bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2274: Metformin use and risk of lung cancer in patients with diabetes.
Authors: Sakoda Lori C. , Achacoso Ninah S. , Quesenberry Charles P. , Peng Tiffany , Ehrlich Samantha F. , Ferrara Assiamira , Habel Laurel A. 
Published: August 2014

Abstract
Observational studies suggest that cancer incidence is lower in patients with type 2 diabetes treated with metformin, relative to patients treated with other diabetes medications. The few studies to examine metformin use in relation to lung cancer risk, however, have produced inconsistent results. To clarify this relationship, we conducted a retrospective cohort study of 50,722 adults aged 40 years or older included in the Kaiser Permanente Northern California Diabetes Registry, who completed a mailed survey administered in 1994 to 1996 on health-related traits and behaviors. All prescribed diabetes medications were identified for each patient from pharmacy records. Patients were followed for lung cancer from 1997 to 2009, with a median follow-up of 8.1 years. Using Cox regression, with age as the time scale, rate ratios (RR) and 95% confidence intervals (CI) were calculated to estimate risk of lung cancer associated with new use of metformin, adjusted for sex, race/ethnicity, smoking status, income, education level, diabetes duration, baseline measures of hemoglobin A1c and creatinine, and ever use of other types of diabetes medications. Measures of metformin use, along with ever use for each type of diabetes medication, were modeled as time-dependent variables. During 389,887 person-years of follow-up, 685 patients were diagnosed with lung cancer. The adjusted RR for ever use of metformin was 0.95 (95% CI, 0.79-1.14). For duration of metformin use, the adjusted RRs for &lt;2.0, 2.0-4.9, and 5.0+ years were 1.01 (95% CI, 0.80-1.28), 0.94 (95% CI, 0.73-1.22), and 0.86 (95% CI, 0.63-1.18), respectively. In analyses stratified by smoking status, the adjusted RRs for ever use of metformin were 0.98 (95% CI, 0.79-1.21) in ever smokers and 0.59 (95% CI, 0.34-1.01) in never smokers. However, in never smokers, the number of users diagnosed with lung cancer was relatively small, and no dose-response decrease in risk with increasing duration of metformin use was found; the corresponding adjusted RRs for &lt;2.0, 2.0-4.9, and 5.0+ years of metformin use were 0.52 (95% CI, 0.23-1.16), 0.58 (95% CI, 0.26-1.26), and 0.70 (95% CI, 0.31-1.58), respectively. Our results suggest that metformin use is not associated with lung cancer risk in former or current smokers with diabetes. Additional research is needed to determine whether metformin use might alter lung cancer risk in never smokers with diabetes.
Citation Format: Lori C. Sakoda, Ninah S. Achacoso, Charles P. Quesenberry, Tiffany Peng, Samantha F. Ehrlich, Assiamira Ferrara, Laurel A. Habel. Metformin use and risk of lung cancer in patients with diabetes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2274. doi:10.1158/1538-7445.AM2013-2274
Abstract 2294: ROCK1 inhibition promotes the self-renewal of a novel mouse mammary cancer stem cell.
Authors: Maurer Jochen , Castro David J. , Oshima Robert G. 
Published: August 2014

Abstract
The differentiation of stem-like tumor cells may contribute to the cellular heterogeneity of breast cancers. We report the propagation of highly enriched mouse mammary cancer stem cells that retain the potential to differentiate both in vivo and in culture and their use to identify chemical compounds that influence both self-renewal and differentiation. We identify epithelial tumor initiating cells (ETICs) that express lineage markers of both basal and luminal mammary cell lineages and retain the potential, from even single cells, to generate heterogeneous tumors similar to the tumor of origin. ETICs can progress through a Rho associated coiled-coil containing protein kinase 1 (ROCK1) dependent, epithelial to mesenchymal transition to generate mesenchymal tumor initiating cells (MTICs) capable of initiating tumors of limited heterogeneity. The propagation of ETICs may allow for the identification of new therapeutic compounds that may inhibit or prevent progression of some types of breast cancer.
Citation Format: Jochen Maurer, David J. Castro, Robert G. Oshima. ROCK1 inhibition promotes the self-renewal of a novel mouse mammary cancer stem cell. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2294. doi:10.1158/1538-7445.AM2013-2294
Abstract 2319: Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression.
Authors: Luo Weibo , Chang Ryan , Zhong Jun , Pandey Akhilesh , Semenza Gregg L. 
Published: August 2014

Abstract
Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that play key roles in breast cancer biology. We hypothesized that interaction of HIF-1 with epigenetic regulators may increase HIF-1 transcriptional activity and thereby promote breast cancer progression. We report that the histone demethylase jumonji domain containing protein 2C (JMJD2C) selectively interacts with HIF-1α, but not HIF-2α, and that HIF-1α mediates recruitment of JMJD2C to the hypoxia response elements (HREs) of HIF-1 target genes. JMJD2C decreases trimethylation of histone H3 at lysine 9, and enhances HIF-1 binding to HREs, thereby activating transcription of BNIP3, LDHA,PDK1, and SLC2A1, which encode proteins that are required for metabolic reprogramming, as well as LOXL2 and L1CAM, which encode proteins that are required for lung metastasis. JMJD2C expression is significantly associated with expression of GLUT1, LDHA, PDK1, LOX, LOXL2, and L1CAM mRNA in human breast cancer biopsies. JMJD2C knockdown inhibits breast tumor growth and spontaneous metastasis to the lungs of mice following mammary fat pad injection. Taken together, these findings establish a novel epigenetic mechanism that stimulates HIF-1-mediated transactivation of genes encoding proteins involved in metabolic reprogramming and lung metastasis in breast cancer.
Citation Format: Weibo Luo, Ryan Chang, Jun Zhong, Akhilesh Pandey, Gregg L. Semenza. Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2319. doi:10.1158/1538-7445.AM2013-2319
Abstract 2321: Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS signaling.
Authors: Will Marie , Toy Weiyi , Yao Zhan , Poulikakos Poulikos , Rodrik-Outmezguine Vanessa , Schneider Claudia , Paul Juliane , Baselga Jose , Liu Ningshu , Rosen Neal , Chandarlapaty Sarat 
Published: August 2014

Abstract
Hyperactivation of the PI3K/AKT/mTOR pathway in tumors causes feedback inhibition throughout the signaling network, including inhibition of receptor tyrosine kinase (RTK) expression and function. Exposure of these tumors to mTOR or AKT inhibitors relieves this feedback and reactivates RTK signaling. RTK reactivation promotes PI3K activity and attenuates the antitumor effects of the drugs. We have now characterized the details of PI3K-induced feedback using a selective class 1 PI3K inhibitor and compared its effects with those elicited by a selective allosteric inhibitor of AKT. In breast cancer cell lines with dysregulation of PI3K signaling, both drugs cause marked inhibition of AKT phosphorylation and relief of feedback inhibition of HER3, IGF1, and insulin RTKs. Whereas both inhibitors cause tumor cells to undergo growth arrest, only the PI3K inhibitor causes a rapid induction of apoptosis within 2 hours of drug addition. As opposed to the PI3K inhibitor, the AKT inhibitor induces PI3K activity and a set of substrates that are inhibited by the PI3K inhibitor. We therefore sought to identify processes that are selectively inhibited by the PI3K inhibitor to explain its selective induction of apoptosis.
AKT inhibition causes the induction of ERK phosphorylation in these cells. In contrast, we found that PI3K inhibition causes rapid inhibition of RAS-GTP levels, RAF activation and ERK phosphorylation in tumor cells with wild type RAS, but not those with mutant RAS. Inhibition of RAS is transient, recovering 2-3 hours after drug addition. We determined that adding MEK inhibitors to AKT inhibitors is similarly associated with a rapid induction of apoptosis within 2 hours. Moreover, addition of EGF to tumor cells co-treated with PI3K inhibitors prevents ERK inhibition and apoptosis, whereas addition of MEK inhibitors to the PI3K inhibitor, EGF treated cells restores the apoptotic phenotype.
We conclude that PI3K is upstream of both RAS and AKT in RAS wild type tumors. Inhibitors of PI3K cause sustained inhibition of AKT and transient inhibition of RAS with both effects required for rapid induction of apoptosis. These data suggest that pulsatile inhibition of PI3K may maximize the therapeutic efficacy of this approach.
Citation Format: Marie Will, Weiyi Toy, Zhan Yao, Poulikos Poulikakos, Vanessa Rodrik-Outmezguine, Claudia Schneider, Juliane Paul, Jose Baselga, Ningshu Liu, Neal Rosen, Sarat Chandarlapaty. Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2321. doi:10.1158/1538-7445.AM2013-2321
Abstract 2330: NSC319726 reactivates zinc-binding p53 mis-sense mutants using a novel dual mechanism.
Authors: Yu Xin , Lubin David , Narayanan Sumana , Vazquez Alexei , Loh Stewart , Levine Arnold J. , Carpizo Darren R. 
Published: August 2014

Abstract
TP53 is the most commonly mutated gene in human cancer for which no effective targeted anti-cancer drug exists. We identified NSC319726 (726) as a mutant p53 reactivating compound, and a lead compound for mutant p53 targeted drug development. Prior evidence indicated that the effects of 726 were allele-specific, by restoring wildtype structure and function to the third most common p53 mis-sense mutant (p53-R175H). This effect was dependent on the zinc-chelating and redox modulating properties of 726. The p53 protein binds a single zinc ion which is necessary for proper p53 structure and function. The p53-R175H mutation impairs the protein from binding zinc causing it to mis-fold and lose transcriptional function. We have investigated these properties of 726 in the mechanism of p53-R175H reactivation and provide evidence for a novel “dual” mechanism where 726 restores wild-type structure to the p53-R175H using a zinc-metallochaperone function to provide an optimal concentration of zinc to facilitate proper folding. We also demonstrate that the redox modulating properties of 726 function to transactivate the newly conformed p53-R175 and induce an apoptotic program. Lastly, we demonstrate that this zinc-metallochaperone function applies to other p53 mis-sense mutants with impaired zinc binding. This later finding extends the potential pool of patients that could be impacted by the clinical development of 726 as a mutant p53 targeted anti-cancer drug.
Citation Format: Xin Yu, David Lubin, Sumana Narayanan, Alexei Vazquez, Stewart Loh, Arnold J. Levine, Darren R. Carpizo. NSC319726 reactivates zinc-binding p53 mis-sense mutants using a novel dual mechanism. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2330. doi:10.1158/1538-7445.AM2013-2330
Abstract 234: Inhibition of the NOTCH transcription factor complex by a novel hybrid protein leads to effective tumor therapy.
Authors: Epenetos Agamemnon A. , Kousparou Christina , Stylianou Spyros , Deonarain Mahendra , Filipovic Aleksandra 
Published: August 2014

Abstract
The Notch pathway has been implicated in the generation and propagation of cancer stem cells and is thus an attractive target for therapy. We have generated a hybrid protein (Antp-DNMAML) consisting of the truncated version of Mastermind-like (MAML) that behaves in a dominant negative (DN) fashion inhibiting Notch, and the cell penetrating peptide Antennapedia (Antp). Results indicate that the Antp-DNMAML translocates into the nucleus, suppresses Notch activation, reverts the transformed phenotype, inhibits the anchorage-dependent growth and induces self contact inhibition and apoptosis in tumorigenic human breast cancer cells. More significantly, there is direct evidence that inhibiting Notch signaling at the transcriptional level with the Antp-DNMAML protein, suppresses the expression of downstream Notch targets and inhibits tumor growth in nude mice, without organ or systemic toxicity. In summary, intracellular delivery of dominant-negative transcription complex proteins using the Antp platform is a new and specific approach for cancer therapy .
Citation Format: Agamemnon A. Epenetos, Christina Kousparou, Spyros Stylianou, Mahendra Deonarain, Aleksandra Filipovic. Inhibition of the NOTCH transcription factor complex by a novel hybrid protein leads to effective tumor therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 234. doi:10.1158/1538-7445.AM2013-234
Abstract 2346: A B-RAF-MEK complex reveals a kinase-independent role for BRAF in MAPK pathway suppression.
Authors: Shiva Malek , Haling Jacob R. , Sudhamsu Jawahar , Morales Tony , Peck Ariana , Yen Ivana , Brandhuber Barbara , Hymowitz Sarah 
Published: August 2014

Abstract
The Ras/RAF/MEK/ERK signaling pathway (MAPK pathway) plays a major role in growth factor-mediated cell proliferation and is frequently activated by mutation in human cancers. The precise mechanism of pathway activation is dependent on the underlying mutation. Thus, the recurrent B-RAFV600E mutation, which is found in more than 60% of melanomas, promotes MAPK pathway signaling independent of RAS activation whereas activating K-RAS mutations drive MAPK signaling through C-RAF activation. The hallmarks of C-RAF activation include B and C-RAF heterodimerization, membrane localization and C-RAF phosphorylation. In this work, we have discovered that in addition to its ability to activate the pathway through B-RAF/C-RAF dimerization, B-RAF suppresses the MAPK pathway through formation of a stable B-RAF/MEK complex in the cytoplasm of B-RAFWT and K-RAS mutant (K-RASMT) tumor lines. To understand the molecular mechanism of the B-RAF/MEK interaction, we have determined the crystal structure of a heterotetrameric B-RAF:MEK1 complex in which B-RAF and MEK1 form a face-to-face dimer with B-RAF side-to-side dimers at the heart of the complex. Structural and biochemical evidence illustrate that the molecular determinants for B-RAF enzymatic activity is distinct from those required for interaction with MEK. Our work also reveals the molecular basis for the paradoxical ability of both BRAF-activating and -inactivating oncogenic mutations to stimulate the MAPK pathway. Taken together, these findings reveal a novel regulatory role for B-RAF in the MAPK pathway that is independent of its catalytic activity but dependent on the conformation of the B-RAF kinase domain.
Citation Format: Malek Shiva, Jacob R. Haling, Jawahar Sudhamsu, Tony Morales, Ariana Peck, Ivana Yen, Barbara Brandhuber, Sarah Hymowitz. A B-RAF-MEK complex reveals a kinase-independent role for BRAF in MAPK pathway suppression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2346. doi:10.1158/1538-7445.AM2013-2346
Abstract 2356: Biomarkers of progressive squamous lung dyplasia.
Authors: Friedman Micah , Tennis Meredith , Dwyer-Nield Lori , Keith Robert , Nemenoff Raphael , Franklin Wilbur , Geraci Mark , Edwards Michael , Michio Sugita , Merrick Dan 
Published: August 2014

Abstract
Lung cancer is the leading cause of cancer death in the United States. Squamous cell lung cancers (SCC) comprise approximately 30% of lung cancer cases, and 48,000 people are projected to die this year in the U.S. from SCC. Bronchial dysplasia (BD) is a precursor of SCC, however not all BDs progress to carcinoma. Persistent or progressive BD is associated with a higher risk for the development of invasive lung cancer. We hypothesize that characterization of the difference between persistent and regressive BD will identify high risk patients and suggest novel therapeutic targets for prevention of progression to lung SCC. Gene expression analysis was used to identify differences between persistent and regressive BD. Subjects recruited to Colorado SPORE in Lung Cancer screening studies that met sputum atypia criteria and underwent multiple bronchoscopies were evaluated. Sixty-three frozen baseline biopsies showing BD by histology were classified as persistent/progressive (group 1) or regressive (group 2) according the presence or absence of BD on follow-up biopsies at the same sites. H&E staining was performed on frozen sections to confirm histology, and RNA was harvested and used to create gene expression arrays. PLK1 was selected as a gene of interest based on significantly increased levels of expression and pathway analyses implicating increased activity of cellular pathways associated with PLK-1 expression. Additionally, bronchial epithelial cells were cultured from fresh biopsies taken immediately adjacent to persistent or regressive bronchial sites, and RNA, DNA, and protein were harvested. qRT-PCR was performed on RNA extracted from these persistent and regressive biopsy epithelial cultures. PLK1 expression in epithelial cultures was shown to be increased in persistent as compared to regressive cell lines suggesting that this cell cycle control enzyme may represent a possible chemoprevention target in persistent/progressive dysplasias. RNA was also extracted from a variety of immortalized cancer cell lines of both squamous and adenocarcinoma subtypes, and qRT-PCR was used to establish baseline expression of these genes in cancer cells. Eleven of 20 lung cancer cell lines showed at least 20 fold higher PKL-1 expression compared to non-tumorigenic cell lines while 4 out of 4 lines of SCC origin showed 75 fold or higher expression further supporting a role for this enzyme in SCC progression.
Citation Format: Micah Friedman, Meredith Tennis, Lori Dwyer-Nield, Robert Keith, Raphael Nemenoff, Wilbur Franklin, Mark Geraci, Michael Edwards, Sugita Michio, Dan Merrick. Biomarkers of progressive squamous lung dyplasia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2356. doi:10.1158/1538-7445.AM2013-2356
Abstract 2357: Prognostic value of placental growth factor expression in patients with metastatic or recurrent non-small cell lung cancer.
Authors: Kim Jung Hoon , Kim Tae Jung , Lee Kyu Sang , Jung Yun Hwa , Woo In Sook , Hong Sook Hee , Han Chi Wha , Park Jae Kil , Byun Jae Ho 
Published: August 2014

Abstract
Background: Placental growth factor (PIGF) is a proangiogenic factor, belonging to the VEGF family. It binds to VEGF receptor 1(VEGFR-1) and stimulates the growth, migration and survival of endothelial cells. PIGF also activates and attracts macrophages that release angiogenic molecules. Increased expression of PIGF has correlated with poor survival of patients in several solid tumors. However, PIGF expression is not consistently elevated in all malignancies. No reports on the clinical implications of PIGF expression in metastatic or recurrent non-small cell lung cancer (NSCLC) are currently available. We investigate the clinical significance of PIGF expression in metastatic or recurrent NSCLC.
Patients and methods: A retrospective review was done for seventy four patients with metastatic or recurrent NSCLC. Immunohistochemical staining for PIGF and its receptor VEGF-R1, neurophilin-1 was performed. Results: Of 74 patients with NSCLC, 73 patients were positive for PIGF, and 72 patients were positive for neurophilin-1. For PIGF expression, significant correlations were demonstrated with female (p=0.007) and nonsquamous histology (p=0.045). Thirty five patients (47%) were classified into low PIGF expression groups, whereas 38 patients (51%) were grouped as showing high PIGF expression. Survival time for patients with high PIGF expressing NSCLC was significantly longer than that for patients displaying low PIGF expression (median survival time, 15.1 months vs. 9.0 months[log-rank, p=0.01]). However, the difference in time to progression between two groups was not statistically significant (median time to progression, 5.1 months vs. 3.9 months [log-rank, p=0.24]).
Conclusions: Low expression of PIGF is associated with poor prognosis in patients with metastatic or recurrent NSCLC. Further studies on larger patients populations are warranted to validate the utility of PIGF as a prognostic biomarker in lung cancer.
Citation Format: Jung Hoon Kim, Tae Jung Kim, Kyu Sang Lee, Yun Hwa Jung, In Sook Woo, Sook Hee Hong, Chi Wha Han, Jae Kil Park, Jae Ho Byun. Prognostic value of placental growth factor expression in patients with metastatic or recurrent non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2357. doi:10.1158/1538-7445.AM2013-2357