bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of PPARγinHelicobacter pyloriInfection and Gastric Carcinogenesis
Authors: Lee Jong-Min , Kim Sung Soo , Cho Young-Seok
Published: August 2012

Peroxisome proliferator-activated receptorγ(PPARγ) is a nuclear receptor that is important in many physiological and pathological processes, such as lipid metabolism, insulin sensitivity, inflammation, cell proliferation, and carcinogenesis. Several studies have shown that PPARγplays an important role in gastric mucosal injury due toHelicobacter pylori(H. pylori). AsH. pyloriinfection is the main etiologic factor in chronic gastritis and gastric cancer, understanding of the potential roles of PPARγinH. pyloriinfection may lead to the development of a therapeutic target. In this paper, the authors discuss the current knowledge on the role of PPARγinH. pyloriinfection and its related gastric carcinogenesis.
Existence of Solutions for Nonlinear Impulsive Fractional Differential Equations of Order α ∈ (2, 3] with Nonlocal Boundary Conditions
Authors: Zhang Lihong , Wang Guotao , Song Guangxing
Published: August 2012

We investigate the existence and uniqueness of solutions to the nonlocal boundary value problem for nonlinear impulsive fractional differential equations of order α ∈ (2, 3]. By using some well‐known fixed point theorems, sufficient conditions for the existence of solutions are established. Some examples are presented to illustrate the main results.
Electronically Tunable Sinusoidal Oscillator Circuit
Authors: Maheshwari Sudhanshu , Verma Rishabh
Published: August 2012

This paper presents a novel electronically tunable third-order sinusoidal oscillator synthesized from a simple topology, employing current-mode blocks. The circuit is realized using the active element: Current Controlled Conveyors (CCCIIs) and grounded passive components. The new circuit enjoys the advantages of noninteractive electronically tunable frequency of oscillation, use of grounded passive components, and the simultaneous availability of three sinusoidal voltage outputs. Bias current generation scheme is given for the active elements used. The circuit exhibits good high frequency performance. Nonideal and parasitic study has also been carried out. Wide range frequency tuning is shown with the bias current. The proposed theory is verified through extensive PSPICE simulations using 0.25 μm CMOS process parameters.
Autoimmune Progesterone Dermatitis: A Case Report
Authors: George Rachana , Badawy Shawky Z. A.
Published: August 2012

Background. Autoimmune progesterone dermatitis is a rare cyclic premenstrual allergic reaction to progesterone produced during the luteal phase of a woman's menstrual cycle. Patients present with a variety of conditions including erythema multiforme, eczema, urticaria, angioedema, and progesterone-induced anaphylaxis.Case. Thirty-eight-year-old woman G2P2002 presents with erythema multiforme and urticarial rash one week prior to her menses starting one year after menarche. She was treated with oral contraceptive pills and the symptoms resolved.Conclusion. This is a typical case of progesterone autoimmunity. The diagnosis is based on cyclic nature of the dermatitis. This differentiates the condition from other allergies or systemic diseases with skin manifestations. Inhibition of ovulation in such cases results in decrease in progesterone secretion and prevention of symptoms.
Benign Intracranial Hypertension: A Diagnostic Dilemma
Authors: Shaw Gary Y. , Million Stephanie K.
Published: August 2012

Benign intracranial hypertension (BIH) (also known as pseudotumor cerebri and empty sella syndrome) remains a diagnostic challenge to most physicians. The modified Dandy criteria consist of, the classic findings of headache, pulsatile tinnitus, papilledema, and elevated cerebrospinal fluid (CSF) pressure, however, these are rarely collectively present in any one patient. Furthermore, these findings can wax and wane over time. Due to the nature of this disease, both signs and symptoms may be intermittent, making definitive diagnosis difficult. Newer imaging studies, particularly the magnetic resonance venogram (MRV) along with a constellation of correlative findings and associated diseases have given new impetus in the diagnosis, treatment, and pathophysiology of this disease. This has led the authors to offer modifications to the classic Dandy criteria. This report presents three representative cases of BIH highlighting many of the newer advances in both diagnosis and treatment of this perplexing disorder.
Hemodialysis Key Features Mining and Patients Clustering Technologies
Authors: Lu Tzu-Chuen , Tseng Chun-Ya
Published: August 2012

The kidneys are very vital organs. Failing kidneys lose their ability to filter out waste products, resulting in kidney disease. To extend or save the lives of patients with impaired kidney function, kidney replacement is typically utilized, such as hemodialysis. This work uses an entropy function to identify key features related to hemodialysis. By identifying these key features, one can determine whether a patient requires hemodialysis. This work uses these key features as dimensions in cluster analysis. The key features can effectively determine whether a patient requires hemodialysis. The proposed data mining scheme finds association rules of each cluster. Hidden rules for causing any kidney disease can therefore be identified. The contributions and key points of this paper are as follows. (1) This paper finds some key features that can be used to predict the patient who may has high probability to perform hemodialysis. (2) The proposed scheme applies k-means clustering algorithm with the key features to category the patients. (3) A data mining technique is used to find the association rules from each cluster. (4) The mined rules can be used to determine whether a patient requires hemodialysis.
Intraoral Laser Welding (ILW) in Implant Prosthetic Dentistry: Case Report
Authors: Fornaini Carlo , Merigo Elisabetta , Cernavin Igor , Lòpez de Castro Gonzalo , Vescovi Paolo
Published: August 2012

The aim of this clinical study was to describe the possibility of using the Nd:YAG laser device utilized in the dental offices to weld metals intraorally. The authors, before applying this technique “in vivo” on human subjects, tested the “in vitro” metal welding efficacy of dental Nd:YAG device firstly by interferometry, SEM, and EDS and subsequently by thermal camera and thermocouples in order to record temperature changes during the welding process on bovine jaws. Four implants were inserted in the edentulous maxillary arch of a 67 years old male patient. Immediately after that, a bar previously made by the dental technician was intraorally welded to the abutments by Nd:YAG laser (Fidelis Plus III, Fotona, Slovenia) with these parameters: 9.90 mJ, 1 Hz, 15 msec, 0.6 mm spot. Then the prosthesis was connected to the bar with four OT Caps. This clinical study, even if preliminary, suggests that laser welding technique may be intraorally used without side effects.
Unambiguous Multipath Mitigation Technique for BOC(n,n) and MBOC-Modulated GNSS Signals
Authors: Rouabah Khaled , Flissi Mustapha , Attia Salim , Chikouche Djamel
Published: August 2012

We propose an efficient scheme for side peaks cancelation and multipath (MP) mitigation in binary offset carrier (n,n) (BOC(n,n)) and multiplexed BOC (MBOC) modulated signals. The proposed scheme reduces significantly the band of variation of MP errors in global navigation satellite system (GNSS). It consists of two versions. The first one is based on the use of maximum likelihood estimator (MLE) of MP signals and reference correlation functions (CFs) like that of pseudorandom noise (PRN) code without BOC subcarrier. In the second version, the former (MLE) is used with the reference BOC(n,n) or MBOC CFs. Unlike traditional BOC(n,n) and MBOC, that have CFs containing multiple peaks leading to potential tracking ambiguities, our proposed scheme does not contain any side peaks. In addition, all the MP signals with medium and long delays have no effect on the estimation of the pseudorange. On the other hand, all the methods proposed for mitigating MP in no-BOC scheme are practical for our scheme due to its CF which is similar to that of the PRN code. The computer simulation results show that the proposed scheme has superior performances in the reduction of the errors produced in the process of the delay estimation of line of sight (LOS) and caused by MP propagation. In fact, the performances of the proposed scheme are better with regard to that of the traditional BOC(n,n) and MBOC. Moreover, in the presence of noise, our proposed scheme keeps better performances than the common side peaks cancelation methods.
SDNN/RMSSD as a Surrogate for LF/HF: A Revised Investigation
Authors: Wang Hui-Min , Huang Sheng-Chieh
Published: August 2012

Thousands of papers involved in heart rate variability (HRV). However, little was known about one important measure of HRV, the root mean square of successive heartbeat interval differences (RMSSDs). Another fundamental measure SDNN indicates standard deviation of normal to normal R-R intervals, where R is the peak of a QRS complex (heartbeat). Compared with SDNN, RMSSD is a short-term variation of heart rate. Through a time-frequency transformation, the ratio of low- and high-frequency power LF/HF represents the sympatho-vagal balance of the autonomic nervous system (ANS). Some research claimed that SDNN/RMSSD was a good surrogate for LF/HF. However, only two special cases supported this hypothesis in the literature survey. The first happened in resting supine state and the other was a group of prefrontal cortex patients. Both of their Pearson correlation coefficients reached 0.90, a reasonable criterion. In our study, a 6-week experiment was performed with 32 healthy young Asian males. The Pearson correlation coefficients had a normal distribution with average values smaller than 0.6 for 3 and 5-minute epochs, respectively. Our findings suggest this surrogate aspect could remain as a hypothesis.
Associations between Intake of Folate, Methionine, and Vitamins B-12, B-6 and Prostate Cancer Risk in American Veterans
Authors: Vidal Adriana C. , Grant Delores J. , Williams Christina D. , Masko Elizabeth , Allott Emma H. , Shuler Kathryn , McPhail Megan , Gaines Alexis , Calloway Elizabeth , Gerber Leah , Chi Jen-Tsan , Freedland Stephen J. , Hoyo Cathrine
Published: August 2012

Prostate cancer (PC) is the second leading cause of cancer death in men. Recent reports suggest that excess of nutrients involved in the one-carbon metabolism pathway increases PC risk; however, empirical data are lacking. Veteran American men (272 controls and 144 PC cases) who attended the Durham Veteran American Medical Center between 2004–2009 were enrolled into a case-control study. Intake of folate, vitamin B12, B6, and methionine were measured using a food frequency questionnaire. Regression models were used to evaluate the association among one-carbon cycle nutrients,MTHFRgenetic variants, and prostate cancer. Higher dietary methionine intake was associated with PC risk (OR = 2.1; 95%CI 1.1–3.9) The risk was most pronounced in men with Gleason sum <7 (OR = 2.75; 95%CI 1.32– 5.73). The association of higher methionine intake and PC risk was only apparent in men who carried at least oneMTHFRA1298C allele (OR=6.7; 95%CI = 1.6–27.8), compared toMTHFRA1298A noncarrier men (OR=0.9; 95%CI = 0.24–3.92) (p-interaction=0.045). There was no evidence for associations between B vitamins (folate, B12, and B6) and PC risk. Our results suggest that carrying theMTHFRA1298C variants modifies the association between high methionine intake and PC risk. Larger studies are required to validate these findings.
Soluble CD200 Is Critical to Engraft Chronic Lymphocytic Leukemia Cells in Immunocompromised Mice
Authors: Wong Karrie K. , Brenneman Fred , Chesney Alden , Spaner David E. , Gorczynski Reginald M.
Published: August 2012

CD200 is a transmembrane molecule with an important immunoregulatory role that is overexpressed on most chronic lymphocytic leukemia (CLL) cells. In this study, we characterized a previously unknown soluble form of this molecule in human plasma termed sCD200. Levels of sCD200 were elevated in the plasma of patients with CLL as compared with healthy controls, and there was a significant correlation with CLL disease stage. Infusion of sCD200hi CLL plasma into severely immunocompromised NOD.SCIDγcnull (NSG) mice enhanced the engraftment of CLL splenocytes as compared with mice receiving sCD200lo normal plasma. CLL cells were detected in both the spleen and peritoneal cavity of animals for up to 75 days. Engraftment of CLL cells did not occur after infusion of CLL plasma depleted of sCD200 and was abolished in mice treated with anti-CD200 or OKT3 monoclonal antibody (mAb), suggesting a role for both sCD200 and T cells in CLL engraftment. Notably, anti-CD200 mAb was as effective as rituximab in eliminating engrafted CLL cells when administered 21 days after engraftment. Taken together, our findings point to sCD200 as a novel prognostic marker and therapeutic target for CLL. Furthermore, the humanized mouse model described here may prove valuable to preclinically assess new treatment regimens for CLL. Cancer Res; 72(19); 4931–43. ©2012 AACR.
Abstract 1002: Induced dependency on amino acid metabolism in proliferating cancer cells upon PKM2 activation
Authors: Kung Charles , Jin Shengfang , Hixon Jeff , Gross Stefan , Gao Yi , Cheng Fang , Wang Xiling , Wang Shaohui , Salituro Francesco , Saunders Jeff , Driggers Ed , Marks Kevin , Woo Hin Koon , Murray Stuart , Choe Sung , Yang Hua , Yen Katherine , Su Michael , Dang Lenny
Published: August 2012

It is well recognized that proliferating tumor cells invariably utilize aerobic glycolysis to support their high metabolic demands. Recent studies have further elucidated the paradoxical observation that this increase in glycolysis in proliferating tumor cells is often coupled with a molecular switch from the constitutively high activity PKM1 isoform to the modulated lower activity PKM2 isoform1,2, effectively constraining lower glycolysis at the last pyruvate kinase step. Here, we report an unanticipated link between glucose metabolism and amino-acid metabolic pathways in cancer cells. We characterized the biochemical and cellular effects of a small-molecule allosteric activator of the M2 isoform of pyruvate kinase (AGX-257) in various cancer cell types. We demonstrate that activation of PKM2 results in a metabolic rewiring of specific cancer cells that results in a profound dependency on the presence of the normally non-essential amino acid serine for continued cell proliferation. The induced serine auxotrophy by PKM2 activation is concomitant with reduced flux through the endogenous serine biosynthetic pathway and increased levels of high affinity serine transporters. PKM2 activators, possibly in combination with agents that modulate the cellular and extracellular serine pools, could form the basis for a new approach toward developing therapy for treating cancer. References: 1 Christofk, H. R. et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230-233 (2008). 2 Clower, C. V. et al. The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proc Natl Acad Sci U S A 107, 1894-1899 (2010).

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 1002. doi:1538-7445.AM2012-1002
Abstract 1024: Mural cell transdifferentiation of glioblastoma stem-like cells drives vasculogenic mimicry in glioblastoma development
Authors: Shao Rong , Scully Steve , Francescone Ralph , Faibish Michael , Bentley Brooke , Taylor Sherry L. , Oh Dennis , Schapiro Robert , Moral Luis , Yan Wei
Published: August 2012

Glioblastomas (GBM) are extremely aggressive and have the poorest prognosis among brain tumors. These tumors display extensive microvasculature that presumably originates from endothelial cell angiogenesis. Indeed, many anti-angiogenic therapies have been accepted for glioblastoma treatment based on this premise. Recent evidence has shown that glioblastoma stem-like cells (GSCs) can differentiate into endothelial cells that participate in angiogenesis (Ricci-Vitiani L et al., Nature 2010;468:824-29, Wang et al., Nature 2010;468:829-33, & Soda et al., PNAS 2011; 108:4274-80). However, it remains to be clarified if these GSC-derived endothelial cells make a significant contribution to tumor vasculature. Here, we surveyed eleven GBM cases and found that glioblastomas consisted of 34.1% of endothelial cell-associated vasculature, while 59.7% of microvasculature arose from mural-like tumor cells that co-express mural cell markers smooth muscle alpha actin and platelet-derived growth factor receptor, and VEGF receptor 2 (Flk-1), but not CD31, CD34 or VE-cadherin. This pattern of vascularization indicates an alternative microvascular circulation known as vasculogenic mimicry (VM). GSCs derived from patients with GBM displayed the multipotency of neuronal stem cells capable of transdifferentiation into mural-like tumor cells that promoted VM. GSCs developed vigorous mural cell-associated vascular channels but few endothelial cell vessels in orthotopic brain tumor models. Furthermore, the development of these tumor cell-associated channels was dependent on expression of VEGF receptor 2 (Flk-1). Suppression of Flk-1 activity and gene expression by a variety of different inhibitory approaches abrogated GSC transdifferentiation and vascularization in vitro, and inhibited VM in xenografted tumor models in vivo. Collectively, this study establishes a pivotal role for transdifferentiation of GSCs in the development of VM, which contributes to an aggressive phenotype of GBM, and points to Flk-1 as a potential target for therapeutic intervention.

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 1024. doi:1538-7445.AM2012-1024
Abstract 103: DCPS as a cutaneous squamous cell carcinoma susceptibility gene
Authors: Gray Kelsey M. , Dworkin Amy M. , Fleming Jessica L. , Toland Amanda E.
Published: August 2012

DCPS is a candidate cutaneous squamous cell carcinoma (SCC) susceptibility gene as determined by allelic imbalance mapping of over 400 matched SCC and normal DNA samples. DCPS is one of three genes located in a region of 11q24 showing strong evidence of preferential allelic loss. Consistently, by immunohistochemistry it shows no protein expression in 23% of SCCs and decreased expression in 30% of SCCs. There are high levels of protein expression in all of the normal skin tissues assessed. DCPS, a decapping scavenger enzyme, impacts aspects of mRNA metabolism, such as pre-mRNA splicing and decay. The hypothesis driving this research is that DCPS acts as a tumor suppressor and that in humans there are alleles conferring greater resistance to tumors, which are selectively lost during tumorigenesis. To test whether DCPS acts as a tumor suppressor, we studied functional effects of increasing and decreasing expression of DcpS in a mouse keratinocyte cell line. Pre-mRNA splicing was examined by quantitative assessment of different splice forms of mini-gene transcripts between low, endogenous, and overexpression cell lines. Preliminary data suggest that first intron splicing occurs more efficiently in DcpS overexpression cell lines and that there is no change in second intron splicing in DcpS overexpression cell lines. In stable DcpS knockdown cell lines, no differences were observed in first or second intron splicing. Differences in mRNA stability were assessed between the three levels of expression by mRNA stability assays. Preliminary data suggest that DcpS knockdown cell lines have more stable mRNA of the two tested transcripts than endogenous and overexpression cell lines. By MTT assays to measure proliferation, DcpS knockdown lines exhibited more growth than endogenous and overexpression lines between 24 and 48 hours, but there were no differences at later time points. Future studies will examine apoptosis, migration, and cell cycle parameters in these cell lines. This research has the potential to identify a new mechanism of cancer susceptibility involving RNA splicing and stability, improve cancer risk screening, and identify therapeutic and preventative targets.

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 103. doi:1538-7445.AM2012-103
Abstract 1031: Estrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy
Authors: Anderson Garnet L. , Chlebowski Rowan T. , Aragaki Aaron K. , Kuller Lewis , Manson JoAnn , Gass Margery , Bluhm Elizabeth , Connelly Stephanie , Hubbell F Allan , Lane Dorothy , Martin Lisa , Ockene Judith , Rohan Tom , Schenken Robert , Wactawski-Wende Jean
Published: August 2012

Background: In contrast to the predominance of observational studies, in the Women's Health Initiative (WHI) trial postmenopausal women assigned to estrogen alone had a lower risk of invasive breast cancer than did those assigned placebo (LaCroix JAMA 2011;305:1305-14). Influence of estrogen use on breast cancer mortality has not been previously reported. Methods: We conducted extended follow-up of the WHI randomized, placebo-controlled trial evaluating conjugated equine estrogen (0.625 mg/d) in 10739 postmenopausal women aged 50-79 years with prior hysterectomy, to determine long term effects of estrogen use on non-invasive and invasive breast cancer incidence, invasive breast cancer characteristics and breast cancer mortality. Comprehensive breast cancer risk assessment was conducted at entry. Screening mammography and clinical breast examinations were performed at entry and yearly thereafter. Breast cancers were confirmed by medical record and pathology report review by centrally-trained physician adjudicators blinded to randomization assignment. Analyses were by intention-to-treat. The study is registered with clinical trials CT.govNCT00000611. Findings: After a mean 10.7 years of follow-up, conjugated equine estrogen use for a median of 5.9 years (range <1 to 10 years) was associated with lower invasive breast cancer incidence compared to placebo (151 vs. 199 breast cancers; annualized rates, 0.27% vs. 0.35%; hazard ratio [HR] 0.77; 95% confidence interval [CI], 0.62 to 0.95, P=0.02) with no difference between intervention-phase and post-intervention-phase effects (P=0.76). Sensitivity analyses adjusting for non-adherence yielded a somewhat stronger association (HR 0.68; 95% CI 0.49-0.95). Mammogram screening exams were comparable between randomization groups throughout. In the estrogen alone group fewer women died from breast cancer (6 vs. 16 deaths; annualized rates 0.009% vs. 0.024%; HR 0.37; 95% CI, 0.13 to 0.91, P=0.03) and fewer women died from all causes after a breast cancer diagnosis (30 vs. 50 deaths; annualized rate 0.046% vs. 0.076%; HR 0.62; 95% CI, 0.39 to 0.97, P=0.04).Interpretation: Use of conjugated equine estrogen for a median of 5.9 years in postmenopausal women reduced the incidence of invasive breast cancer and reduced breast cancer mortality.

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 1031. doi:1538-7445.AM2012-1031
Abstract 1036: Antiproliferative effects of DNA methyltransferase 3B depletion are not associated with DNA demethylation
Authors: Stresemann Carlo , Hagemann Sabine , Mund Cora , Kuck Dirk , Prinz Florian , Brueckner Bodo , Mumberg Dominik , Lyko Frank , Sommer Anette
Published: August 2012

Silencing of genes by DNA hypermethylation contributes to cancer progression and has been shown to occur with increased frequency at specific genomic loci. However, the precise mechanisms underlying the establishment and maintenance of aberrant methylation marks are still elusive. The de novo DNA methyltransferase 3B (DNMT3B) has been suggested to play an important role in the generation of cancer-specific methylation patterns. Previous studies have shown that a reduction of DNMT3B protein levels induces antiproliferative effects in cancer cells that were attributed to the demethylation and reactivation of tumor suppressor genes. However, methylation changes after depletion of DNMT3B protein have not been analyzed in detail yet. We performed short- and long-term RNAi knockdown experiments to reduce DNMT3B protein levels in colon cancer cell lines and analyzed genome-wide DNA methylation changes on HumanMethylation27 and HumanMethylation450 Illumina bead chips. Our results confirm that depletion of DNMT3B specifically reduced the proliferation rate of DNMT3B-overexpressing colon cancer cell lines. All colon cancer cell lines tested contain a mutant K-Ras and we conclude that K-Ras status - in contrast to DNMT3B protein overexpression levels - does not impact on anti-proliferative responses after DNMT3B knockdown. However, in contrast to the dramatic alterations of DNA methylation observed in DNMT1; DNMT3B double knockout cells (DKO), genome-scale DNA methylation profiling failed to reveal methylation changes at putative DNMT3B target genes, even in the complete absence of DNMT3B. These results show that DNMT3B is dispensable for the maintenance of aberrant DNA methylation patterns in human colon cancer cells and they have important implications for the development of targeted DNA methyltransferase inhibitors as epigenetic cancer drugs.

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 1036. doi:1538-7445.AM2012-1036
Abstract 1042: Down-regulation of UTX contributes to lung cancer progression
Authors: Gilbert Jennifer L. , Maresh Erin , Mah Vei , Gower Adam , Goodglick Lee , Gomperts Brigitte
Published: August 2012

Smoking, the main risk factor leading to lung cancer, causes both genetic and epigenetic changes resulting in aberrant gene expression. UTX is a histone demethylase that has been implicated in many cancers and has been shown to regulate both cell cycle and differentiation genes. However, the role of UTX has not been elucidated in lung cancer. We hypothesized that smoking injury leads to a down regulation in UTX expression. This results in an inability of repairing airway epithelial cells to differentiate, resulting in premalignant lesions and ultimately invasive lung cancer. Examination of published lung cancer data sets revealed a down-regulation of Utx gene expression in patients with poorer prognosis, tumor grade, tumor recurrence and in smokers. To assess the involvement of UTX protein expression in lung cancer we stained a lung cancer tissue microarray and found a significant correlation between down-regulation of UTX protein expression and poorer prognosis in metastasis (p=0.0005) and smokers (p= 0.02). UTX expression was found to be significantly lower in squamous cell carcinoma compared to adenocarcinoma, linking down-regulation of UTX in a diseased caused solely by smoking. To test if smoking directly affects Utx expression we treated mouse airway epithelial cells at air-liquid interface with media infused with cigarette smoke for 9 days. After this short time point of acute smoke exposure there was a significant down regulation of Utx gene expression (p=0.03). We carried out UTX overexpression studies to assess the role of UTX in lung cancer cells lines and found up-regulation of UTX results in up-regulation of genes involved in lung development and differentiation, including Nrf2, FoxJ2 and FZD4. Our finding support the hypothesis that smoking causes a reduction in UTX that affects the proliferation and differentiation of airway epithelial cells contributing to lung cancer progression. Re-activation of UTX therefore may be a potential therapeutic target for the prevention of lung cancer progression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1042. doi:1538-7445.AM2012-1042
Abstract 105: Characterizing the exomic profile of MSI colorectal cancer
Authors: Kondelin Johanna K. , Gylfe Alexandra , Tuupanen Sari , Ristolainen Heikki , Katainen Riku , Tanskanen Tomas , Jarvinen Heikki , Mecklin Jukka-Pekka , Vahteristo Pia , Aaltonen Lauri A.
Published: August 2012

Colorectal cancer (CRC) is the third most common cancer in Western countries. Of all CRC tumors, 15% display microsatellite instability (MSI) caused by defective cellular mismatch repair. Cells displaying MSI accumulate a high number of mutations throughout the genome, especially in short repeat areas called microsatellites. Also point mutations occur in excess in these tumors. Sporadic MSI CRCs are caused by biallelic inactivation of the MLH1 gene, usually by promoter hypermethylation. The MSI tumors have a genetic and clinopathological profile that significantly differs from microsatellite stable (MSS) CRC. Overall, MSI tumors have been studied much less than MSS tumors, mainly due to the high number of mutations in MSI tumors, which makes data analysis and identification of relevant mutations challenging. To date, several genes have been proposed as MSI target genes based on targeted searches of their mutation frequency in microsatellite areas. A few systematic sequencing studies on colorectal cancer have been published, but none of them focus on MSI tumors, making this study first of a kind. In this study, the exome of 25 sporadic MSI tumors and corresponding normal samples are sequenced to identify changes of somatic origin. Bioinformatical tools are used to rank the genes and identify true driver genes based on clustering of missense mutations. The most interesting findings will be validated by direct Sanger sequencing. In addition to corresponding normal specimens, samples from healthy Finnish blood donors as well as data from other ongoing sequencing projects and sequence databases are used as controls to exclude polymorphisms. The data of all the 25 tumors has been analyzed and validation of the potential clusters of missense mutations is in process. The pathological nature of the changes will be confirmed by possible functional studies. This way we wish to identify new driver genes in MSI CRC. A detailed understanding of the molecular background of this tumor type is important for the development of more efficient screening methods and personalized treatments. By characterizing changes typical for different MSI tumors, we wish to identify subtypes within the MSI tumor category that could be exploited in treatment. Such understanding of MSI tumors could improve the treatment and hence prognosis of patients diagnosed with MSI type CRC.

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 105. doi:1538-7445.AM2012-105
Abstract 1051: UHRF1 is highly expressed in childhood liver tumors and interacts with DNMT1 and USP7 to guide tumor suppressor gene silencing
Authors: Trippel Franziska , Joppien Saskia , Felle Max , Längst Gernot , Kappler Roland
Published: August 2012

Embryonal tumors are thought to arise from immature tissue during intrauterine or early postnatal development and display apart from specific genetic changes in developmental signaling pathways a relatively normal genomic background. Instead, epigenetic events appear to be involved in key steps of the earliest phases of neoplastic evolution. However, the mechanistic basis responsible for epigenetic alterations in these early-onset tumors and the role of the DNA methylation machinery therein is still not known. In order to define the impact of epigenetic factors in embryonal tumor development we made use of hepatoblastoma (HB), the most common liver tumor of early childhood, as a model for a pristine and genetically “clean” tumor. In this study we identified ubiquitin-like with PHD and ring finger domains 1 (UHRF1) to be highly overexpressed in HB tumors compared to normal liver tissue, a protein known to preferentially bind to hemi-methylated DNA. Using immunoprecipitation, we furthermore show that UHRF1 binds in concert with DNA methyltransferase 1 (DNMT1) and ubiquitin specific peptidase 7 (USP7) as a trimeric complex to promoter regions of tumor suppressor genes relevant in HB, such as hedgehog interacting protein (HHIP), insulin-like growth factor binding protein 3 (IGFBP3), and secreted frizzled-related protein 1 (SFRP1). These genes are epigenetically silenced in HB, as evidenced by heavy DNA methylation and enrichment of the repressive H4K27me3 chromatin mark. Interestingly, knockdown of UHRF1 expression via RNA interference resulted in promoter demethylation and a shift towards the active H3K4me2 chromatin mark of the three tumor suppressor genes. Altogether, these data suggest that aberrant expression of the epigenetic regulator UHRF1 and excessive binding of a trimeric complex consisting of UHRF1/DNMT1/USP7 results in silencing of tumor suppressor genes in HB and may display an important mechanism in the initial phases of embryonal tumorigenesis in general.

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 1051. doi:1538-7445.AM2012-1051
Abstract 1057: Mutation of EZH2 A677 in human B-cell lymphoma promotes hyper-trimethylation of H3K27
Authors: McCabe Michael T. , Graves Alan P. , Ganji Gopinath , Ott Heidi , Diaz Elsie , Halsey Wendy S. , Jiang Yong , Smitheman Kimberly N. , Pappalardi Melissa B. , Allen Kimberly E. , Chen Stephanie , Della-Pietra Anthony , Dul Edward , Hughes Ashley M. , Thrall Sara H. , Tummino Peter J. , Kruger Ryan G. , Brandt Martin , Schwartz Benjamin , Verma Sharad K. , Creasy Caretha L.
Published: August 2012

Trimethylation of histone H3 on lysine 27 (H3K27me3) is a repressive post-translational modification mediated by the histone methyltransferase EZH2. EZH2 is a component of the Polycomb Repressive Complex 2 (PRC2) and its expression and catalytic activity are dysregulated in cancers. While EZH2 may be over-expressed as a result of multiple mechanisms in tumors, only somatic mutation of the EZH2 Y641 residue has thus far been reported to alter its substrate preference and enhance its catalytic efficiency to generate H3K27me3. Herein, we report mutation of the A677 residue of EZH2 to a glycine (A677G) in a lymphoma cell line with aberrantly elevated H3K27me3 levels. Additional EZH2 sequence analysis in 41 primary lymphoma specimens identified another occurrence of this mutation. Biochemical evaluation of recombinant EZH2 complexes revealed that A677G EZH2 possesses catalytic activity with substrate specificity that is novel and distinct from those of wild-type and Y641 mutants. Whereas wild-type EZH2 displayed a preference for substrates with less methylation (i.e. H3K27me0>me1>me2), the Y641 mutants exhibited greatly decreased activity with H3K27me0 and increased activity with H3K27me2. The A677G EZH2, on the other hand, exhibited nearly equal efficiency for all three substrates. A677G EZH2, but not wild-type EZH2, was shown to be capable of significantly increasing global H3K27me3 when transiently expressed in an EZH2 wild-type cancer cell line. Finally, structural modeling suggests that the mutation results in a larger lysine tunnel capable of accommodating the H3K27me2 substrate while retaining the ability to properly orient H3K27me0 and H3K27me1 with the Y641 residue. In addition, functional and biochemical analyses are performed with reversible SAM-competitive EZH2 inhibitors. Therefore, this mutation appears to contribute to the aberrant epigenetic profile observed in certain lymphomas.

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 1057. doi:1538-7445.AM2012-1057
Abstract 1058: Mutations in isocitrate dehydrogenase 1 and 2 are associated with DNA hypermethylation in intrahepatic cholangiocarcinomas
Authors: Wang Pu , Dong Qiong-Zhu , Zhang Chong , Kuan Pei-Fen , Liu Yufeng , Jeck William R. , Andersen Jesper B. , Auman James Todd , Hoskins Janelle M. , Kim Jin Woo , Cibulskis Kristian , Getz Gad , Hunt Heike V. , Thorgeirsson Snorri S. , Roberts Lewis R. , Ye Dan , Guan Kun-Liang , Xiong Yue , Qin Lun-Xiu , Chiang Derek Y.
Published: August 2012

Cholangiocarcinomas are rare but aggressive cancers, with an increasing incidence and a dismal 5-year survival rate of less than 5%. Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in ∼70% of gliomas, ∼20% of myeloid leukemias, ∼56% of chondrosarcomas, and ∼10% of melanomas. We discovered IDH1 and IDH2 mutations in 29 of 305 (9%) intrahepatic cholangiocarcinomas. Tumors with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine and higher 5-methylcytosine levels, as well as increased dimethylation of histone H3K79. Mutations in IDH1 or IDH2 were independently associated with longer time to recurrence of cholangiocarcinoma in multivariate analysis (p = 0.046). We identified 2,267 genes that were significantly hypermethylated in tumors with mutations in IDH1 or IDH2. Hypermethylated CpG sites were significantly enriched in CpG shores and in the 1500 bp upstream of annotated transcription start sites, suggesting a global regulation of transcriptional potential. Gene expression profiling of 7 IDH1/2-mutant and 20 IDH1/2-wildtype tumors revealed increased expression of citric acid cycle and oxidative phosphorylation enzymes, as well as decreased expression of cytoskeleton organization genes. Integrated analyses of DNA methylation and gene expression identified interleukin-6 and several of its downstream targets as candidates for silencing by DNA methylation. Conclusions: Cholangiocarcinomas with mutations in IDH1 or IDH2 represent a molecular subclass with distinct signaling pathway alterations.

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 1058. doi:1538-7445.AM2012-1058
Abstract 106: Chromosomal instability in BRAF mutant, microsatellite stable colorectal cancers
Authors: Bond Catherine E. , Umapathy Aarti , Buttenshaw Ron L. , Wockner Leesa , Leggett Barbara A. , Whitehall Vicki LJ
Published: August 2012

BRAF mutant colorectal cancers can be stratified according to the presence of microsatellite instability (MSI). MSI cancers with a BRAF mutation are associated with an excellent patient prognosis. By contrast, in microsatellite stable (MSS) cancers, a BRAF mutation confers a very poor patient prognosis. The causes of such a detrimental outcome are yet to be thoroughly determined. We have previously reported that BRAF mutant, MSS cancers (BRAFmut/MSS) have a significantly higher rate of p53 mutation and present at more advanced stages than MSI cancers. Frequencies of these features in the BRAFmut/MSS cancers are similar to those observed in BRAF wild type, MSS cancers (BRAFwt/MSS). Chromosomal instability (CIN) is a dominant feature of BRAFwt/MSS cancers, whilst MSI cancers are considered to be diploid. In MSS cancers, CIN has been associated with a worse prognosis. We therefore hypothesised that CIN would be common in BRAF mutant/MSS cancers. BRAFmut/MSS (n=60), and BRAFwt/MSS cancers (n=90) were investigated for CIN using Loss of Heterozygosity (LOH) analysis over 12 loci encompassing chromosomal regions 5q, 8p, 17p and 18q. CIN was assigned if at least 1 marker was positive for LOH, and a cancer was reported as showing no loss if at least 5 markers were informative and none demonstrated LOH. CIN was frequently found in BRAFmut/MSS cancers (41/57, 72%), and this rate was comparable to that observed in BRAFwt/MSS cancers (74/90, 82%). The greatest rate of CIN in BRAFmut/MSS cancers occurred at 8p (26/44, 59%), and the least at 5q (19/49, 39%). BRAFwt/MSS cancers showed most CIN at 17p (43/65, 66.2%), and the least at 5q (43/80, 53.8%). Within the BRAFmut/MSS cancer subgroup, CIN was highly correlated with the CpG Island Methylator Phenotype (17/23, 74%). CIN in BRAFmut/MSS cancers was significantly predominant in those at advanced (15/17, 88%), compared to early AJCC stages of presentation (6/13, 46%) (p=0.02). BRAFmut/MSS cancers with CIN at 18q and 8p significantly associated with worse survival compared to those with no loss (p=0.003, p<0.05) when adjusted for stage. CIN at 5q, 8p and 18q in BRAFmut/MSS compared to BRAFwt/MSS cancers significantly correlated with poorer survival (p=0.002, p<0.001, p<0.001) when adjusted for stage. This study confirms that CIN is common in BRAFmut/MSS colorectal cancers, and indicates that extensive array based analyses of BRAF mutant cancers would be warranted. Moreover, it shows that CIN predominantly occurs in advanced BRAFmut/MSS cancers where it may contribute to poorer survival, and further highlights molecular similarities occurring between these and BRAFwt/MSS colorectal cancers.

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 106. doi:1538-7445.AM2012-106
Abstract 1062: Combinatorial expression of histone modifying enzymes differentiates Ewing's sarcoma family of tumors from mesenchymal stem cells and other sarcomas
Authors: Bennani-Baiti Idriss M. , Aryee Dave , Kovar Heinrich
Published: August 2012

Ewing's sarcoma family of tumors (ESFT) regroups mesenchymal tumors of bone and soft tissues that affect mostly children and young adults. ESFT is characterized by genetic lesions that include chromosomal translocations that generate de novo chimeric fusion oncoproteins between the TLS/EWS/TAF15 family of RNA-binding proteins and members of the ETS family of transcription factors. Contrary to the progress made in uncovering the genetic bases of Ewing's sarcoma, much remains to be discovered in the epigenetic mechanisms underlying ESFT pathogenesis. We have recently shown that alterations in the expression of EZH2 (a.k.a. KMT6), a methyltransferase that catalyzes the H3K27me3 mark, and of LSD1 (a.k.a. KDM1A), an H3K4me3 demethylase, contribute to ESFT pathology and can be targeted with drugs to curtail Ewing's sarcoma cell growth in vitro (EZH2 and LSD1) and in vivo (EZH2). To start deciphering the contribution of epigenetic modifiers to ESFT pathology, we surveyed the expression of all known histone modifying enzymes (HMEs) in four ESFT patient cohorts, totaling 96 tumors. We used the Ican analytical method to infer gene expression significance compared to a mesenchymal stem cell benchmark, as previously reported (Clin. Cancer Res 16: 3769-78, 2010). We show that, in addition to EZH2 and LSD1, several HMEs are up-regulated in ESFT compared to mesenchymal stem cell progenitors, indicating that the combinatorial activities of several HMEs are likely to promote an ESFT-specific epigenomic landscape. These findings represent the first extensive analysis of HMEs in ESFT, suggest a role of HMEs in ESFT pathogenesis and/or maintenance, and offer putative drug targets that may provide much needed novel ESFT epigenetic 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 1062. doi:1538-7445.AM2012-1062
Abstract 1071: Epidermal growth factor induces anterograde lysosome trafficking via activation of p38
Authors: Dykes Samantha S. , Cardelli James A.
Published: August 2012

Previous studies from our laboratory have demonstrated that acidic extracellular pH and activation of c-Met by the Hepatocyte Growth Factor (HGF) in the tumor microenvironment, have the ability to induce anterograde (outward) lysosome trafficking in prostate tumor cells, resulting in an increase in protease secretion and tumor cell invasion. Lysosome redistribution requires microtubules, sodium proton exchangers (NHEs) and PI-3K activity. These processes can be blocked by preventing anterograde lysosome trafficking using NHE inhibitors or anti-diabetic drugs belonging to the thiazolidinedione class. Epidermal Growth Factor (EGF) is another growth factor that is commonly expressed in the tumor microenvironment, including prostate tumors, and is involved in activating a variety of processes leading to tumor progression. Upon binding of the EGF to Epidermal Growth Factor Receptor (EGFR), a variety of cellular survival and stress pathways are activated, ultimately resulting in cytoskeletal changes and altered gene expression that contribute to the increased motility and invasion of tumor cells. Interestingly, we have found that EGFR activation also induces anterograde lysosome trafficking and scattering in DU145 prostate cancer cells by a mechanism that is dissimilar to that of HGF-induced lysosome movement. For instance, we have determined that EGF anterograde lysosome trafficking and scattering is dependent on the activity of the mitogen activated protein kinase p38α, but is not dependent on the activity of PI3K. Conversely, HGF mediated lysosome trafficking and scattering is dependent on the activity of PI3K. Additionally, EGF induced peripheral lysosome movement appears to be independent of the activity of NHE 1 and 3, but treatment with the broad acting NHE inhibitor, EIPA [5-(N-ethyl-N-isopropyl)-amiloride], prevented EGF induced anterograde lysosome trafficking and promoted a clustering of lysosomes around the nucleus, suggesting that multiple NHEs are involved in EGF mediated lysosome trafficking. This was accompanied by a reduction in cell invasion through reconstituted basement membrane in a transwell invasion assay. Also, EGF-induced lysosome repositioning was reversed by troglitazone, an anti-diabetic agent. Together, these data further implicate lysosome positioning as critical to the process of HGF and EGF mediated tumor invasion and provide insight into the mechanism by which EGF induces peripheral lysosome trafficking. This information further supports the notion that inhibition of lysosome repositioning is a potentially viable therapeutic target to block HGF- and EGF-induced tumor cell invasion.

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 1071. doi:1538-7445.AM2012-1071