bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 420: Tet family proteins and 5-hydroxymethylcytosine in esophageal squamous cell carcinoma
Authors: Murata Asuka , Baba Yoshifumi , Karashima Ryuichi , Ida Satoshi , Imamura Yu , Ishimoto Takatsugu , Iwagami Shiro , Sakamoto Yasuo , Miyamoto Yuji , Yoshida Naoya , Baba Hideo 
Published: May 2015

Abstract
Objective: DNA methylation is a fundamental epigenetic process that modulates gene expression. Cancer cells exhibit two types of DNA methylation alterations: global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Although the base 5-methylcytosine (5mc) and the DNA methyltransferase (DNMT) family of enzymes that catalyze DNA methylation are well-studied, the mechanisms of DNA demethylation are poorly understood. The Ten-eleven translocation (Tet) family of enzymes (Tet1, Tet2, and Tet3) has been implicated in DNA demethylation. These enzymes possess the dioxygenase activity and convert 5-mC to 5-hydroxymethylcytosine (5-hmC). Frequent Tet mutational inactivation or reduction has been reported to associate with decreased 5-hmC levels in various types of myeloid leukemia and melanoma. However, the status of 5hmC and Tet expression in esophageal squamous cell carcinoma (ESCC) remains still unknown.
Method: We analyzed the 5-hmC status in DNA from ESCC frozen tissues utilizing the ELISA test, and 5-hmC expression was evaluated by immunohistochemistry. We next examined the expression levels of Tet family mRNA in both normal and tumor tissues by RT-qPCR.
Results: 5-hmC level was significantly lower in ESCC than in paired normal tissue in ELISA test (n=33, P&lt;0.0001). The similar result was observed in immunohistochemistry. We found that the Tet2 mRNA expression was significantly lower in ESCCs than paired normal tissues (n=32, P&lt;0.0001). The expression level of Tet2 mRNA was significantly associated with the 5hmC status (n=31, r=0.54, P=0.0085). Finally, 5-hmC status did not correlate with overall survival (P = 0.65).
Conclusion: The 5hmC expression was decreased in ESCC tissues, and was associated with Tet2 expression level, suggesting that 5hmC and Tet2 might play a crucial role in the development of ESCCs.
Citation Format: Asuka Murata, Yoshifumi Baba, Ryuichi Karashima, Satoshi Ida, Yu Imamura, Takatsugu Ishimoto, Shiro Iwagami, Yasuo Sakamoto, Yuji Miyamoto, Naoya Yoshida, Hideo Baba. Tet family proteins and 5-hydroxymethylcytosine in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 420. doi:10.1158/1538-7445.AM2014-420
Abstract 4203: A transducer module consisting of Toll-like receptor 9 and Bruton's tyrosine kinase triggers acute myeloid leukemia blast proliferation
Authors: Oellerich Thomas , Mohr Sebastian , Bohnenberger Hanibal , Dubey Anjali , Münch Silvia , Wicht Johannes , Oellerich Mark F. , Perske Christina , Bug Gesine , Ströbel Philipp , Urlaub Henning , Serve Hubert 
Published: May 2015

Abstract
Acute myeloid leukemia (AML) is a genetically heterogeneous disease and mutations occur in various genes including those encoding for signaling molecules. A well characterized example is the tyrosine kinase Flt3, which harbours internal tandem duplications in about one third of AML patients that render the kinase constitutively active. AML cells often become addicted to such constitutively activated survival inducing signaling pathways that can be therapeutically exploited by using small molecule kinase inhibitors.
By screening bone marrow biopsies of AML patients for kinase expression profiles, we detected Bruton's tyrosine kinase (Btk) in AML blasts in 26 out of 30 analyzed cases. Btk acts as an oncogene in chronic lymphocytic leukemia as well as in certain B-cell lymphoma subtypes. As compared to diseases of lymphoid origin far less is known about the role of Btk in myeloid neoplasias.
Here, we show that Btk is often constitutively activated in AML and moreover, that genetic as well as pharmacological inhibition of Btk in AML cell lines as well as primary patient-derived AML cultures strongly diminishes AML cell growth. By applying quantitative mass spectrometry, we identified a signalosome consisting of Btk and Toll-like receptor 9 that is needed to constitutively transduce proliferation signals through the NFkB pathway. This newly identified TLR9/Btk signaling axis is of clinical interest as it is effectively druggable by Btk inhibitors which have so far only indications for the treatment of lymphoid malignancies.
Citation Format: Thomas Oellerich, Sebastian Mohr, Hanibal Bohnenberger, Anjali Dubey, Silvia Münch, Johannes Wicht, Mark F. Oellerich, Christina Perske, Gesine Bug, Philipp Ströbel, Henning Urlaub, Hubert Serve. A transducer module consisting of Toll-like receptor 9 and Bruton's tyrosine kinase triggers acute myeloid leukemia blast proliferation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4203. doi:10.1158/1538-7445.AM2014-4203
Abstract 4217: Nuclear expression of BCL10 has a role in the regulation of cell growth and progression of pancreatic cancer through the activation of NF-κB-related signaling
Authors: Kuo Sung-Hsin , Yang Shih-Hung , Yeh Kun-Huei , Yeh Pei-Yen , Tien Yu-Wen , Lee Hsiao-Wei , Chen Li-Tzong , Cheng Ann-Lii 
Published: May 2015

Abstract
Background:
We previously reported that activation of TNF-α results in upregulation of NF-κB and nuclear translocation of BCL3 and BCL10 in breast cancer cell line and lymphoma cell line (J Biol Chem 2006;281:167-75, Blood 2008;112:2927-34). Furthermore, we recently demonstrated that BCL10 plays an important role in controlling the growth of cervical cancer cells through NF-κB dependent cyclin D1 regulation (Gynecol Oncol 2012;126:245-51). Since NF-κB activation has been shown to occur in the pathogenesis of pancreatic cancer, we sought to investigate whether BCL10-signaling possesses clinical significance in relation to pancreatic cancer.
Methods:
Three pancreatic cancer cell lines (PANC-1, AsPC-1, and BxPC-3) were used in this study. Cell cycle was analyzed by flow cytometry. The expression of protein and mRNA of BCL10- and NF-κB- related signaling was assessed by immunoblotting and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. The DNA-binding activity of NF-κB was determined by the luciferase assay. The expression of BCL10, and NF-κB in tumor cells from recurrent, locally advanced, and metastatic pancreatic patients who received chemotherapy was examined using immunohistochemical staining.
Results:
We transfected three pancreatic cancer cell lines with BCL10 small interfering RNA (siRNA), and discovered that the down-regulation of BCL10 inhibited the viability of these pancreatic cancer cells through the G1 arrest. BCL10 siRNA treatment inhibited the expression of p-IKKβ and p-IκB, and nuclear BCL3 translocation, and also down-regulated NF-κB activation and its downstream cell cycle proteins, c-Myc, and cyclin B1. The results of qRT-PCR showed that BCL10 siRNA treatment inhibited the mRNA expression levels of BCL10, BCL3, c-Myc, and cyclin B1. Our results reveal that patients with nuclear BCL10 expression had a worse median overall survival than those without (7.9 months versus 16.9 months, p = 0.007). Furthermore, nuclear expression of BCL10 was closely associated with nuclear BCL3 expression (p &lt; 0.001), and NF-κB activation (p &lt; 0.001).
Conclusions:
Our findings indicate that nuclear BCL10 plays an important role in controlling the growth and progression of pancreatic cancer cells through NF-κB-related signaling pathway.
Citation Format: Sung-Hsin Kuo, Shih-Hung Yang, Kun-Huei Yeh, Pei-Yen Yeh, Yu-Wen Tien, Hsiao-Wei Lee, Li-Tzong Chen, Ann-Lii Cheng. Nuclear expression of BCL10 has a role in the regulation of cell growth and progression of pancreatic cancer through the activation of NF-κB-related signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4217. doi:10.1158/1538-7445.AM2014-4217
Abstract 4228: 6,7,4-Trihydroxyisoflavone, a daidzein metabolites, regulated glycogen synthase kinase 3β/β-catenin signaling and inhibited cell proliferation in MCF10DCIS.com human breast cancer cells
Authors: Park Hyun-Chang , Bao Cheng , Ko Jiwon , Lee Jaehoo , Lee Hong Jin 
Published: May 2015

Abstract
Recent studies have demonstrated that hepatic daidzein metabolites exerted significant activities in regulating different types of cancer including skin and colon. However, the role of daidzein metabolites on breast cancer has not been extensively studied. In this study, we found that 6,7,4′-trihydroxyisoflavone exerted the strongest inhibitory effect on the proliferation of MCF10DCIS.com human breast cancer cells among the daidzein metabolites we tested. Cell cycle at S and G2/M phase were arrested by 6,7,4-trihydroxyisoflavone, which were derived from regulating cyclins and cyclin dependent kinases (CDKs) including cyclin B, CDK1 and CDK2, as well as CDK inhibitor, p27 in a dose dependent manner. Furthermore, 6,7,4′-trihydroxyisoflavone increased the GSK3β activity through inhibiting the phosphorylation at Ser9, which was caused by the enhancement of phosphatase activity. These effects of 6,7,4′-trihydroxyisoflavone led to inhibition of the nuclear translocation of β-catenin, and regulation of cell cycle related proteins, cyclinB and CDK2. Taken together, 6,7,4′-trihydroxyisoflavone regulated GSK3β/β-catenin signaling, and arrested at S and G2/M phase in MCF10DCIS.com human breast cancer cells, and it suggests that the hepatic metabolite of daidzein, 6,7,4′-trihydroxyisoflavone, may be a potent agent in inhibiting MCF10DCIS.com human breast cancer growth.
Citation Format: Hyun-Chang Park, Cheng Bao, Jiwon Ko, Jaehoo Lee, Hong Jin Lee. 6,7,4-Trihydroxyisoflavone, a daidzein metabolites, regulated glycogen synthase kinase 3β/β-catenin signaling and inhibited cell proliferation in MCF10DCIS.com human breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4228. doi:10.1158/1538-7445.AM2014-4228
Abstract 4230: 5α-dihydrotestosterone down-regulates HER2 and sensitizes breast cancer cells to Herceptin-induced apoptosis in vitro
Authors: Sultana Aisha , Naqvi Zulfiqar Ali , Khan Shaista , Siddiqui Anwar Ali , Lalani El-Nasir 
Published: May 2015

Abstract
Androgen inhibits growth of malignant breast cancer (BCa) cells by mechanisms that remain poorly defined. Here, we have investigated how androgen suppress proliferation and induces apoptosis in BCa cells. Treatment of MCF-7 cells with 1nM 5α-dihydrotestosterone (DHT) inhibited cell proliferation as well as endogenous HER2 expression, both at mRNA and protein levels, suggesting a link between androgen receptor (AR) and HER2 signaling pathways. Expression of HER2 and AR was also determined in patients with BCa. We found a survival advantage of AR expression in patients with HER2 positive BCa, whereas, loss of AR expression was associated with poor survival. This finding would suggest that AR loss may provide a growth advantage to HER2 over-expressing tumors. We showed the functional consequence of the stimulation of AR-signaling and inhibition of HER2-signaling on breast epithelial cell growth and on expression of 84 genes involved in BCa and estrogen-mediated signaling pathway. Exposure to a combination therapy of DHT and Herceptin resulted in additive anti-proliferative effect in human MCF-7 cells as compared to either agent alone. Furthermore, combined treatment of DHT with Herceptin reduces the expression of genes predominantly involved in proliferation, invasion, anti-apoptosis and cell cycle regulation.
These findings provide the key insights into how Herceptin and DHT produce anti-proliferative effect in BCa cells. In conclusion, adding DHT to Herceptin may provide a rational treatment option for BCa, not only by direct inhibition of cell proliferation, but also causing changes in the expression of many genes that are critically involved in the control of proliferation. Establishment of any interaction between AR and HER2 may improve the understanding of carcinogenesis and will provide helpful information in the development of novel preventive and therapeutic strategies.
Citation Format: Aisha Sultana, Zulfiqar Ali Naqvi, Shaista Khan, Anwar Ali Siddiqui, El-Nasir Lalani. 5α-dihydrotestosterone down-regulates HER2 and sensitizes breast cancer cells to Herceptin-induced apoptosis in vitro. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4230. doi:10.1158/1538-7445.AM2014-4230
Abstract 4233: Mef2C enhances 1,25-dihydroxyvitamin D3-induced monocytic differentiation of human myeloid leukemia cells by regulating C/EBPβ expression
Authors: Zheng Ruifang , Wang Xuening , Studzinski George P. 
Published: May 2015

Abstract
Myogenic enhancer factors 2 (Mef2) are members of the family of MADS (MCM1-agamous-deficiens-serum response factor)-box transcription factors known to have multiple roles in morphogenesis of skeletal, cardiac and smooth muscle cells. Recently, Mef2C was found to be also involved in hematopoiesis. Bone marrow cells isolated from Mef2C knockout mice demonstrated decreased monocytic differentiation in response to cytokine stimulation, whereas constitutive expression of Mef2C promoted monopoiesis. The above findings led us to examine the role of Mef2C in 1,25-dihydroxyvitamin D3 (1,25D)-induced monocytic differentiation. Human acute myeloid leukemia (AML) cell lines, HL60 and U937, were used in this study. We found that knockdown of Mef2C with small interfering RNA (siRNA) significantly decreased the expression of the monocytic marker CD14, as well as of nonspecific esterase (NSE), suggesting that Mef2C is required for 1,25D-induced monocytic differentiation in AML cells. Our laboratory has previously demonstrated that optimal monocytic differentiation induced by 1,25D requires ERK5, and that ERK5 expression shows positive correlation with Mef2C expression. Here we show that Mef2C knockdown demonstrates similar inhibition of CD14 expression as ERK5 knockdown. CCAAT-enhancer-binding proteins (C/EBPs) α and β are two major transcription factors that can directly regulate CD14 expression. Since 1,25D has been shown to increase both C/EBPα and β expression, and these two transcription factors form heterodimers to enhance CD14 expression, we used siRNA to knock down Mef2C and found decreased expression of 1,25D-induced C/EBPβ, but not C/EBPα. Similar results were obtained using an alternative method to titrate down Mef2C with dsDNA containing its DNA binding sequence. We conclude that Mef2C is a functional downstream target of ERK5, and that 1,25D-induced CD14 and NSE expression is mediated through ERK5/Mef2C activation. (Supported by T32 CA134268 training grant and R01 CA044722 both from the National Cancer Institute, NIH, and by the American Institute for Cancer Research grant 10A049)
Citation Format: Ruifang Zheng, Xuening Wang, George P. Studzinski. Mef2C enhances 1,25-dihydroxyvitamin D3-induced monocytic differentiation of human myeloid leukemia cells by regulating C/EBPβ expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4233. doi:10.1158/1538-7445.AM2014-4233
Abstract 4240: Targeting Galectin-3 to reverse tumor stemness and drug resistance
Authors: Kato Shumei , Seguin Laetitia , Franovic Aleksandra , Kato Hisashi , Camargo Maria , Desgrosellier Jay , Anand Sudarshan , Weis Sara , Shattil Sanford , Cheresh David A. 
Published: May 2015

Abstract
We have recently linked integrin αvβ3 expression to metastatic potential, stemness, and therapy resistance due to its capacity to couple to KRAS. This leads to the induction of RalB/TBK-1 and the activation of NFκB to shift tumor cells to a stem-like phenotype. To understand how integrin αvβ3 couples to KRAS, we generated β3 domain swap mutants containing either the intracellular or extracellular domains of β1 integrin. Each chimera partially reduced KRAS association with αvβ3, suggesting interactions on each side of the plasma membrane may contribute. Since the short β3 cytoplasmic tail has no putative KRAS binding regions, we considered Galectin-3 as a putative scaffolding partner to facilitate the αvβ3/KRAS association due to its reported binding to both KRAS and integrins. Indeed, treating cells with GCS-100, a complex polysaccharide that has the ability to bind to and block the effects of Galectin-3, decreased Galectin-3 surface expression, αvβ3 clustering, and αvβ3/KRAS association. Exposing cells to this drug also decreased tumor stem properties. Our observations provide a molecular basis for the αvβ3/KRAS/Galectin-3 complex and highlight the potential for Galectin-3 blockade as a therapeutic approach to reverse the aggressive behavior of αvβ3-expressing tumors.
Citation Format: Shumei Kato, Laetitia Seguin, Aleksandra Franovic, Hisashi Kato, Maria Camargo, Jay Desgrosellier, Sudarshan Anand, Sara Weis, Sanford Shattil, David A. Cheresh. Targeting Galectin-3 to reverse tumor stemness and drug resistance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4240. doi:10.1158/1538-7445.AM2014-4240
Abstract 4242: Effects of dual inhibition of EGFR and Aurora A kinase in a lung cancer model
Authors: Bagnyukova Tetyana , Pan Xiaofan , Zhang Jiping , Egleston Brian , Astsaturov Igor , Golemis Erica , Borghaei Hossein 
Published: May 2015

Abstract
Lung cancer is the leading cause of cancer related death in the US. Patients with advanced disease generally have a poor prognosis with a median survival of around 10 to 12 months with standard chemotherapy. Astsaturov and colleagues (2010) employed a synthetic lethal screening method and have reported that the combined inhibition of the EGFR and Aurora A kinase pathways had synergistic effect on cancer cell viability in head and neck and colon cancer cell lines suggesting a potential benefit of such combination therapy in patients. Our study aims to examine the effects of combination of erlotinib (E), an EGFR small-molecule inhibitor, and Alisertib (MLN8237, A), an inhibitor of Aurora A kinase, in lung cancer models. Treatment of two human NSCLC cell lines, A549 and H322M, with E+A showed synergistic activity in vitro. These cell lines were chosen for the xenografts studies in CB17 SCID mice. After tumors reached a volume of 100 mm3, mice were treated with E+A for three weeks. The xenografts were sensitive to growth inhibition by E (10 mg/kg/day) and A (20 mg/kg/twice daily) alone and the combination had an additive effect. In order to understand early cell signaling events in tumors treated with these agents we repeated the xenograft experiment by treating mice with a one time dosing of each drug alone and in combination. Three tumors per group were collected at 0 , 6 , 24 , or 48 hours after treatment and a panel of signaling molecules downstream of the EGFR and Aurora A kinase pathways were examined by Western blot. These included EGFR/pEGFR; HER2; HER3; MEK/pMEK; ERK/pERK; Src/pSrc and Akt/pAkt among others. Our results suggest that combined inhibition of both pathways in lung cancer cell lines and xenografts can lead to a reduced proliferative index as indicated by quantitative changes in these proteins and that this combination might be effective as a treatment strategy. A clinical trial with this combination is in progress at our center.
Citation Format: Tetyana Bagnyukova, Xiaofan Pan, Jiping Zhang, Brian Egleston, Igor Astsaturov, Erica Golemis, Hossein Borghaei. Effects of dual inhibition of EGFR and Aurora A kinase in a lung cancer model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4242. doi:10.1158/1538-7445.AM2014-4242
Abstract 4249: The Pi3Kβ/δ inhibitor AZD8186 has potential to treat tumours in combination with key signalling pathway inhibitors
Authors: Barry Simon T. , Cronin Kathryn , Cumberbatch Marie , Ellston Rebecca , Foster Emily , Hancox Urs , Hanson Lyndsey , Harrington Liz , Lenaghan Carol , Symeonides Stefan , Trigwell Cath , Ward Lara 
Published: May 2015

Abstract
AZD8186 inhibits Pi3K isoforms Pi3Kβ and δ, with selectivity over Pi3Kα and γ. In solid tumours Pi3Kβ drives tumour growth when the tumour suppressor PTEN is deleted, mutated or downregulated. It also mediates signals from specific GPCR receptors. Pi3Kδ signals downstream of the B-cell receptor, creating potential for targeted treatment of haematological malignancies such as CLL, MCL & indolent NHL and possibly DLBCL. AZD8186 is differentiated from many other agents that target Pi3K family members as it isn't likely to impact glucose control. AZD8186 has single agent activity in a range of models, although maximal benefit is anticipated when used in combination. Loss of PTEN mediated control, and hence dependency on PI3Kβ occurs in many solid tumour types, and is altered in up to 40-50% of tumours in some individual disease states. Commonly PTEN dysregulation is associated with other activation of other signaling pathways. To explore this we have combined AZD8186 with a number of different agents. In HCC70 (triple negative breast cancer) and PC3 (prostate cancer) xenografts combination of AZD8186 (25mg/kg bid) with single dose docetaxel (15mg/kg) gives &gt;90% tumour growth inhibition (TGI), compared to 40-50% with docetaxel alone. AZD8186 also combines with other targeted agents. In HCC70, AZD8186 (25mg/kg bid) combined with selumetinib (10mg/kg) gave 94% TGI compared to 66%, and 47% with each single agent. In combination with AZD2014 (mTORC1/2 inhibitor) (15mg/kg qd) in HCC70 xenografts AZD8186 (25mg/kg bid) gave regressions (-23%) compared to TGI of 87% and 77% for each agent alone. In 786-0 (renal cancer) xenografts AZD8186 (12.5mg/kg bid) and AZD2014 (15mg/kg qd) gave regression of -82% compared to TGI of 33% and regression of -39% with each agent alone. This data establishes the potential for AZD8186 to be used in combination with a number of different agents including the ability to customise dose and schedule to optimise both tolerability as well as anti-tumour effects. Further exploration of the combination opportunities for AZD8186 with other molecular targeted agents would inform on the potential for inhibitors of Pi3Kβ and δ to give benefit in different tumour types.
Citation Format: Simon T. Barry, Kathryn Cronin, Marie Cumberbatch, Rebecca Ellston, Emily Foster, Urs Hancox, Lyndsey Hanson, Liz Harrington, Carol Lenaghan, Stefan Symeonides, Cath Trigwell, Lara Ward. The Pi3Kβ/δ inhibitor AZD8186 has potential to treat tumours in combination with key signalling pathway inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4249. doi:10.1158/1538-7445.AM2014-4249