bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-234: Suppression of Bruton tyrosine kinase with X-022, a highly selective next-generation irreversible inhibitor
Authors: Mulvihill Mark J. , Chen Xiangyang , Shaw JP , Liu Richard , Ni Haihong , Babiss Lee , Renzetti Louis
Published: May 2015

BTK is a member of the TEC family of kinases and is a critical component of B cell receptor (BCR) signaling, promoting B cell maturation, survival and proliferation. BCR signaling is requisite in all B cell-mediated malignancies where clinical trials with BTK inhibitors have proven efficacious. X-Rx utilized its drug discovery platform and knowhow to advance multiple novel series of BTK inhibitors. X-022 was then identified as a next generation, oral small molecule BTK inhibitor. X-022 irreversibly inhibits BTK with an IC50 of 2.3 nM. In primary human B cell and HWB assays, X-022 inhibited B cell activity with IC50 values of 49 and 93 nM, respectively. X-022 showed superior selectivity against a panel of 456 kinases, only inhibiting at >90% BTK at a concentration of 1000 nM. Oral bioavailability of >20% is observed in mice, rats and dogs. In a mouse PK/PD model, X-022 showed a dose dependent decrease in B cell activation measured over an 8 hour time interval with >98% inhibition observed at 10 mg/kg po. In an established model of collagen induced arthritis in mice, X-022 caused a dose dependent decrease in disease severity consistent with mechanism of action. No safety issues were identified in a pilot study in rodents at doses up to 300 mg/kg po. X-022 is a promising next generation irreversible oral BTK inhibitor for the treatment of B cell malignancies and chronic autoimmune diseases. In addition, the high degree of selectivity combined with favorable molecular properties make X-022 an excellent candidate for co-formulation with other targeted therapeutics.

Citation Format: Mark J. Mulvihill, Xiangyang Chen, JP Shaw, Richard Liu, Haihong Ni, Lee Babiss, Louis Renzetti. Suppression of Bruton tyrosine kinase with X-022, a highly selective next-generation irreversible inhibitor. [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 LB-234. doi:10.1158/1538-7445.AM2014-LB-234
Abstract LB-24: C-terminal PTEN is essential for maintenance of genomic stability and tumor suppression
Authors: Shen Wen H. , Yin Yuxin P.
Published: May 2015

Tumor suppressor PTEN controls genomic stability and inhibits tumorigenesis. It is well established that the N-terminal phosphatase domain of PTEN dephosphorylates lipid PIP3 to PIP2, which antagonizes PI3K/AKT signaling. However, the C-terminal function of PTEN is much less defined. Here we describe a knock-in mouse model of a nonsense mutation that results in deletion of the entire Pten C-terminal region, referred to as PtenΔC. Mice heterozygous for PtenΔC develop multiple spontaneous tumors, including cancers of different origins and B cell lymphoma. We found that heterozygous deletion of the Pten C-terminal domain also causes genomic instability and common fragile site rearrangement. We found that Pten C terminal disruption induces p53 and its downstream targets, causing cell death by apoptosis. Simultaneous depletion of p53 promotes metastasis of thyroid cancer without influencing initiation of tumors, suggesting that p53 mainly suppresses tumor progression but not tumor initiation. This is the first evidence that PTEN and p53 plays distinct roles at different stages of tumor development. Our data highlight the essential role of the PTEN C-terminus in the maintenance of genomic stability and suppression of tumorigenesis. Finally, our work reveals a network of PTEN and p53 that controls cellular responses to environmental stresses.

Citation Format: Wen H. Shen, Yuxin P. Yin. C-terminal PTEN is essential for maintenance of genomic stability and tumor suppression. [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 LB-24. doi:10.1158/1538-7445.AM2014-LB-24
Abstract LB-246: Dietary strawberry phytochemical metabolism in saliva, urine, and genetic biomarkers in smokers and non-smokers
Authors: Ahn-Jarvis Jennifer H. , Clinton Steven K. , Riedl Kenneth M. , Sears Marta T. , Knobloch Thomas J. , Schwartz Steven J. , Weghorst Christopher M. , Vodovotz Yael
Published: May 2015

Background: Epidemiological studies implicate tobacco smoke and alcohol consumption are critical risk factors for oral cancer. Yet diets rich in strawberries have shown in rodent and cell studies to have significant protective effects which lower the risk of oral cancer. A fully-characterized strawberry confection was evaluated for safety and adherence in a 6-week, randomized, placebo-controlled, crossover trial involving smokers (n=12) and non-smokers (n=13).

Methods: Using HPLC with tandem mass spectroscopy, strawberry phytochemicals in strawberry powder, confection and saliva collected during a 30 minute timed intervention were fully characterized. Buccal tissue was evaluated using pre-validated TaqMan Gene Expression assays corresponding to known smoke-altered oral transcriptome biomarkers used for RT-qPCR analysis. UPLC with mass spectroscopy quantified ellagic acid metabolites (dimethyl-, isourolithin A, urolithin A, B, and C) in 24hr urine collections.

Results: Adherence strawberry confections intervention (equivalent to 2 cups of whole strawberries) in smoker (91%) and nonsmokers (99%) was excellent. Toxicities to strawberry intervention was limited to a grade I toxicity (NIH criteria). Significantly less ellagic acid and ellagitannins were observed in saliva compared to confection (p<0.001). Anthocyanin profiles in saliva of smokers differed significantly than non-smokers. One biomarker, Ankyrin Repeat Domain 37 (ANKRD37), was found to be significantly down-regulated in smokers following strawberry confection intervention (p=0.0484). Significant increase (p<0.001) in urolithin A (4.29 ± 1.16 nmol/24hr) and C (0.13 ± 0.03 nmol/24hr) was observed in all participants after strawberry intervention compared to anthocyanin-free diet or placebo intervention. Isourolithin A and urolithin B was observed in 29% and 24% of participants, respectively.

Conclusions: A fully characterized strawberry confection was utilized and significant changes in biomarkers of strawberry exposure from saliva, urine and genomic materials were observed. Both ellagitannin metabolites, urolithin A and C would be reliable biomarkers of strawberry exposure. Moreover, differences in ellagitannin metabolite profiles and in ANKRD37 between smokers and non-smokers warrant further studies.

Citation Format: Jennifer H. Ahn-Jarvis, Steven K. Clinton, Kenneth M. Riedl, Marta T. Sears, Thomas J. Knobloch, Steven J. Schwartz, Christopher M. Weghorst, Yael Vodovotz. Dietary strawberry phytochemical metabolism in saliva, urine, and genetic biomarkers in smokers and non-smokers. [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 LB-246. doi:10.1158/1538-7445.AM2014-LB-246
Abstract LB-248: Development of lipid-based transfection reagents for efficient expression of transgenes in hard-to-transfect cell types
Authors: Yin Dezhong , Wells Joy , Clinton James , Volpe Lysa-Anne , Grady Kevin , Curley Jeanmarie
Published: May 2015

How to balance high efficiency of transgene expression with low cytotoxicity is a central concern for cell biology. Developing lipid-based transfection reagents that have those attributes and can be conveniently used for multiple cell types is critical for studies in cancer biology and cell biology. To address these concerns, ATCC has developed two lipid-based transfection reagents, GeneXPlus and TransfeX™ that provide a powerful tool for efficiently transfecting a broad spectrum of cell types including continuous cancer cell lines, stem cells, immortalized cells, and primary cells with little or no cytotoxicity. For recognized hard-to-transfect cancer cell lines, like THP-1, SH-SY5Y, and Raw 264.7 cells, we have achieved over 30% GFP expression without obvious cytotoxicity by using the GeneXPlus and an EF1α-GFP vector. TransfeX™ has been found to be highly suitable for the transfection of stem cells, immortalized cell lines, and many types of primary cells such as mammary, renal and bronchial epithelial cells, dermal microvascular endothelial cells, and human dermal fibroblasts. We have developed optimized transfection protocols for the TransfeX™ transfection reagent for different cell types and achieved over 50% transfection efficiency and low cytotoxicity. ATCC will provide data showing the broad spectrum of cell types successfully transfected with either GeneXPlus or TransfeX™.

Citation Format: Dezhong Yin, Joy Wells, James Clinton, Lysa-Anne Volpe, Kevin Grady, Jeanmarie Curley. Development of lipid-based transfection reagents for efficient expression of transgenes in hard-to-transfect cell types. [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 LB-248. doi:10.1158/1538-7445.AM2014-LB-248
Abstract LB-25: CD147 promotes reprogramming of glucose metabolism and cell proliferation in HCC cells by inhibiting p53-dependent signaling pathway
Authors: Huang Qichao , Li Jibin , Xing Jinliang
Published: May 2015

Background & Aims: Cancer cells exhibit the reprogrammed metabolism characterized by high level of glycolysis even in the presence of oxygen. Aerobic glycolysis, known as the Warburg effect, supplys cancer cells with the substrates required for biomass generation. To date, several intracellular signaling mediators have been identified in metabolic regulation of cancer cells. However, it remains largely ambiguous how molecules on cell surface are involved in regulation of cancer metabolism. Methods: In the current study, we established several HCC cell lines differing in their CD147 (a typical transmembrane glycoprotein) expression status by zinc-finger nuclease and RNAi techniques. Then, we systematically investigated the role of CD147 in the regulation of Warburg effect in HCC cells and explored the underlying mechanism. Results: We found that CD147 significantly contributed to the reprogramming of glucose metabolism in HCC cells through a p53-dependent way. CD147 facilitated the cell surface expression of MCT1 and lactate export, which led to the activation of PI3K/Akt/MDM2 pathway and thus increased p53 degradation. The gain/loss-of-function studies demonstrated that while CD147 promoted glycolysis mediated by p53-dependent up-regulation of GLUT1 and activation of PFKL; it inhibited mitochondrial biogenesis and functions mediated by p53-dependent down-regulation of PGC1α, TFAM and P53R2. Additionally, proliferation of HCC cells was suppressed by blocking CD147 and/or MCT1 which resulted in down-regulation of glucose metabolism. Conclusions: we demonstrate that CD147 is a crucial regulator of glucose metabolism.

Citation Format: Qichao Huang, Jibin Li, Jinliang Xing. CD147 promotes reprogramming of glucose metabolism and cell proliferation in HCC cells by inhibiting p53-dependent signaling pathway. [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 LB-25. doi:10.1158/1538-7445.AM2014-LB-25
Abstract LB-252: Matrix metalloproteinase-2 dysregulate anti-tumor immunity
Authors: Godefroy Emmanuelle , Gallois Anne , Idoyaga Juliana , Jotereau Francine , Bhardwaj Nina
Published: May 2015

Background: Cancer cells, including melanoma, can be highly resistant to traditional treatments such as chemotherapy and radiotherapy. As a result, a lot of effort has been put into developing immune therapies to treat cancer patients. The main barrier to design effective immunotherapies is the immunosuppression induced by the tumor. Matrix metalloproteinase-2 (MMP-2) is over-expressed in most cancers including melanoma, and its expression is associated with increased dissemination and poorer survival/prognosis. Here, we not only uncovered an immunosuppressive role of MMP-2 in inducing ineffective/detrimental TH2 immune responses, but also the underlying mechanisms.

Methods: Human dendritic cells (DCs) were cultured in the presence of MMP-2 and/or various TLR agonists. DCs responses were monitored using immunostaining, ELISA or cytometric bead array methods. Autologous CD4+ T cells were stimulated using these conditioned tumor-associated antigen (TAA)-pulsed DCs. TAA-specific CD4+ T cells were cloned and characterized using mainly the same techniques as for DCs.

Results: Here we showed that MMP-2-conditioned human DCs primed naïve CD4+ T cells to differentiate into an inflammatory TH2 phenotype, i.e. mainly secreting TNFα, IL-4 and IL-13 and expressing GATA3. Accordingly, we detected MMP-2-specific CD4+ T cells displaying the same inflammatory TH2 profile in tumor-infiltrating lymphocytes from melanoma patients. Patients displaying such responses tended to have a poorer survival outcome. We revealed the underlying mechanisms for these T cell skewing: on the one hand, MMP-2 was found to degrade the type-I IFN receptor IFNAR1, thereby preventing STAT1 phosphorylation, which is necessary for IL-12 production. On the other hand, MMP-2 triggers the Toll-like receptor (TLR)-2 on DCs, which leads to NF-κB activation and OX40L expression. Both lack of IL-12 and over-expression of OX40L were found responsible for skewing T cell responses towards a detrimental TH2 phenotype.

Conclusions: MMP-2, therefore, acts as an endogenous TH2 “conditioner” and may underlie the prevalence of detrimental TH2 responses in cancer. Our findings also described the responsible MMP-2-dependent mechanisms, which open the way to novel therapeutic strategies and/or targets to skew anti-tumor CD4+ T cell responses towards a more efficient anti-tumor TH1 phenotype to treat cancer patients.

Citation Format: Emmanuelle Godefroy, Anne Gallois, Juliana Idoyaga, Francine Jotereau, Nina Bhardwaj. Matrix metalloproteinase-2 dysregulate anti-tumor immunity. [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 LB-252. doi:10.1158/1538-7445.AM2014-LB-252
Abstract LB-26: Androgen receptor splice variant AR3 promotes prostate cancer via modulating expression of autocrine/paracrine factors
Authors: Qiu Yun , Sun Feng , Yang Xi
Published: May 2015

Deregulation of androgen receptor (AR) splice variants have been implicated to play a role in prostate cancer development and progression. To understand their functions in prostate, we established a transgenic mouse model (AR3Tg) with targeted expression of the constitutively active and androgen-independent AR splice variant AR3 (a.k.a. AR-V7) in prostate epithelium. We found that over-expression of AR3 modulates expression of a number of tumor-promoting autocrine/ paracrine growth factors (including Tgfβ2 and Igf1) and expands prostatic progenitor cell population, leading to development of prostatic intraepithelial neoplasia. In addition, we showed that some epithelial-mesenchymal-transition (EMT) associated genes are upregulated in AR3Tg prostates, suggesting that AR3 may antagonize AR activity and halt differentiation process driven by AR and androgen. This notion is supported by our observations that the number of ck5+/ck8+ intermediate cells is increased in AR3Tg prostates after castration, and expression of AR3 transgene in these intermediate cells compromises prostate epithelium regeneration upon androgen replacement. Our results demonstrate that AR3 is a driver of prostate cancer, at least in part, through modulating multiple tumor-promoting autocrine/paracrine factors.

Citation Format: Yun Qiu, Feng Sun, Xi Yang. Androgen receptor splice variant AR3 promotes prostate cancer via modulating expression of autocrine/paracrine factors. [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 LB-26. doi:10.1158/1538-7445.AM2014-LB-26
Abstract LB-270: The role of Ikaros in T cell homeostasis and function in a murine pancreatic cancer model
Authors: Nelson Nadine , Xiang Shengyan , Zhang Xiaohong , Pilon-Thomas Shari , Vohra Nasreen , Ghansah Tomar
Published: May 2015

The alternatively spliced transcription factor Ikaros is crucial for normal lymphocyte development. Ikaros plays a role as a tumor suppressor in murine T cells. In pancreatic cancer hosts, the balance between effector and regulatory T cells is lost, leading to immunosuppression and reduced anti-tumor immunity. In this study, we aim to identify the role of Ikaros in regulating T cell homeostasis and function in a pancreatic tumor microenvironment. Using our murine heterotopic model of pancreatic cancer, we isolated splenocytes from tumor-bearing (TB) and control mice and performed western blot and qRT-PCR analyses to evaluate Ikaros mRNA and protein expression, respectively. Flow cytometry analyses were also used to immunophenotype T cell populations in splenocytes from control and TB mice. Next, magnetic activated cell sorting (MACS) was used to sort CD3+ T cells from TB and control splenocytes for western blot analyses of Ikaros expression. We also carried out in vitro and in vivo experiments using apigenin, a plant flavonoid and protein kinase inhibitor with anti-inflammatory, anti-tumor and anti-proliferative properties, to shed insight into how Ikaros may be regulated and its involvement in T cell development. Our results showed no difference in Ikaros mRNA expression but reduced expression of all Ikaros isoforms in splenocytes from TB mice compared with controls. Ikaros protein expression was also downregulated in sorted TB T cells, compared with control Analyses of T cells by flow cytometry revealed a significant decrease in effector CD4+ and CD8+ T cell percentages but an increase in CD4+CD25+ regulatory T cells (Treg) in TB splenocytes compared with controls.. In vitro, treatment of splenocytes with apigenin stabilized Ikaros’ protein expression. In the presence of Panc02 cells, Ikaros protein expression was downregulated. However, the addition of apigenin to the co-culture blocked this downregulation. These correlated with in vivo findings that showed partial reversal of some Ikaros isoforms in TB mice treated with apigenin. Apigenin treatment also increased CD4+ and CD8+ T cell percentages but had no effect on Treg percentages. We are currently performing experiments to determine how Ikaros may be regulated in T cells and its effect on their functions. Thus far, our findings suggest that PC progression is associated with reduced Ikaros expression, which may lead to loss of T cell homeostasis and function and thus, dampened anti-tumor immune responses.

Citation Format: Nadine Nelson, Shengyan Xiang, Xiaohong Zhang, Shari Pilon-Thomas, Nasreen Vohra, Tomar Ghansah. The role of Ikaros in T cell homeostasis and function in a murine pancreatic 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 LB-270. doi:10.1158/1538-7445.AM2014-LB-270
Abstract LB-277: Irregular menstruation predicts increased risk of subsequent ovarian cancer death in a prospective cohort, The Child Health and Development Studies
Authors: Cohn Barbara A. , Cirillo Piera M. , Wang Erica T. , Cedars Marcelle I.
Published: May 2015

Background. Early detection of ovarian cancer has proved elusive, resulting in poor survival. This is the first prospective study to link a common reproductive condition to risk. Polycystic ovarian syndrome (PCOS) is an endocrine disorder, characterized by irregular menstrual cycles with long-term health consequences. Although some women with PCOS are infertile, the majority achieve pregnancy. It has been suggested that women with less frequent ovulation are protected, however, previous reports are inconsistent. Here we examine whether irregular cycling is associated with subsequent ovarian cancer death in a large prospective pregnancy cohort, The Child Health and Development Studies.

Methods. Subjects were 14,403 pregnant women recruited from the Kaiser Permanente Health Plan in 1959-1967 and followed for over 50 years. Menstrual irregularity, cycles >35 days or anovulation, was a proxy for PCOS, identified from medical record and self-report, at a median age of 26 years in 13% of women. Linkage to California Vital Statistics and National Death Index records identified 64 ovarian cancer deaths diagnosed at a median age of 69 years.

Results. Contrary to expectations, women with irregular cycles had a two-fold greater risk of ovarian cancer (Hazard Ratio=2.4; 95% Confidence Interval=1.3,4.5), independent of age, race, parity, and weight. This association was specific to cancer of the ovary - no association was observed for breast or uterine cancer - and it increased over the follow-up period (p=0.08 for time-dependence).

Conclusions. This is the first large prospective study of irregular cycles as an early marker of ovarian cancer. If confirmed, women with irregular cycles could be targeted for screening. This finding offers a strategy to search for antecedent ovarian cancer biomarkers, creating the opportunity for new early detection strategies.

Citation Format: Barbara A. Cohn, Piera M. Cirillo, Erica T. Wang, Marcelle I. Cedars. Irregular menstruation predicts increased risk of subsequent ovarian cancer death in a prospective cohort, The Child Health and Development Studies. [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 LB-277. doi:10.1158/1538-7445.AM2014-LB-277
Abstract LB-281: Coffee intake reduces hepatocellular carcinoma risk: The Multiethnic Cohort
Authors: Setiawan Veronica Wendy , Wilkens Lynne R. , Hernandez Brenda Y. , Marchand Loic L. , Henderson Brian E.
Published: May 2015

Background: Coffee consumption has been suggested to reduce hepatocellular carcinoma (HCC) risk in epidemiological studies. Yet, data from prospective studies in US populations are nonexistent. Here we evaluated the association between coffee intake and HCC incidence in multiethnic US populations.

Methods: We conducted a prospective analysis of 179,890 African-American, Native Hawaiian, Japanese-American, Latino and white men and women who were recruited into the Multiethnic Cohort Study between 1993 and 1996. Participants reported their coffee consumption and other dietary and lifestyle factors at baseline and were followed up to 18 years for HCC incidence. Serologic testing for hepatitis B (HBV) and C (HCV) infection was performed on a subset of cohort participants (152 HCC cases and 460 non-cases). Hazard rate ratios (RRs) and 95% confidence intervals (CIs) were calculated using Cox regression adjusting for sex, ethnicity, education, alcohol intake, smoking status, body mass index (BMI), and history of diabetes mellitus.

Results: During a median follow-up period of 16.6 years, 498 participants had developed HCC. High levels of regular coffee consumption were associated with reduced risk of HCC (P for trend <0.0001). Compared to non-drinkers/low consumers (up to six cups per week) of coffee, individuals who consumed one to three cups of coffee per day had a 29% reduction in risk of HCC (RR=0.71; 95% CI: 0.60, 0.86) and those who had four or more cups of coffee per day had a 42% reduction in risk of HCC (RR=0.58; 95% CI: 0.36, 0.92). The inverse relationships between coffee and HCC were similar regardless of the participants’ ethnicity, sex, BMI, smoking status, alcohol intake, or diabetes status. Within a subset of cohort participants with available HBV and HCV serologic data, coffee consumption was not associated with infection status (P=0.63).

Conclusions: These results suggest that an increased coffee consumption may reduce the risk of developing HCC in multiethnic US populations.

Citation Format: Veronica Wendy Setiawan, Lynne R. Wilkens, Brenda Y. Hernandez, Loic Le Marchand, Brian E. Henderson. Coffee intake reduces hepatocellular carcinoma risk: The Multiethnic Cohort. [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 LB-281. doi:10.1158/1538-7445.AM2014-LB-281
Abstract LB-286: Aspirin and nonsteroidal anti-inflammatory drug use and the risk of upper aerodigestive tract cancer
Authors: Macfarlane Tatiana V. , Lefevre Karen , Watson Margaret C.
Published: May 2015

Introduction: Aspirin and other NSAIDs are widely used as analgesic and preventative agents. Data on the chemopreventative role of these drugs on the risk of the upper aerodigestive tract (UADT) cancer are insufficient and mostly refer to oesophageal cancer.

Aim: To investigate the effect of aspirin and other NSAIDs use on the risk of UADT cancers. Specific objectives were to investigate risk by cancer sub-site, duration of use and type of NSAIDs.

Methods: A nested case-control study using the Primary Care Clinical Informatics Unit (PCCIU) database. Conditional logistic regression was used for data analysis.

Results: There were 2,392 cases of UADT diagnosed between 1996 and 2010 and 7,165 age, gender and medical practice matched controls from 131 general medical practices. Mean age of cases was 66 years (SD 12), and most cases were males (63%). Aspirin was prescribed in a quarter of cases and controls, COX-2 inhibitors were prescribed in 4% of cases and 5% of controls and other NSAIDs were prescribed in 33% of cases and 36% of controls. Aspirin prescription was associated with non-significant reduced risk of cancer of UADT (OR 0.9 95% CI 0.8, 1.0), head and neck (HN) cancer (OR 0.9, 95% CI 0.7, 1.1) or the oesophagus (OR 0.8, 0.7, 1.0). Similar results were found for COX-2 prescription. Prescription of other NSAIDs was associated with significantly reduced risk of cancer of UADT (adjusted OR 0.8, 95% CI 0.7, 0.9), HN (adjusted OR 0.8, 95% CI 0.7, 0.9) and the oesophagus (OR 0.8, 0.7, 0.9). Significant risk reduction occurred with an increased number of aspirin prescriptions (OR 0.8, 95% CI 0.6, 0.9) for over 29 prescriptions compared to “never” aspirin prescription (test for trend P<0.001).

Conclusion: There is evidence of a decreased risk of UADT cancer associated with ever being prescribed an NSAID (non-COX-2) as well as with increased number of aspirin prescriptions.

Citation Format: Tatiana V. Macfarlane, Karen Lefevre, Margaret C. Watson. Aspirin and nonsteroidal anti-inflammatory drug use and the risk of upper aerodigestive tract cancer. [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 LB-286. doi:10.1158/1538-7445.AM2014-LB-286
Abstract LB-289: Telomere length, genetic variants and gastroesophageal cancer risk: a case-control study in Chinese population
Authors: Du Jiangbo , Zhu Xun , Zhu Chen , Ma Hongxia , Hu Zhibin , Shen Hongbing , Jin Guangfu
Published: May 2015

Backgrounds

Telomeres are protective DNA-protein repeats structure at the extreme end of linear chromosomes that maintain chromosomal stability and integrity. Short telomere in peripheral blood leukocyte has been associated with an increased risk of multiple cancers. Moreover, heterogeneity of inter-individual telomere length is partly determined by hereditary factor. Recent genome-wide association studies (GWAS) have identified several telomere length related loci at 2p16.2 (ACYP2), 3q26 (TERC), 4q32.2 (NAF1), 5p15.33 (TERT), 10q24.33 (OBFC1), 19p12 (ZNF208) and 20q13.3 (RTEL1), some of which were also implicated with cancer risk. However, these findings were mainly observed in populations of European descent, and were not well demonstrated in other populations, especially for gastroesophageal cancer that is high incident in China but not in western countries.

Design and Methods

We measured relative telomere length (RTL) by quantitative real-time polymerase chain reaction in a Chinese case-control study including 1,136 gastric cancer cases, 1,045 esophageal cancer cases and 1,012 matched controls. Moreover, we performed genotyping by TaqMan assay for genetic variants at 2p16.2 (rs11125529), 3q26 (rs10936599), 4q32.2 (rs7675998), 5p15.33 (rs2736100, rs2736108), 10q24.33 (rs4387287), 19p12 (rs8105767), and 20q13.3 (rs755017).

Results

As compared with individuals in the fourth quintile of telomere length (i.e., moderately long telomeres), those with short telomeres were at an increased risk with ORs (95%CI) being 1.19 (0.92-1.55), 1.53 (1.19-1.98) and 3.00 (2.33-3.85) for the third, second and first quintiles, respectively. More interestingly, a significant elevated risk (OR= 1.54, 95%CI: 1.19-2.00) was also found in those at the fifth quintile with extreme long telomeres. We also confirmed that the G allele of rs2736100 at 5p15.33 exhibited a significant association with longer telomere length (r2= 0.106, P = 0.047), which, however, was not significantly associated with gastroesophageal cancer risk. We did not observe significant association of the other loci with telomere length or gastroesophageal cancer risk.

Conclusions

These findings suggest that either short or extreme long telomere may be risk factor for gastroesophageal cancer while telomere length related variants may be less important in the susceptibility to gastroesophageal cancer in Chinese population.

Citation Format: Jiangbo Du, Xun Zhu, Chen Zhu, Hongxia Ma, Zhibin Hu, Hongbing Shen, Guangfu Jin. Telomere length, genetic variants and gastroesophageal cancer risk: a case-control study in Chinese population. [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 LB-289. doi:10.1158/1538-7445.AM2014-LB-289
Abstract LB-290: The influence of body size and weight gain on global and gene promoter methylation in a population-based breast cancer study
Authors: McCullough Lauren E. , Chen Jia , White Alexandra J. , Xu Xinran , Cho Yoon Hee , Bradshaw Patrick T. , Eng Sybil M. , Teitelbaum Susan L. , Terry Mary Beth , Garbowski Gail , Neugut Alfred I. , Hibshoosh Hanina , Santella Regina M. , Gammon Marilie D.
Published: May 2015

Purpose. Little is known about how modifiable lifestyle factors, influence the epigenome. Elevated body mass index (BMI, weight kg/height m2) and adult weight gain are associated with increased risk of postmenopausal breast cancer, but the underlying mechanisms are not well understood. We hypothesized that these anthropometric factors may modify DNA methylation status by altering sex-steroid hormones levels and inflammatory markers.

Methods. Resources from a population-based study (∼650 postmenopausal cases/∼650 postmenopausal controls) were used to construct logistic regression models. We explored potential modification of the global methylation-breast cancer association by BMI and weight gain using two assays: the luminometric methylation assay (LUMA) and long interspersed elements-1 (LINE-1) in white blood cell DNA. Additionally, we estimated associations between anthropometrics and promoter methylation status in a panel of 13 breast cancer-related genes using ∼600 breast tumor tissues.

Results. We observed a multiplicative interaction between LUMA and BMI (p=0.033) in relation to breast cancer. There was a greater than two-fold risk of postmenopausal breast cancer among women in the highest quartile of LUMA for each strata of BMI: age-adjusted odds ratios (95% confidence intervals) were 2.19(1.37, 3.52), 2.91(1.77, 4.80) and 2.51(1.45, 4.33) for women with BMI<25, BMI25-29.9 and BMI≥30, respectively. The observed estimates did not differ, statistically, across BMI categories. Additionally, we found no interactions with LINE-1 and observed no associations between anthropometrics and promoter methylation status in the genes examined.

Conclusions. Our data suggest that the association between BMI, weight gain and postmenopausal breast cancer may arise from mechanisms other than DNA methylation.

Citation Format: Lauren E. McCullough, Jia Chen, Alexandra J. White, Xinran Xu, Yoon Hee Cho, Patrick T. Bradshaw, Sybil M. Eng, Susan L. Teitelbaum, Mary Beth Terry, Gail Garbowski, Alfred I. Neugut, Hanina Hibshoosh, Regina M. Santella, Marilie D. Gammon. The influence of body size and weight gain on global and gene promoter methylation in a population-based breast cancer study. [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 LB-290. doi:10.1158/1538-7445.AM2014-LB-290
Abstract LB-291: Novel germline G660D mutation in HER2 gene detected by whole-exome sequencing can predispose a patient to developing familial lung adenocarcinoma
Authors: Yamamoto Hiromasa , Higasa Koichiro , Sakaguchi Masakiyo , Shien Kazuhiko , Soh Junichi , Ichimura Koichi , Furukawa Masashi , Hashida Shinsuke , Tsukuda Kazunori , Takigawa Nagio , Matsuo Keitaro , Kiura Katsuyuki , Miyoshi Sinichiro , Matsuda Fumihiko , Toyooka Shinichi
Published: May 2015

Familial cancers arising from several organs are often reported including breast and colon cancers, although familial lung cancers are few reported. We encountered a family of Japanese descent in which multiple members developed lung adenocarcinomas. Using whole-exome sequencing, we identified a novel germline mutation in the transmembrane domain of the human epidermal growth factor receptor 2 (HER2) gene (G660D). A novel somatic mutation (V659E) was also detected in the same transmembrane domain of HER2 in one of 253 sporadic lung adenocarcinomas. Because the transmembrane domain of HER2 is considered to be responsible for the dimerization and subsequent activation of the HER family and downstream signaling pathways, we performed functional analyses of these HER2 mutants. Mutant HER2 G660D and V659E proteins were more stable than wild-type protein. Both the G660D and V659E mutants activated Akt, an effector kinase regarding to cell survival. In addition, they activated the other kinase, p38 at a remarkable level, which is thought to promote critically cell proliferation in lung adenocarcinoma. Coupling experiments revealed that mutant HER2 avidly dimerized with EGFR, HER3 and HER4 in the same manner to those with wild type HER2. The formation of mutant HER2 homodimers was also observed, whereas we less detected homodimers of wild type HER2. Our findings strongly suggest that mutations in the transmembrane domain of HER2 are oncogenic, causing hereditary and sporadic lung adenocarcinomas.

Citation Format: Hiromasa Yamamoto, Koichiro Higasa, Masakiyo Sakaguchi, Kazuhiko Shien, Junichi Soh, Koichi Ichimura, Masashi Furukawa, Shinsuke Hashida, Kazunori Tsukuda, Nagio Takigawa, Keitaro Matsuo, Katsuyuki Kiura, Sinichiro Miyoshi, Fumihiko Matsuda, Shinichi Toyooka. Novel germline G660D mutation in HER2 gene detected by whole-exome sequencing can predispose a patient to developing familial lung adenocarcinoma. [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 LB-291. doi:10.1158/1538-7445.AM2014-LB-291
Abstract LB-293: Circulating tumor cells in peripheral and pulmonary venous blood predict poor long-term survival in surgical resected non-small cell lung cancer patients
Authors: Liu Zhidong , Li Yunsong , Su Chongyu , Han Yi , Xu Shaofa
Published: May 2015

Background: We tested the hypothesis that the circulating tumor cells (CTCs) in preoperative peripheral blood (PPB) and intraoperative pulmonary venous blood (IPVB) could predict poor long term survival in surgically resected NSCLC patients.

Methods: CTCs were separated from the blood using magnetic beads coated by antibody against epithelial-cell adhesion molecule (EpCAM) through magnetic activated cell sorting (MACS). The CTCs were quantified with fluorescence labeled antibodies against pan-cytokeratin through flow cytometry. CTCs were prospectively quantified in PPB and IPVB in 23 consecutive stage I-IIIA patients with surgically resected NSCLC. Association between CTCs and prognosis of these patients was evaluated after 5-year follow-up.

Results: In the NSCLC patients, outcomes were assessed according to levels of CTCs at surgery, and compared with CTCs detected in benign pulmonary diseases, and healthy volunteers, where the mean and 95%CI of CTCs counts were all 5 CTCs/15mL in PPB and >50 CTCs/15mL in IPVB. Univariate Cox proportional-hazards regression analysis showed that CTCs count in PPB or IPVB was an independent risk factor for tumor-free and overall survivals. The high risk group of patients had a shorter median tumor-free survival (22 months vs. >60.0 months, P60 months, P<0.0015).

Conclusions: CTCs count in PPB and IPVB was an independent risk factor for tumor-free and overall survival in surgically resected NSCLC patients.

Citation Format: Zhidong Liu, Yunsong Li, Chongyu Su, Yi Han, Shaofa Xu. Circulating tumor cells in peripheral and pulmonary venous blood predict poor long-term survival in surgical resected non-small cell lung cancer patients. [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 LB-293. doi:10.1158/1538-7445.AM2014-LB-293
Abstract LB-301: gp130/Jak/Stat3 inhibition blocks WNT signaling-mediated intestinal tumorigenesis and regeneration
Authors: Ernst Matthias
Published: May 2015

The capacity of crypt stem cells to respond to canonical Wnt signaling enables the adult intestinal epithelium to continuously renew, regenerate after injury and, as a consequence of Apc tumor suppressor mutations, give rise to colon cancers. Likewise, Stat3 signaling is required for stem cell function and therefore also intestinal homeostasis. We previously described that therapeutic inhibition of gp130/Jak/Stat3 signaling suppresses colitis-associated colon cancer in mice [1,2]. We now find that genetic activation of gp130/Jak/Stat3 signaling augments intestinal regeneration and enhances sporadic tumorigenesis in Apc-mutant mice. Conversely, systemic gp130/Jak/Stat3 pathway restriction, or therapeutic Jak inhibition, suppresses regeneration, and also blocks initiation and growth of Apc-mutant mouse tumors, and colon cancer xenografts, without interfering with intestinal homeostasis and despite persisting high Wnt signaling. We identify gp130/Jak/Stat3-dependent induction of Bmi-1 and associated p16/p21 repression as the underlying mechanism. Our findings put in perspective observations that associate complete epithelial Stat3 deletion with reduced crypt stem cell survival and progression of Apc-mutant tumors. We therefore propose that gp130/Jak/Stat3 signaling becomes selectively rate-limiting for Apc-mutant tumor growth by serving as the “rheostat” that links intestinal proliferation to the epithelial wound-healing process hijacked by tumor cells. In turn, our findings provide a rational for therapeutic Jak inhibition in colon cancer.

1 Putoczki et al., Cancer Cell 2013

2 Stuart et al., Mol Cancer Therapy 2014

Citation Format: Matthias Ernst. gp130/Jak/Stat3 inhibition blocks WNT signaling-mediated intestinal tumorigenesis and regeneration. [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 LB-301. doi:10.1158/1538-7445.AM2014-LB-301
Abstract LB-303: A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic ductal adenocarcinoma
Authors: Fujimura Ken , Wright Tracy , Strnadel Jan , Kelber Jonathan , Kaushal Sharmeela , Metildi Cristina , Lowy Andrew , Bouvet Michael , Klemke Richard
Published: May 2015

Deregulation of mRNA translation and protein synthesis is a hallmark of cancer cell proliferation, survival, and metastatic progression. eIF5A1, and its highly related isoform eIF5A2, are critical translation initiation factors implicated in several human malignancies. Interestingly, eIF5A proteins are the only known proteins in nature that are regulated by a distinct posttranslational modification termed hypusination. This unique lysine modification ([N-(4-amino-2-hydroxybutyl)lysine]) involves polyamine biosynthesis and is catalyzed by two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). The highly selective nature of the hypusine modification and its amenability to pharmacological and genetic inhibition make the eIF5A-hypusine pathway an attractive therapeutic target to combat human cancers. Here, we investigated the role of eIF5A1/A2-hypusine pathway in pancreatic ductal adenocarcinoma (PDAC) pathogenesis. Hypusinated eIF5A1/A2 are upregulated in human PDAC tissues and in early stage PanIN tissues isolated from genetically engineered Pdx-Cre:LSL-KRASG12D mice. RNAi-mediated knockdown of eIF5A1/A2 in human PDAC cell lines inhibited cancer cell growth in vitro and inhibited tumor growth orthotopically in mice. In contrast, amplification of eIF5A1/A2 in PDAC cells increased orthotopic growth and tumor formation in mice. The deoxyhypusine hydroxylase inhibitor, CPX, and the deoxyhypusine synthase inhibitor, GC7, inhibited eIF5A1/A2 hypusination, preventing PDAC cell growth. Interestingly, we find that eIF5A1/A2 regulates cancer cell expansion by modulating the expression level of PEAK1, a non-receptor tyrosine kinase essential for PDAC cell growth. Our findings suggest that eIF5A1/A2 utilizes PEAK1 tyrosine kinase as a downstream effector to drive PDAC pathogenesis, and that pharmacological inhibition of the eIF5A1/A2 hypusination-PEAK1 axis may provide a novel therapeutic strategy to combat this deadly disease.

Citation Format: Ken Fujimura, Tracy Wright, Jan Strnadel, Jonathan Kelber, Sharmeela Kaushal, Cristina Metildi, Andrew Lowy, Michael Bouvet, Richard Klemke. A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic ductal adenocarcinoma. [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 LB-303. doi:10.1158/1538-7445.AM2014-LB-303
Abstract LB-304: Smad7-Skp2 complex orchestrates c-Myc stability
Authors: Kim Tae-Aug , Kang Jin-Muk , Niderhuber John , Kim Seong-Jin
Published: May 2015

In most of human cancer, the c-Myc proto-oncogene is highly activated. Dysregulation of c-Myc oncoprotein contributes to drive tumorigenesis in numerous tissues and organs. Thus, targeting c-Myc stability can be a critical step for cancer therapy. Here we report Smad7 as a key molecule to regulate c-Myc stability and activity by recruiting F-box protein, Skp2. Ectopic expression of Smad7 down-regulated the protein level of c-Myc without affecting transcription level and significantly repressed its transcriptional activity, leading to inhibition of cell proliferation and tumorigenic activity. Furthermore, Smad7 enhanced ubiquitination of c-Myc through direct interaction with c-Myc and recruitment of Skp2. Ablation of Smad7 resulted in less sensitivity to the growth inhibitory effect of TGF-β by inducing stable c-Myc expression. In conclusion, these findings that Smad7 functions as a transductory role in c-Myc oncoprotein degradation and enhances the cytostatic effect of TGF-β signaling provide new insightful therapeutic approach for cancer treatment.

Citation Format: Tae-Aug Kim, Jin-Muk Kang, John Niderhuber, Seong-Jin Kim. Smad7-Skp2 complex orchestrates c-Myc stability. [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 LB-304. doi:10.1158/1538-7445.AM2014-LB-304
Abstract LB-309: Interplay between E3 ligases modulate Per2 stability
Authors: liu jingjing , Finkielstein Carla V.
Published: May 2015

Circadian oscillation relies on autoregulatory loops generated by sequential phases of transcription/translation, protein modification, and degradation. Interestingly, disruption of the clock gene period2 (per2) in mice is associated with a hyperplasic phenotype and loss of apoptotic response. When irradiated, per2 knockout mice show a significantly higher frequency of tumor development most likely due to loss of normal circadian control of genes concerned with the regulation of the DNA-damage response as well as partial resistance to radiation-induced apoptosis. Although evidence suggests that the per2 gene functions in tumor suppression, no mechanism of Per2 action is known. Our work show direct evidences of crosstalk mechanisms that involve Per2 and the oncogenic E3-ligase Mdm2. Whereas we know much about the role of b-TrCP in modulating the oscillatory levels of Per2 in the cell, the functional relevance of Mdm2 targeting of Per2 has just been uncovered. Bacterial two-hybrid screenings led to the identification of Mdm2 as a new PER2 binding partner, an interaction that was later validated by immunoprecipitation studies from both ectopicaly expressed and endogenous proteins. In vitro experiment show that recombinantly expressed Per2 serves as a substrate for Mdm2 and polyubiquitination takes place shortly after interaction. These results were later confirmed when Mdm2 was overexpressed and ubiquitination of Per2 was detected in immunoprecipitated samples. Interestingly, knock down of either beta-TrCP or Mdm2 dampened PER2 oscillation, although the mechanism by either E3 ligase seems to act relies in the subcellular localization of the substrate., Lastly, there is an interplay between these two ligases as we showed that downregulation of Mdm2 influences the total levels of beta-TrCP and direct interaction between these protein was confirmed by immunoprecipitation. Moreover, experiments carried out with constitutively negative active forms of each ligase show they are each other targeted for ubiquitination and that Per2 exerts a very relevant control on stability of b-TrCP by binding to Mdm2 and inhibiting its E3-ligase activity.

Citation Format: jingjing liu, Carla V. Finkielstein. Interplay between E3 ligases modulate Per2 stability. [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 LB-309. doi:10.1158/1538-7445.AM2014-LB-309