bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2533: A novel approach to generate anti-Tn antibody for cancer diagnosis and immunotherapy
Authors: Chiang Hsiao-Ling , Lin Chi-Yu , Jan Fan-Dan , Chen Chiao-En , Wu Chia Cheng , Nieh Shin , Lin Chun-Cheng , Hwang Jaulang 
Published: August 2012

Abstract
Alterations in carbohydrate epitopes present on the cell surface are often hallmark of the transition from normal to neoplastic tissue. The concept of using carbohydrate antigens as cancer marker has thus spurred intense research interests into exploiting TACAs for the development of anticancer vaccines. This study presents a novel carrier protein containing a binding domain to the receptor of antigen presenting cells (APC) and cysteine-rich repeat peptide to serve as docking sites for conjugating tumor associated carbohydrate antigens (TACAs) or haptens. This novel carrier protein after conjugation with Tn, (GalNAcα1-O-Ser/Thr), can effectively elicit high titer of IgG1 antibody rather than IgM against Tn with high specificity in immunized mice. We then performed immunohistochemical (IHC) staining of twenty-six prostate cancer samples by staining with anti-Tn antibody, and we observed that the IHC staining with anti-Tn antibody is proportional to the malignancy of prostate cancer. Furthermore, we have examined the anti-Tn vaccine potency in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. TRMAP mice, which were treated with anti-Tn vaccine, showed longer survival rate and delayed tumor growth. We also successfully constructed the cDNA of mouse anti-Tn antibody from hybridoma cell line, and engineer this mouse cDNA as single-chain anti-Tn mouse antibody and anti-Tn immunotoxin. Our preliminary results showed that anti-Tn single-chain antibody can as a diagnostic antibody to distinguish normal prostatic tissue and prostate cancer, and anti-Tn immunotoxin can inhibit tumor cell growth. This study presents that our carrier protein can offer a platform for designing vaccine against tumor-associated weak immunogen and applies a new strategy in cancer immunotherapy in future.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2533. doi:1538-7445.AM2012-2533
Abstract 2535: Regulation of Chk1 by the mTOR pathway is essential for cancer cells to complete DNA replication in response to replication stress
Authors: Shen Changxian , Goto Greicy H. , Oswald Duane J. , Cam Hakan , Kurmasheva Raushan , Kitagawa Katsumi , Houghton Peter J. 
Published: August 2012

Abstract
Oncogenic signaling leads to DNA replication stress, DNA damage and consequently DNA damage response (DDR), a barrier for tumorigenesis. For survival and proliferation, cancer cells must overcome this oncogene-induced DDR, but the molecular mechanism by which this is achieved is largely unknown. Here we report that the mTOR pathway prevents either spontaneous or drug induced DNA damage by sustaining ATR-Chk1 checkpoint in pediatric rhabdomyosarcoma (RMS) both in vivo and in vitro. Pharmacological inhibition of mTOR signaling by the selective TOR kinase inhibitor AZD8055 lead to spontaneous DNA damage and apoptosis as demonstrated by the induction of H2AX phosphorylation and PARP1 cleavage both in cell culture and tumor xenografts of RMS. Treatment RMS Rh30 cells with AZD8055 enhanced hydroxyurea induced H2AX phosphorylation and attenuated ATR-Chk1 checkpoint activation, as shown by decreased levels of phospho-Chk1(S345). We further found that mTOR signaling controls CHK1 expression at the transcriptional level via enhancing the activity of cyclin dependent kinases (CDKs). Consistent with its essential role for cells to survive DNA replication stress, siRNA-mediated knockdown of Chk1, or inhibition of Chk1 function by a Chk1 kinase inhibitor resulted in H2AX phosphorylation, while ectopic increase of Chk1 attenuated the DNA damage induced by mTOR kinase inhibition. Most importantly, the mTOR kinase inhibitor prevented the slow S-phase progression following DNA replication stress, which was accompanied with a decrease of Chk1 protein levels and phospho-Chk1(S345). Our data suggest that the TORC1/TORC2 pathway promotes RMS tumorigenesis by enhancing the cell survival functions of the ATR-Chk1 checkpoint in response to DNA replication stress. Our findings discovered an important unexpected functional linkage between TOR signaling and the ATR-Chk1 checkpoint signaling cascade and may impact targeting these two prominent cancer cell signaling pathways. Supported by CA77776.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2535. doi:1538-7445.AM2012-2535
Abstract 2594: Chamomile (Matricaria chamomilla L.) upregulates heme oxygenase-1 through activation of ERK-Nrf2 signaling: Cytoprotective mechanism against oxidative damage
Authors: Bhaskaran Natarajan , Shukla Sanjeev , Gupta Sanjay 
Published: August 2012

Abstract
Protection of cells from oxidative insult could be attained by directly scavenging the reactive oxygen species or more significantly by stimulating the intracellular antioxidant defense through induction of antioxidant gene expression. It has been well documented that the transcriptional activation of Nrf2 in response to oxidative stress results in increased nuclear translocation and its binding to the antioxidant response elements (AREs) found in the promoters of genes, encoding antioxidant enzymes. Studies have demonstrated that Mitogen Activated Protein Kinase (MAPK) family is important in modulating ARE driven gene expression via Nrf2 activation. In the present study, we investigated which particular MAPK family member plays an important role in the regulation of chamomile-induced Nrf2-dependent ARE activity and ARE-driven antioxidant gene expression in mouse RAW 264.7 macrophage cells. We used aqueous chamomile extract (5, 10, 20 and 40µg/mL) obtained from dried flowers with and without MAPK pharmacological inhibitors to investigate their effect on Nrf2 activation. Pretreatment of macrophages with chamomile significantly induced the expression of antioxidant gene, heme oxygenase (HO)-1 mRNA and protein in concentration and time dependent manner. Chamomile exposure increased the nuclear Nrf2 levels which correlated with Nrf2 phosphorylation and its dissociation from Keap1 in both concentration and time dependent manner. Furthermore, chamomile treatment increased the phosphorylation of ERK1/2, but not other kinases, which might result in Nrf2 phosphorylation. Treatment of macrophages with 5µM U0126 (ERK1/2 inhibitor) was able to reduce chamomile-induced ERK phosphorylation, as well as Nrf2 phosphorylation, affecting the levels of HO-1. To confirm the role of Nrf2 in the induction of HO-1, knockdown of Nrf2 using siRNA in the macrophages resulted in significant inhibition of HO-1 expression. Furthermore, chamomile protected the cells against H2O2-induced oxidative stress and this protective effect was inhibited by U0126 and ZnPP (Zinc protoporphyrin-10µM), a HO-1 inhibitor. Taken together, these data suggest that chamomile augments cellular antioxidant defense capacity through induction of HO-1 via ERK-Nrf2-ARE signaling pathway, thereby protecting the cells from oxidative stress.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2594. doi:1538-7445.AM2012-2594
Abstract 2595: Screening for genomic rearrangements in BRCA1 and BRCA2 genes in Algerian breast/ovarian cancer families
Authors: Cherbal Farid , Salhi Nadjet , Bakour Rabah , Adane Saida , Boualga Kada , Maillet Philippe 
Published: August 2012

Abstract
Background: Breast cancer is the leading cause of cancer death in women in Algeria. To date, few molecular genetics studies of BRCA1 and BRCA2 germline mutations have been reported in the Algerian population. The most frequent mutations encountered in BRCA genes are deletions or insertions of a few bases or single-base substitutions that result in premature stop codons. However, an increasing number of large genomic rearrangements (LGRs) have been identified especially in BRCA1 gene, whereas the frequency of genomic rearrangements in BRCA2 gene is low in many populations. The objective of our study was to characterize genomic rearrangements in 76 Algerian breast/ovarian cancer patients and relatives tested negative for small point mutations in BRCA1 and BRCA2 genes. Methods: MLPA was performed on genomic DNA as described by Schouten et al (2002). Screening for genomic rearrangements in BRCA1 and BRCA2 genes of 76 patients and relatives were performed by using MLPA commercial kits P002-B1, P087-B1 and PO45-B2, PO90-B2 respectively (MRC-Holland, Amsterdam, The Netherlands). To confirm the rearrangement and to determine the exact site of its genomic breakpoints, we performed long-range PCR of genomic DNA using the Expand Long Template PCR System (Roche Diagnostics GmbH, Mannheim, Germany). Results: MLPA analysis of the BRCA1 gene revealed two germline alterations in two unrelated patients among 76. A novel deletion of BRCA1 exon 2 (c.-19-α_80+−del/p.α) and a novel genomic breakpoint in deletion of BRCA1 exon 8 (c.442-α_547+−del/p≤) were identified in two patients with breast/ovarian cancer and bilateral breast cancer, respectively. No LGRs were detected in BRCA2 gene. We found by using Long range PCR technique that our patient with the BRCA1 exon 8 deletion is heterozygous for a 2.6 kb deletion. Investigations aimed at determining the genomic breakpoint of the BRCA1 exon 2 deletion described in our study is on going. Conclusion: For the first time, we report here two genomic rearrangements in BRCA1 gene in Algerian breast/ovarian cancer patients. Our results reinforce the idea that breast/ovarian cancer families tested negatively for small point mutations should be routinely screened with MLPA for large genomic rearrangements in BRCA1 and BRCA2 genes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2595. doi:1538-7445.AM2012-2595
Abstract 2596: Correlation of TGF beta receptor II and pSmad2 expression with clinico-pathological factors in human breast cancer: An immunohistochemical observation from the Shanghai Breast Cancer Study
Authors: Qiu Qingchao , Su Yinghao , Lu Wei , Cai Hui , Zheng Ying , Shu Xiao Ou , Zheng Wei , Cai Qiuyin 
Published: August 2012

Abstract
Loss of transforming growth factor (TGF)-α expression occurs in the early stages of breast carcinogenesis, which contributes to tumor progression. The loss of TGF-β responsiveness frequently occurs at the level of the TGF- ≤ receptor II (TGF-βRII) in breast cancer. Smad2 is a major receptor-activated Smad downstream of TGF-β signaling. Phosphorylated Smad2 (pSmad2) is translocated into the nucleus to modulate transcription of target genes involved in many cell functions. We evaluated the correlation of TGF-βRII and pSmad2 protein expression with clinico-pathological factors in human breast cancer tissue from 435 breast cancer cases from the Shanghai Breast Cancer Study, a population-based, case-control study. Expression of the TGF-βRII and pSmad2 proteins was detected using a double immunofluorescence staining method, which was validated with standard single immunostains. Lab-constructed tissue microarray samples were used as positive and negative controls. The immunofluorescence signals were designated as negative, positive, or strong-positive based on a modified Allred scoring system. Staining patterns of TGF-βRII were classified into membranous or cytoplasmic predominant. TGF-βRII expression intensity was significantly higher in normal and early-stage breast cancers (in situ carcinoma) than that in later stages (in situ carcinoma adjacent to invasive carcinoma, and invasive carcinoma) (P&lt;0.001). The cytoplasmic predominant expression pattern of TGF-βRII was more frequently observed in breast cancer than that in normal breast epithelium on the same tissue section (P&lt;0.001). pSmad2 expression was significantly increased in breast cancer compared with adjacent normal breast epithelium. In addition, the increased pSmad2 expression was significantly associated with higher breast cancer grade (P=0.004). No significant correlations between TGF-βRII/pSmad2 protein expression and other prognostic factors, such as age at diagnosis, menopause status, history of breast cancer, TNM stage, and ER/PR/HER2 status, was found. The results of this study suggest that reduced TGF-βRII expression and its cytoplasmic predominant expression pattern may be associated with the progression of breast cancer, and increased pSmad2 expression may be associated with carcinogenesis and poor differentiation of breast cancer cells. Additional samples are being analyzed to validate these findings and to evaluate the expression of TGF-βRII and pSmad2 in relation to breast cancer survival.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2596. doi:1538-7445.AM2012-2596
Abstract 2607: Genetic variants in the vitamin D pathway and breast cancer disease free survival
Authors: Pande Mala , Thompson Patricia A. , Yoo Suk-Young , Do Kim-Anh , Sahin Aysegul A. , Amos Christopher I. , Bondy Melissa , Brewster Abenaa 
Published: August 2012

Abstract
Objective. Vitamin D deficiency has been associated with poor outcomes in patients with breast cancer. The objective of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in 7 Vitamin D-related genes and disease free survival (DFS). We hypothesized that vitamin D-related genes may modify breast cancer DFS. Methods. A total of 102 SNPs in Vitamin D pathway genes were explored as predictors of DFS among 1030 stage I/II breast cancer patients treated at MD Anderson Cancer Center between 1985 and 2000. Genotyping was performed using the Illumina GoldenGate array. We applied recursive partitioning tree analysis (RPART) to explore interactions of variables predictive of DFS including vitamin D-related SNPs, age at diagnosis, race, stage, nuclear grade, estrogen (ER) and progesterone (PR) receptor status, chemotherapy, hormone therapy and BMI. Results. Results from partitioning identified chemotherapy as the optimum first split for DFS where patients receiving chemotherapy experienced longer DFS. In patients receiving chemotherapy (n=540), SNP rs1118569 (RXRA) followed by rs10881583 (RXRA) were associated with greater DFS. Patients with two major alleles of rs1118569 had the best outcome, whereas those with two minor alleles of rs10881583 and one or two minor rs1118569 alleles had poorer DFS. In patients who did not receive chemotherapy (n=482), stage I patients had longer DFS than stage II. Further, stage I patients who were homozygous for any allele of rs2248098 (VDR) had longer DFS. Among the stage II patients, those with ER/PR negative tumors had poorer DFS with heterozygous carriers of rs344781 in PLAUR having the worst DFS. Conclusion. While exploratory, we show that chemotherapy, stage, ER and PR status and vitamin D-related pathway polymorphisms but not race/ethnicity modified disease free survival in early stage breast cancer patients. Validation of vitamin D-related pathway genes as genetic determinants of patient outcomes would offer insights on alternative approaches for the secondary prevention of breast cancer recurrence considering clinical pathological and treatment characteristics of the patient population.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2607. doi:1538-7445.AM2012-2607
Abstract 2613: Racial/Ethnic specific polygenic models of breast cancer risk
Authors: Thomas Venetta , Liu Zhi , Srinivasan Sathish K. , Chung Ren-Hua , Martin Eden , Levine Edward A. , Freimanis Rita I. , Hu Jennifer J. 
Published: August 2012

Abstract
Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in American women. Earlier family linkage studies have identified high-penetrance breast cancer genes, such as BRCA1, BRCA2, and TP53. Moreover, genes involved in DNA repair, such as CHEK2, ATM, BRIP and PALB2, have been associated with moderate breast cancer risk. Recent Genome-wide Association Studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with breast cancer risk. We evaluated whether breast cancer risk is associated with multiple SNPs in DNA damage signaling and repair and immune and inflammatory responses in addition to SNPs identified from GWAS. We hypothesize that targeting critical candidate pathways may yield important information regarding SNP-SNP interactions in breast cancer risk. We selected SNPs from DNA damage signaling and cell cycle control, base excision repair, nucleotide excision repair, double-strand break repair, mismatch repair, and immune and inflammatory responses. We have genotype results of 3,754 SNPs in 910 controls (763 Whites and 147 African Americans) and 793 breast cancer cases (667 Whites and 116 African Americans). 16.2% and 20.6% of controls and cases (respectively) had a first degree relative with breast cancer. 48% and 55.7% of the controls and cases (respectively) had their first child before or at the age of 24. 40.5% and 42.2% of the controls and cases (respectively) had a history of smoking. Our study results suggest that 6 SNPs were associated with breast cancer risk in Whites: (1) 2 SNPs from GWAS - rs3817198 in LSP1 (p&lt;0.001) and rs3803662 in TNRC9 (p&lt;0.001); (2) 2 SNPs from inflammation - rs1801157 in SDF-1 (p&lt;0.001) and rs12720356 in Tyk2 (p&lt;0.001) and (3) 2 SNPs from DNA repair and apoptosis - rs2992 in CHAF1A (p&lt;0.0001) and rs2231301 in BCL2l2 (p&lt;0.001). Only 1 SNP, rs1990760 in IFIH1 (p&lt;0.01) was associated with breast cancer risk in African Americans. The IFIH1 gene was previously linked to Type 1 diabetes but not in cancer risk. There was significant trend in breast cancer risk with increasing numbers of risk genotypes for rs3817198, rs3803662, rs1801157, rs12720356, rs2992, and rs2231301 (p test for trend &lt;0.0001) in Whites after adjustment for potential confounders. Our results suggest that multiple SNPs contribute to breast cancer risk in a racial/ethnic specific manner and larger studies are warranted to further evaluate our findings. More importantly, functional analysis is under way to corroborate the association of multiple SNPs with breast cancer risk.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2613. doi:1538-7445.AM2012-2613
Abstract 2630: DNA repair single nucleotide polymorphisms interact with indoor tanning and melanoma
Authors: Luo Li , Lilyquist Jenna M. , Stidley Chris , Flores Kristina , White Kirsten , Paine Susan , Gonazales Melissa , Erdei Esther , Vogel Rachel , Lazovich DeAnn , Berwick Marianne 
Published: August 2012

Abstract
Development of melanoma has previously been associated with compromised DNA repair which can be analyzed by genotyping SNPs in DNA repair genes. The Minnesota Skin Health Study collected DNA samples to investigate the hypothesis that DNA repair SNPs are associated with increased risk for melanoma among tanning bed users. 92 SNPs, with minor allele frequencies greater than 0.05, were analyzed in 20 genes for 1659 samples_893 melanoma cases and 766 controls. The SNPs were genotyped on the Illumina BeadExpress GoldenGate platform. The SNPs were then analyzed for individual SNP associations with melanoma, haplotype associations with melanoma, individual SNP interactions with ever/never indoor tanning, and haplotype interactions with ever/never indoor tanning after adjustments for age, gender, and phenotypic index. There were several SNPs that had an association with melanoma including: six SNPs in three nucleotide excision repair genes ERCC4, ERCC6 (rs4253190, adjusted OR=1.19, 95%CI: 1.04-1.37; rs4838518, adjusted OR=0.86, 95%CI: 0.75-0.99; rs4253121, adjusted OR=0.84, 95%CI:0.71-0.99), and XPC, one SNP in base excision repair gene RFC1, one SNP in direct reversal DNA repair gene MGMT, and one SNP in a novel gene FBRSL1(rs4883571, adjusted OR=0.87, 95%CI: 0.75-1.00). There were four haplotype associations with melanoma including one ERCC6 block (rs10745261, rs6537537, rs4253121: GGA, adjusted OR: 0.84, 95%CI: 0.71-0.99), two MGMT blocks, and one XPC block. Additionally, there was one SNP in FBRSL1 (rs4883557, p=0.0056) and one SNP in ERCC6 (rs10745261, p=0.025) that had an interaction with indoor tanning along with two haplotypes including one block in ERCC6 (rs10745261, rs6537537, rs4253121: AAG, p=0.0355) and one block in MGMT. While the interaction analyses were suggestive, the study is limited because none of the SNPs or haplotypes were only significant (p&lt;0.05) before Bonferroni correction. Further analyses of the function of these SNPs will be necessary, particularly for ERCC6, which had SNPs that were significant in every analysis, and FBRSL1, which is a novel gene whose function is unknown.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2630. doi:1538-7445.AM2012-2630
Abstract 264: ENC1, a BTB/Kelch protein, links DNA-damage signals to apoptosis by ubiquitination of retinoblastoma protein
Authors: Yu Rong , Ma Quan 
Published: August 2012

Abstract
ENC1 (ectodermal neuronal cortex 1) is a BTB/Kelch domain-containing protein, whose gene was originally identified in a p53-overexpressing cell line, and was later found to show abnormal expression in various tumor tissues. Here, we report that ENC1 is a new regulator that links DNA-damage signals to apoptosis. ENC1 is induced in different cancer cells by DNA-damage signals. The induced ENC1 protein then interacted with cullin-3 and retinoblastoma protein (Rb), forming an E3 ubiquitin ligase complex and ubiquitinating Rb protein. Upon ubiquitination, Rb protein failed to interact with E2F, allowing for transcriptional activation of E2F-dependent genes. Inhibition of ENC1 by RNA interference or by a dominant-negative mutant attenuated Rb ubiquitination, E2F-depedent gene activation, as well as apoptosis induced by DNA-damage signals. However, epitopic overexpression of ENC1 gene activated E2F-dependent genes, but failed to trigger apoptosis. Deletion and mutation analysis shows that a conserved motif located within Kelch domain at the C-terminus is essential for regulation of Rb function and apoptosis in response to DNA-damage signals.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 264. doi:1538-7445.AM2012-264