bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3825: Prognosis of esophageal adenocarcinoma is dependent on early G1 cyclin-dependent kinase activity
Authors: Ismail Amin , Bandla Santhoshi , Toia Liana , Zhou Zhongren , Gooding William E. , Reveiller Marie , Kalatskaya Irina , Stein Lincoln , D'Souza Mary , Litle Virginia R. , Peters Jeffrey H. , Pennathur Arjun , Lucketich James D. , Godfrey Tony E. 
Published: June 2012

Abstract
Background: Chromosomal gain at 7q21 is a frequent event in esophageal adenocarcinoma (EAC). However, this event has not been mapped with fine resolution in a large EAC cohort and its associations with clinical endpoints and functional relevance are unclear.
Methods: We used a cohort of 116 patients to fine map the 7q21 amplification using SNP microarrays. 7q21 amplification and its gene expression were explored for associations with patient survival. Effects of siRNA-mediated knockdown of CDK6, its homolog CDK4 and the CDK4/6 inhibitor PD-0332991 were studied in vitro.
Results: 34.5% of tumors harbor 7q21 amplification which spans 17 genes with a focal amplicon of 6 genes. The amplification is associated with patient overall survival. Correlation of gene expression and survival identified CDK6 as the only gene in the core amplicon whose expression strongly associates with poor survival. In addition, the expression of CDK4, which is an unamplified homolog of CDK6, correlates with poor survival. The combined expression of both genes is a superior predictor of survival than either alone. siRNA-mediated knockdown of CDK4 and/or CDK6 suggests that they are required for proliferation of EAC cells and that their function is additive. PD-0332991 targets the kinase activity of both molecules and suppresses proliferation and anchorage-independence of EAC cells through activation of the pRB tumor suppressor pathway.
Conclusion: We refined 7q21 amplification in EAC and demonstrate its association with poor survival. We suggest that CDK6 is the driver of the amplicon and that prognosis of EAC is dependent on its expression along with its homolog CDK4. Targeting these molecules may thus constitute a viable new therapy for EAC.
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 3825. doi:10.1158/1538-7445.AM2011-3825
Abstract 3828: RDEA119 synergy the anti-tumor effect of sorafenib in renal cell carcinoma cells
Authors: Kim Mi Joung , Hwang Jung Jin , Choi Jene , Lee Sang-wook , Kim Choung-Soo 
Published: June 2012

Abstract
The MEK signaling pathway is over-expressed in more than 30 percentages of cancers, leading to cell growth and proliferation. Renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) is a particularly vascularized solid tumor where the Raf/MEK/ERK pathway is activated; suggesting that inhibition of this pathway may have therapeutic targets. Sorafenib as a multi-kinase inhibitor against Raf, VEGFR-2, PDGFR, c-kit, and FLT3 approved by the FDA for treatment of advanced renal cell and hepatocellular carcinomas. Since it was reported recently that combination treatment with sorafenib and MEKI exerted synergistic effect on cell proliferation in HCC, we studied the anti-proliferative effect of RDEA119 as a single agent or in combination with sorafenib for the treatment of RCC and HCC. We examined cell death effect on cell viability in 8 kinds of RCC cells and 6 kinds HCC cells. Treatment with RDEA119 inhibited proliferation of TK-10, UO31, A497 (RCC) and HepG2 (HCC) cells.
In the case of combination treatment, pre-treatment with RDEA119 potentiated anti-proliferative effect of sorafenib in A498 cells (ccRCC and VHL-/-). This combination showed synergism in combination index and isobolograms analyzed by CalcuSyn software. Furthermore, the combination treatment activated caspases-3, -9 and -8, which resulted in intrinsic and extrinsic apoptosis. To figure out cell death mechanism activated by this combination, we analyzed the phosphorylation of phospho-ERK (p-ERK) and p-AKT in A498 cells. Single treatment with RDEA119 decreased p-ERK effectively, but increased p-AKT. On the other hand, sorafenib alone decreased p-AKT, but increased p-ERK. However, combination treatment with RDEA119 and sorafenib inhibited phosphorylation of MEK and AKT completely. The combination treatment decreased the level of p-GSK3β and anti-apoptotic protein, MCL-1 which are related to survival. Our study indicates that MEK inhibitor (MEKI) alone suppressed cell proliferation and the combination of MEKI with sorafenib increased apoptosis synergistically by decreasing activation of AKT pathway as well as ERK pathway in A498 cells. These results suggest that it may be a new therapeutic modality for treatment of ccRCC.
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 3828. doi:10.1158/1538-7445.AM2011-3828
Abstract 3836: Identification of PTPsigma as an autophagic phosphatase
Authors: Martin Katie R. , Xu Yong , Looyenga Brendan D. , Davis Ryan J. , Wu Chia-Lun , Tremblay Michel L. , Xu H Eric , Mackeigan Jeffrey P. 
Published: June 2012

Abstract
Macroautophagy is a dynamic process whereby portions of the cytosol are encapsulated in double-membrane vesicles and delivered to the lysosome for degradation. Phosphatidylinositol-3-phosphate (PI(3)P) is concentrated on autophagic vesicles and recruits effector proteins critical for this process. The production of PI(3)P by the class III phosphatidylinositol 3-kinase (PI3K), Vps34, has been well established; however, protein phosphatases which antagonize this early step in autophagy remain to be identified. To identify such enzymes, we screened human phosphatase genes by RNA interference (RNAi) and found that loss of PTPsigma, a dual-domain protein tyrosine phosphatase (PTP), increases cellular PI(3)P. The abundant PI(3)P-positive vesicles conferred by PTPsigma loss strikingly phenocopied those observed in amino acid-starved cells. Accordingly, we discovered that loss of PTPsigma hyperactivates both constitutive and induced autophagy. Finally, we found that PTPsigma localizes to PI(3)P-positive membranes in cells and this vesicular localization is enhanced during autophagy. Our findings propose a novel role for PTPsigma and provide insight into the regulation of autophagy. Mechanistic knowledge of this process is critical for understanding and targeting therapies for several human diseases, including cancer and Alzheimer's disease, in which abnormal autophagy may be pathological.
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 3836. doi:10.1158/1538-7445.AM2011-3836
Abstract 3837: Protein Phosphatase PHLPP regulates protein translation and cell size through directly dephosphorylating p70 S6 kinase
Authors: Liu Jianyu , Stevens Payton , Gao Tianyan 
Published: June 2012

Abstract
PHLPP (PH domain Leucine rich repeats Proten Phosphatase) is a family of Serine/Threonine protein phosphatases that has been identified to dephosphorylate Akt and PKC. We have shown previously that PHLPP functions as a tumor suppressor by negatively regulating Akt signaling in cancer cells. Here we report the identification of p70 S6 kinase (p70S6K) as a novel substrate of PHLPP. Purified PP2C domain of PHLPP specifically dephosphorylated p70S6K at Thr389 site in vitro and reduced its kinase activity towards purified S6 ribosomal protein. The interaction between PHLPP and p70S6K was detected by co-immunoprecipitation. Overexpression of both PHLPP isoforms resulted in a decrease in p70S6K phosphorylation. Furthermore, this PHLPP-mediated dephosphorylation of p70S6K was independent of its effect on Akt signaling, as PHLPP was capable to dephosphorylate p70S6K in Rictor knockout MEF cells. Interestingly, knockdown of PHLPP in 293E and certain colon cancer cells resulted in an increase in p70S6K phosphorylation and a decrease in Akt activity. Consistent with activation of a negative feedback loop via the p70S6K-IRS1-PI3K axis, we showed that IRS1 expression was significantly decreased in the PHLPP knockdown cells. Treating cells with Rapmycin, an mTOR inhibitor, to release the negative feedback regulation, the phosphorylation of Akt was restored more readily in the PHLPP knockdown cells compared to the control cells. Similarly, the phosphorylation of p70S6K induced by insulin was elevated whereas Akt activation was suppressed in PHLPP1 knockout MEF cells. Functionally, the amount of p70S6K bound to translation initiation factor eIF3 was decreased, whereas the amount of phosphorylated S6 ribosomal protein in the initiation complex bound to the cap structure was increased in PHLPP knockdown cells. This correlates with increased cap dependent translation as measured by a luciferase reporter assay. Moreover, the cell size and protein contents were increased in PHLPP knockdown and knockout MEF cells. Taken together, our results demonstrate that loss of PHLPP expression may activate p70S6K-dependent negative feedback loop, and PHLPP is a novel player involved in regulating protein translation initiation and cell size via direct dephosphorylation of p70S6K.
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 3837. doi:10.1158/1538-7445.AM2011-3837
Abstract 3841: RBEL1A, a novel GTPase is an important regulator of cell growth and cell survival
Authors: Lui Ki , Montalbano JoAnne , Shi Jingxue , Corcoran Chad , He Qin , Hong Sun , An Jie , Sheikh Saeed , Huang Ying 
Published: June 2012

Abstract
We have recently reported the characterization of RBEL1 proteins, a novel subfamily of the Ras/Rab-like GTPases. Our studies demonstrate that RBEL1 proteins have Ras-like GTPase activity and differentially regulate the ERK signaling pathway. Our studies also demonstrate that RBEL1A is overexpressed in the majority of breast cancers and a large segment of colon cancers. Knockdown of RBEL1A negatively affects cell growth and induces apoptosis, suggesting that RBEL1A is critical for regulation of cell growth and survival. To investigate the molecular mechanisms by which RBEL1A mediates its function, we have studied a number of RBEL1A-interacting proteins. Our results indicate that RBEL1A interacts with p53 and negatively regulates p53 function via a proteasome-dependent pathway. We have also examined the molecular interactions between RBEL1A and p53 and our results demonstrate that RBEL1A is an important negative regulator of p53 that affects p53-mediated functions.
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 3841. doi:10.1158/1538-7445.AM2011-3841
Abstract 3846: SGEF is over-expressed in advanced glial tumors and mediates glioma cell invasion and survival
Authors: Fortin Shannon P. , Rollo Johnathon , Paquette Kimberly , Chan Amanda , Ross Juli , Symons Marc , Tran Nhan L. 
Published: June 2012

Abstract
Glioblastoma multiforme (GBM) is the most malignant of all primary adult brain tumors, histopathologically characterized by the infiltrative capacity of glioma cells to diffuse into the surrounding normal brain. There are currently no anti-invasion therapies available, and thus the identification and functional understanding of genes that mediate malignant tumor cell dispersion could lead to the discovery of molecular targets which have the potential to respond to therapeutics. We have previously shown that several guanine nucleotide exchange factors for Rho family small GTPases are overexpressed in GBM tumors and play important roles in glioma invasion. Here we report a role for SGEF, a guanine nucleotide exchange factor (GEF) for RhoG, in mediating glioma invasion. SGEF mRNA expression increases in correlation with glioma grade and, within GBM tumors, levels of SGEF expression inversely correlate with patient survival. siRNA-mediated depletion of SGEF decreases in vitro glioma cell migration and ex vivo glioma cell invasion. In addition, genome-wide determination of NF-κB controlled genes in temozolomide-resistant primary GBM xenografts (GBM14-TMZ-R) revealed an increased occupancy of NF-κB on the SGEF gene promoter region via ChIP-on-chip analysis as compared to the parent primary line. In fact, increased phosphorylation of IkBa was detected in GBM-14-TMZ-R. Moreover, inhibition of NF-κB in GBM14-TMZ-R significantly decreases SGEF gene expression, and activation of the NF-κB pathway by TWEAK in GBM cells induces SGEF mRNA expression. Furthermore, siRNA-mediated depletion of SGEF expression enhances chemotherapy-induced cell death in glioma cells. Understanding the role of SGEF in promoting cell motility and chemotherapeutic resistance may direct the development of novel targeted therapeutics for GBM.
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 3846. doi:10.1158/1538-7445.AM2011-3846
Abstract 3860: Differential gene expression and HPV in penile carcinoma
Authors: de Freitas Calmon Marilia , Babeto Erica , Mota Mânlio Tasso Oliveira , Candido Natália Maria , Girol Ana Paula , Oliani Sônia Maria , Bonilha Jane Lopes , Vassallo José , Rahal Paula 
Published: June 2012

Abstract
Penile cancer (PC) is an invasive epithelium tumor, representing more than 10% of the malignancies in men in some developing countries, mainly in Brazil. Studies on the aetiopathogenesis of this cancer have focused on its association with the HPV. Patients with PC without treatment usually die within 2 years after diagnosis, because of uncontrollable loco regional disease or from distant metastasis. The aim of this study is evaluating the possible role of HPV in the development of PC and the use of the RaSH technique to analyze gene expression in normal tissues and penile tumors. HPV detection was done by PCR with generic primers GP5+/GP6+ and HPV typing was done by direct sequencing. RaSH methodology identified differentially expressed genes, generating subtractive cDNA libraries. The presence of HPV was analyzed in 58 samples of patients with PC. It has been observed high prevalence (85.12%) of HPV. Of the 16 samples sequenced, HPV-16 was found in 14 (87.5%) samples, HPV-11 in 1 (6.3%) and HPV-35 in 1 (6.3%). The RaSH subtractive libraries identified the presence of 57 clones differentially expressed between samples, 30 in tumor samples and 27 in the normal tissue. The genes PBEF1, ANXA1, RPL6 and KIAA1033 were overexpressed in the tumors. On the other hand, the gene p16 was overexpressed in the normal tissue. Finally, the expression of the selected genes was confirmed by qPCR. Only ANXA1 was validated with overexpression in 80% of all samples. It was also analyzed ANXA1 protein expression by immunohistochemistry in 25 samples of penile cancer. It was observed overexpression of ANXA1 protein 100% of PC samples compared to normal tissue. The results obtained are capable of revealing differences in patterns of gene expression between normal and tumor tissues. Moreover, it was observed high prevalence of HPV, suggesting an important role of this virus in penile carcinogenesis. Besides, overexpression of ANXA1 was observed in most of the penile cancer samples and such information will contribute to develop a possible marker for penis tumor diagnostic and prognostic, improving the development of directed therapies against this new putative marker.
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 3860. doi:10.1158/1538-7445.AM2011-3860
Abstract 3864: Evaluation of expression of antigens cancer/testis (CTAs) in head and neck squamous cell carcinoma
Authors: Zamunér Fernando T. , Karia Bruno Takao Real , Carvalho André Lopes , de Oliveira André Luiz Vettore 
Published: June 2012

Abstract
Background: Among the ten most common cancers are the head and neck tumors with more than 500,000 new cases diagnosed annually worldwide, the majority (90%) represented by squamous cell carcinomas (HNSCC). Despite of the many strategies used in the treatment for HNSCC, the 5 years overall survival rate is close to 50%, and the development of loco-regional recurrence is the main reason for treatment failure. The head and neck cancer surgery is often mutilating and require extensive reconstruction. The development of new therapies and their integration into the current forms of treatment (including surgery, radiotherapy and chemotherapy) is of great interest to improve the therapeutic efficacy. Immunotherapy may provide an alternative for current treatment scheme, since the natural immune response can be stimulated by active immunotherapeutic interventions which may help control tumor progression and recurrence. A requirement for the development of immunotherapeutic approaches is the identification of immunogenic gene products expressed predominantly in tumor cells. Cancer/testis antigens (CTAs) fulfills this prerequisite as their expression is restricted to tumors with no expression in normal tissues, except germ line cells. Methods: In this study we performed a search on Oncomine, SAGE, CTdatabase and PubMed databases to select among 153 CTAs genes those that might be expressed in HNSCC. The expression of selected genes was investigated in 93 HNSCC samples and 10 normal mucosa samples from healthy individuals using reverse-transcription polymerase chain reaction (RT-PCR). The in silico analysis allowed the selection of 30 CTAs genes to be evaluated in tumors and control samples. The RT-PCR assays identified 6 CTAs with high specificity (100%) and frequently expressed in HNSCC samples (39 – 85%). Noteworthy, 99% of the tumor samples expressed at least one of the 6 CTAS, 91% expressed at least two of them, and 71% expressed at least three of these antigens. The six CTAs were expressed simultaneously in 13% of cases. Conclusion: We identified 6 CTAs genes with high expression and specificity in head and neck cancer. This result could be important for the development of immunotherapy strategies for treating HNSCC patients.
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 3864. doi:10.1158/1538-7445.AM2011-3864
Abstract 3876: Study the role of HEYL in breast tumorigenesis
Authors: Han Liangfeng , Sukumar Saraswati 
Published: June 2012

Abstract
HEYL is a basic Helix-Loop-Helix (bHLH) transcription factor in the HEY family. It is the direct target of Notch pathway and mainly functions in cardiovascular development. The functions of HEYL in cancer have not been studied. In this study, we tested whether HEYL has a direct effect on promoting breast tumorigenesis. Overexpression of HEYL in NIH3T3 cells resulted in transformation of the cells in vivo. Breast cancer cell lines with exogenous HEYL expression showed accelerated cell growth in vitro and in vivo. On the contrary, the reduction of HEYL expression in MDA-MB-231 cells retarded tumor growth in vivo. Consistent with its oncogenic activity, HEYL is found to be overexpressed in 40% of breast cancers. Overall, these data indicated a role of HEYL in enhancing breast cancer development.
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 3876. doi:10.1158/1538-7445.AM2011-3876
Abstract 388: Inhibition of IL-17 in tumor tissue suppressed tumor growth via anti-angiogenesis and CTL activation
Authors: Hayata Keiji , Iwahashi Makoto , Ojima Toshiyasu , Katsuda Masahiro , Iida Takeshi , Nakamori Mikihito , Ueda Kentaro , Nakamura Masaki , Miyazawa Motoki , Yamaue Hiroki 
Published: June 2012

Abstract
[Purpose]It remains controversial whether IL-17 promotes or inhibits cancer progression in tumor bearing mice. We hypothesized that IL-17 locally produced in tumor microenvironment had an important role on tumor growth. Therefore, we investigated inhibition of IL-17 by siRNA in only tumor sites using wild type mice have an effect on tumor progression.[Methods]Adenoviral vector encoding the siRNA against mouse IL-17 gene (Ad-IL-17 siRNA) was generated by the COS-TPC method. MC38 cells or B16 cells were inoculated subcutaneously into C57BL/6 mice, and at day 5, 8, 11 or at day 7,10,13 Ad-IL-17 siRNA with 1 × 109 MOI were injected intratumorally into mice. [Results]Intratumoral injection of Ad-IL-17 siRNA significantly suppressed tumor growth in both tumor models compared with control mice. We confirmed that intratumoral administration of Ad-IL17 siRNA completely suppressed endogenous IL-17 protein expression in tumor sites. To investigate the mechanisms of tumor growth suppression by inhibition of IL-17, in term of the angiogenesis we performed immunohistochemical staining of CD31 and MMP-9. Intratumoral injection of Ad-IL-17 siRNA significantly suppressed CD31 expression and MMP-9 expression in tumor tissue. Next, to investigate the effect of the inhibition of IL-17 in tumor tissue on systemic and local anti-tumor immunity, we assessed CTL activities of CD8+ T cells from splenocytes or tumor-infiltrating lymphocytes (TILs). The cytotoxic activities in CD8+ T cells from TILs in mice treated with intratumoral injection of Ad-IL-17 siRNA were significantly higher than those in control mice, but not splenocytes. To identify why the mechanism of the enhanceing effect on CTL activity by the inhibition of IL-17, especially in tumor microenvironment, we examined the Th1/Th2 phenotype from splenocytes or TILs. The levels of IFNγ+ CD4+ T cells from TILs were significantly higher in Ad-IL-17 siRNA-injected mice compared with those in control mice, but not splenocytes. On the other hand IL-4+ CD4+ T cells from TILs and splenocytes were similar levels in both mice.[Conclusion]The suppression of IL-17 expression in tumor tissues improved the immunological tumor microenvironment by shifting to Th1 dominant environment, resulting in CTL activation in tumor sites. It was suggested that the blockage of IL-17 in tumor tissue contributed to suppressing tumor growth via the inhibition of angiogenesis as well as CTL activation.
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 388. doi:10.1158/1538-7445.AM2011-388