bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 805: mTORC protein levels affect class switch recombination, somatic hypermutation, and antibody production
Authors: Zhang Shuling , Pruitt Margaret , Tran Dena , DuBois Wendy , Robinson Richard , Mock Beverly A. 
Published: June 2012

Abstract
Mammalian target of rapamycin (mTOR) regulates cell growth, cell cycle, and survival through two main complexes, mTORC1 and mTORC2. In our previous studies, striking decreases in both size and number of B cells were seen in mice with constitutive reductions in protein levels of both mTOR complexes. In addition, there were alterations in B cell differentiation with partial blocks in B cell development in the bone marrow. In our current studies, we have focused on their defect in antibody production. When challenged with either NP-CGG (T-dependent antigen) or NP-LPS (T-independent antigens), reduced IgG antibody titers to NP antigens were seen in mice with constitutive reductions in mTOR protein levels, despite equivalent levels of total antibody production; high affinity antibody production was also less. The numbers of germinal centers were reduced in the spleens of the mTORC1/2-compromised mice compared to their wild-type littermates. Fewer B cells from the mTORC1/2-compromised mice were able to undergo class switching from IgM to IgG. In addition, germinal center B cells from these mice exhibited reductions in somatic hypermutation rates of their immunoglobulin loci. Studies are currently underway to evaluate the ability of these mice to respond to an in vivo challenge of live bacteria.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 805. doi:10.1158/1538-7445.AM2011-805
Abstract 822: Withaferin A inhibits breast cancer invasion and metastasis at subcytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation
Authors: Thaiparambil Jose T. , Bender Laura , Ganesh Thota , Kline Erik , Patel Pritty , Liu Yuan , Tighiouart Mourad , Vertino Paula M. , Harvey R Donald , Garcia Anapatricia , Marcus Adam 
Published: June 2012

Abstract
Withaferin A (WFA) is purified from the plant Withania somnifera and inhibits the vimentin cytoskeleton. Vimentin overexpression in cancer correlates with metastatic disease, induction of epithelial to mesenchymal transition, and reduced patient survival. Since WFA has significant anti-tumor activity and vimentin functions in cell motility, we wanted to test the hypothesis that WFA inhibits cancer metastasis by disrupting vimentin function. These data show that WFA has weak antiproliferative and apoptotic activity at concentrations less than or equal to 500 nM, but retains potent anti-invasive activity at these low doses. Live cell imaging in breast cancer cell lines revealed that WFA induces perinuclear vimentin bundling followed by rapid vimentin depolymerization. A concomitant induction of vimentin ser56 phosphorylation was observed, which is consistent with vimentin disassembly. Structure activity relationships were established using a set of chemically modified WFA analogs and showed that the predicted vimentin-binding region of WFA is necessary to induce vimentin ser56 phosphorylation and for its anti-invasive activity. Pharmacokinetic studies in mice revealed that WFA reaches peak concentrations up to 2μM in plasma with a half-life of 1.36 hours following a single 4 mg/kg dose. In a breast cancer metastasis mouse model, WFA showed dose-dependent inhibition of metastatic lung nodules and also induced vimentin ser56 phosphorylation, with minimal toxicity to lung tissue. Based upon these studies, we conclude that WFA is a potent breast cancer anti-metastatic agent and the anti-metastatic activity of WFA is, at least in part, mediated through its effects on vimentin and vimentin ser56 phosphorylation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 822. doi:10.1158/1538-7445.AM2011-822
Abstract 828: Design, synthesis and biological evaluation of peptide inhibitors of the Keap1-Nrf2 protein-protein interaction
Authors: Hancock Rowena , Bertrand Helene , Naz Shama , Tsujita Tadayuki , Hayes John , Wells Geoff 
Published: June 2012

Abstract
Background: Compounds that block the cellular effects of carcinogens have the potential to be cancer chemopreventive agents. A number of dietary constituents such as sulforaphane found in broccoli and curcumin found in turmeric increase the expression of antioxidant response element (ARE) genes involved in detoxifying reactive primary metabolites. The mode of action of these chemopreventive agents has been determined as an interaction with cysteine residues in the protein Keap1, this interaction causes Keap1 to release its binding partner, the transcription factor Nrf2. The free Nrf2 then translocates to the nucleus and up-regulates ARE dependent genes resulting in cellular protection against reactive species (McMahon et al., 2003).
Aims: Our aim is to develop compounds that directly inhibit the Keap1-Nrf2 protein-protein interaction and thereby enhance Nrf2 activity by a mechanism different to that of existing chemopreventive agents. Such compounds will have the potential to be useful molecular probes for studying the Keap1-Nrf2 interaction and the Nrf2 signaling pathway in detail and also as candidate preventive agents for cancer.
Methods: A series of linear peptides based on the high affinity binding motif of Nrf2 (the ETGE sequence) were designed, synthesized and screened to determine the optimum chain length for β-turn formation and interaction with the Keap1 protein. A second generation of peptides with changes to the sequence were synthesized to improve the binding profile. The peptides were synthesized using standard Fmoc chemistry and were purified by preparative HPLC, then lyophilized prior to use. The peptides were characterized by 1H-NMR, HPLC, LC-MS and high resolution MS.
Results: The peptides were synthesized successfully and were shown to cause inhibition of the Keap1-Nrf2 protein-protein interaction, determined using a fluorescence polarization assay developed in our laboratory. A number of the sequence change peptides have equivalent or superior activity to the native Nrf2 sequence.
Conclusion: In vitro tests have shown that the peptide sequence, structure and length are important for inhibition of the protein-protein interaction and the data have allowed us to propose an initial structure activity relationship for the Keap1-peptide interaction. The results and their implications for future drug design will be presented.
Reference: McMahon, M., Itoh, K., Yamamoto, M., Hayes, J. (2003) J. Biol. Chem. 278, 21592-21600
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 828. doi:10.1158/1538-7445.AM2011-828
Abstract 836: Rexinoids induce cellular senescence in ER-negative breast cancer cells and in MMTV-Neu mammary tumors
Authors: Shilkaitis Anne , Green Albert , Bratescu Laura , Peng Xinjian , Steele Vernon , Christov Konstantin T. 
Published: June 2012

Abstract
Retinoids and recently rexinoids have been extensively studied as potential cancer preventive agents. Their effects both in vitro and in vivo have been associated with inhibition of cell proliferation via cell cycle regulatory genes/proteins. In previous studies we have shown that retinoids (atRA, 9cRA), in addition to inhibition of cell proliferation, can also induce cellular senescence (CS) in breast cancer cell lines and in an MNU-model of mammary carcinogenesis in rats. We also found that atRA is more efficacious in inducing CS in ER+ than in ER− breast cancer cell lines.
Here we examined the role of rexinoids (LGD1069) in inducing CS in ER− breast cancer cell lines and in ER− tumors of the MMTV-Neu model of mammary carcinogenesis in mice. CS was determined by SA-β-Gal staining, colony formation assay, heterochromatin condensation and histone H2AX expression. Cells grown on cover slips were treated for 6 days with 1.0 or 5.0 µM of LGD1069 and senescent cells identified. We found that LGD1069 at 1.0 µM is more efficacious in inducing CS in ER+ MCF-7 and T47D cells, 56% and 42% respectively vs. 14% and 9% in control cells. Normal MCF10A, premalignant MCF10AT, and malignant MDA-MB-231 and MDA-MB-468 cells, which are ER−, required 5.0 µM of LGD1069 to increase CS from 3.0, 6,0, 4.0 and 10.0% in control to 14, 24, 26 and 33% in treated cells. For in vivo studies, MMTV-Neu mice with palpable mammary tumors were treated for 4 weeks with 80 or 40 mg/kg body weight LGD1069, given by gavage. Proliferating cells (BrdU-labeled) in mammary tumors decreased from 9.6±2.3% in control animals (No=13) to 7.4±3.0% (p&lt;0.01) (No=10) and to 5.6±2.5% (p&lt;0.001) (No=12) in high and low dose treated animals, respectively. Senescent cells, as detected by SA-β-Gal staining, were rare in control tumors (0.92±0.23%) and significantly increased in LGD1069, 80 mg/kg treated animals (6.8±4.0%) (p&lt;0.001). LGD1069 was unable to affect apoptosis. Our mechanistic studies suggest involvement of p21, RXRα and RARβ in mediating LGD1069-induced CS in ER− breast cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 836. doi:10.1158/1538-7445.AM2011-836
Abstract 844: Acyclic retinoid inhibits diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db mice
Authors: Shimizu Masahito , Sakai Hiroyasu , Shirakami Yohei , Yasuda Yoichi , Kubota Masaya , Moriwaki Hisataka 
Published: June 2012

Abstract
Background and aims: Obesity and the related metabolic abnormalities are associated with increased risk of hepatocellular carcinoma (HCC). Malfunctioning of retinoid X receptor (RXR)-α due to phosphorylation by Ras/MAPK also plays a critical role in liver carcinogenesis. In the present study, we examined the effects of acyclic retinoid (ACR), which targets RXRα, on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BL/KsJ-db/db (db/db) obese and diabetic mice. Methods: Male db/db mice were given tap water containing 40 ppm DEN for 2 weeks, after which they were fed a diet containing 0.03% or 0.06% of ACR throughout the experiment. Results: In mice treated with either dose of ACR for 34 weeks, the development of liver cell adenomas was significantly inhibited as compared to basal diet-fed mice. ACR markedly inhibited the activation of Ras and phosphorylation of the ERK, RXRα, and Stat3 proteins in the livers of experimental mice. It also increased the expression of RARβ and p21CIP1 mRNA, while decreasing the expression of cyclin D1, c-Fos, and c-Jun mRNA in the liver, thereby restoring RXRα function. Administration of ACR improved liver steatosis and activated the AMPK protein. The serum levels of insulin were decreased by ACR treatment, whereas the QUICKI values were increased, indicating improved insulin sensitivity. The serum levels of TNF-α and the expression levels of TNF-α, IL-6, and IL-1β mRNA in the livers of DEN-treated db/db mice were decreased by ACR treatment, suggesting attenuation of the chronic inflammation induced by excessive fatty deposits. Conclusion: ACR may be, therefore, useful in the chemoprevention of obesity-related HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 844. doi:10.1158/1538-7445.AM2011-844
Abstract 85: Detection of promoter methylation of tumor supressor genes in serum DNA of breast cancer patients and controls
Authors: Sturgeon Susan R. , Balasubramanian Raji , Schairer Catherine , Ziegler Regina , Muss Hyman , Arcaro Kathleen 
Published: June 2012

Abstract
Background: Changes in DNA methylation patterns are a common feature of malignant cells. Methylation is an epigenetic change that affects gene expression. Methylation of a cytosine guanine dinucleotide-rich area (CpG island) of the promoter region of a gene that is normally unmethylated is correlated with silencing of that gene. Certain tumor suppressor genes are hypermethylated in breast tumor tissue and rarely methylated in normal breast tissue. Circulating serum DNA, presumably including DNA shed from the tumor, can be tested for promoter hypermethylation. Breast cancer detection with moderate sensitivity has been achieved in several small studies relying on a few genes and suggests that assaying methylation levels in a larger panel of genes might result in a useful serum marker for breast cancer detection.
Methods: Bisulfite-modified serum DNA was evaluated for promoter methylation via pyrosequencing in 12 candidate tumor suppressor genes (GSTP1, SRFP1, RAR-beta, ER1, TWIST, HIN1, APC, ECAD, p16, BRAC1, CyclinD2, RASSF1). Study subjects included approximately 250 node-positive postmenopausal breast cancer cases, 75 node negative postmenopausal breast cancer cases and a comparison group of 250 postmenopausal women with benign breast disease types not strongly associated with breast cancer, all of whom donated blood at the time of diagnosis to the Mayo Serum Bank, a resource established in the 1970's to identify early markers of breast cancer.
Results: As hypothesized, mean percent levels of serum DNA methylation were modestly but statistically higher in node-positive breast cancer cases than controls for TWIST (4.9% vs 3.9%; p-value =.002), CyclinD2 (3.2% vs 2.1%; p=.03), and HIN1 (3.9% vs 2.4%; p=.03). In the nine other genes, percent methylation levels were also moderately higher in node-positive cases than controls but did not reach statistical significance (e.g., SRFP1 [6.3% vs 4.3%; p=.06]). For TWIST, Cyclin D2, HIN1, mean percent levels were intermediate in node-negative patients compared to node-positive cases and controls. Additional analyses evaluating the predictive ability of multivariate sets of DNA methylation markers together with established breast cancer risk factors are underway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 85. doi:10.1158/1538-7445.AM2011-85
Abstract 854: Alternative dosing regimens with the EGFr inhibitors (Gefitinib and Lapatinib) in a mammary cancer model: Prevention efficacy
Authors: Lubet Ronald A. , Bode Ann , Szabo Eva , Grubbs Clinton J. 
Published: June 2012

Abstract
The EGFR inhibitors (Gefitinib, Lapatinib) have proven to be effective in preventing cancers in multiple animal models, including ER and Neu positive breast, head and neck, and urinary bladder cancers when administered daily. However, the development of toxicities (Iressa, skin rashes; Lapatinib, diarrhea) limit their potential use in prevention; and perhaps even in an adjuvant setting. We, therefore, tested whether alternative dosing regimens (which might reduce toxicity) would still achieve preventive and therapeutic efficacy. Female Sprague-Dawley rats were administered a single IV dose of methylnitrosourea (MNU) at 50 days of age. In the prevention study, rats were administered Gefitinib by gavage beginning five days after MNU. MNU treated rats were administered Gefitinib daily (10 mg/kg BW/day, 7x/week) or Gefitinib (70 mg/kg BW, 1x/week). These treatment regimens resulted in 94 and 75% reductions in tumor multiplicity, respectively. Simultaneous measurements of tumor load (number of tumors x tumor weight) showed that both regimens resulted in greater than a 90% decrease. In the therapeutic study (initiating treatment when animals developed a small palpable tumor), both regimens were highly effective. A similar prevention study was performed with Lapatinib (75 mg/kg BW/day, 7x/week or 525 mg/kg BW, 1x/week). While the daily dose reduced cancer multiplicity 90%, the weekly dose caused a 70% reduction. These data show that even a great alteration of the dosing of Gefitinib (EGFR1) or Lapatinib (EGFR 2/1) resulted in a large reduction in mammary cancers. The significant clinical question will be whether this altered dosing will diminish the toxicities associated with these agents. We cannot determine this in the animal model since, at the effective doses employed, the typical toxicities observed in humans were not observed. Supported by NCI contract number HHSN261200433001C.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 854. doi:10.1158/1538-7445.AM2011-854
Abstract 866: D,L-Sulforaphane-induced apoptosis in human breast cancer cells is regulated by growth factor adaptor protein p66Shc
Authors: Sakao Kozue , Singh Shivendra V. 
Published: June 2012

Abstract
D,L-Sulforaphane (SFN), a synthetic racemic analogue of broccoli constituent L-sulforaphane, inhibits chemically-induced cancer in experimental rodents. SFN administration also suppresses cancer development in transgenic mouse models. Anticancer effect of SFN is associated with apoptosis induction but the mechanism of cell death is not fully understood. Using MDA-MB-231 (an estrogen-independent cell line) and MCF-7 (an estrogen-responsive cell line) human breast cancer cells as a model, we now demonstrate that the SFN-induced apoptosis is regulated by growth factor adapter protein p66Shc. Exposure of MDA-MB-231 and MCF-7 cells to SFN resulted in increased Ser36 phosphorylation of p66Shc. Immortalized mouse embryonic fibroblasts derived from p66Shc knockout mouse were significantly more resistant to SFN-mediated growth inhibition (judged by trypan blue dye exclusion assay) and apoptosis induction (judged by cytoplasmic histone-associated apoptotic DNA fragmentation) compared with embryonic fibroblasts from wild-type mouse. Moreover, transient transfection of MDA-MB-231 and MCF-7 cells with p66Shc-targeted siRNA conferred significant protection against SFN-induced cytoplasmic histone-associated DNA fragmentation. Protein level of prolyl isomerase 1 (Pin1), a protein implicated in mitochondrial translocation of p66Shc, was decreased on a 24-hour treatment with SFN in both MDA-MB-231 and MCF-7 cells. However, apoptosis induction resulting from SFN exposure was not affected by ectopic expression of Pin1 (MCF-7). In conclusion, the present study provides novel insights into the molecular circuitry of SFN-induced apoptosis involving p66Shc. This investigation was supported by the USPHS grant RO1 CA115498-05, awarded by the National Cancer Institute.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 866. doi:10.1158/1538-7445.AM2011-866
Abstract 871: A stratified genetic risk assessment for testicular cancer
Authors: Kratz Christian P. , Greene Mark H. , Shi Jianxin 
Published: June 2012

Abstract
Three recent genomewide association studies (GWAS) of testicular germ cell tumors (TGCT) have uncovered predisposition alleles in or near several genes including KITLG, BAK1, SPRY4, TERT, ATF7IP and DMRT1. A candidate study has identified the so-called AZFc region as another risk locus on chromosome Y. We used a statistical approach to dissect the question of whether TGCT risk alleles can be utilized in the clinical setting. We employed the receiver operating characteristic curves for genetic risk models to measure the discriminatory power of a genetic risk model. The newly-discovered variants provided a discriminatory power of 69.2%, which was considerably higher than for other cancers analyzed with this method. This suggested that about 69.2% of the time, a randomly-selected patient with TGCT had a higher estimated risk than the risk for a randomly-selected control subject. Using a multiplicative model, we estimated that white men in the top 1% of genetic risk had a relative risk that was 10.5-fold greater than that for the general white male population in the US. Under the assumption that clinical risk factors such as cryptorchidism are not correlated with TGCT risk variants and do not interact with the TGCT loci as contributors to TGCT risk, white men aged 30-34 years with a history of cryptorchidism who were in the top 1% of genetic risk had an estimated 5-year risk of 4.4%. Other clinical risk factors such as family history and infertility could be also used in a stratified genetic risk assessment approach. Extensive statistical modeling and additional genotyping is required before such accurate risk estimates are feasible. We conclude that a genetic risk assessment is not justified in the general population at this time. However, a stratified genetic risk assessment strategy may be useful for men who have independent clinical risk factors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 871. doi:10.1158/1538-7445.AM2011-871
Abstract 88: Promoter hypermethylation leads to loss of Wnt7a in NSCLC
Authors: Tennis Meredith A. , VanScoyk Michelle , Freeman Scott , Winn Robert 
Published: June 2012

Abstract
The Wnt signaling pathway is critical to normal development but the involvement of the pathway in lung tumorigenesis has not been clearly established. Wnt7a, with its receptor Fzd9, is required for maintenance of epithelial differentiation and inhibits transformed growth. Wnt7a has been shown to be frequently lost in NSCLC cell lines and tumors. We demonstrate that loss of Wnt7a in a non-transformed lung epithelial cell line leads to increased proliferation. Using pyrosequencing, 58 of 81 (72%) of NSCLC tumors we tested had higher methylation in the Wnt7a promoter region compared to adjacent normal lung tissue. We also tested 10 pairs of human NSCLC tumor and normal adjacent lung samples with known loss of expression of Wnt7a in the tumor and 6 (60%) had increased methylation of the Wnt7a promoter region in the tumors. Two NSCLC cell lines demonstrated to have methylated Wnt7a and loss of Wnt7a expression, H157 and H1299, were used to investigate methylation of the Wnt7a promoter. Treatment of these cell lines with 5-aza-2deoxycytidine resulted in increased expression of Wnt7a and increased downstream activity of known targets of Wnt7a-Fzd9 signaling. Methylation of a Wnt7a promoter luciferase resulted in decreased activity of the luciferase compared to an untreated Wnt7a luciferase. NNK is a tobacco carcinogen known to attenuate DNMT1 degradation, leading to increased promoter methylation. Treatment of a non-transformed lung epithelial cell line with NNK resulted in decreased expression of Wnt7a and increased clonogenicity. Together, these results indicate that Wnt7a is frequently lost by methylation in NSCLC and that methylation of Wnt7a leads to decreased expression. Wnt7a could be methylated by exposure to tobacco carcinogens, leading to loss of expression and increased transformed lung cell growth. The clinical use of demethylating agents could restore Wnt7a activity, helping to decrease growth of NSCLC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 88. doi:10.1158/1538-7445.AM2011-88