bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5412: CCR4+CCR6+Th17 cells suppress autologous CD8+ T cell responses in patients with hepatocellular carcinoma
Authors: Zhao Fei , Hoechst Bastian , Gamrekelashvili Jaba , Ormandy Lars , Voigtländer Torsten , Wedemeyer Heiner , Ylaya Kris , Hewitt Stephen , Wang Xin , Manns Michael , Korangy Firouzeh , Greten Tim 
Published: August 2012

Abstract
The role of Th17 cells in cancer patients remains unclear and controversial. We have noticed an increase in Th17 related cytokines (IL-17 and IL-23) in tumor supernatants derived from primary liver cancer, which prompted us to examine Th17 cells in patients with hepatocellular carcinoma (HCC). First we analyzed the frequency of CD4+IL-17+ cells in peripheral blood from patients with HCC, which was increased in comparison to healthy controls. In order to further analyze the function of these cells, we generated Th17 cells in vitro in the presence of IL-1beta, IL-6 and IL-23 cytokines, anti-IL-4 and anti-IFN-gamma antibodies. Th17 cells were than stained using an IL-17 capture antibody and purified by FACS sorting. In vitro primed Th17 cells were further purified into CCR4+CCR6+ and CCR4negCCR6+ Th17 cells. When cultured with autologous CD8+ T cells, CCR4+CCR6+Th17 cells suppressed the lytic function, proliferation and cytokine secretion of both antigen specific and CD3/CD28/CD2 stimulated autologous CD8+ T cells. In contrast, CCR4negCCR6+ CD4+ T cells, which also secrete IL-17, did not affect the CD8+ T cells. Suppression of CD8+ T cells by CCR4+CCR6+Th17 cells was partially dependent on TGF-beta, since neutralization of TGF-beta in cocultures reversed their suppressor function. Based on these findings we evaluated the frequency CCR4+CCR6+Th17 and CCR4negCCR6+Th17 cells in patients with HCC separately. Our analysis revealed also an increase in the frequency of CCR4+CCR6+Th17 cells but not CCR4negCCR6+Th17 cells in peripheral blood of HCC patients and ex vivo isolated CCR4+CCR6+CD4+ T cells from peripheral blood of patients. Finally we demonstrated the suppressor activity of freshly isolated CCR4+CCR6+T cells on autologous CD8+ T cell proliferation. In summary our study not only underlies the importance of analysis of subsets within Th17 cells to understand their function, but also suggests Th17 cells as yet another immune evasion mechanism in HCC. This has important implications when studying the mechanisms of carcinogenesis as well as designing effective immunotherapy protocols for patients with cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5412. doi:1538-7445.AM2012-5412
Abstract 5416: Myeloid-derived suppressor cells (MDSC) are increased and correlated with immune suppression and chronic inflammation in patients with cancer
Authors: Gonda Kenji , Shibata Masahiko , Shimura Tatsuo , Nakamura Izumi , Ohki Shinji , Ohtake Tohru , Suzuki Shinichi , Ohto Hitoshi , Takenoshita Seiichi 
Published: August 2012

Abstract
Chronic inflammation plays a key role in the progress of malignant diseases and has been reported to relate with immune suppression seen in patients with advanced diseases. MDSC: myeloid-derived suppressor cells found as a new type of immune suppressor cells are enhanced by inflammation and have been reported to be present in blood circulation, lymphnodes and tumor tissues in patients with cancer. The suppression of immune function via depleting arginine and producing immune-suppressing cytokines including IL-10 has also been reported. In order to investigate MDSC in patients, peripheral blood mononuclear cells (PBMC) were collected from 18 normal healthy volunteers, 53 patients with gastrointestinal cancer, 65 with breast cancer, 8 with thyroid cancer, and 5 with ovarian cancer. These cells were used for the detection of MDSC (CD11b+CD14−CD33+) by flow cytometry. PBMC was also used for the PHA-blastogenesis of lymphocytes which is a marker of cell mediated immunity (stimulation indices: SI) and for the production assay of cytokines including IL-6 and IL-10. MDSC (%PBMC) of whole patients (5.68 + 5.92%), those of gastrointestinal cancer patients (3.76 + 4.90%) and those of breast cancer patients (2.92 + 4.13%) were significantly higher than those of normal volunteers (p&lt;0.005, p=0.05, p&lt;0.05, respectively, vs 1.59 + 1.08%). MDSC were inversely correlated with the SI (r=−0.271, p&lt;0.05) in patients with gastrointestinal cancer and positively correlated with IL-6 production in whole patients(r=0.287, p=0.05) and with IL-10 production in patients with breast cancer (r=0.363, p&lt;0.05). They were also significantly correlated to neutrophil counts (r=0.287, p&lt;0.05) and neutrophil/lymphocyte ratios (NLR, r=0.623, p=0.05), and inversely correlated to lymphocyte counts (r=−0.251, p&lt;0.01). Thus MDSC were successfully detected in peripheral blood and were significantly higher in patients with cancer. There were strong relationships among the inhibition of cell-mediated immunity, production of type 2 cytokines and inflammatory markers such as NLR. Therefore, MDSC seemed to work as a suppressor of immune reaction and may be an important marker of chronic inflammation in patients with cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5416. doi:1538-7445.AM2012-5416
Abstract 5421: Stage specific inhibitory effect and associated mechanisms of insositol hexaphosphate on tumor progression and angiogenesis in TRAMP model
Authors: Raina Komal , Ravichandran Kameswaran , Jain Anil , Gu Mallikarjuna , Sharma Yogesh , Wadhwa Ritambhara , Agarwal Rajesh 
Published: August 2012

Abstract
Prostate cancer (PCa) is the leading cause of cancer-related deaths in elderly men in US; ACS’ statistical estimates for 2011 report ∼240,890 new PCa cases and 33,720 associated deaths. In recent years, transgenic adenocarcinoma of the mouse prostate (TRAMP) has been the most frequently employed PCa model to evaluate chemopreventive efficacy of various agents. This model closely mimics human form of the disease, wherein prostate carcinogenesis progresses in a step-wise manner with the age of the mouse. The well defined stages of prostate tumor growth, progression and angiogenesis in TRAMP model provide unique opportunity to assess ‘stage specific’ preventive efficacy of an agent. Accordingly, employing TRAMP model, here we assessed stage-specific efficacy of inositol hexaphosphate (IP6) feeding on PCa initiation and growth, progression and angiogenesis, and elucidated the molecular events involved in IP6 effects during these stages. Different groups of male TRAMP mice starting at 4, 12, 20 and 30 weeks of age were fed with regular drinking water or 2% IP6 in regular drinking water for 8-10 weeks. At the end of the study, histopathological analysis of prostate showed that all the mice fed with IP6 at different time-points display less severe prostatic lesions compared to non-IP6 fed positive control mice. During early stages of prostate tumor development, IP6 mediated its chemopreventive effect mostly via anti-proliferative and pro-apoptotic mechanisms. Feeding of IP6 to animals burdened with higher stages of prostate tumor significantly decreased tumor grade via anti-proliferative effect and inhibition of angiogenesis as evidenced by decreased expression of platelet endothelial cell adhesion molecule-1 (PECAM-1/CD-31), vascular endothelial growth factor (VEGF) hypoxia-inducible factor-1a (HIF-1a) and inducible nitric oxide synthase (iNOS). These effects of IP6 also correlated with an alteration of epithelial-mesenchymal transition (EMT) as was evidenced by a decreased expression of mesenchymal markers Snail-1 in the prostatic tissue and retention of epithelial characteristics determined by localization of E-cadherin. Together, the findings in the present study are both novel and highly significant in establishing the dual efficacy of IP6, where it inhibits initiation and progression of primary prostatic tumor and also exerts protective efficacy against angiogenesis. These effects of IP6 should have potential implications to control PCa growth and improve the morbidity and survival time in PCa patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5421. doi:1538-7445.AM2012-5421
Abstract 5425: The catalytic subunit of DNA-dependent protein kinase is downstream of ATM and feeds forward oxidative stress in selenium-induced senescence response
Authors: Cheng Wen-Hsing , Rocourt Caroline R. , Wu Min , Chen Benjamin P. 
Published: August 2012

Abstract
Selenium induces a senescence response through induction of ataxia-telangiectasia mutated (ATM) and reactive oxygen species (ROS). Although a role of the DNA-PK complex, including the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), Ku70 and Ku80, in DNA double strand break repair is established, it is unclear how these proteins function in the response to selenium-induced oxidative stress and senescence induction. In this study we demonstrate that pre-treating normal human diploid fibroblasts with DNA-PK kinase inhibitor NU 7026 suppresses selenium-induced senescence response. Selenium treatment induces phosphorylation of DNA-PKcs on Thr-2647 and Ser-2056, the extent of which is decreased in the presence of ATM kinase inhibitor KU 55933 or the antioxidant N-acetylcysteine or 2,2,6,6-tetramethylpiperidine-1-oxyl. In contrast, the selenium-induced phosphorylation of ATM on Ser-1981 is not affected by NU 7026. Cells deficient in DNA-PKcs or pre-treated with NU 7026 or N-acetylcysteine are defective in selenite-induced ROS formation. Opposed to DNA-PKcs, Ku70 and Ku80 are dispensable for selenite-induced ROS and γH2A.X formation and removal. Taken together, these results indicate a distinct role of DNA-PKcs from Ku70 and Ku80, in which this kinase can respond to and feed forward selenium-induced ROS formation and is placed downstream of ATM in the resultant senescence response.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5425. doi:1538-7445.AM2012-5425
Abstract 543: Estrogen metabolism within prostatic micro-milieu: insights to prostatic carcinogenesis
Authors: Al-Abd Ahmed M. , Abdel-Naim Ashraf B. , Khedr Alaa , Gazzaz Faten S. , Mosli Hisham A. 
Published: August 2012

Abstract
Prostatic cancer is amongst the most common neoplasm in men. Inflammation and accelerated proliferation are important underlying causes for prostatic carcinogenesis. The role of estrogen in prostate physiology and pathophysiology has been growing rapidly. However some estrogen metabolites are more potent relative to parent estrogen. In the current work, the reciprocal role between inflammation and estrogen metabolism in prostatic microenvironment was investigated. Prostatitis was induced in normal and estrogen treated male rats by intraprostatic injection of 2% carragenan solution. After 48 h, animals were euthanized and prostate glands were collected. Prostatic inflammation and proliferation were confirmed by gross visual, histological and elevated TNF-α, PGE2 and cyclin-D1. Expression of estrogen metabolizing enzymes was assessed using real time PCR and estrogen metabolites within prostate tissue were assayed using LC-MS/MS. Inflammation combined with estrogen exposure showed exaggerated inflammatory and proliferative response. Estrogen metabolizing enzymes were over expressed in response to prostatic inflammation with sequential accumulation of catechol estrogens within prostatic tissues. Catechol estrogens were found to accelerate prostatic epithelial cell proliferation and alter their genetic stability. In conclusion, the current work provides experimental evidence that prostatic inflammation enhances estrogen metabolism to generate catechol estrogens within prostatic microenvironment. These may contribute in prostatic inflammation and accelerated proliferation and subsequently prostatic carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 543. doi:1538-7445.AM2012-543
Abstract 5449: Down-regulation of miR-200b and induction of ZEB1 and ZEB2 promote arsenic-transformed cell migration and invasion
Authors: Wang Zhishan , Fisher Theresa , Yang Chengfeng 
Published: August 2012

Abstract
Arsenic is one of the most common environmental contaminants and a well-recognized human carcinogen. Long-term exposure to arsenic causes human bronchial epithelial cell (HBEC) malignant transformation and lung cancer. However, the mechanism of arsenic lung carcinogenesis is not clear; and the migratory and invasive properties of arsenic-transformed cells have been rarely studied. We found that arsenic-transformed HBECs (As-HBECs) were highly migratory and invasive. MicroRNA-200b (miR-200b) expression was down-regulated and epithelial-to-mesenchymal transition-inducing transcription factors ZEB1 (zinc-finger E-box-binding homeobox factor 1) and ZEB2 were up-regulated in As-HBECs. Akt and extracellular signal-regulated protein kinase 1/2 (Erk1/2) were strongly activated in As-HBECs. Stably expressing miR-200b in As-HBECs abolished Akt and Erk1/2 activation, and completely suppressed cell migration and invasion. Pharmacological inactivation of Akt but not Erk1/2 significantly decreased cell migration and invasion. Inhibition of Akt reduced the expression of ZEB1 and ZEB2 and impaired As-HBEC migration and invasion. Our findings indicate that Akt activation plays a critical role in enabling arsenic-transformed HBEC migration and invasion through promoting ZEB1 and ZEB2 expression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5449. doi:1538-7445.AM2012-5449
Abstract 5458: GADD45α nickel induction inhibits JNKs/p38 activity by promoting PP2Cα expression
Authors: Yu Yonghui , Li Jingxia , Wan Yu , Gao Jimin , Huang Chuanshu 
Published: August 2012

Abstract
Growth arrest and DNA damage (GADD) 45α is a member of GADD inducible gene family, which can be induced in cell response to oxidative stresses. GADD45α upregulation is able to induce MKK4/JNK activation in some published experimental systems. However, we demonstrated here that the depletion of GADD45α in mouse embryonic fibroblasts (MEFs) (GADD45α-/-) resulted in an increase in the phosphorylation of MKK4/7, MKK3/6 and consequently specific up-regulated the activation of JNK/p38 and their downstream transcription factors, such as c-Jun and ATF2, in comparison to those in GADD45α+/+ MEFs due to nickel exposure. This up-regulation of MKK-JNK/p38 pathway in GADD45α-/- could be rescued by the re-constitutional expression of HA-GADD45α in GADD45α-/-, GADD45α-/- (HA-GADD45α). Subsequent studies indicated that GADD45α deletion repressed expression of PP2Cα, the phosphotase of MKK3/6 and MKK4/7. Collectively, our results demonstrate a novel function and mechanisms responsible for GADD45α regulation of MKK/MAPK pathway, further provides insight into understanding the big picture of GADD45α in the regulation of cellular responses to oxidative stress and environmental carcinogens.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5458. doi:1538-7445.AM2012-5458
Abstract 5556: Evaluation of maspin expression in primary tumors and metastasis of melanoma patients: Evidences for prognostic significance
Authors: Martinoli Chiara , Gandini Sara , Luise Chiara , Mazzarol Giovanni , Confalonieri Stefano , Testori Alessandro , Ferrucci Pier Francesco 
Published: August 2012

Abstract
Background: Maspin is a member of the serpin family of protease inhibitors that is thought to act as a tumor suppressor in several cancer types, including melanoma. Recent studies have shown that maspin sub-cellular distribution may impact its effect on disease outcome. Similar studies are missing in melanoma. Methods: Using 3 different tissue microarrays (TMA), Maspin expression was evaluated by two pathologists in a blinded manner on 150 primary lesions and 106 metastasis obtained by melanoma patients. Maspin expression in nuclear and cytoplasmic compartments were evaluated separately and correlated with clinicopathological characteristics (logistic model) and disease-free survival (Cox model) of patients included in the study. Results: Maspin was expressed in nuclei of 52% and in cytoplasms of 17% samples of primary melanomas. Nuclear maspin expression was significantly associated with melanoma thickness (p&lt;0.0001), mitotic rate (p&lt;0.0001), ulceration (p=0.003), LN involvement (p=0.0005) and worse prognosis (p=0.02). On the contrary, higher cytoplasmic expression was observed in patients with thin lesions (p=0.007), with mitotic rate &lt;1/mm2 (p&lt;0.005), no LN involvement (p=0.012), and better prognosis (p=0.05). Metastatic samples showed Maspin expression in the nuclei of 33% cases and in the cytoplasms of 10% cases, showing a progressive lost of expression with disease spreading. Conclusion: Our study shows a compartment-dependent effect of maspin expression in primary and metastatic melanomas. Further studies will be aimed to dissect the biological significance of maspin expression and localization during disease progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5556. doi:1538-7445.AM2012-5556
Abstract 5557: Mutation analysis of melanoma tumor samples from ECOG 2603 clinical trial
Authors: Wilson Melissa Ann , Zhao Fengmin , Letrero Richard , D'Andrea Kurt , Rimm David , Kirkwood John , Kluger Harriet , Lee Sandra , Flaherty Keith , Nathanson Katherine 
Published: August 2012

Abstract
The BRAF kinase, a member of the MAP kinase pathway, has emerged as an attractive molecule to target in melanoma. In an initial attempt to target BRAF in melanoma, a randomized, phase III trial (ECOG 2603) of carboplatin, paclitaxel, and sorafenib versus carboplatin, paclitaxel, and placebo was performed. Patients enrolled on the trial had either unresectable, locally advanced Stage III or Stage IV melanoma. We analyzed patients’ tumor samples for 74 mutations in 13 genes using a custom iPlex (Sequenom). We have preliminarily analyzed 157 tumor samples from patients enrolled in this clinical trial. Analysis of the initial data set demonstrates that 62 samples (42%, 62/148, 95% CI 34%,50%) carried BRAF mutations - 60 samples with V600 and two samples having a BRAF V601 mutation. Thirty eight samples (26%, 38/148, 95% CI 19%,33%) were positive for NRAS mutations, with 33 with Q61, two G12 and three G13 mutations. With the exception of one tumor sample, the BRAF and NRAS mutations were negatively correlated with each other, consistent with prior observations. We also observed a number of rare mutations in our samples including one in AKT1, one in AKT3, four in CDK4, five in beta-catenin, two in GNAQ and three in KIT. The results of this study demonstrated no difference between the two treatment arms in OS and PFS and no association with treatment outcome and BRAF and NRAS mutations. Consequently, the treatment arms were collapsed, and we examined the relationship of BRAF and NRAS mutations with OS and PFS. Interestingly, our data demonstrated that the BRAF and NRAS mutations did not correlate with OS or PFS. This sample population is unique in that it provides a large data set of melanoma tumor samples, all of whom were entered on a clinical trial, unselected for pre-existing mutations. Using the Sequenom assay platform, we have identified a number of mutations in a subset of genes known to be involved in melanoma in patient tumor samples. In the future, these tumor samples will be informative as we continue to examine and identify additional genetic alterations in melanoma, providing information regarding the natural history and distribution of certain mutations. Future studies will use array comparative genomic hybridization to further investigate additional somatic mutations occurring in melanoma tumors and correlate these with clinical outcome, as well as provide insight into the pathogenesis of melanoma. These results may lead to further opportunities for clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5557. doi:1538-7445.AM2012-5557
Abstract 5561: Radiogenomic analysis indicates MR images are potentially predictive of EGFR mutation status in glioblastoma multiforme
Authors: Gevaert Olivier , Mitchell Lex , Xu Jiajing , Yu Caroline , Rubin Daniel , Zaharchuk Greg , Napel Sandy , Plevritis Sylvia 
Published: August 2012

Abstract
Objective: To predict mutations of key genes in glioblastoma multiforme (GBM) from MR image features. Methods: We obtained mutational and MR image data from 35 patients in the Cancer Genome Atlas (TCGA) GBM database. T1-weighted axial images pre and post gadolinium contrast MRI were processed as follows: a board certified neuro-radiologist traced a region of interest (ROI) around the enhanced part of the largest lesion in the T1 post-contrast MRI and confirmed by comparing it with the T1 pre-contrast image. This ROI was then used to compute features that characterized the intensity of the enhanced lesion, the sharpness of lesion boundaries and the boundary shape. We used the resulting data set to build a linear regression model with regularization to predict the presence of a mutation in terms of image features. We focused on predicting mutations in EGFR because several drugs target it and because EGFR mutations are prevalent in the TCGA GBM data. We evaluated the performance of predicting EGFR mutations from MR imaging data using 5-fold cross validation (5F-CV) and the area under the ROC Curve (AUC). The optimal ROC operating point was defined as the point with the maximal sum of sensitivity and specificity when the cost of false positives and false negatives are considered equivalent. Results: We found that computationally-derived MR image features can predict the presence of EGFR mutations with an AUC of 0.80. The optimal operating point had a sensitivity and specificity of 83% and 93% respectively. The top ranked features in the image-based EGFR-predictor model suggest that EGFR-mutated tumors have blurrier edges than EGFR-wild-type tumors. Conclusion: Our preliminary radiogenomic analysis of GBM suggests MR images may be used to non-invasively determine the mutation status of EGFR, an important drug target in glioblastoma. The ability to determine important genomic aberrations based on image data suggests a increasingly important role for imaging in personalized medicine and warrants further investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5561. doi:1538-7445.AM2012-5561