bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of the Oxidative Damage Repair GenesNUDT1,OGG1, andMUTYHin Patients from Mismatch Repair Proficient HNPCC Families (MSS-HNPCC)
Authors: Garre Pilar , Briceño Verónica , Xicola Rosa M. , Doyle Brian J. , de la Hoya Miguel , Sanz Julián , Llovet Patricia , Pescador Paula , Puente Javier , Díaz-Rubio Eduardo , Llor Xavier , Caldés Trinidad 
Published: February 2011

AbstractPurpose: Several studies have described molecular differences between microsatellite stable hereditary nonpolyposis colorectal cancer (MSS-HNPCC) and microsatellite unstable Lynch syndrome tumors (MSI-HNPCC). These differences highlight the possibility that other instability forms could explain cancer susceptibility in this group of families.The base excision repair (BER) pathway is the major DNA repair pathway for oxidative DNA damage. A defect in this pathway can result in DNA transversion mutations and a subsequent increased cancer risk. Mutations in MUTYH have been associated with increased colorectal cancer (CRC) risk while no association has been described for OGG1 or NUDT1.Experimental Design: We performed mutational screening of the three genes involved in defense against oxidative DNA damage in a set of 42 MSS-HNPCC families.Results: Eight rare variants and 5 frequent variants were found in MSS-HNPCC patients. All variants were previously described by other authors except variant c.285C&gt;T in OGG1. Segregation studies were done and in silico programs were used to estimate the level of amino acid conservation, protein damage prediction, and possible splicing alterations. Variants OGG1 c.137G&gt;A; MUTYH c.1187G&gt;A were detected in Amsterdam I families and cosegregate with cancer. Analysis of OGG1 c.137G&gt;A transcripts showed an inactivation of the splicing donor of exon 1.Conclusions: Two rare variants (OGG1 c.137G&gt;A; MUTYH c.1187G&gt;A) and one common polymorphism (NUDT1 c.426C&gt;T) were associated with CRC risk. We show that the BER pathway can play a significant role in a number of MSS-HNPCC colorectal cancers. More studies could be of interest in order to gain further understanding of yet unexplained CRC susceptibility cases. Clin Cancer Res; 17(7); 1701–12. ©2011 AACR.
The A/G Allele of Rs16906252 Predicts for MGMT Methylation and Is Selectively Silenced in Premalignant Lesions from Smokers and in Lung Adenocarcinomas
Authors: Leng Shuguang , Bernauer Amanda M. , Hong Chibo , Do Kieu C. , Yingling Christin M. , Flores Kristina G. , Tessema Mathewos , Tellez Carmen S. , Willink Randall P. , Burki Elizabeth A. , Picchi Maria A. , Stidley Christine A. , Prados Michael D. , Costello Joseph F. , Gilliland Frank D. , Crowell Richard E. , Belinsky Steven A. 
Published: February 2011

Abstract
Purpose: To address the association between sequence variants within the MGMT (O6-methylguanine-DNA methyltransferase) promoter–enhancer region and methylation of MGMT in premalignant lesions from smokers and lung adenocarcinomas, their biological effects on gene regulation, and targeting MGMT for therapy.
Experimental Design: Single nucleotide polymorphisms (SNP) identified through sequencing a 1.9 kb fragment 5′ of MGMT were examined in relation to MGMT methylation in 169 lung adenocarcinomas and 1,731 sputum samples from smokers. The effect of promoter haplotypes on MGMT expression was tested using a luciferase reporter assay and cDNA expression analysis along with allele-specific sequencing for methylation. The response of MGMT methylated lung cancer cell lines to the alkylating agent temozolomide (TMZ) was assessed.
Results: The A allele of rs16906252 and the haplotype containing this SNP were strongly associated with increased risk for MGMT methylation in adenocarcinomas (ORs ≥ 94). This association was observed to a lesser extent in sputum samples in both smoker cohorts. The A allele was selectively methylated in primary lung tumors and cell lines heterozygous for rs16906252. With the most common haplotype as the reference, a 20 to 41% reduction in promoter activity was seen for the haplotype carrying the A allele that correlated with lower MGMT expression. The sensitivity of lung cancer cell lines to TMZ was strongly correlated with levels of MGMT methylation and expression.
Conclusions: These studies provide strong evidence that the A allele of a MGMT promoter–enhancer SNP is a key determinant for MGMT methylation in lung carcinogenesis. Moreover, TMZ treatment may benefit a subset of lung cancer patients methylated for MGMT. Clin Cancer Res; 17(7); 2014–23. ©2011 AACR.
Nelfinavir Induces Liposarcoma Apoptosis through Inhibition of Regulated Intramembrane Proteolysis of SREBP-1 and ATF6
Authors: Guan Min , Fousek Kristen , Jiang Chunling , Guo Song , Synold Tim , Xi Bixin , Shih Chu-Chih , Chow Warren A. 
Published: February 2011

Abstract
Purpose: We previously reported that nelfinavir (NFV) induces G1 cell-cycle block and apoptosis selectively in liposarcoma cell lines due to increased SREBP-1 (sterol regulatory element binding protein-1) expression in the absence of increased transcription. We postulate that NFV interferes with regulated intramembrane proteolysis of SREBP-1 and ATF6 (activating transcription factor 6).
Experimental Design: Time-lapse, confocal microscopic studies show that NFV inhibits the nuclear translocation of full-length SREBP-1–EGFP and ATF6–EGFP fusion proteins. siRNA-mediated knockdown of site-1 protease (S1P) and/or site-2 protease (S2P) leads to inhibition of SREBP-1 intracellular trafficking to the nucleus and reduces liposarcoma cell proliferation. Treatment of LiSa-2 liposarcoma cells with 3,4-dichloroisocoumarin, a serine protease inhibitor of S1P, did not affect SREBP-1 processing. In contrast, 1,10-phenanthroline, an S2P-specific inhibitor, reproduces the molecular and biological phenotypes observed in NFV-treated cells, which implicates S2P as a target of NFV. In vivo evaluation of NFV in a murine liposarcoma xenograft model leads to inhibition of tumor growth without significant toxicity.
Results: NFV-induced upregulation of SREBP-1 and ATF6 results from inhibition of S2P, which together with S1P mediates regulated intramembrane proteolysis from their precursor to their transcriptionally active forms. The resulting endoplasmic reticulum (ER) stress and concurrent inhibition of the unfolded protein response induce caspase-mediated apoptosis.
Conclusions: These results provide new insight into the mechanism of NFV-mediated induction of ER stress and cell death in liposarcomas and are the first to report targeting S2P for cancer therapy. Clin Cancer Res; 17(7); 1796–806. ©2011 AACR.
A YKL-40–Neutralizing Antibody Blocks Tumor Angiogenesis and Progression: A Potential Therapeutic Agent in Cancers
Authors: Faibish Michael , Francescone Ralph , Bentley Brooke , Yan Wei , Shao Rong 
Published: February 2011

Abstract
Accumulating evidence has indicated that expression levels of YKL-40, a secreted glycoprotein, were elevated in multiple advanced human cancers. Recently, we have identified an angiogenic role of YKL-40 in cancer development. However, blockade of the function of YKL-40, which implicates therapeutic value, has not been explored yet. Our current study sought to establish a monoclonal anti–YKL-40 antibody as a neutralizing antibody for the purpose of blocking tumor angiogenesis and metastasis. A mouse monoclonal anti–YKL-40 antibody (mAY) exhibited specific binding with recombinant YKL-40 and with YKL-40 secreted from osteoblastoma cells MG-63 and brain tumor cells U87. In the functional analysis, we found that mAY inhibited tube formation of microvascular endothelial cells in Matrigel induced by conditioned medium of MG-63 and U87 cells, as well as recombinant YKL-40. mAY also abolished YKL-40–induced activation of the membrane receptor VEGF receptor 2 (Flk-1/KDR) and intracellular signaling mitogen-activated protein (MAP) kinase extracellular signal–regulated kinase (Erk) 1 and Erk 2. In addition, mAY enhanced cell death response of U87 line to γ-irradiation through decreased expression of pAKT and AKT and accordingly, abrogated angiogenesis induced by the conditioned medium of U87 cells in which YKL-40 levels were elevated by treatment with γ-irradiation. Furthermore, treatment of xenografted tumor mice with mAY restrained tumor growth, angiogenesis, and progression. Taken together, this study has shown the therapeutic use for the mAY in treatment of tumor angiogenesis and metastasis. Mol Cancer Ther; 10(5); 742–51. ©2011 AACR.
Abstract 1230: Nicotine induces expression of integrin-linked kinase in human lung carcinoma cells through A7 nAChR-mediated inhibition of AP-2A
Authors: Zhong XiaoRong , Zheng Ying , Sun XiaoJuan , Ritzenthaler Jeffrey D. , Roman Jesse , Han Shouwei 
Published: February 2011

Abstract
We previously demonstrated that nicotine stimulates non small cell lung carcinoma (NSCLC) cell proliferation through nicotinic acetylcholine receptor (nAChR)-mediated induction of fibronectin expression. However, the mechanisms by which this agent affects human lung cancer occurrence and progression remain incompletely elucidated. Here, we show that nicotine increases the expression of integrin-linked kinase (ILK), a unique intracellular adaptor and kinase that has been implicated in the regulation of cancer cell growth/survival. This effect was blocked by the α7 nAChR antagonist, α-bungarotoxin, and by α7 nAChR siRNA. Silencing of ILK blocked the stimulatory effect of nicotine on phosphorylation of the PI3-K downstream target Akt and on cell growth. Furthermore, nicotine increased ILK gene promoter activity through inhibition of transcription factor AP-2α protein expression. Silencing of AP-2α enhanced, while exogenous expression of AP-2α attenuated, the stimulatory effect of nicotine on ILK expression. These findings appear to be relevant in vivo since we found that nicotine treatment increased tumor growth in animal models. Collectively, our results demonstrate that nicotine increases ILK gene expression through α7 nAChR-mediated inhibition of AP-2α followed by stimulation of PI3-K/Akt signaling. In turn, this leads to increased NSCLC cell growth. This study unveils a novel mechanism by which nicotine promotes human lung carcinoma cell growth/survival.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1230.
Abstract 1293: Neutrophil gelatinase-associated lipocalin regulates the expression of angiogenic cytokines and VEGF in human breast and ovarian cancer cells
Authors: Yang Jiang , Moses Marsha A. 
Published: February 2011

Abstract
Neutrophil gelatinase-associated lipocalin (NGAL; lipocalin 2) is a small extracellular protein (25 kDa) that is a member of the lipocalin protein family. It has been shown to bind ferric siderophores and to play an important role in iron metabolism. Increased NGAL levels have been reported in a variety of epithelial cancers, including breast, ovary, pancreas, colon, esophagus and thyroid cancer. We have recently reported that NGAL promotes breast cancer progression by inducing the epithelial to mesenchymal transition. In the course of these studies, we observed an increase in microvessel density in NGAL-expressing tumors. In the current study, we explored the potential role of NGAL in tumor angiogenesis by studying its effects on the expression of angiogenic factors. We first determined the levels of vascular endothelial growth factor (VEGF) in NGAL-expressing cells derived from the MCF-7 human breast cancer cell line. Using reverse-transcriptase PCR and ELISA, VEGF was found to be induced by NGAL at both the transcript and protein levels. Consistently, HIF-1α, one of the most important transcriptional regulators of VEGF, was observed to be accumulated in the nuclei of NGAL-expressing cells. Silencing of HIF-1α in NGAL-expressing cells significantly reduced VEGF expression. Consistent with this NGAL-induced VEGF production, there was a significant increase in endothelial cell migration towards the conditioned media collected from NGAL-expressing cells. Interestingly, treatment with a VEGF-neutralizing antibody only partially inhibited the migration-inducing activity of the conditioned media, suggesting that NGAL might induce the secretion of other angiogenic factors. To investigate this possibility, a panel of angiogenic factors was compared between the conditioned media collected from NGAL-expressing cells and control MCF-7 cells using antibody arrays. Several angiogenic cytokines, including IL-6, MCP-1 and GM-CSF, were found to be upregulated with NGAL expression. The effects of NGAL on VEGF and angiogenic cytokine production were also studied in SKOV-3 ovarian cancer cells. In this study, NGAL was silenced in SKOV-3 cells using specific siRNAs. The levels of both VEGF and IL-6 were found to be reduced after NGAL silencing, suggesting that NGAL's control of VEGF and cytokine production may be common among cancer cell types. These results suggest a novel mechanism through which NGAL may promote tumor angiogenesis and progression. (This work is supported by NIH R01 CA118764, P01 CA045548 and The Advanced Medical Foundation.)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1293.
Abstract 1608: Novel lipogenic enzyme ELOVL7 is involved in prostate cancer growth through saturated long-chain fatty acid metabolism
Authors: Tamura Kenji , Makino Asami , Hullin-Matsuda Francoise , Kobayashi Toshihide , Furihata Mutsuo , Chung Suyoun , Ashida Shingo , Miki Tsuneharu , Fujioka Tomoaki , Shuin Taro , Nakamura Yusuke , Nakagawa Hidewaki 
Published: February 2011

Abstract
A number of epidemiologic studies have indicated a strong association between dietary fat intake and prostate cancer development, suggesting that lipid metabolism plays some important roles in prostate carcinogenesis and its progression. In this study, through our genome-wide gene expression analysis of clinical prostate cancer cells, we identified a novel lipogenic gene, ELOVL7, coding a possible long-chain fatty acid elongase, as overexpressed in prostate cancer cells. ELOVL7 expression is regulated by the androgen pathway through SREBP1, as well as other lipogenic enzymes. Knockdown of ELOVL7 resulted in drastic attenuation of prostate cancer cell growth, and it is notable that high-fat diet promoted the growth of in vivo tumors of ELOVL7-expressed prostate cancer. In vitro fatty acid elongation assay and fatty acid composition analysis indicated that ELOVL7 was preferentially involved in fatty acid elongation of saturated very-long-chain fatty acids (SVLFA, C20:0). Lipid profiles showed that knockdown of ELOVL7 in prostate cancer cells affected SVLFAs in the phospholipids and the neutral lipids, such as cholesterol ester. Focusing on cholesterol ester as a source of de novo steroid synthesis, we show that ELOVL7 affected de novo androgen synthesis in prostate cancer cells. These findings suggest that EVOLV7 could be involved in prostate cancer growth and survival through the metabolism of SVLFAs and their derivatives, could be a key molecule to elucidate the association between fat dietary intake and prostate carcinogenesis, and could also be a promising molecular target for development of new therapeutic or preventive strategies for prostate cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1608.
Abstract 17: Preclinical and phase 1 trial results of JI-101, a novel, oral tyrosine kinase inhibitor that selectively targets VEGFR2, EphB4, and PDGFRβ
Authors: Velleca Mark , Miller Linda , Sharma Sunil , Gordon Michael , Brittelli David , Elkin Lisa , Govindarajan Raman , Klein Udo , Mitchell Scott , N Nandhagopal , Qian Dapeng , Qian Xiaobing , Stephen Thomas , Srinivasa Sreesha , Stern Warren 
Published: February 2011

Abstract
Introduction
JI-101 is a highly selective and potent angiogenesis inhibitor with unique EphB4 activity that distinguishes it from other agents in clinical development. We report the preclinical pharmacology and early clinical experience with this compound.
Procedures
Lead optimization was used to identify cgi1842 (now JI-101) with a targeted activity profile that is selective and unique. JI-101 was tested in binding, enzymatic, and cell-based assays for activity against kinase and non-kinase targets. Preclinical in vivo testing for PK, PD, efficacy, and safety pharmacology was performed in mouse, rat, guinea pig, and dog. A Phase I clinical trial is underway: 12 patients have been treated thus far with 28-day oral daily dosing at 100 mg, 200 mg, 400 mg QD or at 200 mg BID. PK, PD, and imaging analyses have been performed.
Data
JI-101 has a MW of 466D and high (&lt;100 nm) potency against VEGFR2, EphB4, and PDGFR in enzymatic and cell-based assays. Broad kinase cross-screening (Ambit KinomeScan, 445 kinases) reveals that JI-101 is highly selective for angiogenic kinases with only 23 kinases demonstrating a Kd 15). JI-101 was co-administered with paclitaxel in a MDA-MB-231 mouse xenotransplant model, resulting in greater efficacy and no increased toxicity. Based on 28-day GLP toxicology studies conducted in rat and dog, a 100 mg qd starting dose (2 × 50 mg capsules) was chosen for Phase I studies. JI-101 appears to be very well-tolerated to date with no dose limiting toxicities. Patients have received 1-9 cycles with most receiving multiple cycles and 5 remain on study at 100 mg (1 pt), 200 mg (1 pt), and 400 mg (3 pt). Manageable hypertension has been seen in all cohorts indicating a possible PD effect. Hand-foot syndrome of short duration was seen at the 400mg dose level. Further clinical details of the PK, PD, tolerability and efficacy of JI-101 will be presented.
Conclusions
JI-101 potently inhibits 3 critical angiogenic kinases (VEGFR2, EphB4, and PDGFR) and is the only such “triple” angiogenesis inhibitor currently in development. JI-101 shows robust preclinical and clinical pharmacology and is well-tolerated to date in human trials. In tumors where EphB4 may play an oncogenic role, such as head and neck cancer, JI-101 may have anti-proliferative effects in addition to anti-angiogenic effects and should be amenable to combination therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 17.
Abstract 2241: Role of tissue markers in the prediction of bone metastases from breast cancer
Authors: Sacanna Emanuele , Ibrahim Toni , Gaudio Michele , Mercatali Laura , Ricci Rossana , Scarpi Emanuela , Ricci Marianna , Serra Patrizia , Serra Luigi , Arienti Chiara , Bravaccini Sara , Amadori Dino 
Published: February 2011

Abstract
Introduction: Bone metastasis is a frequent event in patients with breast cancer. OPG (osteoprotegerin) protects bone from excessive resorption by binding to RANK-L (receptor activator of nuclear factor-kB-ligand) and by preventing it from binding to RANK. These molecules are closely involved in the process of metastasization to bone. CXCL12/SDF-1α, the ligand of CXCR4, is overexpressed in bone, and the local chemokine milieu is now emerging as a key determinant in organ selectivity by tumor cells. We carried out a retrospective analysis to evaluate the potential role of these biological markers in predicting bone metastasization in breast cancer patients.
Materials and methods: OPG and CXCR4 expression was determined by avidin-biotin immunohistochemistry using a polyclonal (H-249, Santa Cruz) and monoclonal (Ab58176, Abcam) antibody, respectively. Immunohistochemical staining was carried out on sections from paraffin-embedded blocks of 40 primary breast cancers. Ten patients (median age of 64 years, range 48-78) were disease-free (DF) at a median of 9.8 (range 6.9-11.5) years, while 30 (median age 67 years, range 42-87) had relapsed. In the latter group, 10 (median age 66 years, range 42-87) had visceral metastases (VM) and 20 (median age 69 years, range 42-87) had bone metastases (BM).
Results: Considering only strong cytoplasmic expression as positive, 22.5% of tumors were positive for OPG and 25% for CXCR4. In particular, OPG was expressed in 20% of tumors in DF patients and in 25% in BM patients. Conversely, CXCR4 was expressed in 10% of tumors in DF patients and in 45% in BM patients. OPG was expressed in only 20% of tumors in VM patients. There was no correlation between OPG and CXCR4 expression, and positivity to at least one of the two markers was observed in 30% of tumors in DF patients, 20% in VM patients and 55% in BM patients. In this last subgroup, there were no statistically significant associations between marker expression and tumor characteristics. Furthermore, no relation was observed between marker expression and disease-free or overall survival in BM patients.
Conclusions: Our preliminary results suggest that cytoplasmic CXCR4 expression in primary breast cancers could play a role in predicting bone metastases. Enrolment of breast cancer patients in a larger study is ongoing to confirm these data and to evaluate the predictive role of RANK and RANK-L in bone metastasization.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2241.