tumor regressions and improved animal survival, in a dose-dependent manner. There was no toxicity observed in any dose group in any of the in vivo models tested. Our findings offer evidence of the potent antitumor activity of RG7204 against melanomas harboring the mutant BRAFV600E gene. Cancer Res; 70(13); 5518–27. ©2010 AACR.
Targeted Activation of RNA Helicase Retinoic Acid–Inducible Gene-I Induces Proimmunogenic Apoptosis of Human Ovarian Cancer Cells
Authors: Kübler Kirsten , Gehrke Nadine , Riemann Soheila , Böhnert Volker , Zillinger Thomas , Hartmann Evelyn , Pölcher Martin , Rudlowski Christian , Kuhn Walther , Hartmann Gunther , Barchet Winfried 
Published: June 2010

AbstractMost malignant cells are poorly immunogenic and fail to elicit an effective antitumor immune response. In contrast, viral infections of cells are promptly detected and eliminated by the immune system. Viral recognition critically hinges on cytosolic nucleic acid receptors that include the proinflammatory RNA helicase retinoic acid–inducible gene-I (RIG-I). Here, we show that targeted delivery of RIG-I agonists induced ovarian cancer cells to upregulate HLA class I and to secrete the proinflammatory cytokines CXCL10, CCL5, interleukin-6, tumor necrosis factor-α, and IFN-β. Ovarian cancer cells stimulated via RIG-I became apoptotic and were readily phagocytosed by monocytes and monocyte-derived dendritic cells, which in turn upregulated HLA class I/II and costimulatory molecules and released CXCL10 and IFN-α. Our findings offer proof of principle that mimicking viral infection in ovarian cancer cells triggers an immunogenic form of tumor cell apoptosis that may enhance immunotherapy of ovarian cancer. Cancer Res; 70(13); 5293–304. ©2010 AACR.
Clinical Implications of Gene Dosage and Gene Expression Patterns in Diploid Breast Carcinoma
Authors: Parris Toshima Z. , Danielsson Anna , Nemes Szilárd , Kovács Anikó , Delle Ulla , Fallenius Ghita , Möllerström Elin , Karlsson Per , Helou Khalil 
Published: June 2010

AbstractPurpose: Deregulation of key cellular pathways is fundamental for the survival and expansion of neoplastic cells. In cancer, regulation of gene transcription can be mediated in a variety of ways. The purpose of this study was to assess the impact of gene dosage on gene expression patterns and the effect of other mechanisms on transcriptional levels, and to associate these genomic changes with clinicopathologic parameters.Experimental Design: We screened 97 invasive diploid breast tumors for DNA copy number alterations and changes in transcriptional levels using array comparative genomic hybridization and expression microarrays, respectively.Results: The integrative analysis identified an increase in the overall number of genetic alterations during tumor progression and 15 specific genomic regions with aberrant DNA copy numbers in at least 25% of the patient population, i.e., 1q22, 1q22-q23.1, 1q25.3, 1q32.1, 1q32.1-q32.2, 8q21.2-q21.3, 8q22.3, 8q24.3, and 16p11.2 were recurrently gained, whereas 11q25, 16q21, 16q23.3, and 17p12 were frequently lost (P &lt; 0.01). An examination of the expression patterns of genes mapping within the detected genetic aberrations identified 47 unique genes and 1 Unigene cluster significantly correlated between the DNA and relative mRNA levels. In addition, more malignant tumors with normal gene dosage levels displayed a recurrent overexpression of UBE2C, S100A8, and CBX2, and downregulation of LOC389033, STC2, DNALI1, SCUBE2, NME5, SUSD3, SERPINA11, AZGP1, and PIP.Conclusions: Taken together, our findings suggest that the dysregulated genes identified here are critical for breast cancer initiation and progression, and could be used as novel therapeutic targets for drug development to complement classical clinicopathologic features. Clin Cancer Res; 16(15); 3860–74. ©2010 AACR.
Economic Evaluation of the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) Randomized Controlled Trial
Authors: Reed Shelby D. , Whellan David J. , Li Yanhong , Friedman Joëlle Y. , Ellis Stephen J. , Piña Ileana L. , Settles Sharon J. , Davidson-Ray Linda , Johnson Johanna L. , Cooper Lawton S. , O'Connor Christopher M. , Schulman Kevin A. ,   for the HF-ACTION Investigators
Published: June 2010

Background—
Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) assigned 2331 outpatients with medically stable heart failure to exercise training or usual care. We compared medical resource use and costs incurred by these patients during follow-up.

Methods and Results—

Extensive data on medical resource use and hospital bills were collected throughout the trial for estimates of direct medical costs. Intervention costs were estimated using patient-level trial data, administrative records, and published unit costs. Mean follow-up was 2.5 years. There were 2297 hospitalizations in the exercise group and 2332 in the usual care group (
P
=0.92). The mean number of inpatient days was 13.6 (standard deviation [SD], 27.0) in the exercise group and 15.0 (SD, 31.4) in the usual care group (
P
=0.23). Other measures of resource use were similar between groups, except for trends indicating that fewer patients in the exercise group underwent high-cost inpatient procedures. Total direct medical costs per participant were an estimated $50 857 (SD, $81 488) in the exercise group and $56 177 (SD, $92 749) in the usual care group (95% confidence interval for the difference, $−12 755 to $1547;
P
=0.10). The direct cost of exercise training was an estimated $1006 (SD, $337). Patient time costs were an estimated $5018 (SD, $4600).

Conclusions—
The cost of exercise training was relatively low for the health care system, but patients incurred significant time costs. In this economic evaluation, there was little systematic benefit in terms of overall medical resource use with this intervention.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00047437.
Buddha-Relics in the Lives of Southern Asian Polities
Authors: Blackburn Anne 
Published: June 2010

AbstractDrawing on literary and inscriptional evidence from Sri Lanka and mainland Southeast Asia, this essay examines the place of Buddha-relics — potent traces of a Buddha — in the life cycle of southern Asian political formations. In the formation of new polities and/or new dynasties, relics were drawn into the physical landscape and literary memory of the state, in order to provide protection and to claim desirable lineage and authority. At times of heightened military and political activity, when kingdoms were at risk, the protection and deployment of relics, and their ritual engagement, formed part of the state's central technologies. During periods of victory and restoration, relic festivals and the enhancement of a landscape embedded with relics, were used to display, affirm, and protect the royal court.
Kingship and Ancestral Cult in the Northwest Palace at Nimrud
Authors: Brown Brian 
Published: June 2010

AbstractBuilt in the early 9th century BCE, the Northwest Palace at Nimrud presented a new “imperial” architecture and iconography that was related to Assyrian expansionism at this time. Yet it also contained specific points of contact with the past via the royal Assyrian ancestors. A monument in the throneroom, the “center” of the state, provided the “public” view of this ideology, while one of the palace’s more secluded wings was devoted to the performance of ancestral cult. Through these and other means, rapid and fundamental socio-political change was accompanied by the idea of a logical and direct continuity with the history of Assyria.
Discrepancy between strong cephalic arterial dilatation and mild headache caused by prostaglandin D2(PGD2)
Authors: Wienecke Troels , Olesen Jes , Ashina Messoud 
Published: June 2010

Introduction: Prostaglandins (PGs) are involved in nociception and mast cell degranulation. Prostaglandin D2(PGD2) is a vasodilatator released during mast cell degranulation. The headache-eliciting effect of PGD2has not been studied in man.Subjects and methods: Twelve healthy volunteers were randomly allocated to receive intravenous infusion of 384 ng/kg/min PGD2over 25 min in a placebo-controlled, double-blind cross-over study. We recorded headache intensity and associated symptoms, velocity in the middle cerebral artery (VMCA) and diameter of the superficial temporal artery (STA) and radial artery (RA) using ultrasonography.Results: In the period 0–14 h, 11 subjects reported headache on PGD2compared to one subject on placebo ( P = 0.002). During the in-hospital phase (0–120 min), the area under the headache curve was larger on PGD2compared to placebo ( P < 0.05). Median peak headache, 1 (0–1), occurred 10 min after start of PGD2infusion. There was no difference in incidence of headache in the post-hospital phase between PGD2( n = 3) and placebo ( n = 1). There was a decrease in VMCA( P < 0.001), increase in STA ( P < 0.001) and RA ( P < 0.006) diameter during PGD2infusion compared to placebo. Peak decrease in VMCAwas 28.3% after 10 min and peak increase in STA was 55.7% after 20 min on the PGD2day. Conclusions: The present study shows that PGD2is a very strong vasodilator of MCA, STA and RA, but causes only mild headache.