bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1891: Tanshinone IIA is a novel agent for melanoma prevention and therapy
Authors: Wang Zhibo , Cui Naiqiang , Ferrone Soldano , Wu Xianzhong , Herberman Ronald , Wang Wenjun 
Published: February 2011

Abstract
Background: Tanshinone IIA (TIIA) is a non-toxic natural compound isolated from traditional Chinese herb, Salvia Miltiorrhiza that has been used for prevention and therapy of a wide array of diseases such as vascular diseases and cancers in other countries. It has been documented outside the United States that TIIA has the biological functions of being pro-differentiation, anti-oxidant, anti-inflammation, anti-carcinogenesis and anti-tumor. However, TIIA has not been studied for melanoma prevention and therapy up to date.
Methods: Purified standard substance of TIIA has been use for this pilot study. Human adult epidermal melanocyte HEMa-LP and primary human melanoma cell MEL526 were used. Western blot, flow cytometry, ELISA and immunofluorescence techniques were employed to probe the biomarkers interested pre and post treatment of TIIA.
Results: TIIA inhibited MEL526 proliferation and induced MEL526 apoptosis at 20 µM that is below far away from TIIA plasma therapeutic concentrations in vivo. TIIA inhibited MEL526 cell motility at concentrations of 2.5µM or 5µM. TIIA (1.25 µM, 2.5 µM and 5 µM) prevented melanocyte epigenetic transdifferentiation to malignant melanoma cell induced by MEL526 conditioned cell culture medium, while TIIA is not toxic to normal melanocytes at those concentrations. TIIA induced transformed-HEMa-LP cell apoptosis at the above concentrations addressed. TIIA consistently down-regulated, at various ratios of drug concentration/cell density, the expression of melanoma stem cell biomarker CD133, and the expression of chondroitin sulfate proteoglycan 4 that is associated positively with melanocytic malignant transformation/progression and melanoma stem cell biomarker expression. STAT5-mediated up-regulation of Foxp3 has been documented in regulatory T cell differentiation and function, but not in melanocyte; and the higher expression level of STAT5a predicts the lower degree of atypia of nevi. In this study it was fund that TIIA increased the expression of STAT5a in MEL526 while the expression of Foxp3, a cancer suppressor gene, was up-regulated. TIIA inhibited the activation EFGR, which activation promotes carcinogenesis and progression of skin cancers. It was not found that TIIA regulated other biomarkers tested such as HLA Class I and B7H1 antigens. In addition, it was found that TIIA promoted human PBMC to produce IFNγ.
Conclusion: TIIA is a potential novel agent used for melanoma prevention and therapy. However, further studies of TIIA are needed to prove the biological function and mechanisms in vivo.
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 1891.
Abstract 1893: Soy consumption and colorectal cancer risk in humans: a meta-analysis
Authors: Yan Lin , Spitznagel Edward L. , Bosland Maarten C. 
Published: February 2011

Abstract
The purpose of the present study was to determine the relationship between soy consumption and colorectal cancer risk in humans by conducting a meta-analysis of available epidemiologic studies. We systematically reviewed publications obtained through a Medline literature search and identified four cohort and seven case-control studies on soy and colorectal cancer risk that met the inclusion criteria. We extracted the risk estimate (hazard ratio, relative risk or odds ratio) of the highest and the lowest reported categories of intake from each study and conducted this analysis using a random-effects model. Our analysis did not find that soy consumption was associated with colorectal cancer risk (combined risk estimate: 0.90, 95% CI: 0.79, 1.03) nor the separate analyses on colon cancer (combined risk estimate: 0.88, 95% CI: 0.74, 1.06) and rectal cancer (combined risk estimate: 0.88, 95% CI: 0.67, 1.14). However, when separately analyzed on the basis of gender, we found soy was associated with an approximately 21% reduction in colorectal cancer risk in women (combined risk estimate: 0.79, 95% CI: 0.65, 0.97; P = 0.026), but not in men (combined risk estimate: 1.10, 95% CI: 0.90, 1.33). Thus, consumption of soy foods may be associated with a reduction in colorectal cancer risk in women, but not in men.
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 1893.
Abstract 19: Identification of a novel mode of kinase inhibitor resistance: An F604S exchange in FIP1L1-PDGFRA modulates FIP1L1-PDGFRA protein stability in a SHP-2 and SRC-dependent manner
Authors: Sivahari Gorantla P. , Bubnoff Nikolas Von , Illert Ana Lena , Schneider Nicolas , Peschel Christian , Duyster Justus 
Published: February 2011

Abstract
FIP1L1-PDGFR alpha is a constitutively activated protein kinase which was reported in chronic eosinophilic leukemia (CEL) and in cases of hypereosinophilic syndrome and mastocytosis with eosinophilia. Imatinib is clinically active against FIP1L1-PDGFRA positive disease. However, clinical resistance to imatinib has been observed in FIP1L1-PDGFRA positive leukemia and was shown to occur due to a secondary mutation (T674I) in the PDGFR alpha kinase domain. Using a screening strategy to identify imatinib resistant mutations, we generated numerous imatinib resistant cell clones. Analysis of the PDGFRA kinase domain in these cell clones revealed a broad spectrum of resistance mutations including the clinically reported exchange T674I. Interestingly, one of the abundant mutations was a Phe to Ser exchange at position 604 (F604S), which occurred alone or in combination with other exchanges. Surprisingly, FIP1L1-PDGFRA/F604S in contrast to D842H and F604+D842H did not increase the biochemical or cellular IC50 value to imatinib when compared to wild-type (wt). However, F604S and F604S+D842H transformed Ba/F3, NIH3T3 and mouse bone marrow more efficiently compared to wt and D842H, respectively. Immunoprecipitation and immunoblotting indicated increased amounts of FIP1L1-PDGFRA protein in F604S versus wt cells. Pulse chase analysis revealed that FIP1L1-PDGFRA/F604S is strongly stabilised compared to wt. SRC coimmunoprecipitated with FIP1L1-PDGFRA in wt, but not F604S cells. Co-expression of SRC in 293T cells augmented degradation of wt, but not F604S FIP1L1-PDGFRA, indicating that SRC is a negative regulator of FIP1L1-PDGFRA protein stability. Importantly both, the SRC inhibitor PD166326 and SRC siRNA mimicked the F604S phenotype and resulted in stabilization of the wt protein. Importantly, phosphatase inhibitor treatment of FIP1L1-PDGFRA/F604S led to destabilization and SRC recruitment indicating that phosphatases might be responsible for the enhanced stability of FIP1L1-PDGFRA/F604S. In fact, coimmunuprecipitaion experiments identified the phosphatase SHP2 as a specific binding partner of F604S mutated FP. Together, these results suggest that stabilization of FIP1L1-PDGFRA/F604S is due to dephosphorylation by SHP-2 leading to lesser activation of the SRC and Cbl mediated ubiquitination machinery. In summary, imatinib resistance screening identified a novel class of resistance mutations in FIP1L1-PDGFRA, that do not act by impeding drug binding to the target, but increased target stability and abundance by interfering with SRC- mediated degradation.
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 19.
Abstract 191: Azacitidine induces differentiation of acute myeloid leukemia cell lines along the granulocytic/monocytic lineage
Authors: Nguyen Aaron N. , Luna-Moran Antonio , Richard Normand , Belka Igor , Brady Helen , MacBeth Kyle J. 
Published: February 2011

Abstract
Acute myeloid leukemia (AML) is characterized by blast cells that are unable to mature into functional, terminally-differentiated hematopoietic cells. Inducing leukemic cells to differentiate restores a natural cell death program and inhibits proliferation. Azacitidine (AZA; 5-azacytidine; Vidaza) is a cytidine nucleoside analog used clinically for the treatment of myelodysplastic syndromes (MDS) and AML. AZA therapy was recently shown to significantly increase median overall survival in higher-risk MDS and World Health Organization AML (20-30% bone marrow blasts) patients compared with conventional care regimens, and a phase III clinical trial of AZA in patients with more advanced AML has been activated. We have shown previously that AZA induces dose-dependent cytotoxicity to AML cell lines; however, at sub-micromolar AZA concentrations, complete cell kill is not achieved. To explore an additional anti-leukemic mechanism of AZA in AML, we assessed the effect of AZA on induction of AML cell differentiation in vitro. AML cell lines, encompassing several FAB classifications, were evaluated, using all-trans retinoic acid (ATRA) and 1,25-dihydroxyvitamin D3 (VD3), two potent inducers of AML cell differentiation, as control compounds. Differentiation along the granulocytic/monocytic lineage was assayed by CD11b expression (antigen detection by flow cytometry and mRNA by Luminex) and nitroblue tetrazolium (NBT) reduction. ATRA, VD3, and AZA induced CD11b RNA and protein expression and NBT reduction in HL-60 and AML-193 cell lines. Gene expression profiles (GEPs) in HL-60 and AML-193 cells revealed significant overlap in the genes regulated by AZA-treatment vs. VD3- or ATRA-treatment. GEPs of HL-60 and AML-193 cells treated with AZA strongly correlated with publicly-available gene sets representing differentiated eosinophils, neutrophils, and monocytes, but negatively correlated with those of differentiated erythrocytes and megakaryocytes. Similar studies in primary AML cells are ongoing. Our results demonstrate that AZA can induce cellular differentiation of AML cell lines along the granulocytic/monocytic lineage in vitro, and suggest that cellular differentiation may contribute as one of multiple mechanisms of AZA's anti-leukemic activity in vivo.
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 191.
Abstract 1911: Influence of gap-junction formation on melanoma specific-CD8 T cells function
Authors: Benlalam Houssem , Carré Thibault , Jalil Abdelali , Avril Marie-Françoise , Kieda Claudine , Mami-Chouaib Fathia , Chouaib Salem 
Published: February 2011

Abstract
Gap-junction channels (GJ) constitute a new potential pathway involved in the regulation of the tumor immunity. We previously showed, in a 3D construct model, that connexin43-based-GJ permitted the transfer of antigenic peptide from melanoma cell line to autologous endothelial cells. This antigenic peptide was cross-presented by endothelial cells leading to their specific recognition and lysis by specific autologous CD8+ CTL. We further investigate the potential role of GJ in the interaction between endothelial and melanoma cells. Using histological sections staining, our results indicate that gap-junction formation can occur in vivo from melanoma patients. Morever, we found that GJ are colocalized in the immunological synapse between CD8+ CTL and melanoma or melanoma-derived endothelial cells. Analysis of intracellular traffic of connexin43-GFP, using confocal live imaging, corroborates this observation since a translocation of intracellular connexin43-GFP to the contact area between CTL and target cells was observed. Our data demonstrate that CTL and melanoma cell lines exchange their intracytoplasmic content through GJ formation during the formation of the immunological synapse. The characterization of the GJ role and the influence of transferred molecules between cells will be discussed. These data open a new perspective on gap-junction importance in the anti-tumor activity of CTLs.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 1911.
Abstract 1920: Chemo-resistant regulatory T cells inhibit the augmentation of antitumor immunity during homeostatic T cell proliferation
Authors: Baba Junko , Watanabe Satoshi , Ichikawa Kosuke , Koshio Jun , Miyabayashi Takao , Tanaka Junta , Tanaka Hiroshi , Kagamu Hiroshi , Yoshizawa Hirohisa , Narita Ichiei 
Published: February 2011

Abstract
It has been demonstrated that lymphodepletion by cytotoxic regimens, such as chemotherapy and radiotherapy, augments antitumor immune response. Although the mechanism underlying this stimulation of antitumor immunity remains unclear, possible explanations have been proposed; depletion of suppressor cells, improvement of tumor-antigen presentation, and elimination of lymphocytes competing activation cytokines. We previously reported that CD4+CD25+Foxp3+ regulatory T cells were increasing in sublethally (500 rad) irradiated mice. Those radio-resistant regulatory T cells inhibited the development of antitumor immunity during recovery from lymphopenia. Depletion of regulatory T cells after irradiation enhanced generation of antitumor effector T cells and significantly suppressed tumor progression.
We hypothesized that chemotherapy-resistant, as well as radio-resistant, regulatory T cells inhibited antitumor immune response. In this study, C57/BL6 mice were administered 200 or 400 mg/kg of cyclophosphamide to deplete lymphocytes. On the same day, naïve spleen T cells were transferred intravenously followed by subcutaneous injection of MCA205 tumor cells. We found that the percentage of regulatory T cells increased from 4-5% in normal mice to 16% in lymphopenic mice injected with cyclophosphamide. Transfer of naïve T cells into cyclophosphamide injected lymphopenic mice showed some antitumor effects, and further elimination of regulatory T cells by anti-CD25 antibodies (PC61) following administration of cyclophosphamide significantly inhibited skin-tumor growth. It is well known that transforming growth factor-beta (TGF-beta) is critical differentiation cytokine for regulatory T cells. Thus, we examined the effects of anti-TGF-beta antibodies (1D11) on regulatory T cells during recovery from lymphopenia. Injection of anti-TGF-beta antibodies after lymphodepletion stimulated antitumor immune responses and delayed tumor progression.
The results indicate that regulatory T cells are resistant to cytotoxic regimens. The combination of cytotoxic therapy and inhibition of regulatory T cells efficiently increases antitumor immune response.
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 1920.
Abstract 1924: The paraproteins of patients with familial MGUS / multiple myeloma (MM) target family-specific antigens: Experience with paratarg-7 and paratarg-8
Authors: Grass Sandra , Preuss Klaus-Dieter , Wikowicz Aleksandra , Thome Stephan , Weisenburger Dennis D. , Witt Vinetta , Lynch Jane , Mahlknecht Ulrich , Pfreundschuh Michael , Lynch Henry 
Published: February 2011

Abstract
Background: Antigenic targets of paraproteins in monoclonal gammopathy of undetermined significance (MGUS) and multiple Myeloma (MM) might play a role in the pathogenesis of these neoplasms by chronic antigenic stimulation. However, very few antigens have been identified, of which most were specific for one individual paraprotein only. In contrast, we recently described paratarg-7 (P-7), a protein of unknown function which is expressed in all human tissues as the target of 15% of IgA and IgG paraproteins in MGUS and MM (Grass et al. Lancet Oncology 2009; 10: 950-956). MGUS/MM patients with P-7 specific paraproteins all carry a hyperphosphorylated variant of P-7 (pP-7), which is inherited in a dominant fashion, explaining pP7-posistive cases of familial MGUS/MM. pP-7 is the first molecularly defined autosomal-dominant risk factor for MGUS/MM and is associated with the highest odds ratio (7.9) of all risk factors for MGUS/MM known to date. Since not all cases of familial MGUS/MM have a P-7 specific paraprotein, we set out to identify the antigenic targets of paraproteins in cases of familial MGUS/MM that are not carriers of pP-7. Methods: The sera of 28 members of a family with familial MGUS/MM (Lynch et al. N Engl J Med 2008;359:152-157) were tested for antibody reactivity against antigens represented in a fetal brain derived protein macroarray using a modified SEREX approach (Preuss et al. International J. Cancer 2009;125, 656-661). Results: Sera from 28 family members were analyzed. The sera of all 6 family members affected by MGUS (n=3) and MM (n=3) reacted with paratarg-8, which is encoded by the ATG13 gene, a member of the “autophagy regulatory complex” family of genes. The titers ranged from 1:107 to 1:108. No antibody reactivity was detected in the sera of non-affected family members nor in the paraproteins from &gt;300 other patients tested. Conclusions: The paraproteins of members affected by familial MGUS/MM are directed against family-specific antigenic targets, suggesting that the genetic background shared by these patients entertains a chronic auto-immune response. Paratarg-7 and paratarg-8 are the first family-specific antigens that have been molecularly defined to date. Whether the antigen/paraprotein interaction is an epiphenomeon or invovled in the pathogenesis of familial cases of MGUS/MM can now be addressed using specific molecular tools.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 1924.
Abstract 1925: MHC class I-restricted MART-127-35 specific TCR engineered human CD4+ and CD8+ T cells exhibit polyfunctional properties
Authors: Ray Swagatam , Chhabra Arvind , Chakraborty Nitya G. , Ribas Antoni , Economou James S. , Mukherji Bijay 
Published: February 2011

Abstract
The “polyfunctional” property of antigen specific T cells has turned out to be an important element in successful host immune responses in AIDS and in malignancies. We have shown that human CD4+ CD25- T cells engineered to express MHC Class I-restricted MART-127-35 epitope specific TCR show cytolytic activity, secret Th1 type cytokines. We have now carried out an extended analysis of the functional dimension of MART-127-35 epitope specific TCR engineered CD4+ and CD8+ T cells. Freshly isolated circulating CD4+ and CD8+ T cells, transduced with MART-127-35 epitope specific DMF5 TCR containing retrovirus, were tested for proliferative, cytokine secretory and for cytolytic capacity (polyfunctionality analyzed with intracytoplasmic immunofluorescence staining for IL-2, IFN-γ, TNF-α, MIP-1β and CD107a using the SPICE software). The TCR engineered CD4+ T cells were also tested for their potential for “helping” cytolytic T cells response by CD8+ T cells in in vitro CTL generation cultures.
The TCR-engineered CD4+ as well as CD8+ T cells were found to be polyfunctional. For example, they underwent multiple rounds of division following stimulation by peptide pulsed dendritic cells and by melanoma cells, synthesized multiple cytokines (IFN-γ, TNF-α, IL-2, MIP1ß) and lysed target cells. The TCR engineered CD4+ T cells also amplified the CD8+ CTL burst size in vitro. Multiparametric analyses revealed that a single TCR-engineered CD4+ T cell could perform as many as five different functions. Nearly 100% MART-127-35 specific TCR expressing CD4+ as well as CD8+ T cells could be generated through retroviral vector-based transduction and one round of in vitro stimulation by the peptide pulsed DC. MHC class I-restricted tumor epitope specific TCR-transduced CD4+ T cells, therefore, could be useful in immunotherapeutic strategies for melanoma or other human malignancies.
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 1925.
Abstract 193: Dissecting satellite and imprinting genes methylation status in cloned bovine: Aberrant methylation in imprinting loci
Authors: Shen Chih-Jie , Ling Chiao-Chieh , Shen Perng-Chih , Cheng Winston T. K. , Chen Hsiao-Ling , Chen Chuan-Mu 
Published: February 2011

Abstract
In mammals, genome-wide epigenetic reprogramming systems exist in primordial germ cells and zygote. It plays a crucial role in regulating genome functions at critical stages of embryo development and confers stability of gene expression during mammalian development. Inappropriate reprogramming of donor nuclei in somatic cell resulted in neonatal death and preimplantation defects during animal cloning technique. Specific demethylation events in differentiated tissues could then lead to further changes in gene expression as needed. In this study, six cloned bovines created by ear fibroblast nuclear transfer with short life span and multiple organ defects were used as the experimental materials. We focus on three imprinting genes included two growth factor genes IGF-2, H19 and Xist (X chromosome inactive regulated gene) by combined bisulfite and restriction assay (COBRA). Bisulfite sequencing was also applied to analyze the aberrant CpG sites in different imprinted genes loci in these cloned bovine genomes. Our data show that loss of imprinting (LOI) phenomenon was frequently appeared in IGF-2, Xist and H19 imprinted loci in several tissues of these cloned bovines. Furthermore, we detected the cloned bovine NTG-2 expression of these imprinting genes with quantitative real time PCR (Q-PCR). The data suggested that IGF-2 and H19 are extremely overexpressed in liver, vein, ear, skin and uterus. The IGF-2 mRNA expression in uterus and liver of NTG-2 cow are almost 1,200 and 800 folds compared to WT cow. The H19 expression level in liver of NTG-2 also exhibited a 34,000-fold higher than that of WT cow. According to our research, the extensively overexpression of IGF-2 and H19, probably were the major reason to cause the cloned bovine NTG-2 not only organ defects, but also aberrant embryonic development. In conclusion, the death of clones may be due to aberrant DNA methylation at the loci of imprinting genes and disruption of incompletely reprogrammed after nuclear transfer.
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 193.