bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4645: Decreased CD4+ naive and effector memory T cell counts, and CD8+ naïve T cell counts, are associated with trichloroethylene exposure
Authors: Hosgood H. Dean , Zhang Luoping , Tang Xiaojiang , Vermeulen Roel , Shen Min , Smith Martyn , Qiu Chuangyi , Ge Yichen , Ji Zhiying , Xiong Jun , Reiss Boris , Hao Zhenyue , Liu Songwang , Xie Yuxuan , Guo Weihong , Galvan Noe , Li Laiyu , Rothman Nat , Huang Hanlin , Lan Qing
Published: June 2012

Trichloroethylene (TCE) is a volatile chlorinated organic compound that is commonly used in the workplace as a degreaser for metal parts and general-purpose solvent for lipophilic compounds. Although TCE is considered an animal carcinogen, its carcinogenic potential in humans is uncertain. Occupational exposure to TCE has been associated with increased risk of kidney cancer and non-Hodgkin lymphoma in some studies, but findings are not fully consistent. We have carried out a cross-sectional study of 80 workers exposed to TCE and 96 unexposed controls matched on age and sex in Guangdong, China to study TCE's early biologic effects. We previously reported that the total lymphocyte count (but not the granulocyte count) and each of the major lymphocyte subsets (i.e., CD4+ T cells, CD8+ T cells, natural killer (NK) cells, and B cells) were decreased in TCE-exposed workers compared to controls. These findings suggested a selective effect of TCE exposure on lymphoid progenitors and/or lymphocyte survival. To further study which subsets of lymphocytes are affected specifically, we investigated the effect of TCE exposure on the numbers of CD4+ naïve and memory T cells, CD8+ naïve and memory T cells, and regulatory T cells by FACS analysis. Linear regression using the natural logarithm (ln) of each subset was used to test for differences between exposed workers and controls adjusting for potential confounders such as age, sex, smoking status, alcohol consumption, recent infections, and body mass index. We observed that CD4+ and CD8+ naïve T cell counts were about 8% (p = 0.056) and 17% (p = 0.0002) lower, respectively, among exposed workers. Strikingly, CD4+ effector memory T cell counts were decreased by about 20% among TCE exposed workers compared to controls (p = 0.001) whereas the CD4+ central memory T cell population was not significantly changed. Intriguingly, the numbers of CD4+ central memory T cells, and CD8+ memory T cells including central and effector memory population, as well as regulatory T cells were not significantly different between the controls and exposed workers. Thus, TCE selectively targets CD4+ naïve and CD4+ effector memory T cells, and CD8+ naïve T cells. These findings provide further insights into the biologic response of human immune cells upon exposure to TCE, which may include immunosuppression through reduced capacity to respond to antigens.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4645. doi:10.1158/1538-7445.AM2011-4645
Abstract 4649: Association between serum 25-hydroxyvitamin D and risk of female thyroid cancer in Korea
Authors: Shin Myung-Hee , Chung Jae Hoon , Kim Jung Han , Son Young-Ik
Published: June 2012

The incidence of female thyroid cancer is rapidly increasing in Korea. However, factors that would account for this increase are unclear other than the increase in frequency of screening. Vitamin D has shown anticarcinogenic effect on many cancers in experimental studies. Dietary and circulating vitamin D have shown inconclusive, yet promising, inverse associations with colorectal, breast, and prostate cancer in epidemiological studies. Evidences on the association between circulating vitamin D and thyroid cancer are rare. We investigated the association between serum 25-hydroxyvitamin D3 (25(OH)D3) and the risk of thyroid cancer among Korean women. A total of 158 incident thyroid cancer and 144 non-cancer control patients from one large hospital in Seoul were interviewed on their life-style factors between April, 2006 and December, 2007. Among the total participants, 91 cancer (all thyroid papillary cancer) and 105 control patients who agreed to donate their blood were included in this study. The blood of cancer patients was collected at the inpatient wards while the patients were admitted for the operation. The blood of control patients was collected at the inpatient wards or outpatient clinics of four different clinical departments. All blood samples were centrifuged within 1 hour of collection and the serum vials were stored in -80 °C. Serum 25(OH)D3 concentration was measured using radioimmunoassay (RIA). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression adjusted for the month of blood collection, body mass index, physical exercise, breast feeding, and menopausal status. The OR of thyroid cancer for the highest quintile (17.2-30.1ng/ml) of serum 25(OH)D3 concentration compared to the lowest quintile (4.0-8.7ng/ml) was 0.30 (95%CI = 0.10-0.85, ptrend=0.04). The inverse association between serum 25(OH)D3 and risk of thyroid cancer was observed in both premenopausal (OR=0.50, 95%CI=0.09-2.68) and postmenopausal women (OR=0.24, 95%CI=0.05-1.09) although statistical significance was not reached in both groups. Women with lower BMI (<23kg/m2) or with no history of breast feeding showed stronger association between serum 25(OH)D3 and risk of thyroid cancer. Our results suggest higher serum 25(OH)D3 may reduce the risk of thyroid papillary cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4649. doi:10.1158/1538-7445.AM2011-4649
Abstract 465: Alternatively activated bone marrow-derived macrophages enhance tumor growth and metastasis in a 4T1 mammary cancer model
Authors: Cho Han Jin , Lim Do Young , Jung Jae In , Her Song , Park Jung Han Yoon
Published: June 2012

Tumor microenvironment consists of a number of components including malignant cells, stromal cells, endothelial cells, infiltrating immune cells, and extracellular matrix. Because inflammation plays an important role in cancer development and progression, tumor-associated macrophages (TAMs) can be one of key regulators of tumor microenvironment. Recent evidence has shown that TAM is associated with poor prognosis in a variety of cancers, including breast, lung, and pancreatic cancer. TAMs account for up to 50% of the total tumor mass, resemble M2-macrophages, and exhibit a number of pro-tumoral functions, including the expression of growth factors and matrix proteases, the promotion of angiogenesis, and the suppression of adaptive immunity. In the present study, we examined the effect of M2 macrophages on the development of and metastasis of mammary cancer using a 4T1-orthotopic tumor model. Monocytes were isolated from mouse bone marrow and treated with IL-4 to induce differentiation into an M2 phenotype. In order to determine whether or not M2 microphages stimulate mammary cancer growth and progression, 4T1 mammary carcinoma cells were injected into the inguinal mammary fat pad of syngeneic BALB/C mice, either alone or coupled with bone marrow-derived alternatively-activated macrophages (BMDAM). Co-injection of 4T1 cells with BMDAM increased solid tumor volumes (at 2 weeks after inoculation) and lung metastasis (at 3 weeks after inoculation). We prepared 4T1-luc cells that stably express firefly luciferase which allows for direct examination of tumor growth in animals by estimating the luciferase activity of 4T1 cancer cells via an in vivo imaging system. Luminescence was quantified, and the results demonstrated that the accumulation of 4T1-luc cells was significantly more pronounced when 4T1 cells were co-injected with BMDAM. Immunohistochemical staining of tumor tissues revealed that the proportion of Ki67 (proliferation index)-positive cells was increased in tumor tissues when 4T1 cells were co-injected with BMDAM. We also observed that co-injection of BMDAM with 4T1 cells increased the expression of hypoxia-inducible factor-1α and CD31 (a glycoprotein expressed on endothelial cells and in platelets)-positive cells. These results indicate that TAM increases the proliferation of mammary tumor cells, which may lead to the stimulation of lung metastasis in the 4T1 mammary carcinoma model.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 465. doi:10.1158/1538-7445.AM2011-465
Abstract 4656: Relationship of nicotine and carcinogen biomarkers to lung cancer risk among smokers in the Shanghai cohort study
Authors: Murphy Sharon E. , Berg Jeannette Zinggeler , Wang Renwei , Wickham Katherine M. , Gao Yu-Tang , Hecht Stephen S. , Yuan Jian-Min
Published: June 2012

Individuals who develop lung cancer are predominantly tobacco users and further risk profiling within this group is important to better understand cancer susceptibility and could be used to target interventions. A nested case-control approach was used to evaluate risk factors for lung cancer in a population of Chinese men from Shanghai, China (317 cases and 317 controls). All participants were current smokers at baseline and controls were matched for age, neighborhood, and date of biospecimen collection. Biomarkers assessed in urine were nicotine and its major metabolites, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, a tobacco carcinogen), and r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT, a biomarker of polyaromatic hydrocarbons). The odds ratio for developing lung cancer were greatest for men with the highest versus lowest quintile of urinary cotinine (cotinine + cotinine glucuronide), OR (95% CI); 8.79 (4.42-17.47) unadjusted, and 5.26 (2.39-11.57) adjusted for years of smoking, cigarettes per day, NNAL, and PheT. Cotinine levels are influenced both by nicotine exposure and metabolism. Nicotine and cotinine are metabolized by cytochrome P450 2A6 which is polymorphic and ∼15% of the Chinese population carry low activity alleles. In contrast, nicotine equivalents is a biomarker of exposure that is less influenced by metabolism as it is the sum of nicotine and its metabolites excreted in urine. Higher odds ratios of lung cancer were also observed for increasing nicotine equivalents but this was a weaker biomarker compared to cotinine in this population, OR (95% CI); 4.86 (2.72-8.69) unadjusted, and 2.58 (1.32-5.03) adjusted for years of smoking, cigarettes per day, NNAL, and PheT. The ratio of trans-3′-hydroxycotinine to cotinine per nicotine equivalents was evaluated as a biomarker of oxidation phenotype. Previously the ratio of trans-3′-hydroxycotinine to cotinine has been used to phenotype individuals for P450 2A6 activity, and to account for variation in nicotine dose during smoking the ratio was expressed per nicotine equivalents. Unexpectedly, the highest quintile of the metabolite ratio was associated with a decreased risk of lung cancer compared to the lowest quintile, OR (95%CI); 0.26 (0.15-0.47). This group would include individuals who have a low nicotine metabolism phenotype and smoke an average-to-high amount. Higher urinary NNAL and PheT were also risk factors for lung cancer albeit the odds ratios were lower than for cotinine.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4656. doi:10.1158/1538-7445.AM2011-4656
Abstract 466: Bone marrow and cancer cells mutually affect each other
Authors: Suetsugu Atsushi , Hassanein Mohamed K. , Osawa Yosuke , Nagaki Mashito , Saji Shigetoyo , Moriwaki Hisataka , Bouvet Michael , Hoffman Robert M.
Published: June 2012

Kaplan et al (Nature 438, 820-827, 2005) demonstrated that bone marrow cells can home to tumor-specific pre-metastatic sites thereby providing a permissive niche for incoming metastatic cells. In the present study, bone marrow cells, which were harvested from tumor-bearing mice, were able to form a strong niche compared to bone marrow cells which were harvested from non-tumor-bearing mouse upon co-implantation with cancer cells. When GFP-bone marrow cells from non-tumor-bearing mice, RFP-bone marrow cells from tumor-bearing mice and dual color MMT mouse breast cancer cells expressing GFP in the nucleus and RFP in the cytoplasm were co-transplanted in the spleen of nude mice, much more RFP-bone marrow cells were observed in liver metastases formed by the breast cancer cells compared to GFP-bone marrow cells. Thus bone marrow derived from tumor bearing animals appeared to play a role in metastasis formation compared to bone marrow derived from naïve animals. The results suggest that bone marrow and cancer cells mutually affect each other.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 466. doi:10.1158/1538-7445.AM2011-466
Abstract 4660: The National Cancer Human Biobank: CaHUB
Authors: Sawyer Sherilyn J. , Myers Kimberly , Anthony Dickherber , Benkesser Rachel , Fombonne Benjamin , Litwack David , Thomas Mary , Lockhart Nicole , Rogers Joyce , Vaught Jim , Compton Carolyn
Published: June 2012

The Cancer Human Biobank (caHUB) is the first centralized and public biorepository for human biospecimens in the United States. Established by the National Cancer Institute (NCI) Office of Biorepositories and Biospecimen Research (OBBR), caHUB builds upon the foundation of evidence-based biospecimen resource management practices established by the OBBR Biospecimen Research Network (BRN) and the NCI Best Practices for Biospecimen Resources. The mission of the caHUB is to ensure an adequate and continuous supply of high-quality, highly annotated human biospecimens and provide unique biobanking services for the cancer research community. With a goal of fostering collaboration, communication, education, and the public trust, caHUB will be established as a public-private partnership, working with the broader cancer community, including basic and clinical researchers, advocacy organizations, and pharmaceutical and biotechnology companies.

caHUB is a unique centralized biospecimen resource. In response to input from the scientific community, caHUB is focused on providing biospecimens and data collected according to the highest technical and ethical standards, developing biospecimen reference samples that serve as benchmarks for specimen integrity and molecular type, conducting research that supports evidence-based biospecimen best practices, and creating opportunities for collaboration and information exchange across the research enterprise. Through caHUB, the NCI seeks to address the shortage of highly-annotated research biospecimens collected under rigorous standards too costly for private organizations to pursue but required to address difficulties in validation of human biospecimen research results for scientific and regulatory purposes.

caHUB is actively seeking the involvement of the cancer research community and supports engagement through three models of collaboration: 1) as customers seeking access to caHUB‘s Biospecimen Collections and Services; 2) as collaborative research partners who require caHUB to assist with specimen collections and analysis; and 3) as partners interested in information exchange with or financial support of this public initiative. For all interested parties, more information is available at http://cahub.cancer.gov.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4660. doi:10.1158/1538-7445.AM2011-4660
Abstract 4661: Analysis of DNA adducts: Development of a high-performance analytical platform to meet challenges in human health
Authors: Schmitz Oliver Johannes , Deibel Eduard , Ebersbach Ina
Published: June 2012

The outstanding selectivity and sensitivity of the atmospheric pressure laser ionization (APLI), which is a two-photon ionization process, in combination with a mass spectrometric detection, is demonstrated for the analysis of DNA adducts.

Preparative HPLC with a HILIC-phase and a fraction sampler was used to separate the polar 4-hydroxy-1-(3-pyridyl)-butanone (HPB) and 4-hydroxy-1-(3-pyridyl)-butanol (Diol), which will be formed after acid hydrolysis of the POB- and PHB-DNA adducts. The adducts eluted in the fractions to be analyzed were collected, concentrated to dryness and dissolved in dichloromethane. Then 4-(dimethylamino)pyridine as a base, N,N′-dicyclohexylcarbodiimide as an activator and anthracene-9-yl-methoxyacetic acid as an ionization marker, in analogy to a fluorescence marker, were added, and after several hours at 35 °C the sample was injected into an HPLC-APLI-TOF(MS). With this novel method, only aromatic compounds are ionizable; because the ionization marker of the DNA adducts carries an aromatic group, this allows ionization by the two-photon process.

For the first time we have used a new strategy to analyse DNA adducts by HPLC-APLI-TOF(MS) after derivatization with an ionization marker. To demonstrate the utilizability of this method, we analyzed POB and PHB adducts, which are formed by metabolic activation pathways from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N′-nitrosonornicotine (NNN).

In summary, we have demonstrated that the derivatization strategy significantly increases the analytical applicability of APLI-MS and shows new methods for the important DNA adduct analysis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4661. doi:10.1158/1538-7445.AM2011-4661
Abstract 4669: Genetic variations in telomere pathway genes and ovarian cancer risk, survival and treatment response
Authors: Wang Yan , Lu Karen H. , Lin Jie , Huang Maosheng , Wu Xifeng , Liang Dong
Published: June 2012

Telomere dysfunction has been associated with genomic instability and cancer development. Genetic variations in telomere pathway genes may lead to telomere dysfunction and affect cancer risk and outcome. In this retrospective study, we evaluated the associations between common genetic variations in telomere pathway genes and ovarian cancer risk, survival and treatment response in a population of 417 cases and 417 controls. 472 single nucleotide polymorphisms (SNPs) were selected from 42 genes potentially influencing telomere length, telomerase activity, and telomere-associated protein complex. Twenty SNPs were associated with overall ovarian cancer risk at P < 0.01. Two synonymous SNPs from the TEP1 gene, rs938887 and rs2228026, exhibited the strongest association with odds ratios (ORs) of 3.88 (95% CI, 1.42-10.59) and 3.28 (95% CI, 1.72-6.29), respectively. Seven SNPs were associated with overall survival of ovarian cancer at P < 0.01, and five of them presented higher-order gene-gene interactions as suggested by survival tree analysis. Survival tree analysis categorized patients into low, medium and high risk groups with progressively decreased medium survival time based on distinct genotype combinations. In the analysis of response to chemotherapy, 15 SNPs reached a significance level of P ≤ 0.01. SNP rs7826180 in the intronic region of PINX1 gene was shown to substantially increase the risk of poor response with an OR of 6.77 (95% CI, 1.68-27.27). There were significant gene-dosage effects as evidenced by the increased risk of cancer, risk of death, and risk of poor response with the increasing number of unfavorable genotypes. Our results suggest that common genetic variations in telomere pathway genes are significantly associated with ovarian cancer risk, survival, and treatment response. With further validation, these results may contribute to improve personalized risk assessment, prognosis, and treatment of ovarian cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4669. doi:10.1158/1538-7445.AM2011-4669
Abstract 4676: Survival of gastric cancer differs by ethnicity: A population-based experience from British Columbia, Canada
Authors: Bashash Morteza , Hislop T Greg , Shah Amil , Le Nhu , Brooks-Wilson Angela , Bajdik Chris
Published: June 2012

Introduction: Prognostic factors can be classified into three broad groups: i) tumor-related, ii) host-related, and iii) environment-related (health care, treatment, lifestyle) factors. The current study was conducted to examine the effect of ethnicity as a host-related factor for survival of gastric cancer patients in British Columbia, Canada.

Methods: Data were obtained from the population-based BC Cancer Registry for patients diagnosed with invasive gastric cancer between 1984 and 2006. The ethnicity of patients was estimated according to their names and categorized as Chinese, South Asian, Iranian or Other (more than 80% of “Other” are British and Western Europeans). Cox proportional hazards regression analysis was used to estimate the effect of ethnicity adjusted for patient sex and age, disease histology, tumor location, disease stage and treatment.

Results: Results from this study indicate significantly different survival of gastric cancer patients depending on their ethnic group (p<0.01). When considered separately according to the presence or absence of metastatic disease, significant differences were only found for non-metastatic disease (p<0.01). Furthermore, the association between survival and ethnicity was only significant for patients with non-metastatic disease who received therapeutic surgery (p<0.01). In multivariate analyses adjusting for patient factors, disease factors and treatment, there was a significant difference among ethnic groups. Only Chinese had significantly longer survival compared to the Other ethnicities, but this survival advantage was only seen for non-metastatic disease (HR=0.78, 95% CI=0.64-0.95).

Conclusion: The difference observed in patient survival is not likely to be due to healthcare disparities among minority groups, as all BC residents are covered for healthcare through the BC Medical Services Plan (MSP). Ethnicity may represent underlying genetic factors. Such factors could influence host-tumor interactions by altering the tumor's etiology and therefore its chance of spreading. Alternatively, genetic factors may determine response to treatments. Finally, ethnicity may represent non-genetic factors that affect survival. Differences in survival support the importance of ethnicity as a prognostic factor, and may provide clues for the future identification of genetic or lifestyle factors that underlie these observations.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4676. doi:10.1158/1538-7445.AM2011-4676
Abstract 4678: Post-diagnosis use of lipophilic statins and breast cancer recurrence: A Danish nationwide cohort study
Authors: Ahern Thomas P. , Pedersen Lars , Cronin-Fenton Deirdre P. , Tarp Maja , Silliman Rebecca A. , Sørensen Henrik Toft , Lash Timothy L.
Published: June 2012

Statins may affect non-cardiovascular endpoints, including cancer incidence and survival. These effects may depend on the solubility of the specific medicine. Our objective was to measure the association between post-diagnosis lipophilic and hydrophilic statin use and recurrence among non-metastatic breast cancer patients.

We ascertained incident cases of stage I-III invasive breast cancer diagnosed in Denmark between 1996 and 2006 from the Danish Breast Cancer Cooperative Group registry, and linked these records to the Register of Medicinal Products (RMP), which automatically logs pharmacy transactions in Denmark. We determined statin prescriptions filled by cohort members by searching the RMP for appropriate ATC codes. Statins were classified by solubility (Table 1) and exposure status was updated yearly. Follow-up began upon completion of primary therapy and continued until the first of breast cancer recurrence, death from any cause, emigration from Denmark, or the end of 2006. Associations were estimated with time-dependent crude and multivariate Cox regression models.

We enrolled 18,769 breast cancer patients, with a median follow-up of 6.2 years. Of the 3,282 women ever prescribed a statin after diagnosis, 2,518 were exclusively prescribed lipophilic statins and 210 were exclusively prescribed hydrophilic statins.

Crude and multivariate models yielded similar estimates. Lipophilic (but not hydrophilic) statin use was associated with a reduced rate of breast cancer recurrence (compared with no statin use: multivariate HR for lipophilic statin use = 0.65, 95% CI: 0.55, 0.76; multivariate HR for hydrophilic statin use = 0.89, 95% CI: 0.61, 1.3). Associations were similar when estimated in the subset of women with no pre-diagnosis statin exposure.

In this population-based prospective cohort study with complete information on prognostic and treatment variables, breast cancer patients who took lipophilic statins had a reduced rate of breast cancer recurrence.

(a) Hazard ratios adjusted for age, menopausal status, tumor stage, ER status, adjuvant hormonal therapy, type of surgery, comorbidity, and co-prescription of aspirin. Estimates were similar in models further adjusted for chemotherapy, type of surgery, receipt of radiotherapy, and co-prescription of hormone replacement therapy, NSAIDs, anticoagulants and ACE inhibitors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4678. doi:10.1158/1538-7445.AM2011-4678
Abstract 4679: A multi-stage genome-wide association study on response to chemotherapy in ovarian cancer
Authors: MacGregor Stuart , Lu Yi , Johnatty Sharon , Beesley Jonathan , Chen Xiao Qing , Fridley Brooke , Webb Penny , Gurney Howard , Harnett Paul , Haber Michelle , Goode Ellen , De Fazio Anna , Chenevix-Trench Georgia
Published: June 2012

We performed a multi-stage genome-wide association study (GWAS) for drug response in ovarian cancer. We selected 313 chemotherapy treated patients from the Australian Ovarian Cancer Study (AOCS). Patients were treated with paclitaxel/carboplatin and the trait of interest was Progression Free Survival (PFS). We maximized power for a fixed genotyping budget by genotyping individuals from the tails of the distribution: 94 with good survival and 94 with poor survival, taking into account extent of residual disease following surgery. Patients were genotyped on Illumina HumanOmni1-Quad arrays (1140419 loci).Two further cohorts with measures of PFS and whole genome data available; 134 ovarian patients from the Mayo clinic (genotyped on Illumina HumanHap 610 arrays, 620901 loci) and 68 patients from The Cancer Genome Atlas ovarian cancer set (genotyped on Illumina Human1M arrays, 1199187 loci) were meta-analyzed with the AOCS set (stage 1).

We have imputed all the stage 1 samples with reference of the 1000 Genome data to allow more direct comparison of SNPs not common to all of the arrays used (up to 6 million SNPs with good imputation quality).

Based on the chemotherapy treatment received by each patient, we assigned the patients into primary and secondary analysis, with primary analysis using a more strictly defined treatment subgroup.

We followed up the stage 1 findings by genotyping 26 SNPs in more than 3,000 samples collected from 8 study sites of Ovarian Cancer Association Consortium (OCAC). These 26 SNPs were mainly genotyped SNPs, chosen from 23 distinct regions showing the strongest association with chemotherapy response from either primary or secondary analysis. 2 SNPs showed nominal significance in the replication sample (chr 12: rs1861932, chr 22: rs708444). We are currently genotyping more regions to seek replication of the initial findings.

In summary, we sought to identify genes that underlie individual differences in chemoresistance. In the future, typing variations in these genes will be important for personalizing drug regimes for patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4679. doi:10.1158/1538-7445.AM2011-4679
Abstract 4684: Vitamin D may impair glucocorticoid cytotoxicity in acute lymphoblastic leukemia cells
Authors: Antony Reuben , Sheng Xia , Pramanik Rocky , Ehsanipour Ehsan A. , Klemm Lars , Ichihara Brian , Ng Pik Lam , Mittelman Steven D.
Published: June 2012

Vitamin D deficiency has been associated with increased incidence and mortality in several types of cancer. Vitamin D has been shown to be cytotoxic to cancer cells in vitro, and may act synergistically with chemotherapy to kill cancer cells. Although vitamin D deficiency is common in children with cancer, the clinical implications of this remain unclear. Since acute lymphoblastic leukemia (ALL) is the most common type of cancer in children and relapsed leukemia remains a major problem, the present study was designed to test our hypothesis that active Vitamin D (Calcitriol) would induce apoptosis in ALL cells and potentiate the effect of chemotherapy on ALL cells.

We cultured several human ALL cell lines and primary human ALL cells with and without Calcitriol, and quantified survival using trypan blue exclusion. Contrary to our hypothesis, Calcitriol did not negatively affect the viability or impair proliferation in the human ALL cell lines RS4; 11, SD1, BV173, or RCH-ACV, or in primary human ALL cells US7 or TXL 2. We then tested whether Calcitriol would synergize with dexamethasone, a glucocorticoid used almost universally in the treatment of childhood ALL. Again, contrary to our hypothesis, we found that rather than augment dexamethasone-induced cytotoxicity, supraphysiological doses of Calcitriol protected RS4;11 cells from the cytotoxic effect of 72 hour exposure to 100 nM dexamethasone (dexamethasone alone: 10±5% of initially plated cells viable; dexamethasone plus 300 nM Calcitriol: 27±14% of initially plated cells viable, n=4, p=0.04). More physiological doses of Calcitriol (10nM) showed similar protection (12.5±5% vs 31.5±19% of initially plated cells were viable at 72 hrs, n=4, p=0.05). Preliminary flow cytometry using Annexin/7AAD suggests that Calcitriol decreases dexamethasone-induced apoptosis in RS4;11 cells (dexamethasone alone: 94% of cells in apoptosis; dexamethasone plus 100 nM Calcitriol: 75% of cells in apoptosis, n=1)

In summary, the active form of vitamin D appears to protect ALL cells from dexamethasone. This finding could be important, since glucocorticoid sensitivity of ALL cells is highly predictive of outcome and likelihood of relapse. Our findings could have major health implications given the high prevalence of Vitamin D deficiency in children and adolescents worldwide.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4684. doi:10.1158/1538-7445.AM2011-4684
Abstract 4687: Novel functions of the AMPK pathway to maintain spindle orientation during mitosis
Authors: Thaiparambil Jose T. , Marcus Adam I.
Published: June 2012

AMP activated protein kinase (AMPK) functions as an energy sensor that regulates cell signaling. It is phosphorylated by the tumor suppressor, LKB1 at times of energy stress in both the cell polarity and motility pathways. Here we show that phosphorylated AMPKα (Thr-172) localizes to the spindle poles at gamma tubulin sites during mitosis in an LKB1-independent manner and serves as an essential regulator of mitotic spindle orientation. Phosphorylated AMPK levels peak during mitosis and siRNA-based disruption AMPK-α1& α2 function, results in spindles that are mis-oriented relative to the normal spindle axis. This phenotype is accompanied by an aberrant, double-ring actin cage that encompasses the microtubule spindle, as well as reduced astral microtubules. Similar results were obtained by live cell imaging using compound C (AMPK pharmacological inhibitor) treated cells. Molecular studies show that AMPK regulates spindle orientation through a PI3k-AKT pathway at the spindle poles that signals to myosin regulatory light chain (MRLC). We postulate that AMPK is regulating astral microtubule docking onto actin through this pathway and when compromised spindles become misaligned. Taken together, this study reveals a novel PI3K-AKT-p-AMPK-MRLC mitotic signaling axis that regulates spindle orientation during mitosis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4687. doi:10.1158/1538-7445.AM2011-4687
Abstract 4688: Met receptor tyrosine kinase cross-talk in tumorigenesis
Authors: Lai Andrea , Park Morag
Published: June 2012

The Met receptor tyrosine kinase (RTK) is a cell surface, transmembrane protein that is activated in response to the growth factor Hepatocyte Growth Factor (HGF) and initiates multiple downstream signaling pathways that predominantly promote cell migration and invasive cell growth. These processes are essential for Met-dependent signals during development. Dysregulated signaling of Met has been characterized in cancers, and include mechanisms such as point mutations, gene amplification, overexpression, and loss of negative regulation and more recently evidence of Met cross talk with other RTKs has been established. However, the role of Met cross-talk with other cell surface receptors in tumorigenesis, is still poorly understood.

Recent studies in non-small cell lung cancer cell lines have established that amplification of MET contributes to acquired resistance to the EGFR inhibitor gefitinib through phosphorylation of HER3, a member of the EGF receptor family of RTKs. As HER3 phosphorylation was demonstrated to occur under conditions of MET amplification, we have investigated whether HER3 phosphorylation and signaling is a common event in other cell lines where MET is amplified. In gastric cancer cell lines with MET amplification where Met is overexpressed and constitutively active, HER3 is phosphorylated. Met and HER3 are also found in a complex, as established through co-immunoprecipitation. Interestingly, upon treatment with a small molecule kinase inhibitor targeting Met, HER3 phosphorylation and association between the two receptors decreases. Thus, in cells that express high levels of constitutively active Met, cross-talk with other receptors, such as HER3, may be another mechanism through which Met promotes tumorigenesis. The interaction of Met with HER3 will be addressed at the mechanistic level and these data will be presented.

Kinase inhibitors that target single RTKs have proven susceptible to resistance. Inhibition of one RTK often results in upregulation of signaling through another receptor, and in this way, re-establish pathways essential for tumorigenesis. Determining how and under what conditions RTKs cross-talk with one another may allow identification of potential resistance mechanisms, as well as other targets for multi-targeted therapies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4688. doi:10.1158/1538-7445.AM2011-4688
Abstract 4692: IAP inhibitors prime childhood leukemia cells to chemotherapy-induced apoptosis in a strictly RIP1-dependent manner and exert anti-leukemic activity in a NOD/SCID mouse model in vivo
Authors: Löder Sandra , Fakler Melanie , Vanlangenakker Nele , Bertrand Mathieu , Vandenabeele Peter , Jeremias Irmela , Debatin Klaus-Michael , Fulda Simone
Published: June 2012

Defects in apoptosis contribute to poor outcome in high risk pediatric acute lymphoblastic leukemia (ALL), calling for novel strategies that counter apoptosis resistance. “Inhibitor of Apoptosis” (IAP) proteins present promising targets, since they are expressed at high levels in acute leukemia.

In the present study, we investigated the effect of small molecule IAP inhibitors alone and in combination with chemotherapeutics in ALL cell lines, primary leukemic blasts, normal peripheral blood lymphocytes and in a mouse model of pediatric ALL.

Here, we report that IAP inhibitors at subtoxic concentrations cooperate with various anticancer drugs (i.e. AraC, Gemcitabine, Cyclophosphamide, Doxorubicin, Etoposide, Vincristine, Taxol) to induce apoptosis in ALL cells in a highly synergistic manner as calculated by combination index (CI index 0.3). Also, IAP inhibitors act in concert with AraC to reduce clonogenic survival, thus demonstrating also a long-term anti-leukemic effect. Importantly, we identify RIP1 as a critical regulator of this synergism of IAP inhibitors and AraC that mediates the formation of a RIP1/FADD/caspase-8 complex via an autocrine/paracrine loop of TNFα. Knockdown of RIP1 abolishes formation of this complex and subsequent activation of caspase-8 and -3, mitochondrial perturbations and apoptosis. Similarly, pharmacological inhibition of RIP1 kinase activity by Necrostatin-1 inhibits IAP inhibitor- and AraC-triggered interaction of RIP1, FADD and caspase-8 and apoptosis. In addition, blockage of TNFα by a TNFα-neutralizing antibody profoundly attenuates the cooperativity of IAP inhibitor and AraC to induce formation of the RIP1/FADD/caspase-8 complex and apoposis. Of note, IAP inhibitors potently trigger cell death in leukemic blasts from children with ALL ex vivo and also sensitize primary leukemia cells for chemotherapy-induced cell death. In contrast to malignant cells, IAP inhibitors and AraC at equimolar concentrations are non-toxic to both resting and activated normal peripheral blood lymphocytes, pointing to a therapeutic window. Most importantly, IAP inhibitors exert potent anti-leukemic activity in vivo in a mouse model of pediatric ALL engrafted in NOD/SCID mice.

In conclusion, our findings provide first evidence that IAP inhibitors present a promising strategy to prime childhood ALL cells for chemotherapy-induced apoptosis in a RIP1-dependent manner. These data have important implications for the development of apoptosis-targeted therapies in childhood leukemia.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4692. doi:10.1158/1538-7445.AM2011-4692
Abstract 4696: TRAF2 plays a critical role in maintaining lymphocyte homeostasis by regulating the basal activities of IKK and caspase-8
Authors: Zhang Laiqun , Blackwell Ken , Yeh Wen-Chen , Mak Tak Wah , Habelhah Hasem
Published: June 2012

TRAF2 and TRAF5 are RING domain proteins, and their RING domain-mediated RIP1 ubiquitination is believed to be essential for NF-κB activation and inhibition of caspase-8-mediated cell death in response to TNFα stimulation. We have previously reported instead that TRAF2/5 double knockout (DKO) cells exhibit high basal IKK activity in unstimulated conditions, and that TNFα stimulation further increases IKK activity in the absence of RIP1 ubiquitination in TRAF2/5 DKO cells. These findings potentially revise the currently accepted model for the role of TRAF2/5 in TNFα signaling. However, most of the conclusions in the field regarding the role of TRAF2/5 in TNFα signaling are based on the studies performed in immortalized MEFs, as TRAF2 KO mice die within 10 days after birth. Notably, elimination of either TNFα or TNFR1 enhances the survival of TRAF2 KO mice. Thus, to examine the role of TRAF2 in NF-κB activation versus cell death in primary cells, we generated TRAF2 KO and TNF/TRAF2 DKO mice. Surprisingly, both IKK and caspase-8 are constitutively activated to a certain degree in thymus and spleen, but not in muscle and liver, of one week old TRAF2 KO mice. In TNF/TRAF2 DKO mice, on the other hand, the basal caspase-8 activity is completely suppressed in thymus and spleen, while the basal IKK activity still remained high compared to that in wild-type mice. In addition, caspase-8 substrates such as RIP1 and cFLIP are constitutively cleaved in thymus and spleen, but not in muscle and liver, of TRAF2 KO mice, and these cleavages were completely inhibited in TNF/TRAF2 DKO mice. Functional assays performed in primary MEFs, bone marrow macrophages and T-cells revealed that TRAF2 suppresses basal IKK activity and p100 processing through the NIK-dependent and -independent pathways. Moreover, both the basal and TNFα-induced expression of anti-apoptotic proteins are normal in these primary cells isolated from TNF/TRAF2 DKO embryos and adult mice, yet these cells remain sensitive to TNFα-induced cell death, due to the impaired recruitment of cIAP1/2 to the TNFR1 complex in the absence of TRAF2. Collectively, these data demonstrate that TRAF2 maintains lymphocyte homeostasis by negatively regulating the basal activities of IKK and caspase-8 in thymus and spleen, and that TRAF2 inhibits TNFα-induced cell death by recruiting anti-apoptotic proteins to the TNFR1 complex rather than by activating the NF-κB pathway.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4696. doi:10.1158/1538-7445.AM2011-4696
Abstract 4700: Identification and functional analysis of 9p23-24 amplified genes in human breast cancer
Authors: Wu Jack , Liu Suling , Liu Gang , Dombkowski Alan , Abrams Judith , Wicha Max , Ethier Stephen , Yang Zeng-Quan
Published: June 2012

Gene amplification is a major mechanism used by cancer cells to increase gene expression and subsequently gain a growth and survival advantage. Previously, we identified a novel amplicon at 9p23-24 region in human esophageal and breast cancer and originally cloned a novel gene GASC1 (Gene Amplified in Squamous Cell Carcinoma 1) from this amplicon. Accumulating evidence suggests common amplicons that occur in breast and other cancers contain multiple oncogenes that could play a role in cancer initiation and progression. In the current study, we aimed to comprehensively characterize the 9p23-24 amplified genes in human breast cancer. We performed array CGH analysis on a panel of cancer cell lines with the Agilent 244K microarray chip and narrowed the shortest region of overlapping (SRO) of the 9p23-24 amplicon to ∼2 Mb. Eleven genes within the SRO regions were examined for their mRNA expression by quantitative RT-PCR (qRT-PCR). Based on statistical association between copy number and expression, we confirmed GASC1 as a top candidate oncogene and identified three new potential oncogenes, UHRF2, KIAA1432 and C9orf123. Our more recent studies indicated that GASC1 is a member of a new class of oncogenes that are involved in the deregulation of histone methylation in cancer cells. We found that GASC1 induces the expression of core stemness transcription factors NANOG, SOX2 and OCT4, as well as classical oncogenes, including NOTCH1 and MYC, in breast cancer cells. On the other hand, UHRF2 encodes a nuclear protein that is involved in cell-cycle regulation. Knocking down UHRF2 slowed cell growth and inhibited colony formation of 9p23-24 amplified breast cancer cells. Furthermore, we demonstrated that expression levels of key tumor suppressing genes, including p16/INK4a, p21/WAF1 and p27/KIP1, were increased after knocking down UHRF2 in breast cancer cells. Collectively, our studies support the notion that the 9p23-24 amplicon contains multiple candidate oncogenes and may play an important role in human tumorigenesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4700. doi:10.1158/1538-7445.AM2011-4700
Abstract 4703: Mitochondrial DNA mutations affect respiratory complex-I in never-smoker lung cancer patients and contribute to lung cancer cell growth
Authors: Dasgupta Santanu , Soudry Ethan , Shao Chunbo , Mukhopadhyay Nitai D. , Yee John , Lam Stephen , Lam Wan L. , Fisher Paul B. , Sidransky David
Published: June 2012

Lung cancer is a deadly disease worldwide with smoking being the most important risk factor. In the United States, it is estimated that there will be over 222,550 cases of lung cancer resulting in 157,300 deaths in 2010. Despite significant improvement in therapeutic modalities, the overall 5-year survival rate is still only 15%. The high morbidity is due to the lack of early detection and therapeutic intervention. Other than nuclear genetic alterations, mitochondrial DNA mutations were reported in different human cancers and implicated to have a potential role in biomarker development. However, mtDNA alteration patterns and their potential involvement are unknown in lung cancer patients that have never smoked. In the present study, we sequenced the entire mitochondrial genome and measured the mtDNA content index by quantitative PCR in 60 lung cancer patients. Of the 60 patients, 30 never smoked and the remaining 30 patients were current smokers. Forty five percent of patients (27/60) displayed at least one somatic mtDNA mutation and a total of 41 mutations were detected which were mostly homoplasmic in nature. Strikingly, mtDNA mutations were significantly higher (P=0.0025) among the non-smokers as compared to the current smoking lung cancer patients and these mutations significantly affected (P=0.025) mitochondria encoded respiratory complex-I. The patients of Asian origin also had significantly higher (P=0.015) mtDNA mutations compared to the Caucasian patient populations. The mtDNA content index also significantly increased (P=0.037) in the non-smokers compared to the smoker lung cancer patients. Forced overexpression of a frequently observed mtDNA mutation from the ND5 gene of respiratory complex-I resulted in increased superoxide production, in vitro proliferation and invasion of lung cancer cells. Frequent mtDNA alterations are detectable in non-smoker lung cancer patients and may contribute to lung cancer progression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4703. doi:10.1158/1538-7445.AM2011-4703