bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 474: Cx43 mutant mice show delayed formation of palpable mammary gland tumors but are more susceptible to lung lesions
Authors: Plante Isabelle , Barr Kevin , Stewart Micheal K.G. , Allan Alisson , Laird Dale W. 
Published: February 2011

Abstract
Gap junctional intercellular communication is essential for the regulation of cell proliferation, differentiation and tissues homeostasis. Gap junctions are composed of channels, formed by proteins called connexins (Cx). It has been proposed that connexins can act as tumor suppressors in a wide variety of tumor types. However, their role in breast cancer remains poorly understood. We previously showed that Gja1Jrt/+ (G60S) mice, harboring a G60S dominant-negative Cx43 mutation, have reduced levels of Cx43 in the mammary gland. This study aimed to determine if low levels of Cx43 render mice more susceptible to breast cancer and/or result in more aggressive tumors. G60S mice were crossbred with ErbB2 mice (or FVB control mice), that spontaneously develop mammary gland tumors. Similar to G60S mice, G60S-ErbB2 mice showed decreased Cx43 protein levels and fewer gap junction plaques, compared to control ErbB2 mice (WT-ErbB2). Mice were exposed to 5 weekly doses of 7,12-dimethylbenz(a)anthracene (DMBA) starting at 7 weeks old and sacrificed when tumors reached approximately 1 cm3 or when mice showed signs of illness. Tumor onset and progression were evaluated by palpation every week. Surprisingly, while tumors were detected in 50% of WT-ErbB2 and WT-FVB mice by 32 and 36 weeks of age, respectively, only 14% of G60S-ErbB2 and 44% of G60S-FVB mice had palpable tumors by week 42, suggesting that low levels of Cx43 delay the onset of tumors. Tumor growth rates were similar in all groups, but while tumors from WT-ErbB2 and WT-FVB mice reached the threshold of 1 cm3, most Cx43 mutant mice started to show labored breathings around 40 weeks, independent of the presence of palpable tumors. Lung examination revealed the presence of lesions in 80% of WT-FVB and 69% WT-ErbB2 mice, compared to 100% for G60S-ErbB2 and G60S-FVB mice. Moreover, Cx43 mutant mice had an average of 20 visible lung lesions compared to only 6 for WT groups. Preliminary results showed that at least some of the mutant mice present signs of mammary gland hyperplasia, suggesting that low levels of Cx43 could potentially result in more aggressive hyperplasic breast cells that metastasize to the lungs. Future experiments will determine whether lesions are of lung or breast origin. Together, our results suggest that low levels of Cx43 delayed the presence of palpable tumors in mammary gland, but increased the number of lung lesions. Supported by the CBCRA, CIHR and FRSQ.
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 474.
Abstract 4742: NOTCH2 in breast cancer: Association of SNP rs11249433 with gene expression in ER-positive breast tumors without p53 gene mutations
Authors: Fu Yi-Ping , Edvardsen Hege , Kaushiva Alpana , Arhancet Juan , Howe Tiffany M. , Kohaar Indu , Shah Anushi , Porter-Gill Patricia , Fossa Sophie D. , Naume Bjørn , Ambs Stefan , Børresen-Dale Anne-Lise , Kristensen Vessela N. , Prokunina-Olsson Ludmila 
Published: February 2011

Abstract
Background: A recent genome-wide association study (GWAS) has identified a single nucleotide polymorphism (SNP) rs11249433 in the 1p11.2 region as a novel genetic risk factor for breast cancer, and this association was stronger with estrogen receptor (ER)-positive than with ER-negative cancer. We aimed to identify a biologically relevant molecular phenotype of this association.
Methods: NOTCH2 expression was measured with custom-designed TaqMan assays on 226 breast tumor samples and 319 blood samples of breast cancer patients. PANTHER analysis based on expression in NCI-60 cell lines (Affymetrix HG-U133 arrays) was used to examine enrichment of pathways, biological processes, or molecular functions for transcripts significantly correlated with NOTCH2 expression.
Results: We found evidence of a functional relationship between SNP rs11249433 and expression of the NOTCH2 gene located in the 1p11.2 region. NOTCH2 expression differed in subgroups of 226 breast tumor samples, being lowest in tumors with mutations in the p53 gene and highest in p53 wild-type/ER-positive tumors (p=0.0059). In the latter group, the NOTCH2 expression was particularly increased in carriers of risk genotypes (AG/GG) of rs11249433 when compared to the non-risk AA genotype (p=0.0062). This effect is tissue-specific since rs11249433 was not associated with NOTCH2 expression in blood samples of 319 breast cancer patients. Pathway enrichment analysis of NOTCH2 in the NCI-60 cell lines indicated role of NOTCH2 in integrin signaling, cell-cell interactions, and cell structure and motility.
Conclusion: This is the first study to explain genetic association between SNP rs11249433 and breast cancer risk by showing that NOTCH2 expression in breast tumors differs in subgroups of patients and between patients with the risk rs11249433 genotypes when compared to the non-risk genotype. The NOTCH pathway has key functions in stem cell differentiation of ER-positive luminal cells in the breast. Therefore, increased expression of NOTCH2 in carriers of rs11249433 may promote development of ER-positive luminal ductal tumors. The exact mechanisms of regulation of NOTCH2 expression by rs11249433 as well as the role of NOTCH2 in breast cancer development remain to be determined.
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 4742.
Abstract 4744: Sequence-specific p53-DNA binding to gene regulatory elements is altered by single-nucleotide polymorphisms
Authors: Bandele Omari , Wang Xuting , Noureddine Maher , Campbell Michelle , Pittman Gary , Bell Douglas 
Published: February 2011

Abstract
Single nucleotide polymorphisms (SNPs) may influence disease susceptibility by modifying cellular responses to environmental stresses. Regulatory SNPs occur in non-coding gene regions and can modify gene expression in an allele-specific manner by altering transcription factor binding. The tumor suppressor p53, a transcription factor, coordinates the expression of an intricate network of genes in response to DNA damage. Importantly, sequence-specific DNA binding is essential for p53 tumor suppressive activity. Unfortunately, lack of robust computational methods and laborious experimental assays have hampered the discovery and characterization of the effects of SNPs in p53 response elements (p53REs). Therefore, we developed a refined bioinformatics approach to identify SNPs in bona fide and putative p53-DNA binding sites. We also developed the microsphere assay for protein-DNA binding (MAPD) to assess the impact of genetic variation on p53-RE binding following cellular exposure to DNA-damaging agents.
Thirty-two SNPs (within 12 bona fide and 20 putative p53REs) identified by our bioinformatics approach were evaluated using the MAPD assay. We monitored p53-DNA binding in nuclear extracts from doxorubicin- or IR-treated human lymphoblastoid and U2OS osteosarcoma cells. Significant increases in p53 binding over the negative control were observed for the majority of the p53REs. p53 bound several candidate elements at levels comparable to the positive control (p21 p53RE). Alleles that were predicted to lower p53 binding indeed displayed reduced binding toward 23 of the 32 sequences. Of these alleles, 10 diminished p53 binding by ≥50%. Base substitutions at conserved C and G bases had the greatest impact on p53-DNA binding. In addition, five p53RE SNPs altered gene expression in a set of genotyped lymphoblastoid cell lines. Cellular binding of p53 to putative REs are currently being validated by ChIP-seq. These findings demonstrate that our bioinformatics approach combined with MAPD and gene expression analysis can identify SNPs that alter p53 activity in response to DNA damage and discover novel genes within the p53 transcriptional network. This strategy also can be employed to identify functional SNPs for future studies in human populations.
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 4744.
Abstract 475: Resection of primary tumor improves survival in mouse metastatic breast cancer model
Authors: Rashid Omar M. , Nagahashi Masayuki , Ramachandran Subramaniam , Milstien Sheldon , Spiegel Sarah , Takabe Kazuaki 
Published: February 2011

Abstract
Introduction: Removal of the primary tumor is not currently standard treatment for metastatic breast cancer. It is thought that doing so would induce metastatic proliferation and death. However, multiple retrospective studies over the last decade suggest a possible survival benefit from primary tumor resection. The purpose of this study, therefore, is to evaluate the role of primary tumor resection in metastatic breast cancer using a mouse model. However, because there is no consensus on which model best mimics human breast cancer metastasis, the first objective is to compare the different mouse models. Then, using the best mouse model, the primary tumor in metastatic cancer is removed to evaluate the effect on metastatic progression and survival.
Methods: The models evaluated include tail vein (TV), subcutaneous (SQ), percutaneous mammary (PM) and open mammary (OM) implantation of 4T1-luc2 cells,a luciferase transfected murine estrogen receptor negative breast cancer cell line. Tumor burden was quantified in vivo by measuring the photons emitted after injection of luciferin. After mice were diagnosed with metastatic breast cancer, they were prospectively randomized to two groups; primary tumor resection versus observation. Student's t-test and Kaplan-Meier survival statistical analysis were used.
Results: TV produces a 50% tail tumor rate and SQ produces intradermal and intramuscular implamantation. When compared to other methods, OM provides the most reproducible method of implanting cells into the mammary fat pad. In addition, OM produces more cancer proliferation and invasion 4 days after implantation than the other methods. When compared to SQ, OM produces larger tumors (p&lt;0.02) and greater mortality (40% versus 0% at 28 days). In addition, OM breast cancer cells in mice metastasize to the axillary lymph nodes prior to metastasizing to distant organs, similar to human breast cancer. Although OM takes slightly more time to perform than other methods, it is easy to learn even for the inexperienced. Resection of the primary tumor in metastatic breast cancer does not induce metastatic proliferation. In fact, primary tumor resection instead provides a significant survival benefit in mice, 100% mortality in the observation group at 46 days versus 80% mortality in the surgery group at 75 days (p&lt;0.02).
Conclusions: OM is the mouse model which best mimics human breast cancer metastasis. Reducing tumor burden by primary tumor resection provides a significant survival benefit in mice with metastatic breast cancer.
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 475.
Abstract 4750: Clinical and Immune Data From an Ongoing Phase II Trial of an Adenovirus/PSA Vaccine for Prostate Cancer
Authors: Lubaroff David M. , Williams Richard D. , Vaena Daniel , Joudi Fadi , Smith Mark , Zehr Pamela , Flanders Erica , Eastman Julie , Griffith Karen , Madsen Tammy , Johnson Christine 
Published: February 2011

Abstract
Introduction and Objectives:
Our Phase I adenovirus/PSA vaccine trial has proved that this vaccine is safe. We are conducting a Phase II clinical trial with two separate protocols for patients with recurrent or hormone refractory prostate cancer assessing toxicity, immune responses, and changes in PSA levels.
Methods:
In Protocol #1 men with recurrent prostate cancer following definitive initial treatment for their disease were placed in one of two arms: Arm A; men receive the vaccine alone at days 0, 30, and 60; Arm B; men receive the vaccine 14 days after the initiation of androgen deprivation therapy (ADT). In Protocol #2 men with hormone refractory disease receive the vaccine alone using the same 3 injection schedule. Each injection consists of 108 pfu of the Ad/PSA vaccine suspended in a collagen matrix. All patients return at regular intervals for physical, chemical, radiologic, and immunologic evaluations.
Results:
To date fifteen patients have been enrolled and have been followed a median of 10.5 months. The patients have a median age of 70 years, and median enrollment PSA levels of 1.67 ng/ml in Protocol #1 and 8.70 ng/ml in Protocol #2. In our preliminary results at this early stage of the trial, seventy seven percent of the patients in both protocols demonstrated anti-PSA T cell responses above preinjection levels. Sixty four percent of the patients demonstrated an increase in PSA doubling time (PSADT).
Conclusions:
In an attempt to follow up on the success of our Phase I clinical trial of the Ad/PSA vaccine we have initiated a Phase II trial to investigate the therapeutic efficacy of the vaccine in men with recurrent prostate cancer, either following definitive therapy prior to other treatments or hormone refractory. Early results from the first fifteen patients demonstrate the induction of anti-PSA T cells responses in a high percentage of the vaccinated patients and increase in PSADT in more than half of the patients. No serious vaccine-related toxicities have been identified in the patients.
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 4750.
Abstract 4751: Peptide vaccine induces apoptosis of antigen-specific CD8+ T cells
Authors: Daisuke Muraoka , Nishikawa Hiroyoshi , Kato Takuma , Wang Linan , Maeda Yuka , Harada Naozumi , Noguchi Takuro , Kawakami Yutaka , Shiku Hiroshi 
Published: February 2011

Abstract
CD8+ cytotoxic T lymphocytes (CTL) play a critical role in anti-tumor immunity. Although multiple trials of cancer vaccines, particularly using short peptides recognized by CD8+ T cells, have resulted in the development of measurable immune responses, only a minority of patients has experienced clinical benefit such as tumor regression. On the other hand, accumulating data show that peptide immunization induces either tolerance or activation of peptide-specific T cells depending on doses, routes and frequency of peptide administration. In some experiments, vaccination with peptides recognized by CD8+ T cells caused enhanced tumor outgrowth associated with peptide-induced tolerance. However, the detailed mechanism(s) involved in this unfavorable immune response by peptide vaccinations has not been determined. In the present study, we analyzed NY-ESO-1 peptide vaccinations using a new tumor model of BALB/c transplanted tumors expressing NY-ESO-1, which is a cancer/testis (CT) antigen discovered by SEREX (serological identification of antigens by recombinant expression cloning) using the serum of an esophageal cancer patient. Whereas peptide immunization with an H2-Dd-restricted CTL epitope derived from NY-ESO-1 (NY-ESO-1 p81-88) induced NY-ESO-181–88-specific CD8+ T cells in draining lymph nodes and spleens, tumor growth was significantly enhanced. Single cell analysis of specific CD8+ T cells revealed that peptide immunization induced apoptosis of &gt; 80% of NY-ESO-181–88-specific CD8+ T cells at tumor sites and repetitive immunization further diminished the number of specific CD8+ T cells. This phenomenon was associated with elevated surface expression of Fas and PD-1. When peptide vaccination was combined with an adjuvant, a TLR9 ligand CpG, the elevated Fas and PD-1 expression and apoptosis induction were not observed, and resulted in strong tumor growth inhibition. These augmented anti-tumor responses were correlated with CpG-induced DC maturation, as CpG-matured DCs, but not immature DCs could reduced Fas and PD-1 expression on the surface of antigen-specific CD8+ T cells. Taken together, selection of appropriate adjuvants is essential for development of effective cancer vaccines, with protection of effector T cells from peptide vaccine-induced apoptosis.
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 4751.
Abstract 4753: Anti-tumor effect of dendritic cell-based immunotherapy in combination with chemotherapy in the patients with advanced colorectal cancer
Authors: Akiyama Shinichiro , Tsukada Jun , Tomoda Takeshi , Abe Hiroyuki , Okamoto Masato 
Published: February 2011

Abstract
Background and objective: Tumor-specific cytotoxic T lymphocytes (CTLs) can be activated in vivo by dendritic cell (DC)-based vaccination. However, clinical responses to the immunotherapy with DC vaccination have only been observed in a minority of patients with solid cancer. Combination with other treatment modalities such as chemotherapy may overcome immunoresistance of cancer cells. In the current study, the clinical efficacy of the DC vaccine pulsed with the peptide derived from colorectal cancer-associated antigens in combination with chemotherapy has been evaluated in the patients with advanced, inoperable colorectal cancer.
Patients and Methods: Thirty-two patients with advanced, inoperable colorectal cancer refractory to standard treatment were entered the study. DCs which were generated from CD14+ monocytes from leukapheresis by 6-day cultivation with granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4, were matured by OK-432, a streptococcal agent, and were pulsed with the pancreatic cancer-associated antigens, such as WT1, MUC1. These DCs (1 × 107) were intradermally administered 5 times at 14-day intervals.
Results: Of the 32 patients, complete response (CR) was observed in 0 (0%), partial response (PR) in 7 (21.9%), stable disease (SD) in 12 (37.5%), progressive disease (PD) in 13 (40.6%). Response rate was 21.9%. Tumor control rate was 59.4%. Survival rate, quality of life, performance status were markedly increased. Severe side effects of more than grade 3 which were assessed in accordance with NCI-Common Toxicity Criteria v.2.0, were not observed.
Conclusions: It was strongly suggested that the DC vaccination pulsed with cancer associated-peptides in combination with chemotherapy was safety and effective in the patients with the inoperable colorectal cancer refractory to standard treatment.
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 4753.
Abstract 4763: Administration of a vaccine composed of dendritic cells pulsed with premalignant oral lesion lysate: immunologic effects in mice bearing carcinogen-induced premalignant oral lesions
Authors: Clark Anna-Maria A. , Young M R. 
Published: February 2011

Abstract
Most studies with dendritic cell vaccines have focused on eliminating or preventing the progression of already established malignancies. This is complicated by the immune suppression that is often exhibited in the presence of solid carcinomas. The goal of this study is to determine if an immune response can be elicited by administering a dendritic cell vaccine during the premalignant stages of oral squamous cell carcinoma (OSCC), prior to the development of systemic immune suppression. Mice treated with the carcinogen 4-nitroquinoline-1-oxide (4NQO) in drinking water develop premalignant oral lesions which subsequently progress to OSCC. As previous studies in our lab demonstrated that premalignant lesions and OSCC share overexpression of common tumor antigens, bone-marrow derived dendritic cells were pulsed with premalignant lesion lysate and administered to 4NQO-treated C57/BL6 mice exhibiting premalignant lesions. Immunohistochemical analysis demonstrated a similar increase in the number of CD8+ and CD4+ cells in the tongues of both the 4NQO-treated mice immunized with premalignant lesion-pulsed dendritic cells (DCpm) and the 4NQO-treated mice immunized with keratinocyte-pulsed dendritic cells (DCker) compared to 4NQO-treated mice injected with saline. However, the tongues of 4NQO-treated DCpm mice exhibited a dramatic decrease in the number of Foxp3+ cells compared to both 4NQO-treated control groups. In addition, splenocytes from 4NQO-treated DCpm mice released greater amounts of both IFN-γ and IL-2 in response to challenge with premalignant lysate compared to splenocytes from 4NQO-treated DCker mice in response to challenge with keratinocyte lysate. These studies indicate that stimulated dendritic cells, regardless of pulsing with premalignant lesions or keratinocytes, may be able to elicit an upregulation of T cells in the tongue. However, DCpm immunization specifically appears to result in a decrease in immune inhibitory regulatory T cells in the tongue and an increase in splenocyte secretion of immune stimulatory cytokines in response to antigenic challenge.
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 4763.