bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 645: DNA methylation marker discovery for the prediction of nodal metastases in head and neck cancer.
Authors: Clausen Martijn , Melchers Lieuwe J. , Bruine de Bruin Leonie , Mastik Mirjam F. , Slagter-Menkema Lorian , Groen Harry J. , van der Vegt Bert , Van der Laan Bernard F. , De Meyer Tim , Van Criekinge Wim , Wisman G Bea , Roodenburg Jan L. , Schuuring Ed 
Published: August 2014

Abstract
Annually 650,000 new patients are diagnosed with Head and Neck cancer, making it the sixth most common cancer worldwide. The 5-year survival is only 60% due to inaccurate detection of nodal metastases in the cervical or submandibular region (N-status). Our goal is to find new DNA methylation markers in the primary tumor that predict nodal metastases to improve diagnostics and treatment. For biomarker discovery we used a new approach combining global methylation assessment, next generation sequencing, quantitative methylation and microarray expression profiling. Here we report the success of this new approach and the further validation of novel biomarkers. We performed MethylCap-Seq on DNA from 6 oral squamous cell carcinomas (OSCC) with nodal metastases (N+) and 6 OSCC without nodal metastases (N0) to measure global methylation levels. After comparison of the sequenced reads a list was composed of the 5000 most differentially methylated genes between the two groups. The most significantly differentially methylated genes were validated using Quantitative Methylation Specific PCR (QMSP) and Pyrosequencing on a independent series of 20 N+ and 20 N0 OSCC. In addition, the MethylCap-Seq methylation data was combined with microarray expression data of 696 genes for a N-status validation cohort containing 222 OSCC (Hoof et al.; J Clin Oncol. 2012 Oct 8). Based upon the assumption that hypermethylation is associated with downregulation of gene expression, we selected hypermethylated and downregulated genes distinguishing between the two groups. The effect of DNA methylation on gene expression will be measured by (Q)RT-PCR and immunohistochemistry on a N-status validation panel. The most promising methylation markers will be further validated by Pyrosequencing and QMSP on DNA of a N-status validation cohort containing 463 cases for which complete clinicopathological and follow-up data are available. These markers might contribute to better diagnosis, improved quality of life and may be associated with increased survival.
This research was supported by the Center for Translational Molecular Medicine (project AIRFORCE).
Citation Format: Martijn Clausen, Lieuwe J. Melchers, Leonie Bruine de Bruin, Mirjam F. Mastik, Lorian Slagter-Menkema, Harry J. Groen, Bert van der Vegt, Bernard F. Van der Laan, Tim De Meyer, Wim Van Criekinge, G Bea Wisman, Jan L. Roodenburg, Ed Schuuring. DNA methylation marker discovery for the prediction of nodal metastases in head and neck 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 645. doi:10.1158/1538-7445.AM2013-645
Abstract 662: Role of FAM3B as a novel tumor suppressor gene in gastric cancer.
Authors: Kim Hyojung , Park Sujin , Kang Jin Muk , Kim Staci Jakyong , Kim Seong-Jin 
Published: August 2014

Abstract
PANcreatic-DERived factor (PANDER, FAM3B) is a member of the FAM3 family of cytokine molecules. FAM3B expression is originally identified in the endocrine pancreas and also expressed in in colon and stomach. Initial characterization of FAM3B revealed a potential role in pancreatic islet apoptosis. However, the biological function of FAM3B has still remained elusive. Here we show that FAM3B level is decreased in 11 out of 14 cancer tissues samples (78.5%) as well as in gastric cancer cell lines. Ectopic expression of FAM3B leads to inhibition of cell growth and reduction of single cell colony forming activity and tumorigenicity of gastric cancer cells. FAM3B not only induces reduction of AKT phosphorylation, which is involved in cell survival, but also upregulation of p21, an inhibitor of cell cycle progression. We also demonstrated that FAM3B gene is silenced by epigenetic modification in gastric cancer cell lines. MS-275, a synthetic inhibitor of histone deacetylase, induced FAM3B gene expression. In conclusion, our data suggest the role of FAM3B as a putative tumor suppressor through downregulation of oncogenic AKT signaling pathway in gastric cancer.
Citation Format: Hyojung Kim, Sujin Park, Jin Muk Kang, Staci Jakyong Kim, Seong-Jin Kim. Role of FAM3B as a novel tumor suppressor gene in gastric 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 662. doi:10.1158/1538-7445.AM2013-662
Abstract 668: DNA methylation of apoptosis-related genes as clinical biomarker in rectal cancer.
Authors: Benard Anne , Zeestraten Eliane C.M. , Goossens-Beumer Inès J. , Putter Hein , Kuo Christine , van de Velde Cornelis J.H. , Kuppen Peter J.K. , Hoon Dave S.B. 
Published: August 2014

Abstract
Background: To prevent over- and undertreatment of rectal cancer patients, there is a need for the development of new biomarkers that can complement the current staging system. We have previously shown that apoptosis plays an important role in local tumor recurrence after TME surgery. We studied the epigenetic regulation of several key apoptosis genes in rectal cancer tissues, using methylation-sensitive restriction enzymes.
Materials and methods: DNA was obtained from frozen specimens of 138 patients representative for the non-irradiated arm of the Dutch Total Mesorectal Excision (TME) trial. Isoschizomers HpaII (CpG methylation sensitive) and MspI (not sensitive) were used for restriction enzyme digestion of tumor DNA, followed by real-time PCR for apoptosis genes Apaf1, Bcl2, TrailR2, Fas and p53. A pilot series consisted of 50 patients with tumor stages I-III and 10 normal rectal tissues. For the validation study stage III patients (n=88) and 18 normal rectal tissues were selected.
Results: Single marker analyses showed a significant correlation between methylation status and apoptotic status (measured by immunohistochemical staining of M30) of Fas (p=0.005) and Apaf1 (p=0.052). Combining intrinsic pathway markers Apaf1, Bcl2 and p53, significant differences were observed between the methylation groups in survival and recurrence analyses (log rank test), with overall survival (p=0.054), cancer specific survival (p=0.014) and distant recurrence free survival (p=0.006).
Conclusion: Methylation of apoptosis genes is representative for the apoptotic status of a tumor and is correlated to survival and recurrence in rectal cancer patients. The apoptotic status of a tumor may be used to guide treatment strategies for individual patients.
[A.B. and E.C.M.Z contributed equally to this work.]
Citation Format: Anne Benard, Eliane C.M. Zeestraten, Inès J. Goossens-Beumer, Hein Putter, Christine Kuo, Cornelis J.H. van de Velde, Peter J.K. Kuppen, Dave S.B. Hoon. DNA methylation of apoptosis-related genes as clinical biomarker in rectal 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 668. doi:10.1158/1538-7445.AM2013-668
Abstract 671: Identification of potent BET bromodomain inhibitors for treatment of cancer.
Authors: Sasmal Sanjita , Shrimali Rajeev Kumar , Abbineni Chandrasekhar , Arumalla Kamala Kumari , Lakshminarasimhan Anirudha , Narasingapuram Arumugam Karthikeyan , Tiwari Nirbhay Kumar , Rao Narasimha K. , AB Aravind , Hosahalli Subramanya 
Published: August 2014

Abstract
Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression. Histone lysine acetylation is one of the most abundant epigenetic modifications central to control of gene transcription. Bromodomains are the only known readers of this specific lysine acetylation code, playing an important role in transcriptional regulation of diverse cellular processes such as inflammatory gene expression, mitosis and viral/host interactions. Recently, the human BET family bromodomains which consists of BRD2, BRD3, BRD4 and BRDT has emerged as new druggable target class for the development of specific protein interaction inhibitors, enabling a novel strategy for the development of new therapies for various diseases. Here we report the identification of potent BET bromodomain inhibitors using structure based drug design principle. Multiple distinct series of compounds have been identified with low nM potency in biochemical binding assay. Crystal structures of BRD4 in complex with hit compounds have been solved to assist in optimization. The lead compounds showed very good cell based activity and favorable ADME properties. The compounds demonstrated dose dependent inhibition of c-Myc expression confirming the mechanism of action. Further optimization of these compounds and profiling in relevant pre-clinical disease models is in progress.
Citation Format: Sanjita Sasmal, Rajeev Kumar Shrimali, Chandrasekhar Abbineni, Kamala Kumari Arumalla, Anirudha Lakshminarasimhan, Karthikeyan Narasingapuram Arumugam, Nirbhay Kumar Tiwari, Narasimha K. Rao, Aravind AB, Subramanya Hosahalli. Identification of potent BET bromodomain inhibitors for treatment of 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 671. doi:10.1158/1538-7445.AM2013-671
Abstract 685: Epigenetic modulators and calcium-sensing receptor expression in colorectal cancer cells.
Authors: Fetahu Irfete Sh. , Höbaus Julia , Aggarwal Abhishek , Tennakoon Samawansha , Mesteri Ildiko , Baumgartner-Parzer Sabina , Kallay Enikoe 
Published: August 2014

Abstract
Introduction: Epidemiological studies suggest a role for calcium in prevention of colorectal cancer. The antiproliferative action of calcium in colon might be mediated by the calcium-sensing receptor (CaSR). The CaSR expression is lost in human colorectal cancer. We hypothesized that DNA methylation and histone modifications may be the cause of CaSR silencing in tumors.
Material and methods: We analyzed CaSR mRNA and protein expression in colorectal tumors and cell lines by real time qRT-PCR and immunofluorescence. We determined the methylation pattern in the second promoter of the CaSR that contains a large CpG island by bisulfite sequencing. To induce the expression of the CaSR we treated colon tumor cell lines with 5-aza-2-deoxycytidine (5-aza-dC) and RG108, two DNA methyltransferase inhibitors, three different histone deacetylase inhibitors (HDACIs) Trichostatin A, suberoylanilide hydroxamic acid, sodium butyrate in the presence or absence of a lysine specific demethylase 1 (LSD1) inhibitor to prevent demethylation of mono- and dimethylated histone H3 lysine 4.
Results: In our patient cohort we observed significantly less CaSR mRNA expression (n=57, P&lt;0.001) in colorectal tumors compared with adjacent mucosa from the same patient. Immunofluorescence staining confirmed downregulation of CaSR protein in tumors. The CaSR promoter was stronger methylated in tumors compared with adjacent mucosa and we found an inverse correlation between extent of methylation and mRNA expression (n=20, Spearman's rho = - 0.3, P&lt;0.05). Treatments with 5-aza-dC and the HDACIs restored the expression of CaSR in a compound and cell line dependent manner. However, treatments with the LSD1 inhibitor caused only modest increase of CaSR expression.
Conclusion: In summary, DNA methylation and histone deacetylation seem to be important factors in silencing the expression of CaSR in colorectal cancer, although additional mechanism or factors might be also involved.
Citation Format: Irfete Sh. Fetahu, Julia Höbaus, Abhishek Aggarwal, Samawansha Tennakoon, Ildiko Mesteri, Sabina Baumgartner-Parzer, Enikoe Kallay. Epigenetic modulators and calcium-sensing receptor expression in colorectal cancer cells. [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 685. doi:10.1158/1538-7445.AM2013-685
Abstract 687: Variations in promoter methylation levels of DNA repair genes and breast cancer risk in the New York site of the Breast Cancer Family Registry.
Authors: Kappil Maya A. , Terry Mary Beth , Liao Yuyan , Santella Regina 
Published: August 2014

Abstract
Reduced DNA repair capacity contributes to genomic instability, a hallmark of carcinogenesis. The link between DNA repair capacity and cancer is especially relevant in breast cancer, where women with suboptimal repair capacity have been reported to have up to a five-fold increase in breast cancer risk compared to women with better repair capacity. We investigated promoter methylation levels of DNA repair-related genes and their association with breast cancer risk among participants of the New York site of the Breast Cancer Family Registry, comparing sisters affected with breast cancer to their unaffected sisters. We analyzed DNA extracted from viable mononuclear cells from 218 sisters (N=538 women) using pyrosequencing assays designed to target CpG islands in the promoter regions of BRCA1, MSH2, and MLH1. Breast cancer risk was not significantly associated with the promoter methylation level of BRCA1 (OR=1.09 [0.98-1.20]), MLH1 (OR=1.18 [0.90-1.54]) or MSH2 (OR=0.87 [0.47-1.59]). We assessed the Spearman correlation between methylation and previously generated data on expression level of BRCA1 and MSH2, where we had observed a significant increase in breast cancer risk among women in the lowest quartile of expression for MSH2. Among the affected women, no significant correlation was observed between methylation and expression level for MSH2 (-0.04, p=0.39) or BRCA1 (r=-0.05, p=0.39). These findings suggest that while MSH2 may have implications for breast cancer risk, as suggested by the previously observed increase in risk with decrease in expression level of MSH2, the lack of an association between gene promoter methylation levels of MSH2 and breast cancer risk and the lack of a correlation with expression level in the current study, indicate that other mechanisms impacting the reduction in expression level of this gene may be more relevant to explain the observed increase in breast cancer risk.
Citation Format: Maya A. Kappil, Mary Beth Terry, Yuyan Liao, Regina Santella. Variations in promoter methylation levels of DNA repair genes and breast cancer risk in the New York site of the Breast Cancer Family Registry. [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 687. doi:10.1158/1538-7445.AM2013-687
Abstract 707: MK1775-mediated gemcitabine sensitization correlates with prolonged DNA damage signaling in S-phase cells.
Authors: Parsels Leslie A. , Parsels Joshua D. , Morgan Meredith A. , Lawrence Theodore S. , Maybaum Jonathan 
Published: August 2014

Abstract
Pancreatic cancer remains among the most lethal cancers with an overall 5-year survival of &lt;5%. Wee1 inhibition has emerged as a potential approach to sensitize pancreatic cancer to gemcitabine (Gem), the current standard therapy for both local control and metastatic disease. In this study, we first characterized the ability of MK1775, a small molecule Wee1 inhibitor now entering Phase II clinical trials, to sensitize pancreatic cancer cells to Gem. Using a clonogenic survival assay, we tested the effects of MK1775 in a panel of pancreatic cancer cells and found MK1775-mediated Gem sensitization ranged from 80-fold in MiaPaCa2 cells to 12-fold in Panc1 cells. This sensitization was associated with aberrant mitotic entry in MiaPaCa2 and Panc1 cells, but not in the other cells lines tested. In addition, MK1775 potentiated and prolonged Gem-induced DNA damage signaling (γ-H2AX) as determined by 2-parameter flow cytometry. For example, 48 h post-Gem, 35±12% of BxPC3 cells remain γ-H2AX-positive compared to 76±3.7% of cells treated with Gem + MK1775. Using immunofluorescent staining, we further determined that Wee1 inhibition with MK1775 qualitatively changed Gem-induced γ-H2AX nuclear foci to high intensity pan-nuclear γ-H2AX pan-staining. Finally, we tested the ability of the CDK inhibitor roscovitine (Ros) to attenuate MK1775-mediated chemosensitization. Ros not only prevented aberrant mitotic entry in MiaPaCa2 and Panc1 cells, but in each cell line sensitized to Gem by MK1775, Ros inhibited both high-intensity γ-H2AX staining after treatment with Gem + MK1775 and chemosensitization. These results suggest the effects of MK1775 on DNA repair in S-phase cells may be more important for Gem chemosensitization than the effects of MK1775 on the G2-M checkpoint.
Citation Format: Leslie A. Parsels, Joshua D. Parsels, Meredith A. Morgan, Theodore S. Lawrence, Jonathan Maybaum. MK1775-mediated gemcitabine sensitization correlates with prolonged DNA damage signaling in S-phase cells. [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 707. doi:10.1158/1538-7445.AM2013-707
Abstract 71: Meningioma: response to retinoids and radiation therapy.
Authors: Ren Xuan , Lo Hannah , Vanderwaal Robert , Jaboin Jerry 
Published: August 2014

Abstract
Meningioma represents one third of all primary central nervous system neoplasms. Most meningiomas are effectively addressed by surgical resection. However unresectable, partially resected, recurrent and high grade meningiomas are also typically treated with adjuvant or definitive radiation therapy.
Retinoids are a class of compounds structurally related to Vitamin A. Retinoic acid (RA), the active derivative of vitamin A and the first diffusible morphogen in vertebrates, has recently been evaluated for its chemotherapeutic and chemopreventive attributes in solid tumors. Additionally, a novel orally bioavailable synthetic retinoid, fenretinide, has been tested with different pharmacokinetics, side effect profile, and mechanism of action than the classic retinoids, all-trans retinoic acid (ATRA) and 13-cis-retinoic acid (13CRA). In this project, we study the effects of retinoic acid agents alone and in combination with ionizing radiation in meningioma cell lines (IOMM-Lee and CH157MN).
We demonstrate that ATRA, 13CRA and fenretinide have similar (increasing) toxicity profiles in both cell lines at doses above 1μM; but below this concentration there are minimal changes on cellular proliferation. Pretreatment of meningioma cell lines with ≤1μM doses of ATRA and 13CRA protected cells from radiation-induced cell death, while pre-treatment with fenretinide had no effect. Using flow cytometric analysis, we demonstrated that RA inhibited radiation-induced G2/M phase accumulation. Western blot result showed that ionizing radiation increased Phospho-Chk1 and -Chk2 levels, and decreased the levels of cdc25c, Phospho-cdc25c (Ser126) and Phospho cdc25c(THr68), Pre-treatment with RTRA reversed each of these effects in a dose- and time-dependent manner.
These data suggest a role for the classic RAs in radiation protection through modulation of DNA repair through cell cycle checkpoint pathways. Fenretinide, however, works through a different mechanism, and does not result in radiation protection. These divergent roles suggest that fenretinide may escape the concerns of radiation protection of earlier retinoids making it a promising agent for tumor treatment in the periradiotherapy period.
Citation Format: Xuan Ren, Hannah Lo, Robert Vanderwaal, Jerry Jaboin. Meningioma: response to retinoids and radiation therapy. [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 71. doi:10.1158/1538-7445.AM2013-71
Abstract 710: Telomerase-specific oncolytic adenovirus OBP-301 kills quiescent peritonially disseminated cancer cells.
Authors: Yano Shuya , Tazawa Hiroshi , Kishimoto Hiroyuki , Fujiwara Toshiyoshi , Hoffman Robert M. 
Published: August 2014

Abstract
MKN45 human gastric cancer cells can develop peritonitis carninomatosa where the cancer cells form aggregated structures. The cells are mostly in G0/G1 phase, as imaged by fluorescent ubiquitination-based cell cycle indicator (FUCCI). However, most cytotoxic agents target only proliferating cancer cells. The telomerase-specific adenovirus, OBP-301 was injected into the peritoneal cavity 7 days after inoculation of FUCCI-expressing MKN45. Control mice had approximately 5 ml bloody ascites with big tumor masses in the peritoneal cavity after 60 days. Cisplatin-treated mice also had approximately 5 ml bloody ascites with a big tumor masses in the peritoneal cavity. Paclitaxel-treated mice also had big tumor masses. There were many tumor spheres in the bloody ascites, and the tumors in the peritoneal cavity consisted of cancer cells mostly in G0/G1 phase. In contrast, OBP-301 treated mice had no ascites and only small tumor nodules consisting of cancer cells in S/G2 phases in the peritoneal cavity. These data suggest that OBP-301 is effective against peritonially disseminated cancer cells which are mostly in G0/G1.
Citation Format: Shuya Yano, Hiroshi Tazawa, Hiroyuki Kishimoto, Toshiyoshi Fujiwara, Robert M. Hoffman. Telomerase-specific oncolytic adenovirus OBP-301 kills quiescent peritonially disseminated cancer cells. [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 710. doi:10.1158/1538-7445.AM2013-710