bluuebunny/crossref_metadata_2025_split huggingface dataset:
Refactoring references for library migration
Authors: Kapur Puneet , Cossette Brad , Walker Robert J. 
Published: February 2011

Automated refactoring is a key feature of modern IDEs. Existing refactorings rely on the transformation of source code declarations, in which references may also be transformed as a side effect. However, there exist situations in which a declaration is not available for refactoring or would be inappropriate to transform, for example, in the presence of dangling references or where a set of references should be retargeted to a different declaration.
We investigate the problem of dangling references through a detailed study of three open source libraries. We find that the introduction of dangling references during library migration is a significant real problem, and characterize the specific issues that arise. Based on these findings we provide and test a prototype tool, called Trident, that allows programmers to refactor references. Our results suggest that supporting the direct refactoring of references is a significant improvement over the state-of-the-art.
CARM1 Is an Important Determinant of ERα-Dependent Breast Cancer Cell Differentiation and Proliferation in Breast Cancer Cells
Authors: Al-Dhaheri Mariam , Wu Jiacai , Skliris Georgios P. , Li Jun , Higashimato Ken , Wang Yidan , White Kevin P. , Lambert Paul , Zhu Yuerong , Murphy Leigh , Xu Wei 
Published: February 2011

Abstract
Breast cancers with estrogen receptor α (ERα) expression are often more differentiated histologically than ERα-negative tumors, but the reasons for this difference are poorly understood. One possible explanation is that transcriptional cofactors associated with ERα determine the expression of genes which promote a more differentiated phenotype. In this study, we identify one such cofactor as coactivator-associated arginine methyltransferase 1 (CARM1), a unique coactivator of ERα that can simultaneously block cell proliferation and induce differentiation through global regulation of ERα-regulated genes. CARM1 was evidenced as an ERα coactivator in cell-based assays, gene expression microarrays, and mouse xenograft models. In human breast tumors, CARM1 expression positively correlated with ERα levels in ER-positive tumors but was inversely correlated with tumor grade. Our findings suggest that coexpression of CARM1 and ERα may provide a better biomarker of well-differentiated breast cancer. Furthermore, our findings define an important functional role of this histone arginine methyltransferase in reprogramming ERα-regulated cellular processes, implicating CARM1 as a putative epigenetic target in ER-positive breast cancers. Cancer Res; 71(6); 2118–28. ©2011 AACR.
NRF2 Blockade Suppresses Colon Tumor Angiogenesis by Inhibiting Hypoxia-Induced Activation of HIF-1α
Authors: Kim Tae-Hyoung , Hur Eu-gene , Kang Su-Jin , Kim Jung-Ae , Thapa Dinesh , Lee You Mie , Ku Sae Kwang , Jung Yunjin , Kwak Mi-Kyoung 
Published: January 2011

Abstract
Transcription factor NRF2 is an important modifier of cellular responses to oxidative stress. Although its cytoprotective effects are firmly established, recent evidence suggesting important roles in cancer pathobiology has yet to be mechanistically developed. In the current study, we investigated the role of NRF2 in colon tumor angiogenesis. Stable RNAi-mediated knockdown of NRF2 in human colon cancer cells suppressed tumor growth in mouse xenograft settings with a concomitant reduction in blood vessel formation and VEGF expression. Similar antiangiogenic effects of NRF2 knockdown were documented in chick chorioallantoic membrane assays and endothelial tube formation assays. Notably, NRF2-inhibited cancer cells failed to accumulate HIF-1α protein under hypoxic conditions, limiting expression of VEGF and other HIF-1α target genes. In these cells, HIF-1α was hydroxylated but pharmacological inhibition of PHD domain-containing prolyl hydroxylases was sufficient to restore hypoxia-induced accumulation of HIF-1α. Mechanistic investigations demonstrated that reduced mitochondrial O2 consumption in NRF2-inhibited cells was probably responsible for HIF-1α degradation during hypoxia; cellular O2 consumption and ATP production were lower in NRF2 knockdown cells than in control cells. Our findings offer novel insights into how cellular responses to O2 and oxidative stress are integrated in cancer cells, and they highlight NRF2 as a candidate molecular target to control tumor angiogenesis by imposing a blockade to HIF-1α signaling. Cancer Res; 71(6); 2260–75. ©2011 AACR.
Suppression of Glucosylceramide Synthase Restores p53-Dependent Apoptosis in Mutant p53 Cancer Cells
Authors: Liu Yong-Yu , Patwardhan Gauri A. , Bhinge Kaustubh , Gupta Vineet , Gu Xin , Jazwinski S. Michal 
Published: January 2011

Abstract
Tumor suppressor p53 plays an essential role in protecting cells from malignant transformation by inducing cell-cycle arrest and apoptosis. Mutant p53 that is detected in more than 50% of cases of cancers loses its role in suppression of tumors but gains in oncogenic function. Strategies to convert mutant p53 into wild-type p53 have been suggested for cancer prevention and treatment, but they face a variety of challenges. Here, we report an alternative approach that involves suppression of glucosylceramide synthase (GCS), an enzyme that glycosylates ceramide and blunts its proapoptotic activity in cancer cells. Human ovarian cancer cells expressing mutant p53 displayed resistance to apoptosis induced by DNA damage. We found that GCS silencing sensitized these mutant p53 cells to doxorubicin but did not affect the sensitivity of cells with wild-type p53. GCS silencing increased the levels of phosphorylated p53 and p53-responsive genes, including p21Waf1/Cip1, Bax, and Puma, consistent with a redirection of the mutant p53 cells to apoptosis. Reactivated p53-dependent apoptosis was similarly verified in p53-mutant tumors where GCS was silenced. Inhibition of ceramide synthase with fumonisin B1 prevented p53 reactivation induced by GCS silencing, whereas addition of exogenous C6-ceramide reactivated p53 function in p53-mutant cells. Our findings indicate that restoring active ceramide to cells can resuscitate wild-type p53 function in p53-mutant cells, offering preclinical support for a novel type of mechanism-based therapy in the many human cancers harboring p53 mutations. Cancer Res; 71(6); 2276–85. ©2011 AACR.
Identification of a Tumor Suppressor Relay between the FOXP3 and the Hippo Pathways in Breast and Prostate Cancers
Authors: Li Weiquan , Wang Lizhong , Katoh Hiroto , Liu Runhua , Zheng Pan , Liu Yang 
Published: January 2011

Abstract
Defective expression of LATS2, a negative regulator of YAP oncoprotein, has been reported in cancer of prostate, breast, liver, brain, and blood origins. However, no transcriptional regulators for the LATS2 gene have been identified. Here we report that spontaneous mutation of the transcription factor FOXP3 reduces expression of the LATS2 gene in mammary epithelial cells. shRNA-mediated silencing of FOXP3 in normal or malignant mammary epithelial cells of mouse and human origin repressed LATS2 expression and increased YAP protein levels. LATS2 induction required binding of FOXP3 to a specific sequence in the LATS2 promoter, and this interaction contributed to FOXP3-mediated growth inhibition of tumor cells. In support of these results, reduced expression and somatic mutations of FOXP3 correlated strongly with defective LATS2 expression in microdissected prostate cancer tissues. Thus, defective expression of LATS2 is attributable to FOXP3 defects and may be a major independent determinant of YAP protein elevation in cancer. Our findings identify a novel mechanism of LATS2 downregulation in cancer and reveal an important tumor suppressor relay between the FOXP3 and HIPPO pathways which are widely implicated in human cancer. Cancer Res; 71(6); 2162–71. ©2011 AACR.
A Phase I Study of the Heat Shock Protein 90 Inhibitor Alvespimycin (17-DMAG) Given Intravenously to Patients with Advanced Solid Tumors
Authors: Pacey Simon , Wilson Richard H. , Walton Mike , Eatock Martin M. , Hardcastle Anthea , Zetterlund Anna , Arkenau Hendrik-Tobias , Moreno-Farre Javier , Banerji Udai , Roels Belle , Peachey Heidi , Aherne Wynne , de Bono Johan S. , Raynaud Florence , Workman Paul , Judson Ian 
Published: January 2011

Abstract
Purpose: A phase I study to define toxicity and recommend a phase II dose of the HSP90 inhibitor alvespimycin (17-DMAG; 17-dimethylaminoethylamino-17-demethoxygeldanamycin). Secondary endpoints included evaluation of pharmacokinetic profile, tumor response, and definition of a biologically effective dose (BED).
Patients and Methods: Patients with advanced solid cancers were treated with weekly, intravenous (i.v.) 17-DMAG. An accelerated titration dose escalation design was used. The maximum tolerated dose (MTD) was the highest dose at which ≤1/6 patients experienced dose limiting toxicity (DLT). Dose de-escalation from the MTD was planned with mandatory, sequential tumor biopsies to determine a BED. Pharmacokinetic and pharmacodynamic assays were validated prior to patient accrual.
Results: Twenty-five patients received 17-DMAG (range 2.5–106 mg/m2). At 106 mg/m2 of 17-DMAG 2/4 patients experienced DLT, including one treatment-related death. No DLT occurred at 80 mg/m2. Common adverse events were gastrointestinal, liver function changes, and ocular. Area under the curve and mean peak concentration increased proportionally with 17-DMAG doses 80 mg/m2 or less. In peripheral blood mononuclear cells significant (P &lt; 0.05) HSP72 induction was detected (≥20 mg/m2) and sustained for 96 hours (≥40 mg/m2). Plasma HSP72 levels were greatest in the two patients who experienced DLT. At 80 mg/m2 client protein (CDK4, LCK) depletion was detected and tumor samples from 3 of 5 patients confirmed HSP90 inhibition. Clinical activity included complete response (castration refractory prostate cancer, CRPC 124 weeks), partial response (melanoma, 159 weeks), and stable disease (chondrosarcoma, CRPC, and renal cancer for 28, 59, and 76 weeks, respectively).
Couclusions: The recommended phase II dose of 17-DMAG is 80 mg/m2 weekly i.v. Clin Cancer Res; 17(6); 1561–70. ©2011 AACR.
Expression of p16 and Retinoblastoma Determines Response to CDK4/6 Inhibition in Ovarian Cancer
Authors: Konecny Gottfried E. , Winterhoff Boris , Kolarova Teodora , Qi Jingwei , Manivong Kanthinh , Dering Judy , Yang Guorong , Chalukya Meenal , Wang He-Jing , Anderson Lee , Kalli Kimberly R. , Finn Richard S. , Ginther Charles , Jones Siân , Velculescu Victor E. , Riehle Darren , Cliby William A. , Randolph Sophia , Koehler Maria , Hartmann Lynn C. , Slamon Dennis J. 
Published: January 2011

Abstract
Purpose: PD-0332991 is a selective inhibitor of the CDK4/6 kinases with the ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. Here we investigate the role of CDK4/6 inhibition in human ovarian cancer.
Experimental Design: We examined the effects of PD-0332991 on proliferation, cell-cycle, apoptosis, and Rb phosphorylation using a panel of 40 established human ovarian cancer cell lines. Molecular markers for response prediction, including p16 and Rb, were studied using gene expression profiling, Western blot, and array CGH. Multiple drug effect analysis was used to study interactions with chemotherapeutic drugs. Expression of p16 and Rb was studied using immunohistochemistry in a large clinical cohort of ovarian cancer patients.
Results: Concentration-dependent antiproliferative effects of PD-0332991 were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb-proficient cell lines with low p16 expression were most responsive to CDK4/6 inhibition. Copy number variations of CDKN2A, RB, CCNE1, and CCND1 were associated with response to PD-0332991. CDK4/6 inhibition induced G0/G1 cell cycle arrest, blocked Rb phosphorylation in a concentration-and time-dependent manner, and enhanced the effects of chemotherapy. Rb-proficiency with low p16 expression was seen in 97/262 (37%) of ovarian cancer patients and was independently associated with poor progression-free survival (adjusted relative risk 1.49, 95% CI 1.00–2.24, P = 0.052).
Conclusions: PD-0332991 shows promising biologic activity in ovarian cancer cell lines. Assessment of Rb and p16 expression may help select patients most likely to benefit from CDK4/6 inhibition in ovarian cancer. Clin Cancer Res; 17(6); 1591–602. ©2011 AACR.
TGF-β Blockade Controls Ascites by Preventing Abnormalization of Lymphatic Vessels in Orthotopic Human Ovarian Carcinoma Models
Authors: Liao Shan , Liu Jieqiong , Lin Peichun , Shi Tony , Jain Rakesh K. , Xu Lei 
Published: January 2011

Abstract
Purpose: Ovarian cancer patients with malignant ascites have poor prognosis. The accumulation of ascites is caused by an imbalance between fluid extravasation from the blood vessels and reabsorption by lymphatic vessels. Whereas, the role of TGF-β in tumor progression has been well studied, the role of TGF-β in lymphatic vessel function is far from understood. Here, we sought to dissect the role of TGF-β blockade in the formation of ascites.
Experimental Design: We used soluble TGF-β Receptor II (sTβRII) to block TGF-β signaling in two orthotopic human ovarian carcinoma models: SKOV3ip1 and Hey-A8. We measured tumor proliferation, apoptosis, lymphangiogenesis, and angiogenesis by immunohistochemical staining, and examined diaphragm lymphatic vessel network by intraperitoneal injection of a fluorescent dye. Diaphragm lymphatic vessel function was assessed by tracking fluorescent beads in the diaphragm and measuring their drainage rate.
Results: TGF-β blockade impaired tumor growth in both models, accompanied by a decreased tumor cell proliferation and angiogenesis. More strikingly, TGF-β blockade almost completely abolished ascites formation. TGF-β blockade significantly inhibited the expression of VEGF, which is the major contributor to ascites formation. At the same time, TGF-β blockade prevent ‘abnormalization’ of diaphragm lymphatic vessels and improved ascites drainage.
Conclusions: TGF-β blockade decreased ascites by both inhibiting ascites formation and improving ascites drainage. Based on our finding, it is reasonable to consider the use of TGF-β blockade as a palliative treatment for symptomatic ascites. Clin Cancer Res; 17(6); 1415–24. ©2011 AACR.
Genomic and Epigenomic Integration Identifies a Prognostic Signature in Colon Cancer
Authors: Yi Joo Mi , Dhir Mashaal , Van Neste Leander , Downing Stephanie R. , Jeschke Jana , Glöckner Sabine C. , de Freitas Calmon Marilia , Hooker Craig M. , Funes Juan M. , Boshoff Chris , Smits Kim M. , van Engeland Manon , Weijenberg Matty P. , Iacobuzio-Donahue Christine A. , Herman James G. , Schuebel Kornel E. , Baylin Stephen B. , Ahuja Nita 
Published: January 2011

Abstract
Purpose: The importance of genetic and epigenetic alterations maybe in their aggregate role in altering core pathways in tumorigenesis.
Experimental Design: Merging genome-wide genomic and epigenomic alterations, we identify key genes and pathways altered in colorectal cancers (CRC). DNA methylation analysis was tested for predicting survival in CRC patients using Cox proportional hazard model.
Results: We identified 29 low frequency-mutated genes that are also inactivated by epigenetic mechanisms in CRC. Pathway analysis showed the extracellular matrix (ECM) remodeling pathway is silenced in CRC. Six ECM pathway genes were tested for their prognostic potential in large CRC cohorts (n = 777). DNA methylation of IGFBP3 and EVL predicted for poor survival (IGFBP3: HR = 2.58, 95% CI: 1.37–4.87, P = 0.004; EVL: HR = 2.48, 95% CI: 1.07–5.74, P = 0.034) and simultaneous methylation of multiple genes predicted significantly worse survival (HR = 8.61, 95% CI: 2.16–34.36, P &lt; 0.001 for methylation of IGFBP3, EVL, CD109, and FLNC). DNA methylation of IGFBP3 and EVL was validated as a prognostic marker in an independent contemporary-matched cohort (IGFBP3 HR = 2.06, 95% CI: 1.04–4.09, P = 0.038; EVL HR = 2.23, 95% CI: 1.00–5.0, P = 0.05) and EVL DNA methylation remained significant in a secondary historical validation cohort (HR = 1.41, 95% CI: 1.05–1.89, P = 0.022). Moreover, DNA methylation of selected ECM genes helps to stratify the high-risk stage 2 colon cancers patients who would benefit from adjuvant chemotherapy (HR: 5.85, 95% CI: 2.03–16.83, P = 0.001 for simultaneous methylation of IGFBP3, EVL, and CD109).
Conclusions: CRC that have silenced genes in ECM pathway components show worse survival suggesting that our finding provides novel prognostic biomarkers for CRC and reflects the high importance of integrative analyses linking genetic and epigenetic abnormalities with pathway disruption in cancer. Clin Cancer Res; 17(6); 1535–45. ©2011 AACR.
Chinese Red Yeast Rice Inhibition of Prostate Tumor Growth in SCID Mice
Authors: Hong Mee Young , Henning Susanne , Moro Aune , Seeram Navindra P. , Zhang Yanjun , Heber David 
Published: January 2011

Abstract
Prostate cancer is a slowly developing but very common cancer in males that may be amenable to preventive strategies that are not toxic. Chinese red yeast rice (RYR), a food herb made by fermenting Monascus purpureus Went yeast on white rice, contains a mixture of eight different monacolins that inhibit cholesterogenesis in addition to red pigments with antioxidant properties. Monacolin K is identical to lovastatin (LV), but LV unlike RYR can be used in individuals intolerant to statins due to muscle pain. Both LV and RYR inhibit de novo cholesterogenesis, which is critical to the growth of tumor cells. Long-term use of statin drugs has been associated with a reduced risk of prostate cancer. We have previously shown that RYR inhibited androgen-dependent and androgen receptor–overexpressing androgen-independent prostate cancer cell proliferation in vitro. This study was designed to determine whether RYR and LV inhibit prostate tumor growth in SCID mice. RYR significantly reduced tumor volumes of androgen-dependent and androgen-independent prostate xenograft tumors compared with animals receiving vehicle alone (P &lt; 0.05). Inhibition by RYR was greater than that observed with LV at the dose found in RYR, showing that other compounds in RYR contributed to the antiproliferative effect. There was a significant correlation of tumor volume to serum cholesterol (P &lt; 0.001). RYR decreased gene expression of androgen synthesizing enzymes (HSD3B2, AKR1C3, and SRD5A1) in both type of tumors (P &lt; 0.05). Clinical studies of RYR for prostate cancer prevention in the increasing population of men undergoing active surveillance should be considered. Cancer Prev Res; 4(4); 608–15. ©2011 AACR.
Microscopic and Early-Stage Ovarian Cancers in BRCA1/2 Mutation Carriers: Building a Model for Early BRCA-Associated Tumorigenesis
Authors: Yates Melinda S. , Meyer Larissa A. , Deavers Michael T. , Daniels Molly S. , Keeler Elizabeth R. , Mok Samuel C. , Gershenson David M. , Lu Karen H. 
Published: January 2011

Abstract
Risk-reducing salpingo-oophorectomy (RRSO) is the cornerstone of ovarian cancer prevention in BRCA1/2 mutation carriers. Occult fallopian tube and ovarian cancers have been reported in a small percentage of BRCA1/2 mutation carriers undergoing RRSO. Here, we review our single-institution experience with RRSO in BRCA1/2 mutation carriers to characterize cases of microscopic cancers in these patients. At the time of RRSO, 7.9% of BRCA1 mutation carriers were diagnosed with microscopic fallopian tube or ovarian cancers and no cases were diagnosed in BRCA2 mutation carriers. The majority of the microscopic cancers include cases that were confined to the fallopian tubes, although there were also cases involving ovaries only or peritoneal washings only. This suggests that the site of origin may be in the ovary, fallopian tube, or peritoneum for BRCA-associated serous cancers. However, an analysis of early-stage (stages I and II) ovarian and fallopian tube cancers diagnosed in BRCA1/2 mutation carriers confirms that the ovary is a preferred site for tumor growth with 11 of 14 early-stage cancers having a dominant ovarian mass. Overall, these data suggest that cancer initiation may occur in the ovary, fallopian tube, or peritoneum, but tumor growth and progression are favored in the ovary. We present an updated model for BRCA1/2 mutation–associated ovarian and fallopian tube carcinogenesis, which may aid in identifying improved prevention strategies for high-risk women who delay or decline RRSO. Cancer Prev Res; 4(3); 463–70. ©2011 AACR.
Effect of Timing of Chronic Preoperative Aspirin Discontinuation on Morbidity and Mortality in Coronary Artery Bypass Surgery
Authors: Jacob Miriam , Smedira Nicholas , Blackstone Eugene , Williams Sarah , Cho Leslie 
Published: February 2011

Background—
Aspirin (ASA) has been shown to reduce postoperative coronary artery bypass grafting (CABG) mortality and ischemic events; however, the timing of chronic ASA discontinuation before surgery is controversial because of concern about postoperative bleeding. We evaluated the effect of the timing of ASA discontinuation before CABG on major adverse cardiovascular outcomes and postoperative bleeding using the Cleveland Clinic Cardiovascular Information Registry database.

Methods and Results—

At the Cleveland Clinic between January 1, 2002, and January 31, 2008, 4143 patients undergoing CABG were taking preoperative chronic ASA. Of these, 2298 discontinued ASA 6 or more days before surgery (early discontinuation), and 1845 took ASA within 5 days of the surgery (late use). Because of substantial differences between these 2 groups, propensity score analysis, and matching based on 31 variables were used for fair comparison of outcomes. This resulted in 1519 well-matched pairs of patients (73%). There was no significant difference between those with early discontinuation and late ASA use with regard to the composite outcome of in-hospital mortality, myocardial infarction, and stroke (1.7% versus 1.8%,
P
=0.80). Late use was associated with more intraoperative transfusions (23% versus 20%,
P
=0.03) and postoperative transfusions (30% versus 26%,
P
=0.009) but a similar number of reoperations for bleeding (3.4% versus 2.4%
P
=0.10).

Conclusions—
Among patients undergoing isolated CABG, late discontinuation of ASA resulted in no difference in postoperative cardiovascular outcomes; however, there was an increased transfusion requirement. Thus, we recommend weighing the risks and benefits of late ASA use in these patients.