bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1260: Generation of human T cells directed against an agonist epitope of a transcription factor involved in epithelial to mesenchymal transition (EMT).
Authors: Tucker Jo A. , Poole Diane J. , Palena Claudia , Jochems Caroline , Schlom Jeffrey , Tsang Kwong Y. 
Published: August 2014

Abstract
Purpose: The T-box family transcription factor Brachyury is overexpressed in a variety of human carcinomas, including lung, breast, colon, ovarian and prostate. Brachyury has been shown to promote epithelial to mesenchymal transition (EMT) in tumor cells, a critical step in the path to metastasis. An HLA-A2 epitope of Brachyury has been shown to expand human T cells that are capable of lysing Brachyury-expressing tumor cells in an HLA-dependent manner. This study sought to define an agonist of this epitope in order to increase T cell activation and tumor lysis.
Experimental Design: A novel agonist epitope of Brachyury was generated by residue substitution of the native epitope. Characterization of this epitope as an agonist included; comparison of HLA binding affinity and stability, interferon γ production by epitope-specific T cell lines, as well as Brachyury-and HLA-specific lysis of tumor cells. The presence of Brachyury-specific T cells that would recognize the agonist peptide, within the circulating PBMC of cancer patients, was determined by ELISPOT.
Results: The agonist epitope was shown to bind HLA-A2 with higher affinity and stability than the native. T cell lines generated from both the native and agonist epitopes produced higher levels of interferon γ in response to stimulation with the agonist epitope. The agonist-specific T cell line was able to lyse a variety of Brachyury-expressing tumor cells more efficiently than the T cell line generated with the native epitope, and specificity of lysis was confirmed by cold-target inhibition and HLA-A2 blocking. Tetramer staining revealed Brachyury agonist-specific T cells in the PBMC of a prostate cancer patient after in vitro stimulation with the agonist peptide. PBMC from colon and ovarian cancer patients reacted to the agonist peptide in an interferon γ ELISPOT assay.
Conclusions: An agonist epitope for Brachyury has been identified, which increased T cell activation and function as compared to the native epitope. T cells that react to the agonist peptide were detected in patients with carcinomas known to express high levels of Brachyury. This study supports the use of Brachyury as a cancer vaccine strategy, including the Brachyury agonist epitope.
Citation Format: Jo A. Tucker, Diane J. Poole, Claudia Palena, Caroline Jochems, Jeffrey Schlom, Kwong Y. Tsang. Generation of human T cells directed against an agonist epitope of a transcription factor involved in epithelial to mesenchymal transition (EMT). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1260. doi:10.1158/1538-7445.AM2013-1260
Abstract 1265: Sustained PI3-kinase signaling is mediated by ICOS, not CD28, for anti-tumor T-cell responses elicited by anti-CTLA-4.
Authors: Chen Hong , Fu Tihui , Tsavachidou Dimitra , Wen Sijin , Ng Tang Derek , He Qiuming , Sun Jing Jing , Sharma Padmanee 
Published: August 2014

Abstract
The generation of anti-tumor T-cell responses requires at least two distinct signals consisting of T-cell receptor signaling and CD28-costimulation to mediate PI3-kinase signaling. In previous studies, we reported that cancer patients treated with anti-CTLA-4 had a significant increase in T-cells expressing inducible costimulator (ICOS). Here, we observed that PI3-kinase signaling was significantly increased in ICOShi as compared to ICOSlow CD28+ T-cells from anti-CTLA-4 treated patients. Our data also indicate that after T-cell activation, ICOS-mediated PI3-kinase signaling plays an important role in downstream T-cell responses such as expression of the T-bet transcription factor and anti-tumor Th1 cytokine production. An ICOS-specific siRNA transfected into activated human T-cells leads to diminished PI3K-signaling and T-bet expression, which controls production of anti-tumor Th1 cytokines. Furthermore, T-cells from ICOS-deficient mice have impaired PI3-kinase signaling after in vitro activation. Our data also demonstrate that T-cells from ICOS-deficient mice have impaired PI3-kinase signaling in vivo, which correlates with impaired tumor rejection after treatment with anti-CTLA-4. These data offer strong evidence to support that CD28-mediated PI3-kinase signaling is limited and ICOS provides a critical third signal to enable sustained PI3-kinase signaling for optimal anti-tumor T-cell responses in the setting of anti-CTLA-4 therapy.
Citation Format: Hong Chen, Tihui Fu, Dimitra Tsavachidou, Sijin Wen, Derek Ng Tang, Qiuming He, Jing Jing Sun, Padmanee Sharma. Sustained PI3-kinase signaling is mediated by ICOS, not CD28, for anti-tumor T-cell responses elicited by anti-CTLA-4. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1265. doi:10.1158/1538-7445.AM2013-1265
Abstract 1272: Myeloid leukemia cell lines suppress T cell activation and proliferation.
Authors: Tanimoto Kazushi , Ito Sawa , Miner Samantha , Muranski Pawel , Hensel Nancy F. , Melenhorst J. Joseph , Barrett A. John 
Published: August 2014

Abstract
In preliminary experiments to develop the K562 human leukemia cell line as an artificial antigen presenting cell we found that K562 cells strongly inhibited T cell proliferation. To explore this phenomenon further we tested CD4+CD25- T cells from healthy donor PBMC as targets of proliferation suppression. Targets were co-cultured with 3 chronic myeloid leukemia (CML) derived cell lines (K562, BV173 and CML1 established from a CML patient in our laboratory), two monocytic leukemia derived cell lines (THP-1 and U937), the myeloid leukemia derived cell line (KG1a) and the Burkitt lymphoma cell line (Daudi). To evaluate early activation, CD154 expression was tested by flow cytometry 16h after stimulation with CD3/CD28 beads. T cell proliferation was tested by CFSE dilution in T cells stimulated for 72h. All myeloid lines blocked CD154 expression (10.9-62.8% of control at 1:8 target: suppressor ratio). In CFSE proliferation assay, K562, KG1a, CML1, THP-1 and U937 induced comparable suppression (28.4-93.9%, at 1:8 ratio). In contrast, BV173 and Daudi cells were the least suppressive (4.96-23.0%, P&lt;0.01). Strikingly, CML1 cell line and THP-1 showed more suppressive effect on T cell proliferation than CD4+CD25+CD127- autologous regulatory T cell (Treg). Our result showed that myeloid leukemia cell lines but not B cells strongly inhibit both T cell activation and T cell proliferation. Suppression of proliferation was greatest in acute myeloid and monocytic leukemia derived lines. These data indicate that myeloid lekemia cell lines exhibit features of myeloid-derived suppressor cells (MDSC) which can induce T cell tolerance to tumors. Our findings raise the possibility that myeloid leukemias may actively evade immune control through T cell suppression. We plan to use such cell lines to further define the mechanism of MDSC related T cell suppression.
Citation Format: Kazushi Tanimoto, Sawa Ito, Samantha Miner, Pawel Muranski, Nancy F. Hensel, J. Joseph Melenhorst, A. John Barrett. Myeloid leukemia cell lines suppress T cell activation and proliferation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1272. doi:10.1158/1538-7445.AM2013-1272
Abstract 1276: UV radiation interacts with Endothelin 3 and loss of nucleotide excision repair pathway to promote melanomagenesis.
Authors: Benaduce Ana Paula , Batista Deannys , Grilo Gabriel , Jorge Karen , Kos Lidia 
Published: August 2014

Abstract
Melanomagenesis is influenced by the interaction of environmental (such as UV radiation) and genetic factors. The Xpa gene is important in the Nucleotide Excision Repair (NER) pathway. Similar to humans afflicted with Xeroderma Pigmentosum, which results from mutations in genes that play a role in NER, Xpa deficient mice show high sensitivity to UV light, leading to skin cancer development. However, Xpa deficient mice do not develop melanoma even upon UV exposure. The Endothelin 3 (Edn3) signaling pathway is essential for proliferation, survival and migration of melanocyte precursor cells. In humans, this pathway has also been implicated in melanoma progression and its metastatic potential. The purpose of this study is to develop a UV induced melanoma mouse model that combines Xpa deficiency with the over-activation of the Edn3 pathway. To this end, transgenic mice over-expressing Edn3 under the control of the keratin 5 promoter (K5-Edn3) and carrying a targeted mutation in Xpa were exposed to a single suberythemal neonatal dose of UV radiation. A subgroup of mice was also exposed to a second dose of UV radiation at 6 weeks of age. Histomorphology and immunostaining were used to confirm the melanocytic origin of primary skin tumors and metastases. Melanoma was only found in animals with the K5-Edn3 transgene. High penetrance was observed in animals exposed to one dose of UV radiation that were Xpa null (100%, n=3) when compared to Xpa heterozygous (73%, n=11) or Xpa wild type (43%, n=7). Enlarged and hyperpigmented lymph nodes were present in animals with melanoma skin lesions and these were diagnosed as local metastases. These results indicate that UV radiation exposure, in conjunction with over-activation of the Edn3 pathway is sufficient to lead to melanomagenesis in mice.
Citation Format: Ana Paula Benaduce, Deannys Batista, Gabriel Grilo, Karen Jorge, Lidia Kos. UV radiation interacts with Endothelin 3 and loss of nucleotide excision repair pathway to promote melanomagenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1276. doi:10.1158/1538-7445.AM2013-1276
Abstract 1280: Pterostilbene exerts full protection against UVB-induced skin carcinogenesis.
Authors: Ortega Angel , Rodriguez Maria L. , Sirerol Joan A. , Pulido Ines , Crespo Daniel , Carretero Julian , Asensi Miguel A. , Mena Salvador , Estrela Jose M. 
Published: August 2014

Abstract
Epidemiological, clinical and laboratory studies have demonstrated that solar ultraviolet (UV) radiation is the main cause of nonmelanoma skin cancer (i.e., basal cell and squamous cell carcinoma) and it is also a prime factor in the etiology of cutaneous melanoma. The cancer-causing effects of solar exposure on the skin are mainly produced by UV-B radiation in the 290- to 320-nm range, the same range that produces burning in human skin (erythema), inflammation, oxidative stress, DNA damage, etc. Thus, and considering the alarming numbers of skin cancers being diagnosed around the world, it is increasingly evident the need of an effective protection against UV radiation. Polyphenols (PFs) are abundant in many fruits and vegetables, wine, tea, and various dietary supplements. The role of these natural molecules as potential anticarcinogens and photoprotectors has been postulated (e.g. Clifford JL & DiGiovanni J. Cancer Prev Res 3: 132-5, 2010). Resveratrol (trans-3,5,4′-trihydroxystilbene; RES) is a phytoalexin present in a wide variety of plant species, where its synthesis is induced by stress conditions. The cancer chemopreventive activity of RES was first reported by Jang et al [Science 275, 218 - 220 (1997)] in a model of skin carcinogenesis where topic administration of this polyphenol inhibited multistage mouse skin carcinogenesis. Equally promising action is exerted by resveratrol analogues, mainly pterostilbene (3,5-dimethoxy-4′-hydroxy-transstilbene: PTER), which shows a higher half-life and more potent anticancer effects in vivo than RES. The long-term UV-B administration (180 mJ/cm2; 3 doses/week; for a total of 30 weeks) reproduces, in an animal model, which are the consequences in humans of receiving chronic UV-B radiations. We observed that pretreatment of the skin with PTER prevented UV-B-induced skin tumorigenesis (∼90 % of tumor free-mice at the end of treatment, n=20; P&lt;0.01). Our aim was to study the key molecular mechanisms involved in this strong anticancer effect elicited by PTER. Our results indicate that PTER efficiently avoid skin carcinogenesis induced by solar radiation by decreasing DNA mutagenesis, and protein and lipid oxidation.
Citation Format: Angel Ortega, Maria L. Rodriguez, Joan A. Sirerol, Ines Pulido, Daniel Crespo, Julian Carretero, Miguel A. Asensi, Salvador Mena, Jose M. Estrela. Pterostilbene exerts full protection against UVB-induced skin carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1280. doi:10.1158/1538-7445.AM2013-1280
Abstract 1285: Smad4 loss leads to reduced DNA repair and skin cancer.
Authors: Mitra Doyel , Fernandez Pamela , Li Bian , Song Ningjing , Han Gangwen , Wang Xiao-Jing 
Published: August 2014

Abstract
Solar ultraviolet (UV) radiation is the primary cause of skin cancer. Non-melanoma skin cancer, including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), is the most common form of skin cancer and accounts for 2-3 million worldwide cases of cancer each year. The transcription factor Smad4 is a central mediator in the transforming growth factor β (TGFβ), activin, and bone morphogenetic protein (BMP) signaling pathways. Smad4 loss occurs frequently in human skin squamous cell carcinoma (SCC), but it is unknown if this event is causal to ultraviolet-induced (UV) carcinogenesis, a major etiological factor in human skin cancer. In the present study, we exposed mice with keratinocyte-specific Smad4 deletion (K14.Smad4−/−) and wildtype (WT) mice to chronic UV irradiation. Compared to WT littermates, K14.Smad4−/− mice exhibited increased susceptibility to UV-induced skin cancer. Histological examination revealed that UV-induced Smad4−/− tumors were all SCCs. Moreover K14.Smad4−/− skin shows increased DNA damage due to reduced expression of DNA repair genes compared to WT skin. We have identified a novel mechanism by which Smad4 suppresses skin cancer by promoting repair of UV-induced DNA lesions.
Citation Format: Doyel Mitra, Pamela Fernandez, Bian Li, Ningjing Song, Gangwen Han, Xiao-Jing Wang. Smad4 loss leads to reduced DNA repair and skin cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1285. doi:10.1158/1538-7445.AM2013-1285
Abstract 1289: Role of deregulation of Pol III-dependent transcription in phenotypic alteration.
Authors: Zhong Shuping , Zhang Qingsong , Shi Ganggang 
Published: August 2014

Abstract
The products of RNA polymerase III (Pol III)-dependent genes, such as tRNAs and 5S rRNA, are elevated in both transformed and tumor cells suggesting that they play a crucial role in tumorigenesis. An increase in Brf1 (TFIIIB-related factor 1), a subunit of TFIIIB in Pol III transcription machinery, augments Pol III gene transcription and is sufficient for cell transformation and tumor formation (1). We have demonstrated, for the first time, that enhancement of Brf1 expression and Pol III gene transcription are correlated to liver tumor formation in mice (2). This implies that Brf1 may be a key molecule during liver tumor development. Our early study demonstrated that MSK1 (mitogen- and stress-activated protein kinase 1) mediates H3S28ph (3), Our recent study have indicated that reduction of H3S28ph (histone H3 phosphorylation at serine 28) results in repression of Brf1 and Pol III gene transcription (4). Blocking MSK1 inhibits cell transformation (5) and tumor formation (6). To further determine the role of Brf1 and the signaling and epigenetic regulating events in phenotypic alteration induced by DEN (diethylnitrosamine) which is a chemical carcinogen and is used to induce liver tumor (7), we utilized DEN (200μg/ml) to treat AML-12 cells, an immortalized mouse hepatocyte line to extract cell lysates and total RNA. Our results indicate that DEN treatment increased Brf1 expression and Pol III gene, tRNALeu and 5S rRNA, transcription. DEN strongly induced phosphorylation of MSK1 at serine 376 and Threonine 581. DEN also induces H3phs at both H3S10ph and H3S28ph in AML-12 cells. Interestingly, DEN-induced H3ph in tumor stem cells of mouse liver is significantly stronger than in non-tumor AML-12 cells. MSK1 chemical inhibitor, H89 decreased the induction of Pol III genes. DEN increased the rate of AML-12 cell proliferation. Furthermore, DEN induced colony formation of AML-12 cells in soft agar. Repression of Brf1 by its siRNA reduced Pol III gene transcription and inhibited the cell transformation by DEN. Taken together, these results demonstrate that DEN activates MSK1 and induces H3ph, which in turn mediate Brf1 expression to upregulate RNA Pol III transcription, resulting in increasing in cell proliferation and cell transformation. These studies will allow us to further uncover a novel molecular mechanism of hepatocellular carcinoma by using MSK KO mice and conditional Brf1 KO mice.
[This project was supported by NIH grant AA017288 and AA021114 to Shuping Zhong.]
Citation Format: Shuping Zhong, Qingsong Zhang, Ganggang Shi. Role of deregulation of Pol III-dependent transcription in phenotypic alteration. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1289. doi:10.1158/1538-7445.AM2013-1289
Abstract 129: Race-specific social gradients in breast cancer burden in Maryland: 1992-2003.
Authors: Klassen Ann C. , Pankiewicz Aaron , Curriero Frank 
Published: August 2014

Abstract
There is substantial evidence linking adverse breast cancer characteristics, including more aggressive histology, larger tumor size, and advanced stage at diagnosis, to both African American race, and lower social class. However, it is not well known if social class affects black and white women similarly, and what behavioral or environmental factors may contribute to the social class gradient for each racial group.
Using data from approximately 55,000 cases of breast cancer reported to the Maryland Cancer Registry between 1992-2003, we used multi-level random effects models to examine the relationship between case race, age, year of diagnosis, area-level social class indices (area-level rates of high school graduation, employment, white collar work, and income) and three characteristics associated with adverse cancer outcomes: SEER stage at diagnosis (stage 2-7 versus 1), large tumor size at diagnosis (&gt;2 cm versus &lt;=2 cm), and aggressive histological grade of tumor (grade 3 or 4, versus 1 or 2). We then examined the additional contribution to the model of an estimate of area-level smoking behavior, using estimates of area-level average per household tobacco spending. Finally, we examined whether effects of social class and tobacco use varied for white and black women.
Results demonstrate that black women were more likely to be diagnosed with later stage cancers (O.R. =1.29, 95% C.I.= 1.22,1.35), larger tumors (O.R.= 1.45, 95% C.I.= 1.34, 1.56), and more aggressive tumor histology (O.R. 1.65, 95% C.I.= 1.56,1.74). Social class was protective for all three outcomes, but statistically significant interactions showed that this protective effect of social class was reduced for black women compared to white women. In addition, each $1000 increase in average household level of tobacco spending was significantly associated with aggressive grade (O.R.=1.01 per $1000) and larger tumor size (O.R. =1.03, 95% C.I.=1.01,1.06) but not significantly associated with late stage diagnosis. There were no statistically significant interactions of tobacco spending by race, indicating that the effect of tobacco spending are similar for black and white cases.
Findings suggest that social class effects differ by race, and that intersectionality - the context-based understanding of multiple simultaneous social effects on health - may be an important approach to understanding excess breast cancer burden in women. This analysis also suggests that health risk behaviors, such as group-level tobacco use, may contribute additional risk, and should be further explored with more robust designs and data.
Citation Format: Ann C. Klassen, Aaron Pankiewicz, Frank Curriero. Race-specific social gradients in breast cancer burden in Maryland: 1992-2003. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 129. doi:10.1158/1538-7445.AM2013-129