bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4087: Microbiomic subprofiles and MDR1 promoter methylation in head and neck squamous cell carcinoma
Authors: Bebek Gurkan , Bennett Kristi L. , Funchain Pauline , Campbell Rebecca , Seth Rahul , Scharpf Joseph , Burkey Brian , Eng Charis 
Published: August 2012

Abstract
Background: Clinical observations and epidemiologic studies suggest that the incidence of head and neck squamous cell carcinoma (HNSCC) correlates with dental hygiene, implying a role for bacteria-induced inflammation in its pathogenesis. Differences in microbiota in HNSCC compared to matched normal oral mucosa, and whether these differences are accompanied by epigenetic modifications in selected HNSCC-associated genes and clinico-pathologic features has not yet been investigated. Standard microbiologic culturing techniques miss many fastidious organisms. Methods: Human genomic DNA and associated microbial DNA were isolated from 42 prospectively accrued consecutive HNSCC tumors and paired normal oral mucosae. Microbiomic profiling was carried out by serially characterizing bacteria-specific 16S rRNA and taxa classified by the presence of specific polymorphisms in the 16S rDNA genes. Promoter methylation and microbial populations of each sample was determined. Microbiomic profiles were compared between HNSCC and matched normal mucosa, to specific promoter methylation in four genes (MDR1, IL8, RARB, TGFBR2) previously linked to HNSCC or inflammation, and to clinico-pathologic features. Results: Specific microbiomic profiles significantly associate with HNSCC over normal mucosae. While methylation of both MDR1 (p&lt;10-9) and IL8 (p&lt;0.02) genes significantly associate with HNSCC, only MDR1 methylation associates with specific microbiomic profiles in HNSCC over normal mucosae. Furthermore, MDR1 methylation correlates with regional nodal metastases in the context of two specific bacterial taxa, Enterobacteriaceae and Tenericutes. Additionally, microbial populations can separate tumors by tobacco status (p&lt;0.005), but not by alcohol status (p=0.37). Conclusions: Specific microbial populations may contribute to HNSCC pathogenesis, possibly by triggering inflammation and consequent aberrant DNA methylation. These associations could lead to better understanding of the pathogenesis and treatment of HNSCC, suggesting novel roles for demethylating agents and probiotic adjuncts particularly for patients with advanced or refractory disease.
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 4087. doi:1538-7445.AM2012-4087
Abstract 4088: Cotreatment with decitabine and paclitaxel is affected by the re-expression of drug-metabolising enzymes
Authors: Cosentino Laura , Masrour Nahal , Burns Julie , Fang Weishuo , Brown Robert , Burns Phil , Pors Klaus 
Published: August 2012

Abstract
The literature describes the role of DNA methylation in regulation of tumour suppressor genes, DNA repair genes, but not much attention has been paid to drug metabolising enzymes (DMEs). Some evidence has been reported and includes methylation of the promoter regions of CYP450 and ABC transporters. Cotreatment with decitabine (DAC) and paclitaxel (PAC) has been reported in several studies, but few of these have reported in a focused manner on the effect on DMEs. As a consequence, the major DMEs involved in the detoxification of PAC (namely ABCB1, CYP2C8 and CYP3A4) were investigated. The aldehyde dehydrogenase enzymes (ALDH1A1, ALDH2 and ALDH3A1) were also explored, as they have recently been shown to play a chemo-protective role against taxanes. Analysis of the CpG island methylation level indicated that all the above-mentioned DMEs were densely methylated and that treatment of MCF-7 cells with DAC for 24 h resulted in a decrease in methylation within the gene promoter region. Furthermore, correlation of decrease in DNA methylation with increase in mRNA level of ABCB1, CYP3A4, ALDH2 and ALDH3A1 was observed, but not for CYP2C8 and ALDH1A1. However, only the ABCB1 protein level was shown to significantly increase. Chemosensitivity of DAC combined with PAC was tested in MCF-7 cells: treatment with DAC for 24 h was followed by PAC exposure on days 4, 6 or 8. Evaluation of the cotreatment on cell survival demonstrated that the cytotoxic potential of PAC was reduced proportionally to the exposure time to DAC before PAC treatment, suggesting that ABCB1 protein confers chemo-protection on the cells. To investigate whether this resistance was applicable to other taxanes with proven efficacy against MDR-resistant cells, the preclinical agent Lx2-32c (aziditaxel) was evaluated. Lx2-32c also lost potency similar to PAC, indicating that ABCB1 is responsible for loss of activity of these two taxanes. The same experiments were also carried out in HeLa cells as they were shown to contain low level of DNA methylation of the above-mentioned DME genes including the ABCB1 gene. DAC treatment did not lead to significant reactivation at protein level and cotreatment of DAC and PAC produced a synergistic effect on cell killing. In conclusion, our data demonstrate that cotreatment of DAC and PAC can produce a synergistic effect, but that it is affected by the re-expression of DMEs. Our observations provide useful information for clinical evaluation of combination strategies comprising DAC and PAC, and chemotherapeutics in general that are affected by DMEs.
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 4088. doi:1538-7445.AM2012-4088
Abstract 4100: Aberrant methylation of the PTPRO gene in peripheral blood as a potential biomarker in esophageal squamous cell carcinoma patients
Authors: Zhang Hao , You Yanjie , Chen Yuping , Zheng Xiaoxuan , Meltzer Stephen J. 
Published: August 2012

Abstract
Purpose: Compared with tyrosine kinases, our understanding of protein-tyrosine phosphatases (PTPs) in cancer is limited, and further knowledge could provide new therapeutic targets and diagnostic markers. Inactivation of protein tyrosine phosphatase receptor-type O (PTPRO), a new member of the PTP family, by hypermethylation has been described in several forms of cancers. We evaluated PTPRO hypermethylation as a potential epigenetic biomarker in esophageal squamous cell carcinoma (ESCC). Experimental Design: In 36 primary ESCC tissue specimens and matched peripheral plasma and buffy coat samples, we determined the methylation status of PTPRO by performing methylation-specific PCR. Correlations with PTPRO methylation and clinicopathologic features were also examined. Results: PTPRO hypermethylation was observed in 27 (75%) of 36 primary tumors and correlated significantly with depth of invasion (T-stage, P = 0.013). Among matched peripheral blood samples from ESCC patients, 13 (36.1%) of 36 had detectable methylated PTPRO in plasma, and 15 (41.7%) of 36 had it in the buffy coat. No methylated PTPRO was observed in normal peripheral blood samples from 10 healthy individuals. In addition, promoter methylation correlated with loss of PTPRO mRNA expression, and demethylation by 5-aza-dC treatment led to gene reactivation in PTPRO-methylated and -silenced ESCC cell lines. Conclusions: This is the first report for detection of PTPRO as a non-invasive biomarker for solid tumors in peripheral blood. Our findings suggest that hypermethylated PTPRO occurs frequently in ESCC. Its detection in the peripheral blood of ESCC patients illustrates its potential clinical application as an epigenetic biomarker for noninvasive diagnosis and disease monitoring.
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 4100. doi:1538-7445.AM2012-4100
Abstract 4103: Hepatocellular carcinoma-specific isoforms of methylated DNA-binding protein 2 and their therapeutic and diagnostic potential
Authors: Machnes Ziv M. , Stefanska Barbara , Szyf Moshe 
Published: August 2012

Abstract
Liver cancer is the fifth most common cancer in the world. It is particularly prevalent in developing countries in Asia and Africa. In the US alone, it is estimated that 26,190 adults will be diagnosed with primary liver cancer this year, and 19,590 people will die of the disease. Hepatocellular carcinoma has no efficient cure, has a 5-year survival rate of 14% and is highly metastatic. In the last couple of decades, it has been established that many types of cancer involve major changes in the DNA methylation machinery and in turn, widespread yet highly specific changes in cytosine methylation. DNA methylation is a chemical modification on the DNA associated with gene inactivation, and in contrast to genetic mutation, is dynamic and reversible, making it a preferable target for therapeutics. Methylated-DNA Binding Proteins (MBD) have been shown to play a critical role in the progression and metastasis of cancers in general and specifically in hepatocellular carcinoma. We have identified two isoforms of the MBD2 protein (hcMBD2) that have not been previously reported in any somatic cells: these isoforms are totally silenced in normal liver cells and active in hepatocellular carcinoma. Specific inhibition of these isoforms of MBD2 in hepatocellular carcinoma (HePG2 cell line) has a dramatic effect on cell growth and cellular transformation, but no effect in normal cells, where the isoforms are not expressed. Knockdown experiments show dramatic reduction in cell invasiveness, reduced cell growth rate and increased cell death in HepG2 cells, while primary liver hepatocytes remain largely unaffected. A survey of several types of cancers and their surrounding tissue of origin shows the expression of hcMBD2 in several other types of cancer, such as breast cancer. These results position hcMBD as a promising candidate for cancer diagnostics and therapeutics.
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 4103. doi:1538-7445.AM2012-4103
Abstract 4144: Circulating microRNAs as specific biomarkers for breast cancer
Authors: Park In Hae , Lee Keun Seok , Kang Joo Hyun , Ro Jungsil 
Published: August 2012

Abstract
Background It has been reported that the cancer associated specific microRNAs were detected in blood. The objective of this study was to discover a panel of circulating microRNAs as potential ER+/HER2- breast cancer biomarkers. Methods We compared the levels of circulating microRNAs in blood samples from 11 ER+/HER2- advanced breast cancer patients with age-matched 5 control subjects by using microarray-based expression profiling, which was subsequently validated by real-time quantitative polymerase chain reaction (RT-qPCR). We found that 4 microRNAs (miR-1280, miR-1260, miR-1274b, miR-720) were up-regulated in blood from breast cancer patients (P&lt;0.05, constrained by at least two-fold expression change). We identified the levels of above 4 and additional three microRNAs (miR-21, miR-195, and let-7a) in 40 control subjects, 44 early breast cancer patients (EBC), and 22 metastatic breast cancer patients (MBC). The levels of miR-1280 and miR-1260 in blood were significantly different by the disease status (control&lt;EBC&lt;MBC) (Table 1). The level of let-7a was higher in cancer patients (P&lt;0.001), while there was no difference in the level of let-7a between patients with EBC and those with MBC (P=0.422). Using receiver operational curve (ROC) analysis, blood levels of miR-1280 could detect patients with breast cancer with 85% specificity and 81% sensitivity; while blood let-7a levels could discriminate cancer patients with 90% specificity and 95.2% sensitivity. Conclusions These findings suggest that blood microRNAs are differentially expressed in breast cancer patients, which can be used as potential biomarkers for breast cancer. Table 1. Mean expression levels (SD) of target microRNAs in blood from breast cancer patients compared with blood from healthy controls.

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 4144. doi:1538-7445.AM2012-4144
Abstract 4176: Activated NRAS mediates self-renewal capacity in AML
Authors: Sachs Zohar , Rathe Susan K. , Diaz-Flores Ernesto , Diers Miechaleen D. , Shannon Kevin , Largaespada David A. 
Published: August 2012

Abstract
NRAS mutations are found in 11-14% of AML (Schubbert et al. Nat Rev Cancer 2007, Bowen et al. Blood 2006), implicating NRAS signaling pathways as potential targets for clinical intervention. However, the specific effects of targeting these pathways on AML physiology are currently unclear. We employ a manipulatable murine model of AML to elucidate these phenomena for therapeutic applications. This model harbors a tetracycline repressible, activated NRAS (NRASG12V) transgene along with an Mll/AF9 transgene. Primary leukemia cells are then transplanted into SCID mice and, upon development of clinically evident leukemia, NRASG12V transgene expression is repressed with doxycycline. NRASG12V repression leads to apoptosis and disease remission (Kim et al. Blood 2009). To dissect the critical signaling networks directing remission, immunophenotypic markers, along with the phosphorylation status of critical signaling intermediates, were analyzed by flow cytometry after NRASG12V repression. This analysis revealed that NRAS withdrawal led to an enrichment of less differentiated Mac1/Gr1 negative cells indicating that, in addition to well-described effects on proliferation, NRAS affects leukemia differentiation status. Furthermore, we only found modifications in known NRAS signaling effectors in the less differentiated, Mac1 negative leukemia cells. Therefore, in addition to affecting the differentiation status of the leukemia, oncogene withdrawal leads to cell-type specific signaling alterations. We hypothesize that these signaling alterations mediate remission-induction by altering the self-renewal capacity of the leukemia at the gene expression level. Parallel RNA sequencing and gene expression microarrays were performed to address this hypothesis and revealed that the gene expression pattern of NRASG12V-expressing cells is enriched with hematopoietic self-renewal genes (Krivtsov et al. Nature 2006, Ivanova et al. Science 2002, Gene Set Enrichment Analysis per Subramanian et al. PNAS 2005). Withdrawal of the oncogene led to loss of this self-renewal gene expression program and an enrichment of genes expressed in terminally differentiated, mature cells. Furthermore, the NRASG12V-dependent gene expression program mimics the Mll/AF9-determined, Myb-mediated self-renewal program seen in a similar AML model (Zuber et al. Genes & Dev 2011). These data suggest that the Mll/AF9-mediated self-renewal program requires the continued expression of NRASG12Vand support a novel role for NRASG12V in maintaining the self-renewal capacity AML.
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 4176. doi:1538-7445.AM2012-4176
Abstract 418: Development and characterization of cancer stem cell model from mouse iPS cells
Authors: Chen Ling , Matsuda Shuichi , Kasai Tomonari , Sugii Yuh , Okada Masashi , Igarashi Koichi , Satoh Ayano , Kudoh Takayuki , Kudoh Takayuki , Fu Li , Seno Masaharu 
Published: August 2012

Abstract
The cancer stem cells in capable of continuous proliferation and self-renewal are proposed to play significant roles in oncogenesis, tumor growth, metastasis and cancer recurrence. Cancer stem cells are considered derived from normal stem cells affected by the tumor microenvironment although the mechanism of development is not clear yet. In 2007, Yamanaka's group succeeded in generating Nanog mouse induced pluripotent stem (iPS) cells, in which green fluorescent protein has been inserted into the 5′ untranslated region of the Nanog gene. Usually, iPS cells are considered to be induced into progenitor cells, which differentiate into various normal phenotypes depending on the normal niche. We hypothesized that cancer stem cells could be derived from Nanog mouse iPS cells in the conditioned culture medium of cancer cell lines, which is a mimic of carcinoma microenvironment. As a result, the cells exhibited a high tumorigenicity in vivo with a capacity of self-renewal and the expression of markers associated with stem cell properties and an undifferentiated state. The cells efficiently formed spheroids expressing green fluorescent protein in suspension culture, vasculogenic tubes in MatriGel in vitro and exhibited extensive angiogenesis in vivo, which was confirmed by magnetic resonance imaging and by histochemical analysis. Thus we concluded that a model of cancer stem cells was originally developed using mouse iPS cells and proposed the conditioned culture medium might perform as niche for producing cancer stem cells. It is worthwhile noticing that the mouse iPS cells co-cultured with cancer-derived cells did not form malignant tumors in vivo. This implies that cell-to-cell contact may have inhibitory effect on the conversion of mouse iPS cells into cancer stem cells. Furthermore, demonstration of the genetic alterations and the secreted factors in the tumor microenvironment which convert mouse iPS cells to cancer stem cells, and identification of potentially bona fide markers of cancer stem cells will help the development of novel anti-cancer therapies.
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 418. doi:1538-7445.AM2012-418
Abstract 4183: Overexpression of PTPN2 promotes lung cancer cell proliferation through ERK activation
Authors: Lin Sheng-Yi , Lai Yi-Hua , Wang Chi-Chung , Tsai Meng-Feng , Yu Sung-Liang , Chang Gee-Chen , Chen Jeremy J.W. 
Published: August 2012

Abstract
Lung cancer is the most common cause of cancer deaths in the world, and the incidence is increasing each year. Protein tyrosine phosphatases (PTPs) and their associated signaling pathways are crucial for the regulation of numerous cell functions including growth, motility, mitogenesis and metabolism. PTPN2, also known as TCPTP, is an intracellular protein tyrosine phosphatase, which is ubiquitously expressed. There are two splice variants of TCPTP in human cells, TC45 and TC48, which vary at their C-terminal ends. The TC48 isoform is present in the endoplasmic reticulum and also in the nuclear membrane. However, its role and function on human non-small cell lung cancers remain unknown. In this study, we induced ectopic expression of PTPN2 (TC48) in CL1-0 and H1299 cells to investigate its effect on cell migration, invasion, and colony formation. The interacting proteins of PTPN2 are identified by yeast two-hybrid assay. The results showed that PTPN2 inhibited lung cancer cell proliferation, anchorage-dependent and -independent growth, but not migration and invasion. Yeast two-hybrid assay revealed that PTPN2 interacted with CD74 (major histocompatibility complex class II invariant chain) and PRDX6 (Peroxiredoxin 6) which could promote cell proliferation in previous studies. We also found that overexpression of PTPN2 increased the phosphorylation of ERK. Moreover, activation of ERK was enhanced by co-expression of PTPN2 and CD74 or PRDX6. Taken together, we speculated that PTPN2 might modulate ERK activity through interaction with CD74 and PRDX6 and further promoted lung cancer cell proliferation.
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 4183. doi:1538-7445.AM2012-4183
Abstract 4186: An extensive microRNA-mediated network of RNA-RNA interactions regulates established oncogenic pathways in glioblastoma
Authors: Sumazin Pavel , Califano Andrea , sheng Chiu Hua , Yang Xuerui 
Published: August 2012

Abstract
By analyzing gene expression data in gliobastoma in combination with matched microRNA profiles, we have uncovered a post-transcriptional regulation layer of surprising magnitude, comprising over 248,000 microRNA -mediated interactions. These include ∼7,000 genes whose transcripts act as microRNA ‘sponges’ and 148 genes that act through alternative, non-sponge interactions. Biochemical analyses in cell lines confirmed that this network regulates established drivers of tumor initiation and subtype, including PTEN, PDGFRA, RB1, VEGFA, STAT3, and RUNX1, suggesting that these interactions mediate crosstalk between canonical oncogenic pathways. RNA silencing of 13 microRNA-mediated PTEN regulators, whose locus deletions are predictive of PTEN expression variability, was sufficient to downregulate PTEN in a 3′ UTR-dependent manner and to increase tumor-cell growth rates. Thus, this microRNA -mediated network provides a mechanistic, experimentally validated rationale for the loss of PTEN expression in a large number of glioma samples with an intact PTEN locus.
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 4186. doi:1538-7445.AM2012-4186
Abstract 4189: Excess c-Myc loads tissue-specific enhancers in tumor cells
Authors: Lin Charles , Rahl Peter B. , Loven Jakob , Kagey Michael H. , Burge Christopher B. , Young Richard A. 
Published: August 2012

Abstract
Excessive expression of c-Myc occurs frequently in human cancers, where high levels are associated with tumor aggression and poor clinical outcome. It is well established that the c-Myc protein forms a heterodimer with Max, binds to E-box sequences typically located near the core promoter elements of target genes involved in cellular proliferation, and alters expression of these genes. It is not yet clear, however, how altering the levels of c-Myc affects its activity across the genome to enhance the oncogenic state of cells. We show here that c-Myc occupies occupies enhancer elements only in tumor cells with elevated levels of c-Myc. The enhancers that are occupied are often tumor-specific and associated with the cell-of-origin of the tumor. These and additional results provide insights into a key mechanism by which c-Myc overexpression alters the transcriptional state of cancer cells to enforce their tumorigenic state and malignant potential.
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 4189. doi:1538-7445.AM2012-4189