bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 759: Metformin enhances the benefit of ALK inhibitors in ALK translocation-positive non-small cell lung cancer cells
Authors: Kim Mi Young , Kim Geum Ock , Shin Dong Hoon , Kim Tae Min , Kim Jin-Soo 
Published: August 2015

Abstract
Background: Crizotinib is an effective tyrosine kinase inhibitor (TKI) against non-small cell lung cancers (NSCLCs) with anaplastic lymphoma receptor tyrosine kinase (ALK) translocation. Recently, the second generation ALK inhibitors, including alectinib (CH5424802) and ceritinib (LDK378) are actively investigated in clinical trials and show strong anti-tumor effect both in crizotinib-naïve and refractory NSCLC patients with ALK translocation. Unfortunately, the efficacy of these ALK inhibiting TKIs is limited due to primary and acquired resistance to these agents. Metformin is a widely used antidiabetic drug and shows promising anti-tumor effect in several cancers. Here, we define a therapeutic synergism between ALK inhibitors and metformin.
Material and Methods: NSCLC cells with ALK translocation-positive (ALK+) and crizotinib-sensitive H2228 and H3122, and ALK+, crizotinib-resistant SNU2535 and ALK translocation-negative H226 were evaluated. We assessed response of these NSCLC cells to crizotinib, alectinib and ceritinib alone or in combination with metformin by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay and anchorage independent growth in soft agar. Combination indices (Cis) were calculated by CalcusynTM (Biosoft, Cambridge, UK). Western blots were performed to assess biochemical changes, especially those related with ALK signaling components.
Results: The combination of ALK inhibitors with metformin induced a strong anti-proliferative effect only in ALK+ cell lines (CI of crizotinib and metformin: 0.31 - 0.79, CI of alectinib and metformin: 0.40 - 0.86, CI of ceritinib and metformin: 0.38 - 0.65). Alectinib and ceritinib effectively inhibited growth of crizotinib-resistant SNU2535, while crizotinib did not. Notably, synergistic effects of these ALK inhibitors and metformin were also shown in SNU2535 cells. Compared to ALK inhibitor alone, the combination of ALK inhibitor plus metformin resulted in decreased phosphorylation of ALK and downstream targets, such as AKT or ERK, both in crizotinib-sensitive and resistant ALK+ cells.
Conclusion: Collectively, these data support that ALK inhibitors and metformin are synergistic in ALK+ NSCLC cells. Resistance to crizotinib as well as alectinib and ceritinib might be overcome by addition of metformin.
Citation Format: Mi Young Kim, Geum Ock Kim, Dong Hoon Shin, Tae Min Kim, Jin-Soo Kim. Metformin enhances the benefit of ALK inhibitors in ALK translocation-positive non-small cell lung cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 759. doi:10.1158/1538-7445.AM2015-759
Abstract 772: Anti-tumor efficacy of the selective pan-FGFR Inhibitor BAY 1163877 in preclinical squamous cell carcinoma models of different origin
Authors: Héroult Mélanie , Ocker Matthias , Kopitz Charlotte , Zopf Dieter , Hägebarth Andrea , Ziegelbauer Karl , Ince Stuart , Ellinghaus Peter 
Published: August 2015

Abstract
Squamous cell carcinoma (SCC) is a common subtype of lung cancer and is strongly associated with smoking. In contrast to adenocarcinomas of the lung, SCCs do not significantly harbor epidermal growth factor (EGFR) mutations or ALK, ROS1 or RET translocations, which are therapeutically tractable. SCC of the lung and SCC of the head and neck region and esophagus not only share risk factors, morphologic features and mechanisms of tumorigenesis but also frequent fibroblast growth factor receptor 1 (FGFR1) gene alterations. In addition, we found that FGFR2 and FGFR3 expression were also altered in patient derived models of SCC of various origins. FGFRs may thus represent viable therapeutic targets for the treatment of SCC.
BAY 1163877, an orally available and potent inhibitor of FGFR1, FGFR2 and FGFR3, inhibited SCC cell proliferation as well as downstream FGFR signaling in vitro. When applied in vivo, BAY 1163877 was able to reduce growth of a FGFR1-overexpressing lung SCC xenograft model, a FGFR1-overexpressing esophageal SCC xenograft model, and a FGFR3-overexpressing head and neck SCC xenograft model, achieving reductions in tumor growth by 67 to 92% as compared to the vehicle control. BAY 1163877 was very well tolerated in all models performed.
These data suggest that selective inhibition of FGFR1 to 3 with BAY 1163877 might have therapeutic potential for the treatment of SCC malignancies. A phase I clinical trial (NCT01976741) to determine the safety, tolerability and recommended Phase 2 dose in advanced cancer patients is ongoing.
Citation Format: Mélanie Héroult, Matthias Ocker, Charlotte Kopitz, Dieter Zopf, Andrea Hägebarth, Karl Ziegelbauer, Stuart Ince, Peter Ellinghaus. Anti-tumor efficacy of the selective pan-FGFR Inhibitor BAY 1163877 in preclinical squamous cell carcinoma models of different origin. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 772. doi:10.1158/1538-7445.AM2015-772
Abstract 8: Differential roles of OCT3/4, SOX2 and NANOG for constitutive high NOXA expression levels in embryonal carcinoma (EC) cells
Authors: Bayha Christine , Gutekunst Matthias , Aulitzky Walter E. , van der Kuip Heiko 
Published: August 2015

Abstract
Recently we found that hypersensitivity of embryonal carcinoma (EC) to chemotherapy is mediated by high constitutive levels of NOXA protein. This pro-apoptotic BH3-only protein primes EC cells to undergo rapid and massive apoptosis in response to p53 activation. Both hypersensitivity as well as high NOXA protein levels were lost upon differentiation in these cells. We here investigated the role of three key regulators of pluripotency, namely OCT3/4, SOX2 and NANOG for NOXA protein and transcript (PMAIP1) expression in two EC cell lines, the pluripotent NTERA-2D1 and the nullipotent 2102EP. We found that siRNA-mediated silencing of POU5F1 (OCT3/4) led to a down-regulation of PMAIP1 mRNA by ∼80% and to an almost complete loss of NOXA protein (by &gt;90%). On the other hand, silencing of SOX2 or NANOG only slightly reduced transcript levels (by ∼20% and ∼30%, respectively). At the same time, a distinct down-regulation of NOXA protein levels (by ∼75%) was observed in SOX2- and NANOG-deprived cells, respectively. These data indicate that the high constitutive levels of NOXA in EC cells depend on two independent mechanisms, (1) transcriptional regulation predominantly mediated by OCT3/4, and (2) post-transcriptional regulation mediated by either one of the stem cell factors. Indeed, we found that siRNA-mediated loss of one stem cell factor led to a ∼2fold reduction of NOXA protein stability in both cell lines reaching a NOXA half-life of approximately 2 hours, which was comparable to that observed in PHA stimulated lymphocytes from normal donors.
These data demonstrate that the high constitutive levels of NOXA protein in EC cells are due to OCT3/4 dependent induction of the PMAIP1 transcript and a prolonged NOXA protein stability mediated by either one of the stem cell factors.
Citation Format: Christine Bayha, Matthias Gutekunst, Walter E. Aulitzky, Heiko van der Kuip. Differential roles of OCT3/4, SOX2 and NANOG for constitutive high NOXA expression levels in embryonal carcinoma (EC) cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 8. doi:10.1158/1538-7445.AM2015-8
Abstract 807: Parental radiation elicits increased intestinal tumorigenesis in the F1 generation of APCMin/+ and APC1638N/+ mice
Authors: Suman Shubhankar , Kumar Santosh , Moon Bo-Hyun , Fan Ziling , Fornace Albert J. , Datta Kamal 
Published: August 2015

Abstract
The risk of colorectal cancer (CRC) has been reported to increase with radiation exposures as well as with a positive family history. Radiation exposure has also been implicated in inducing heritable changes in parental germline cells and thus increasing risk of cancer in the offspring. However, effects of parental radiation exposure on trans-generational colorectal carcinogenesis in offspring have not been explored yet. We employed two well-characterized mouse models (APCMin/+ and APC1638N/+) of human CRC to determine trans-generational effects of low dose radiation on colorectal carcinogenesis. Male APCMin/+ and APC1638N/+, and female C57BL/6J mice were exposed to whole body 25 cGy of x rays. Mating was initiated two days after radiation exposure, F1 offspring were genotyped, and male and female APCMin/+ and APC1638N/+ were grouped and housed separately. APCMin/+ mice were euthanized 150 days after birth, APC1638N/+ mice after 210 days, and tumor frequency and size in intestine and colon were noted. Significantly increased intestinal tumor frequency and increased numbers of larger tumors were observed in F1 mice of irradiated parents relative to F1 mice of sham-irradiated parents. Greater trans-generational tumorigenic effects of radiation were observed in male offspring relative to female offspring. In conclusion, here we present an early report for the first time that low dose radiation exposure has a trans-generational effect on intestinal tumorigenesis with potential implications for radiation exposure-related human health consequences.
Citation Format: Shubhankar Suman, Santosh Kumar, Bo-Hyun Moon, Ziling Fan, Albert J. Fornace, Kamal Datta. Parental radiation elicits increased intestinal tumorigenesis in the F1 generation of APCMin/+ and APC1638N/+ mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 807. doi:10.1158/1538-7445.AM2015-807
Abstract 809: BrafV637E mutation as an early change in hepatocarcinogenesis induced by neonatal treatment with diethylnitrosamine in B6C3F1 mice
Authors: Yamamoto Masahiro , Tanaka Hiroki , Bing Xin , Nishikawa Yuji , Yamazaki Kohsuke , Shimizu Keiko , Ogawa Katsuhiro 
Published: August 2015

Abstract
Neonatal treatment of B6C3F1 mice with diethylnitrosamine (DEN) is often employed as an experimental model for hepatic tumors. In this model, microscopic preneoplastic foci emerge in the early stage and subsequently progress into adenomas, from which hepatocellular carcinoma (HCC) is finally developed. We detected the BrafV637E mutation, that is correspondent to the human BrafV600E mutation, in 4/4 DEN-induced hepatic tumors at 13 months after DEN treatment by whole exome analysis, and further in 16/17 (94.1%) late tumors by the PCR-direct sequencing method. By microdissection, the BrafV637E mutation was also detected in 16/18 (88.8%) and 22/28 (78.5%) microscopic lesions (preneoplastic foci and microadenomas) respectively at 5 and 8-9 months after DEN treatment. Meanwhile, although the BrafV637E mutation was detected in 5/7 (71.4%) hepatic tumors induced by neonatal DEN treatment followed by repeated CCl4 administration, it was not found in 24 hepatic tumors induced by CCl4 alone and 6 spontaneous hepatic tumors in B6C3F1 mice, indicating that the BrafV637E mutation is specific to the DEN-initiated hepatic tumors, presumably being derived from the genotoxic action of DEN. The DEN-induced tumors showed hyperphosphorylation of MEK and ERK1/2, indicating that the BrafV637E mutation activated the downstream MAPK pathway. Furthermore, the DEN-induced tumors overexpressed the pro-survival/pro-proliferative cytokines/chemokines such as complement C5/C5a, soluble intercellular adhesion molecule (sICAM-1), IL-1 receptor antagonist (IL-1ra) and chemokine CXCL9 as well as the oncogene-induced senescence (OIS) markers, p15Ink4b and p19Arf mRNAs, suggesting that the BrafV637E mutation might influence the gene expression that is involved either in cellular growth/survival or OIS. Transgenic mice expressing BrafV637E specifically in the liver under the control of albumin promoter showed enlarged hepatic mass as large as 4-5 times of normal liver, and whole liver was consisted of small basophilic hepatocytes resembling the cells in the early preneoplastic lesions induced by neonatal treatment with DEN. These results indicate that the BrafV637E mutation plays a pivotal role in the DEN-induced hepatocarcinogenesis.
Citation Format: Masahiro Yamamoto, Hiroki Tanaka, Xin Bing, Yuji Nishikawa, Kohsuke Yamazaki, Keiko Shimizu, Katsuhiro Ogawa. BrafV637E mutation as an early change in hepatocarcinogenesis induced by neonatal treatment with diethylnitrosamine in B6C3F1 mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 809. doi:10.1158/1538-7445.AM2015-809
Abstract 838: Household stove improvement and lung cancer mortality in Xuanwei, China: A 33-years’ follow-up study
Authors: Seow Wei Jie , Li Wen-Qing , Chapman Robert S. , Hu Wei , Vermeulen Roel , He Xingzhou , Bassig Bryan A. , Kim Christopher , Rothman Nathaniel , Lan Qing 
Published: August 2015

Abstract
Background: Household stove improvement from unvented stoves to stoves with chimney (vented stoves) and portable stoves has been shown to reduce lung cancer mortality in our prior cohort study in Xuanwei county, China (1976-1992). It remains unclear whether the protective effects against lung cancer mortality persist over time with extended follow-up (1993-2009). In our study, we examined the associations between vented stove and portable stove use with risk of lung cancer mortality based on a 33 years’ follow-up in Xuanwei.
Methods: A total of 42,422 individuals in Xuanwei were retrospectively followed from 1976 through 1992, and prospectively followed to 2009. Extensive information on household stove and fuel use at different age periods during the lifetime was collected in the 1992 and 2009 follow-up surveys. Lung cancer mortality data were obtained by integrating the information from hospital records and death certificates. Multivariable Cox regression models were used to estimate the hazard ratio (HR) of lung cancer mortality associated with stove improvement, adjusting for potential confounders.
Results: We observed a significant reduction in lung cancer mortality associated with improvement to vented stoves (multivariate-adjusted HR = 0.43, 95% confidence interval (CI) = 0.40-0.47) and portable stoves (multivariate-adjusted HR = 0.21, 95% CI = 0.19-0.24). There was a monotonic trend towards a decreased risk of lung cancer mortality with increasing years since stove improvement to vented stoves and portable stoves (P-trend for both &lt;0.0001). Similar associations were observed for both men and women.
Conclusions: Household stove improvement to both vented stoves and portable stoves were inversely associated with risk of lung cancer mortality. These findings have important public health implications for nearly 3 million people who still use solid fuels for cooking and heating in homes, particularly in developing countries.
Citation Format: Wei Jie Seow, Wen-Qing Li, Robert S. Chapman, Wei Hu, Roel Vermeulen, Xingzhou He, Bryan A. Bassig, Christopher Kim, Nathaniel Rothman, Qing Lan. Household stove improvement and lung cancer mortality in Xuanwei, China: A 33-years’ follow-up study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 838. doi:10.1158/1538-7445.AM2015-838
Abstract 850: Hepatitis B virus genotype, mutations, human leukocyte antigen polymorphisms and their interactions in hepatocellular carcinoma: a multi-centre case-control study
Authors: Wen Juan , Song Ci , Jiang Deke , Jin Tianbo , Zhai Xiangjun , Xu Jianfeng , Shen Hongbing , Hu Zhibin 
Published: August 2015

Abstract
Objective:Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Our aim was to evaluate the effects of the hepatitis B virus (HBV) genotype, mutations, HLA single nucleotide polymorphisms (SNPs) and their interactions on HCC risk.
Methods: A multi-centre case-control study of 1,507 HBV-related HCC cases and 1,560 HBV persistent carriers as controls was performed. HBV genotype, mutations and genome-wide association studies (GWAS)-identified HLA-DQ/DR SNPs (rs9272105 and rs9275319) were detected.
Results: We found that the frequencies of the HBV genotypes B and BC (coinfection) were varied among the studied areas, but genotype C was consistently more frequent in HBV-related HCC (80.6% among HCC vs. 34.4% among the controls). Moreover, 11 HBV hotspot mutations in the EnhII/BCP/PC region were independently and significantly associated with HCC risk. We also detected significant interactions of HLA-DQ/DR rs9272105 with both the HBV genotype and mutations (P &lt; 0.05 for each), but there were not significant interactions for rs9275319. Through a stepwise regression analysis, the HBV genotype, the 11 mutations, HLA-DQ/DR rs9272105 and rs9275319, and the interaction of the mutation A1752G with rs9272105 were all entered into the prediction model of HCC, and the area under the curve (AUC) for the panel including the HLA-DQ/DR SNPs, HBV genotype and mutations was 0.840 (sensitivity = 81.3%, specificity = 74.8%).
Conclusions: The HBV genotype, the mutations and the HLA-DQ/DR SNPs may serve as biomarkers for the surveillance of HBV persistent carriers. Large studies with prospective designs are warranted to further evaluate our results.
Note: This abstract was not presented at the meeting.
Citation Format: Juan Wen, Ci Song, Deke Jiang, Tianbo Jin, Xiangjun Zhai, Jianfeng Xu, Hongbing Shen, Zhibin Hu. Hepatitis B virus genotype, mutations, human leukocyte antigen polymorphisms and their interactions in hepatocellular carcinoma: a multi-centre case-control study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 850. doi:10.1158/1538-7445.AM2015-850
Abstract 862: Association of non-steroidal anti-inflammatory drugs with colorectal cancer by subgroups in the Vitamins and Lifestyle (VITAL) Study
Authors: Wang Xiaoliang , Peters Ulrike , Potter John D. , White Emily 
Published: August 2015

Abstract
Background: There is substantial evidence that use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of colorectal cancer (CRC), but no subgroup has been identified for which the chemoprevention effect outweighs the risk of side effects. Methods: We tested the interaction between NSAID use and multiple risk factors on CRC risk in the VITAL cohort. A total of 73,458 individuals aged 50-76 completed a questionnaire between 2000 and 2002, and 674 incidental colorectal cancer cases were identified through 2010. Results: In stratified analysis, high use of any type of NSAIDs (4+days/week for 4+ years) was statistically significantly associated with a lower risk of CRC across all subgroups stratified by sex, BMI, physical activity, smoking, alcohol intake, screening and dietary factors, with a suggestion of stronger association among men, obese individuals, and heavier drinkers; however, none of these tests for interaction reached statistical significance. The associations were almost identical for subjects with higher overall CRC risk scores (HR: 0.62; 95% CI: 0.49-0.79) and those with lower risk scores (HR: 0.61; 95% CI: 0.42-0.88). Differential effects by cancer subsites and stages were tested. NSAID use was associated with a greater risk reduction of proximal colon cancer vs distal (p for difference = 0.06) and distant stage vs local (p for difference = 0.04). Conclusion: The association between high use of NSAIDs and CRC risk does not differ significantly among subgroups. Impact: Our results suggest that NSAIDs have a generally beneficial role in colorectal cancer prevention, largely unmodified by other exposures.
Citation Format: Xiaoliang Wang, Ulrike Peters, John D. Potter, Emily White. Association of non-steroidal anti-inflammatory drugs with colorectal cancer by subgroups in the Vitamins and Lifestyle (VITAL) Study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 862. doi:10.1158/1538-7445.AM2015-862
Abstract 865: Physical inactivity increases the risk of endometrial cancer and premenopausal breast cancer
Authors: Johnsson Anna , Broberg Per , Johnsson Anders , Tornberg Åsa , Olsson Håkan 
Published: August 2015

Abstract
Background. Epidemiological studies indicate that physical activity reduces the risk of cancer. Physical inactivity or sedentary behavior, has recently been suggested as a risk factor independent of physical activity level. Breast and endometrial cancer incidence have both been associated with physical activity, and endometrial cancer incidence with physical inactivity/sedentary behavior. The purpose of the present study was to investigate physical inactivity as a risk factor for breast cancer, divided into pre- and postmenopausal subtypes, and for endometrial cancer, and to explore possible dose-response relations regarding the level of physical inactivity.
Methods. In a population-based prospective cohort study, 29 520 women in the southern part of Sweden, in ages between 25 and 64 years, participated. A questionnaire-based survey was performed 1990-92. Their reported professions were classified as sedentary or not which together with reported participation in competitive sports constituted the basis for classification into three activity-levels; (1) physical inactivity, defined as having sedentary occupation and no participation in competitive sports, (2) partly inactive, defined as either having a sedentary occupation or non- participation in competitive sports, (3) Physical active, defined as not having a sedentary occupation and participation in competitive sports. The association between physical inactivity and pre and postmenopausal breast and endometrial cancer incidence were analyzed by Cox regression, adjusted for hormonal factors, family history of cancer, body mass index (BMI) and age.
Results. Physical inactive women had a significantly increased risk of endometrial cancer (HR = 2.41, 95% CI 1.14-5.11) and premenopausal breast cancer (HR = 2.40, 95% CI 1.14-5.02), compared with women who were less physical inactive. No such association was found for postmenopausal breast cancer. Analysis of linear trend showed a significant dose-response relationship with increased risk of both premenopausal breast cancer (ptrend 0.02) and endometrial cancer (ptrend &lt;0.01).
Conclusions. In the current study we found an increased incidence of premenopausal breast cancer and endometrial cancer in physical inactive women and a linear trend indicating dose-response relationship. Not only physical activity but also the avoidance of physical inactivity may reduce the risk of premenopausal breast cancer and endometrial cancer.
Citation Format: Anna Johnsson, Per Broberg, Anders Johnsson, Åsa Tornberg, Håkan Olsson. Physical inactivity increases the risk of endometrial cancer and premenopausal breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 865. doi:10.1158/1538-7445.AM2015-865