bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR4: Regulation of the Fanconi anemia pathway by a SUMO-like delivery network
Authors: Yang Kailin , Moldovan George-Lucian , Vinciguerra Patrizia , Murai Junko , Takeda Shunichi , D'Andrea Alan D. 
Published: June 2012

Abstract
Objective: The USP1/UAF1 complex is a critical regulator of the FA pathway. The USP1/UAF1 complex deubiquitinates the Fanconi Anemia proteins, FANCD2/FANCI, and promotes homologous recombination and DNA crosslink repair. USP1/UAF1 also deubiquitinates PCNA-Ub, a key player in translesion DNA synthesis. This step requires the PCNA interacting protein, hELG1. The goal of our study is to identify the molecular mechanism of USP1/UAF1 complex targeting to the FANCD2-Ub/FANCI-Ub heterodimer and tothePCNA-Ub/hELG1 complex.
Methods: Using bioinformatics, we identified a tandem repeat of SUMO-like domains (SLD) in the C-terminus of UAF1 (SLD1 and SLD2). A SLD sequence is a domain of approximately 100 amino acids with significant sequence identity and homology to the small ubiquitin-like modifier (SUMO). We tested the function of a mutant form of UAF1 lacking the SLD2 domain. Interestingly, this mutant UAF1 protein bound and stimulated the deubiquitinating activity of USP1 but failed to complement UAF1 knockout DT40 cells. We then discovered a SUMO-like-domain interacting motif (SIM) on both FANCI and hELG1. We therefore investigated the functional importance of the SLD-SIM interaction in regulating the Fanconi anemia pathway.
Results: The SLD2 domain of UAF1 is dispensable for activating USP1 in vitro. However, complementation analyses using UAF1 knockout DT40 cells showed that the SLD2 is critical for the deubiquitination of USP1 substrates in vivo and for homologous recombination. We demonstrated that the SLD2 domain of UAF1 binds directly to the SIM sequence on FANCI and hELG1, and thereby regulates the deubiquitination of FANCD2-Ub and PCNA-Ub respectively. Disruption of these SLD-SIM interactions blocked the deubiquitination of FANCD2-Ub and/or PCNA-Ub, rendering cells DNA repair deficient. We also modeled the 3-D structure of SLD2 and identified critical residues involved in SLD-SIM interaction.
Conclusions: Our study demonstrates that unique SLD-SIM interactions mediate the targeting of the USP1/UAF1 deubiquitinating complex to its monoubiquitinated substrates, FANCD2/FANCI and hELG1/PCNA, and thereby coordinate homologous recombination. This is a novel mechanism of DNA repair regulation, and it may have relevance to other DNA repair pathways.
The SLD-SIM interaction sites are potential drug target sites for agonists or antagonists of the FA pathway. They may be useful in screening drugs for the treatment of FA patients and cancer patients from the general (non-FA) population.
This abstract is also presented as Poster B38.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr PR4.
Abstract PR8: From prediction to prognosis and therapeutics: The power of breast cancer transcriptional networks
Authors: Zhang Bin , Derry Jonathan , Schadt Eric , Friend Stephen , Zhu Jun , Dai Xudong , Wang Zhi , Meng Fanyan , Tran Linh , Zhang Zhan , Guinney Justin , Clurman Bruce , Wu Guojun 
Published: June 2012

Abstract
Complex human diseases such as cancer are driven by interacting networks at molecular, cellular and environmental levels. Increasingly available large-scale high-throughput genetic and genomic data makes it possible to reconstruct predictive molecular networks that characterize diseases and indentify causal drivers for therapeutic intervention. Here we present an integrative network approach to analyze multiple large scale gene expression datasets in breast cancer.
We compiled four large-scale breast cancer gene expression datasets (van't Veer, Dai et al. 2002; Miller, Smeds et al. 2005; Wang, Klijn et al. 2005; Sotiriou, Wirapati et al. 2006). Gene coexpression networks were first constructed on individual datasets to derive gene modules comprised of highly interconnected genes. Gene modules significantly conserved in multiple co-expression networks were then grouped into consensus modules. Meanwhile, Bayesian networks (BN) were also constructed from the individual datasets and combined by union of directed links to form a super BN. The consensus gene modules were used to partition the combined BN into a number of functional regions to derive module based regulatory subnetwork for which key regulators were then identified through key driver analysis. Novel pathways such as ARFs pathways were uncovered to be essential for breast cancer progression and subsequently validated. The predicted novel drivers were systematically validated through a large number of siRNA experiments. The driver genes are not only predictive of survival time and chemotherapy response but also effective in elucidating drug mechanisms. An FDA approved anti-hypertensive drug, predicted by our integrative network analysis to be effective on breast cancer, dramatically and selectively inhibits proliferation of breast cancer cells through inhibition of cell cycle activity while keeping the majority of normal cells alive.
Such an integrative network approach and the findings will have significant impact on breast cancer research and drug development, while more broadly facilitating study and treatment of complex human diseases.
This abstract is also presented as Poster B21.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr PR8.
Abstract A104: Leptin and leptin receptor genes in relation to premenopausal breast cancer incidence and grade in Caucasian women
Authors: Gu Fangyi , Kraft Peter , Rice Megan , Michels Karin B. 
Published: June 2012

Abstract
Background: Body mass is inversely related to breast cancer risk among premenopausal women. Leptin, an essential cytokine regulating food intake, energy expenditure, glucose and fat metabolism may be part of the mechanistic pathway.
Methods: We investigated 50 tagging and candidate SNPs in the leptin (LEP) and leptin receptor (LEPR) genes, for associations with premenopausal breast cancer incidence using 405 cases and 810 controls nested within the Nurses' Health Study II. We also examined associations between these SNPs and circulating leptin (among 910 women) and breast cancer grade (among 267 patients). Permutation tests were performed to adjust for multiple testing.
Results: We did not detect a significant association between SNPs in the LEP or LEPR gene and either breast cancer incidence or plasma leptin levels. However, among cases, 14 SNPs of the LEPR gene were significantly associated with cancer grade, and rs1137101 (Q223R) survived multiple testing adjustment (adjusted p=0.04). The G carriers of rs1137101 were more likely to have poorly differentiated than well differentiated cancers. Conclusions: Our data suggest that common genetic variation in the LEP or LEPR gene has no strong association with premenopausal breast cancer risk. The LEPR gene might be associated with breast cancer grade.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A104.
Abstract A115: Natural history of HPV in cervical tumors: Identification of genotypes from formalin-fixed cervical tissues
Authors: Bukhari Mulazim Hussain , Saba Kanwal , Zainab Maidah , Ghayyor Ahmad , Qadri Ishtiaq 
Published: June 2012

Abstract
Background: Since the identification of HPV as the necessary cause of cervical cancer, knowledge of its natural history for cervical infection; genotypes, load and form, is essential to prevent and predict cervical carcinoma. A cross sectional study was conducted to see the natural history and genotypes of HPV in cervical neoplastic lesions.
Materials and Methods: Two diagnostic modalities, IHC and PCR, were performed on 102 diagnosed cases of cervical premalignant and malignant lesions (Cervical Neoplastic Lesions: CNL) and lesions by histopathology.
Results: Out of the102 cases there were 12, 44,40 and 6 cases of Squamous cell Papilloma(SCP), Squamous Cell Dysplasia(CD), Squamous Cell Carcinoma(SCC) and Adenocarcinoma(ADC) respectively. There were 82 CNL, which showed positive HPV reaction on IHC while 88 CNL showed presence of HPV (56/88:64% HPV-18 and 32/88:36% HPV-18) on PCR. There was significant association between the presence of HPV and p53 mutation among different CNL. There was no statistical difference in lesions with respect to positivity of HPV and P53 suggesting that the expression of this suppressor gene was affected by the presence of the HPV genome, p-value&gt;0.05.IHC scoring of CNL was not significantly affected with HPV infection (p-value&gt;0.05). The overall sensitivity, Specificity and accuracy of IHC against PCR was 93%,70,89% merits and demerits of each modality has also been given in detailed. The major mode of infection of HPV-16 was host nuclear integration (p:0.000) with different variant with predominant E-350G genotype(p:0.000). High Viral load was seen in infected cervical tissues.
Conclusion: HPV-18&16 were detected;E-350 G genotype was most common form while predominant way of infection was host nuclear integration of HPV. The etiological involvement of HPV in the development of CNL was found because of high viral load and significant association with p53 protein expression with HPV infection.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A115.
Abstract A12: Validity of aberrant crypt foci using as a surrogate biomarker for colorectal cancer
Authors: Sakai Eiji , Takahashi Hirokazu , Nakajima Atsushi 
Published: June 2012

Abstract
Introduction: Aberrant crypt foci (ACF) are considered to be useful as surrogate biomarker for colorectal cancer (CRC), but the biological significance of ACF remains controversial. We attempted to investigate the relationship between the presence of ACF and human colorectal carcinogenesis using a relatively large sample size.
Methods: We performed high-magnification chromoscopic colonoscopy to identify ACF in 861 subjects undergoing a diagnostic endoscopy at the Yokohama City University Hospital. The present study compared the prevalence and number of ACF in three subject groups (normal subjects, adenoma cases, and CRC cases). The correlations between the demographic and behavioral characteristics of the subjects and the prevalence of ACF were also assessed.
Results: The prevalence of ACF was 64%, 88% and 95%, and the mean number of ACF was 3.6, 6.2 and 10.1, in normal subjects, adenoma cases, and CRC cases, respectively. Older age and men had increased prevalence and number of ACF. When differences in the prevalence and number of ACF among age- and sex-stratified subject groups were examined, significant stepwise increments from normal subjects to adenoma cases to CRC cases were apparent (P&lt;0.001). Moreover, an age- and sex-adjusted multiple logistic regression analysis revealed that smoking and alcohol habits had a synergistic effect, increasing the prevalence of ACF as well as the risk of CRC (P&lt;0.001).
Conclusions: These results suggested that ACF may serve as a reliable surrogate biomarker for human colorectal carcinogenesis. The use of ACF as an endpoint may enable the size, duration, and cost of CRC chemoprevention studies to be reduced.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A12.
Abstract A18: Detection rates of thyroid, breast, and prostate cancers by medical check-up programs for asymptomatic adults in Korea
Authors: Choi Yoon-Ho , Jeong Ok-Soon 
Published: June 2012

Abstract
Purpose: We investigated retrospectively the detection rates of thyroid and breast cancers in women and prostate cancer in men by medical check-ups for screening purpose in asymptomatic volunteers. The cancer detection rates were compared with natural incidences of each cancer from National Cancer Registry (NCR) in Korea.
Materials and Methods: More than 50,000 apparently healthy adults take comprehensive medical check-ups in a year at Center for Health Promotion, Samsung Medical Center, with their own payments of 1,000 US dollars on average. A total of 283 thyroid cancers were detected among 29,498 thyroid ultrasounds in women for 2 years from 2008 to 2009. A total of 72 breast cancers were detected among 34,741 mammographies or breast ultrasounds in women during the same period. And a total of 77 prostate cancers were detected among 41,898 PSA (prostate-specific antigen) tests in men during the same period. The annual detection rate of each cancer was transformed to a cancer incidence per 100,000 persons through multiplying by 100,000. These cancer incidences from organ-specific and facility dependent tests were compared with crude incidences from 2007 National Cancer Registry according to age groups.
Results: Cancer detection rates of check-up programs for asymptomatic adults were much higher than natural incidences in general population for these three cancers. The average costs for thyroid ultrasound, mammography, breast ultrasound, and PSA in Korea are one third of those in US respectively.
Thyroid cancer by age (F) 20∼29 30∼39 40∼49 50∼59 60∼69 70∼
Incidence by check-up 892.9 807.6 1097.3 893.2 865.8 977.2
Natural incidence by NCR 28.8 80.9 144.3 159 108.7 37
Breast cancer by age (F) 20∼29 30∼39 40∼49 50∼59 60∼69 70∼
Incidence by check-up 0.0 165.1 246.8 188.9 242.3 0.0
Natural incidence by NCR 4.7 40.1 110.7 101.7 73.6 39.3
Prostate cancer by age 20∼29 30∼39 40∼49 50∼59 60∼69 70∼
Incidence by check-up 0.0 0.0 22.4 115.1 437.2 835.4
Natural incidence by NCR 0.0 0.1 1.4 18.3 110.7 262.4
Conclusions: Screening asymptomatic individuals is the effective strategy to detect early-stage disease. Specific imaging methods and blood-based test of reasonable prices showed high yields for prevalent cancers in this study. Well-designed check-up programs with considerations for costs and risks may contribute to national projects to detect cancers early. Further investigations are needed to evaluate issues on long-term mortality and possible disadvantages of screening for thyroid, breast or prostate cancers, especially in older people.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A18.
Abstract A27: Comprehensive analysis of glycans on α1-acid glycoprotein from various cancer patients by MALDI-TOF-MS for assigning a prognostic predictor
Authors: Asao Takayuki , Nishimura Toyo , Hayashi Takashi , Kuwano Hiroyuki , Yazawa Shin 
Published: June 2012

Abstract
α1-Acid glycoprotein (AGP) is well-known as an acute-phase protein, a major plasma glycoprotein with highly glycosylated, branched N-linked glycans and one of the markers for inflammation. In our previous study (Cancer 101:2825–2836, 2004), with the aid of crossed affinoimmunoelectrophoresis (CAIE), glycoforms of plasma AGP from various cancer patients could be easily determined based on the degrees of branching and extent of fucosylation characterized by reactivities with Con A lectin and Aleuria aurantia lectin, respectively. Results clearly indicated that patients with advanced malignancies who had AGP glycoforms that contained highly fucosylated tri- and tetraantennary glycans for long periods after surgery were likely to have a poor prognosis. However, patients who had AGP glycoforms with no such changes were expected to have a good prognosis irrespective of their clinical stages.
In this study, we purified AGP from plasma samples of the same patients and then analysed detailed structures of their glycans involving a new tumor marker using a high throughput glycosylation kit (BlotGlyco, Sumitomo Bakelite, Tokyo, Japan) combined with MALDI-TOF-MS analysis. More than two hundreds of glycan structures were assigned and relative abundance of each glycan was calculated. Follow-up studies of the relative abundance of glycans indicated that the abundance of fucosylated tri- and tetraantennary glycans in patients with a poor prognosis was quite high, and most of which were estimated to form sialyl-LeX structures (NeuAcα2,3Galβ1,4[Fucα1,3]GlcNAcβ) with the non-reducing end sialyl residues. Whereas, in those with a good prognosis, such an abundance was found to be as low as in healthy controls. These results indicated that no distinct difference was observed from our previous CAIE data and that more precise glycan structures instead of glycoforms could be easily assigned by the present method, providing an aberrant marker for predicting the fate of patients after surgery.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A27.
Abstract A35: A role for drug resistance in hepatocellular carcinoma: Upregulatation of CD133, activation of IGF-1R signaling, and IGF-1R nuclear translocation
Authors: Bodzin Adam S. , Wei Zhengyu , Hurtt Reginald S. , Doria Cataldo 
Published: June 2012

Abstract
Introduction: Hepatocellular carcinoma (HCC) is an aggressive neoplasm that is resistant to chemotherapy with mechanisms underlying this drug resistance not well understood. CD133 is a known cancer stem cell (CSC) marker whose high expression is associated with aggressive tumor behavior and poor prognosis. The insulin-like growth factor 1 receptor (IGF-1R) signaling pathway has been shown to play a significant role in tumor behavior. To examine possible mechanisms of drug resistance in HCC, we investigated the role of CD133 expression and IGF-1R signaling activation using geftinib.
Methods: We evaluated and separated five different human HCC cell lines (Mahlavu, Huh7, HepG2, Hep3B, PLC/PRF/5) using based on CD133 expression. We subjected these cells to geftinib at different doses, and determined IGF-1R signaling pathway activation using immunoblotting against relevant proteins in the pathway. CD133 mRNA level was examined using quantitative real-time PCR and its expression level was detected using immunofluorescence imaging and flow cytometry after drug treatment. Cell viability and sensitivity to drug treatment were measured using the MTT assay.
Results: HCC cell lines showed variable percentages of total cell populations expressing CD133: Mahlavu 0.12 %, HepG2 46 %, Huh7 80.2 %, Hep3B 98.2 %, and PLC/PRF/5 83.5 %. Mahlavu and PLC/PRF/5 were found to be the most resistant cell lines even at higher doses (17.5 uM). Since Mahlavu cells displayed reduced CD133 expression, experiments were focused on this cell line to evaluate the CD133 expression changes after geftinib treatment. After three rounds (9 days) of high dose geftinib treatment, CD133 expression was increased in a dose dependent manner; the percentages of total cell populations expressing CD133 increased to 43.9 % at 10 uM concentration and 52.9 % at 15 uM concentration as compared to 0.12 % in untreated cells. In addition, we found a significant increase in IGF-1R and AKT phosphorylation as well as IGFBP3 expression in those geftinib treated cells. Furthermore, after cell sorting of Huh7 cells by CD133 expression using flow cytometry, we observed that CD133 positive cells showed more resistant to geftinib treatment. Immunofluorescence imaging analysis demonstrated that increased IGF-1R protein translocated to nuclei after geftinib treatment.
Conclusion: Geftinib treatment enhanced CD133 expression level and activated IGF-1R signaling in HCC Mahlavu cells, one of the possible mechanism could be the nuclear translocation of IGF-1R. Our findings underscore the importance of a combined therapeutic approach with geftinib and IGF-1R blockage in the treatment of human HCC.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A35.
Abstract A46: Glycolysis and oxidative phosphorylation in cervical cancer: Correlation with FDG PET/CT and its prognostic implication
Authors: Chung Hyun Hoon , Kim Kidong , Song Yong-Sang 
Published: June 2012

Abstract
Purpose: The usefulness of 2-[18F]-fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) can help predict the presence and the extent of malignant cells. The aims of current study were to investigate the expression patterns of genes or enzymes in glucose metabolism, and to determine whether the FDG PET/CT finding correlates with these proteomic markers in surgical specimens. Patients and Methods: Fifty patients with uterine cervical cancer who underwent [18F]FDG PET/CT before treatment were included in this study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (GLUT1), glucose transporter 3 (GLUT3), hypoxia-inducible factor-1α (HIF-1α), hexokinase 2 (HK2), glycolysis markers (pyruvate kinase M2 (PKM2), phosphofructokinase (PFK), glycoaldehyde-phosphate dehydrogenase (GAPDH), pyruvate dehydrogenase (PDH)), electron transporter chain marker (β-F1-ATPase), mitochondrial transcription factor A (TFAM), oncogene (c-Myc), and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α).
Results: In vivo glucose uptake of primary cervical cancer (R = −0.298, P = 0.036) and metastatic lymph nodes (R = −0.298, P = 0.037), as assessed by FDG uptake inversely correlates with the mitochondrial biogenesis determined by immunohistochemical staining of PGC-1α. Cellular GLUT1 expression was also inversely correlated with the expression of PGC-1α (R = −0.413, P = 0.003). Moreover, the level of mitochondrial oxidative phosphorylation expressed by β–F1-ATPase inversely correlates with that of PFK (r = −0.337, P = 0.021). Expression of PGC-1α was lower in squamous cell carcinoma than that of adenocarcinoma (P &lt; 0.001), however, GLUT1 expression was higher in squamous cell carcinoma (P = 0.003). Of interest, HK2 expression in primary tumor was significantly lower in patients with lymph node metastasis (P = 0.003).
Conclusion: The results highlight the relevance of the alteration of the glucose metabolism by aerobic glycolysis in cervical cancer, and affording a mechanistic explanation for FDG PET/CT imaging.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A46.