bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 344: Subpopulations of lung neuroendocrine cells mirror neuronal development.
Authors: Suau Florent , Linnoila Ilona , Naizhen Xu 
Published: August 2014

Abstract
Pulmonary neuroendocrine cells (PNECs) which comprise less than 1% of airway epithelium were recently shown to be the cell of origin for small cell lung cancer (SCLC). SCLC is the most aggressive form of human lung cancers and characterized by early dissemination or metastases and neuroendocrine features. We used immunohistochemistry (IHC) and animal models in order to delineate the cellular hierarchy of PNEC potentially leading to cancer.
PNECs were first identified in the early lung development (E12.5) as positive for the proneural basic helix-loop-helix transcription factor Achaete-scute homolog-1 (Ascl1) which is pivotal for PNEC differentiation and highly expressed in SCLC. Later in the development (E16.5) and in adulthood, PNECs coexpressed Ascl1 and calcitonin gene-related peptide (CGRP), a primary neuropeptide in mouse lung.
Interestingly, we showed that doublecortin (DCX), a marker of immature migrating neurons, is transiently expressed in PNECs during the early development. Later in the development (E16.5), we observed a subpopulation expressing the neural-specific β3-tubulin (TUBB3), a neuronal marker. We also observed that neural cell adhesion molecule (NCAM), a marker of SCLC, is transiently expressed in a low number of PNECs in the late embryonic period. In parallel, using the transgenic CC10-hASH1 mouse model, where Ascl1 is overexpressed in non-neuroendocrine airway epithelial cells, we determined that it is not sufficient to induce neuroendocrine differentiation or expression of DCX, TUBB3 and NCAM.
We conclude that Ascl1, DCX and TUBB3 are consecutively expressed in PNECs during development, similarly to the pattern observed during neuronal development. However, Ascl1 expression seems to be maintained even in the mature PNECs unlike in the mature neurons where it is turned off. On the other hand, NCAM expression in PNECs is transient and maybe reactivated during the instance of SCLC. To establish the relationships between the different PNEC populations and Ascl1 expression, we are currently evaluating Cre-dependent conditional Ascl1 deletion in mouse lung. Further work will be necessary to address the functional potential of the PNEC subpopulations in tumorigenesis.
Citation Format: Florent Suau, Ilona Linnoila, Xu Naizhen. Subpopulations of lung neuroendocrine cells mirror neuronal development. [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 344. doi:10.1158/1538-7445.AM2013-344
Abstract 3442: Olaparib increases antitumor effects on epigenetically RAD51C-deficient human cancer cells.
Authors: Min Ahrum , Kim Seongyeong , Im Seock-Ah , Yoon Young-Kwang , Song Sang-Hyun , Nam Hyun-Jin , Hur Hyung-Seok , Lee Kyung-Hun , Han Sae-Won , Oh Do-Youn , Kim Tae-You , O'Connor Mark J. , Kim Woo-Ho , Bang Yung-Jue 
Published: August 2014

Abstract
Background: The poly (ADP-ribose) polymerase (PARP) inhibitor, olaparib, has been found to have a therapeutic potential for treating cancers that have an impaired DNA repair ability. RAD51C has been reported to play an essential role in DNA repair mediated by homologous recombination. In addition, RAD51C is a gene that affects human cancer susceptibility, similar to BRCA1 and BRCA2. RAD51C-defective cancers can therefore be potentially treated with olaparib because DNA damage induced by olaparib cannot be effectively repaired by HR since RAD51C deficiency interferes with RAD51-mediated HR.
Materials and Methods: We studied the growth inhibitory effects of olaparib on human cancer cell lines using clonogenic survival assays. Cell cycle analysis and molecular changed induced by olaparib were also performed. DNA methylation status in cancer cells and tumor tissue samples was also determined by using bisulfate sequencing.
Results: Olaparib is effective to RAD51C-defective cells. Olaparib leads to the accumulation of unrepaired DSBs due to dysfunctional RAD51 foci formation along with increased caspase 3-dependent cell death and G2/M arrest in RAD51C-defective cells. Moreover, the growth of RAD51C-deficient SNU601 tumor cells in a xenograft model decreased significantly following treatment with olaparib. Furthermore, RAD51C expression was significantly decreased in cancer and the lack of RAD51C was attributed to DNA methylation and histone modification. Our findings showed that the loss of RAD51C expression due to epigenetic silencing leads to olaparib sensitivity in cancer cells.
Conclusion: The loss of RAD51C expression was frequently associated with human cancers. We used a novel synthetic lethal approach using PARP inhibitors and observed that RAD51C was a participant in the DNA repair pathway. Our findings have potential clinical application for treating cancers with RAD51C deficiencies. Furthermore, we determined that RAD51C may serve as a novel biomarker for identifying olaparib-sensitive patients, thereby allowing physicians to select the most effective modalities for treating these individuals.
Citation Format: Ahrum Min, Seongyeong Kim, Seock-Ah Im, Young-Kwang Yoon, Sang-Hyun Song, Hyun-Jin Nam, Hyung-Seok Hur, Kyung-Hun Lee, Sae-Won Han, Do-Youn Oh, Tae-You Kim, Mark J. O`Connor, Woo-Ho Kim, Yung-Jue Bang. Olaparib increases antitumor effects on epigenetically RAD51C-deficient human cancer cells. [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 3442. doi:10.1158/1538-7445.AM2013-3442
Abstract 3445: Specific inhibitors of nuclear export (SINE) for cancer therapy: from bench to bedside.
Authors: Azmi Asfar S. , Bao Bin , Kauffman Michael , Shacham Sharon , Mohammad Ramzi M. 
Published: August 2014

Abstract
Nuclear protein transport is an evolutionary conserved mechanism that controls aberrant cell proliferation through balanced nuclear expression of tumor suppressor proteins (TSPs). In cancers, overexpression of exportin protein chromosome region maintenance 1 (CRM-1) disrupts this balance leading to nuclear exclusion of TSPs leading to the low efficacy of traditional anti-cancer drugs. Our recent screening of pancreatic, colon, triple negative breast cancer (TNBC) and non-Hodgkin's lymphoma (NHL) patient samples showed over-expression of CRM-1. These important finding suggests that therapeutic targeting of CRM-1 leading to restoration of TSPs in the nucleus is an attractive strategy against cancer. Earlier attempts to develop CRM-1 inhibitor were not successful as exemplified by the failure of the Leptomycin B in a single clinical trial due to severe off-target toxicity. Since then the field has not witnessed any serious attempts to develop newer classes of CRM-1 inhibitors that could be used clinically. We have developed specific inhibitors of nuclear export (SINE) that are highly specific, orally active drugs with excellent pharmacokinetic parameters. We tested SINEs as targeted inhibitors of CRM-1, in a panel of pancreatic, colon, prostate, breast, NHL cell lines. SINE showed cancer selectivity (IC50s in low nano molar range in cancer cells and &gt;20 micro Molar in normal lymphocytes, fibroblasts and NIH-3T3 cells). SINE induces global re-alignment of important tumor suppressors such as IKB, FOXO, p53, p73 and p27. SINEs were ineffective in killing cancer cells that were transduced with cys528 mut-CRM-1 proteins (a binding site for SINE) confirming the drugs selectivity. In in vivo studies, the clinical grade SINE induced significant tumor growth inhibition in subcutaneous and orthotopic solid and disseminated NHL xenografts. Our new class of SINEs has excellent pharmacokinetic parameters and has passed advanced toxicity profiling. Based on our strong preclinical data, SINE has entered clinical trials for both solid tumors and hematological malignancies.
Citation Format: Asfar S. Azmi, Bin Bao, Michael Kauffman, Sharon Shacham, Ramzi M. Mohammad. Specific inhibitors of nuclear export (SINE) for cancer therapy: from bench to bedside. [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 3445. doi:10.1158/1538-7445.AM2013-3445
Abstract 3449: Development of small molecule Bcl-XL inhibitors for treatment of lung cancer.
Authors: Park Dongkyoo , Magis Andrew T. , Li Rui , Owonikoko Taofeek K. K. , Sica Gabriel L. , Sun Shi-Yong , Ramalingam Suresh S. , Khuri Fadlo R. , Curran Walter J. , Deng Xingming 
Published: August 2014

Abstract
Bcl-XL is a major anti-apoptotic protein in the Bcl-2 family whose overexpression is more widely observed in human lung cancer cells than that of Bcl-2, suggesting that Bcl-XL is more biologically relevant and therefore a better therapeutic target for lung cancer. Here, we screened small molecules that selectively target the BH3 domain (aa 90-98) binding pocket of
Bcl-XL using the UCSF DOCK 6.1 program suite and the NCI chemical library database.
We identified two new Bcl-XL inhibitors (BXI-61 and BXI-72) that exhibit selective toxicity against lung cancer cells compared with normal human bronchial epithelial cells. Fluorescence polarization assay reveals that BXI-61 and BXI-72 preferentially bind to Bcl-XL protein but not
Bcl2 in vitro with high binding affinities. Treatment of cells with BXI-72 results in disruption of Bcl-XL/Bak interaction, oligomerization of Bak and cytochrome c release from mitochondria.
These two BXI compounds potently repress lung cancer xenografts in vivo without significant normal tissue toxicity within effective doses. Importantly, BXI-72 can also overcome acquired radioresistance of lung cancer. Based on our findings, the development of BXI(s) as a new class of anticancer agents is warranted and represents a novel strategy for improving lung cancer outcome.
Citation Format: Dongkyoo Park, Andrew T. Magis, Rui Li, Taofeek K. K. Owonikoko, Gabriel L. Sica, Shi-Yong Sun, Suresh S. Ramalingam, Fadlo R. Khuri, Walter J. Curran, Xingming Deng. Development of small molecule Bcl-XL inhibitors for treatment of 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 3449. doi:10.1158/1538-7445.AM2013-3449
Abstract 3472: Excision repair cross complementing group 1 (ERCC1) and regulatory subunit of Ribonucleotide Reductase (RRM1) as prognostic and predictive markers for ovarian cancer.
Authors: Zhou Jun , Ahmed Quratulain , Chen Wei , Li Xin , Morris Robert , Ali-Fehmi Rouba , Bepler Gerold 
Published: August 2014

Abstract
Background: Ninety percent of ovarian cancers are epithelial in nature (EOC); the standard approach for treatment is surgery followed by platinum and taxane based chemotherapy. Gemcitabine has been evaluated recently in combination with platinum and taxane for platinum sensitive recurrence and as a single agent for platinum refractory or resistant recurrent EOC. ERCC1 and RRM1 are involved in DNA synthesis and repair derived from genotoxic stress, and they have also been reported as predictive markers for therapeutic efficacy in patients with lung and pancreatic cancers. Their expression, association and clinical significance in ovarian carcinoma remain uncertain.
Design: 198 archived cases of epithelial cell ovarian cancer were reviewed and divided into three subtypes: borderline tumor (BLT), Type I and Type II. 2mm TMAs were developed with duplicate cores per case. Immunofluorescence combined with Automated Quantitative Analysis (AQUA) was used to assess the expression of ERCC1 and RRM1. The average of duplicate cores was used for analysis and Greedy search was used for establishing the high and low score cutoff points.
Results: 44 cases (22%) were BLT, 29 (15%) were Type I tumors, 121 (61%) were
Type II tumors, and 4 cases (4%) were unclassified. Type II tumors were significantly higher among elderly Caucasian women (p&lt;0.001) as compared to African American women. Kaplan Meier curves showed no statistically significant difference in overall survival (OS) between Type I and Type II cancers. Low ERCC1 scores were significantly associated with lower OS rates (hazard ratio (HR) = 1.46), when compared with high ERCC1 scores. In contrast, low RRM1 scores were associated with better overall survival (HR = 0.36). Scores for both markers were not significantly associated with tumor type, histology grade or stage. On multivariate analysis including ERCC1, RRM1, tumor stage, tumor type, age and race; only age and tumor type (BLT I&II) persisted as independent prognostic factors for poor overall survival.
Conclusion: Our study suggests that low expression of ERCC1 and high expression of RRM1 are associated with poor survival in ovarian cancer patients. Large studies are warranted to elucidate whether or not the expression of ERCC1 and RRM1 can be used as prognostic or predictive markers.
Citation Format: Jun Zhou, Quratulain Ahmed, Wei Chen, Xin Li, Robert Morris, Rouba Ali-Fehmi, Gerold Bepler. Excision repair cross complementing group 1 (ERCC1) and regulatory subunit of Ribonucleotide Reductase (RRM1) as prognostic and predictive markers for ovarian 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 3472. doi:10.1158/1538-7445.AM2013-3472
Abstract 3499: Anti-adenoma Adnab-9 antibody recognizes a serum GI cancer candidate biomarker.
Authors: Tobi Martin , Weinstein Douglas , Vizgoft Emma , Pedersen Susanne 
Published: August 2014

Abstract
Population-based serum banks may allow for the early detection of shed markers of common gastrointestinal cancers. Few GI pan-biomarkers are available for serum testing and those that are lack specificity and universal sensitivity for colorectal, gastric and pancreatic cancers. The p87 antigen recognized by the Adnab-9 antibody may be an ideal candidate for such a biomarker. It has both diagnostic and prognostic biomarker ability for these GI cancers but its ability to detect the antigen in serum is unknown. Methods: In order to gauge feasibility of serum testing we conducted a literature search to determine the existence of model established serum banks internationally. An indirect Adnab-9 ELISA was performed on a validation set of sera from 20 CRC patients and 10 controls. A known positive stool extract was used as the positive control. Results: Six countries were found to possess serum banks with the numbers of specimens ranging from 1,982 to 2,132,215. Of these 6 countries, age-adjusted mortality from CRC was highest in the Netherlands at 21/100,000, from gastric cancer highest in Japan 35/100,000 and from pancreatic cancer highest in the USA 11/100,000. The validation sera set Australian patient demographics were similar for gender and ethnicity. The controls were significantly younger than the cancer patients (64±10.3 versus 52.2±3.4 years [p&lt;0.002]) but there was no direct linear correlation between OD450 and age (r2=0.104;p=0.102). Dilution of serum at both 1:1 and 1:3 ratios showed significantly different mean OD450 values between cancer and control patients of 0.076±0.007 (x±STDEV) versus 0.069±0.006 (p&lt;0.025) and 0.083±0.008 versus 0.074±0.004 (p&lt;0.02) respectively. Eighty percent of cancer patients’ serum were positive versus 30% of controls (OR 9.3; CI 1.6-53.2;p&lt;0.015). Signal to noise ratios of the positive control was satisfactory with the lowest OD450 reading at 0.085 obtained at a 1:6,400 dilution with a linear dilution-reaction curve. Conclusions: National serum banks already exist that could allow for graduated targeted screening of a specific disease based on relative mortality rates. The Adnab-9 antibody is a promising candidate for a pan-biomarker based on the outcome of the indirect ELISA. Since sensitivity of Adnab-9 stool binding is lowest for CRC compared to gastric and pancreatic, it is likely that serum testing for the other 2 cancers would yield comparable results. In order to elucidate this further, testing in prospective studies should be undertaken.
Citation Format: Martin Tobi, Douglas Weinstein, Emma Vizgoft, Susanne Pedersen. Anti-adenoma Adnab-9 antibody recognizes a serum GI cancer candidate biomarker. [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 3499. doi:10.1158/1538-7445.AM2013-3499
Abstract 350: Inhibition of SHP2 impairs oncogenic activity of EGFR mutants in non-small cell lung cancer.
Authors: Schneeberger Valentina E. , Ren Yuan , Luetteke Noreen , Berns Hartmut , Chen Liwei , Lawrence Harshani R. , Lawrence Nicholas J. , Lopez Alex S. , Haura Eric B. , Coppola Domenico , Wu Jie 
Published: August 2014

Abstract
Activating mutations of epidermal growth factor receptor (EGFR) are found in 5-15% of non small cell lung carcinomas (NSCLC) and are targets of NSCLC treatment. However, most patients treated with EGFR tyrosine kinase inhibitors eventually acquire drug resistance, pointing to the need of evaluating other molecules as potential targets for developing new therapy for NSCLC. The protein tyrosine phosphatase (PTP) SHP2 mediates signaling of growth factor receptors including that of EGFR. SHP2 is activated by EGFR mutants in lung adenocarcinoma. Inhibition of SHP2 with the SHP2 PTP inhibitor SPI-112Me or SHP2 knockdown suppressed proliferation of EGFR-dependent HCC827 and H1975 cells. To assess the role of Shp2 in the transgenic mouse model of EGFR mutant-driven lung cancer, we generated transgenic mice carrying a doxycycline (dox)-inducible, PTP-defective SHP2 (tetO-SHP2CSDA). Bitransgenic CCSP-rtTA/tetO-SHP2CSDA mice were crossed with tetO-EGFRL858R mice. F1 offspring of dox-induced transgenic mice were analyzed. Erk1/2 and Src were activated by EGFRL858R in bitransgenic CCSP-rtTA/tetO-EGFRL858R mice. Both of them were suppressed by SHP2CSDA in CCSP-rtTA/tetO-EGFRL858R/tetO-SHP2CSDA tritransgenic mice. Importantly, expression of SHP2CSDA significantly inhibited EGFRL858R-induced lung tumor in the tritransgenic mice. These results suggest that SHP2 is critical for lung tumorigenesis mediated by EGFR mutations.
Citation Format: Valentina E. Schneeberger, Yuan Ren, Noreen Luetteke, Hartmut Berns, Liwei Chen, Harshani R. Lawrence, Nicholas J. Lawrence, Alex S. Lopez, Eric B. Haura, Domenico Coppola, Jie Wu. Inhibition of SHP2 impairs oncogenic activity of EGFR mutants in 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 350. doi:10.1158/1538-7445.AM2013-350
Abstract 352: Murine model of chordoma: Sonic Hedgehog promoter-driven Cre activation of Brachyury (T) expression induces spinal disk abnormalities and perinatal lethal developmental defects.
Authors: Alcorta David A. , Maier Jennifer A. , Harfe Brian D. , Kelley Michael J. 
Published: August 2014

Abstract
Introduction: Chordoma is a rare malignancy arising in the axial skeleton from notochord remnants. The T-box transcription factor, Brachyury (T), is associated with familial chordoma, is expressed in over 90% of chordomas, and is a driver of cell growth in cultured chordoma cells. Suppression of T expression or function in vitro results in down-regulation of cell growth pathways and reduction in matrix formation. To further understand the mechanisms of T's oncogenic properties, we sought to generate a murine model of constitutive, notochord-directed T expression.
Methods: To produce elevated expression of T in the notochord-derived (ND) cells, we generated a murine transgenic animal in which a cassette (T/GFP) containing the β-actin promoter, a transcriptional stop sequence flanked by LoxP sites (FS), the murine T cDNA, an intragenic ribosomal entry sequence and a GFP cDNA was homologously recombined into the ROSA26 locus. We termed these animals FS-T/GFP mice. FS-T/GFP mice were mated to mice with Cre expression regulated by the developmentally-timed and tissue-specific control of the Sonic Hedgehog promoter (Shh-Cre mice).
Results: Excision of the FS sequence by Cre was confirmed to result in constitutive expression of T and GFP in 293 cells prior to transgenic creation, and subsequently in cultured fibroblasts from ear punches of the transgenic animals. Mice containing homozygous FS-T/GFP at ROSA26 were healthy with no apparent physiologic or developmental defects and with the expected Mendelian ratios of sex and genotype. A cross of FS-T/GFP with Shh-Cre mice resulted in T/Cre pups that died perinatally with grossly evident heart, lung and kidney defects. In addition, these animals showed incomplete fusion of the vertebral bodies, and dysmorphic spinal disks. Elevated T protein levels and GFP co-expression in disk cells was demonstrated by immunofluorescent detection in tissue sections.
Summary: Constitutive expression of T in ND lineage cells results in alteration of the morphology of intervertebral disks possibly indicative of a proliferative effect of Brachyury on ND cells. Expression of T in “off-target” tissues that express Sonic Hedgehog likely results in perinatal death.
Citation Format: David A. Alcorta, Jennifer A. Maier, Brian D. Harfe, Michael J. Kelley. Murine model of chordoma: Sonic Hedgehog promoter-driven Cre activation of Brachyury (T) expression induces spinal disk abnormalities and perinatal lethal developmental defects. [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 352. doi:10.1158/1538-7445.AM2013-352
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.