bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-164: Ran Binding Protein 9 (RanBP9) is a novel mediator of cellular DNA damage response in lung cancer cells
Authors: Palmieri Dario , Scarpa Mario , Tessari Anna , Uka Rexhep , Amari Foued , Lee Cindy , Richmond Timothy , Sheetz Tyler , Parvin Jeffrey , Ludwig Thomas , Croce Carlo M. , Coppola Vincenzo 
Published: August 2015

Abstract
Currently, most of the anti-neoplastic treatments for lung cancer patients are based on DNA-damaging cytotoxic therapies such as platinum-containing compounds and radiotherapy. Therefore, a better understanding of the molecular mechanisms involved in the cellular response to genotoxic stresses is required in order to improve the clinical management of lung cancer.
Ran Binding Protein 9 (RanBP9, also known as RanBP-M) is a ubiquitous and evolutionary conserved scaffold protein that shuttles between the nucleus and the cytoplasm, and interacts with many major players in tumor biology. However, its biological functions are not well studied and still debated.
Here, we show that RanBP9 interacts with and is phosphorylated by ATM, one of the apical activators of the DNA damage response (DDR) following DNA Double-Strand Breaks (DSBs). Following ATM-dependent phosphorylation, RanBP9 rapidly accumulates into the nucleus of lung cancer cells. By using three different lung cancer cell lines (A549, H460, and H1299), we found that stable silencing of RanBP9 (ShRanBP9) significantly affects the DDR. In fact, stable ShRanBP9 clones display a delayed and/or reduced activation of key components of the cellular response to Ionizing Radiation (IR), including ATM, Chk2, H2AX-γ and p53. Accordingly, abrogation of RanBP9 expression significantly affected Homology-Directed repair of damaged DNA. On the other hand, stable silencing of RanBP9 results in increased IR-induced senescence and apoptosis.
In summary, here we present evidence that RanBP9 is a novel mediator of the cellular DDR, whose recruitment into the nucleus upon IR is dependent on ATM kinase activity. In turn, nuclear RanBP9 participates to the efficient activation of cellular DDR. On the contrary, its absence hampers the repair of damaged DNA following DSBs, resulting in enhanced lung cancer sensitivity to genotoxic stresses.
Taken together, our findings suggest that targeting RanBP9 might represent a new potential approach to increase sensitivity of lung cancer cells to genotoxic anti-neoplastic treatments.
Citation Format: Dario Palmieri, Mario Scarpa, Anna Tessari, Rexhep Uka, Foued Amari, Cindy Lee, Timothy Richmond, Tyler Sheetz, Jeffrey Parvin, Thomas Ludwig, Carlo M. Croce, Vincenzo Coppola. Ran Binding Protein 9 (RanBP9) is a novel mediator of cellular DNA damage response in 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 LB-164. doi:10.1158/1538-7445.AM2015-LB-164
Abstract LB-167: The role of Sirt1 in tumorigenesis
Authors: Ren Natalie Shunxiang 
Published: August 2015

Abstract
SIRT1 is a highly conserved NAD+-dependent protein deacetylase. Homologs of SIRT1 in lower model organisms are able to delay the aging process in response to nutrients. Although the SIRT1 protein deacetylase activities have been shown to regulate numerous transcription factors and co-factors (eg. PCG-1, p53), modulate cellular metabolism and promote cell survival and stress resistance, the role of SIRT1 in cancer metabolism, growth and survival is still highly controversial. Colorectal cancer is one of the most common malignancies in the world. However, there are few studies revealing the clinical relevance of the expression of SIRT1 and related markers in colorectal cancer with human tissue. Although recent studies have revealed that SIRT1 plays an important role in colorectal tumorigenesis, the exact role of SIRT1 in colorectal tumorigenesis is still controversial. Thus far, our data demonstrates that knocking out SIRT1 induces the acetylation of p53 and alters cellular metabolism. Deletion of SIRT1 in MEFs decreases glutamine uptake and increases cell death by trigging apoptosis pathways. As a result, SIRT1 KO MEFs fails to induce tumors in a xenograft model in nude mice. We have recently generated a mouse colon cancer model on SIRT1 intestine knockout mouse strains (SIRT1 iKO) and discovered that SIRT1 iKO mice display a reduced rate of tumorigenesis. To further confirm the role of SIRT1 on colon cancer, we propose to analyze the association of SIRT1 expression and the prognosis in colorectal cancer.
Citation Format: Natalie Shunxiang Ren. The role of Sirt1 in tumorigenesis. [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 LB-167. doi:10.1158/1538-7445.AM2015-LB-167
Abstract LB-176: Identification of mutations in histone modification genes in Hodgkin lymphoma
Authors: Liang Winnie S. , Salhia Bodour , Helland Adrienne , Sekar Shobana , Garrido-Laguna Ignacio , Fanale Michelle , Oki Yasuhiro , Westin Jason R. , Davis R. Eric , Meric-Bernstam Funda , Janku Filip 
Published: August 2015

Abstract
Background: Understanding genetic aberrations in cancer has led to discoveries of new targets for cancer therapies. The genomic landscape of Hodgkin lymphoma (HL) has not been fully described.
Methods: We performed targeted next generation sequencing (NGS) on 13 archival tumor samples from patients with relapsed/refractory HL treated in the phase I clinical trial with the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat using the Foundation One NGS panel (Foundation One, Foundation Medicine, MA). Subsequently, we performed whole exome and RNA sequencing on pre- and post-treatment tumor biopsies from 3 patients treated in the same study.
Results: In archival samples from 13 HL patients tested using the Foundation One panel, a total of 21 gene aberrations across 13 genes were detected; 12 (92%) tumor samples had mutations in genes involved in immune response, apoptosis, and cell proliferation pathways (SOCS1, PIM1, MCL1, BRCA1, TP53, TNFAIP3, B2M, XPO1, BCL6) and 7 (54%) samples had mutations in DNA repair pathway genes (TP53, BRCA1, ATM, PIM1). In addition, whole exome and RNA sequencing of pre- and post-treatment tumor and germline (peripheral blood mononuclear cells) samples from HL patients treated with sirolimus and vorinostat (complete response, n = 1; stable disease for 3 months, n = 1; progression, n = 1) identified missense point mutations in key histone modification genes not included in the Foundation One panel, including HDAC8 (histone deacetylase 8), JMJD1C (jumonji domain containing 1C), and KDM2A (lysine-specific demethylase 2A) in the patient who progressed on therapy. This same patient additionally had a B2M missense mutation (M1R) affecting the same residue as the B2M event (M1I) identified in the archival cohort. Furthermore, there was a trend towards increased burden of molecular aberrations (median, 67 aberrations) in pre- and post- tumor samples of the patient who progressed compared to the other 2 patients (median, 6 aberrations), who did not progress.
Conclusion: While analysis of additional HL specimens is needed, our data suggest that testing for molecular aberrations with NGS is feasible and somatic missense mutations in HDAC8, JMJD1C, and KDM2A may be associated with lack of clinical response to sirolimus and vorinostat.
Citation Format: Winnie S. Liang, Bodour Salhia, Adrienne Helland, Shobana Sekar, Ignacio Garrido-Laguna, Michelle Fanale, Yasuhiro Oki, Jason R. Westin, R. Eric Davis, Funda Meric-Bernstam, Filip Janku. Identification of mutations in histone modification genes in Hodgkin lymphoma. [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 LB-176. doi:10.1158/1538-7445.AM2015-LB-176
Abstract LB-188: Epigenome-wide study in prediagnostic samples from the European Prospective Investigation into Nutrition and Cancer (EPIC-Italy) cohort: Differentially methylated microRNAs in subjects who developed breast cancer
Authors: Naccarati Alessio , Polidoro Silvia , Fiorito Giovanni , Cordero Francesca , Ferrero Giulio , Campanella Gianluca , Sacerdote Carlotta , Mattiello Amalia , Panico Salvatore , Masala Giovanna , Palli Domenico , Agnoli Claudia , Krogh Vittorio , Frasca Graziella , Tumino Rosario , Vineis Paolo 
Published: August 2015

Abstract
The crosstalk between microRNAs (miRNAs) and other epigenetic factors may lead to novel hypotheses about carcinogenesis identifying new targets for research. Since a single miRNA can regulate multiple downstream target genes, its altered expression may potentially be a very sensitive biomarker to detect early malignant transformation and improve diagnosis and prognosis. In the current study, we used a genome-wide approach to test the hypothesis that altered methylation of miRNA encoding genes may be related to dietary and lifestyle factors and may be associated with deregulated mature miRNA expression ultimately leading to cancer.
In a case-control study nested in a prospective cohort (EPIC-Italy), we analysed DNA methylation levels of miRNA encoding genes (2,191 CpG probes related to 517 genes) that are present in the Infinium Human Methylation450 BeadChip array in prediagnostic peripheral white blood cells of subjects who developed Colorectal Cancer (CRC, n = 159) and Breast Cancer (BC, n = 166) and matched subjects who remained clinically healthy. In the whole cohort, several differentially methylated miRNA genes were observed in association with age, sex, smoking habits and physical activity. Interestingly, in the case-control study, 8 differentially methylated miRNAs were identified in subjects who went on to develop BC (miR-328, miR-675, miR-1307, miR-1286, miR-1275, miR-1910, miR-24-1, and miR-548a-1; all Bonferroni-adjusted p-values &lt; 0.05). No significant associations were found with CRC.
Assuming that altered methylation of miRNAs may be present before diagnosis, it may represent a biomarker for early detection or risk of cancer and may help to understand the cascade of events preceding tumour onset.
Citation Format: Alessio Naccarati, Silvia Polidoro, Giovanni Fiorito, Francesca Cordero, Giulio Ferrero, Gianluca Campanella, Carlotta Sacerdote, Amalia Mattiello, Salvatore Panico, Giovanna Masala, Domenico Palli, Claudia Agnoli, Vittorio Krogh, Graziella Frasca, Rosario Tumino, Paolo Vineis. Epigenome-wide study in prediagnostic samples from the European Prospective Investigation into Nutrition and Cancer (EPIC-Italy) cohort: Differentially methylated microRNAs in subjects who developed 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 LB-188. doi:10.1158/1538-7445.AM2015-LB-188
Abstract LB-192: A single catastrophic genomic event is required for the development of osteosarcoma
Authors: Bilke Sven , Meltzer Paul 
Published: August 2015

Abstract
Over sixty years ago, the groundbreaking works by Nordling1, Armitage and Doll2 found a deep connection between the age dependent incidence rates of cancer with elementary mutational processes in cancer. However, their method to estimate the number of driver mutations from the characteristic increase of adult cancer risk with patient age implicitly assumes tissue homeostasis. It can therefore not be used for developmental cancers emerging from growing tissues.
Osteosarcoma (OS), a bone cancer most frequently occurring during adolescence, is one prominent example. Here we combine a model of bone growth and maintenance with somatic mutation theory. Based on age dependent stature3` and morphometric data, we find that our model accurately reproduces epidemiological OS incidence rates4`. We conclude that the OS risk can be explained by the cell cycle rate in the osteoblast lineage. Other risk factors, such as endocrine and paracrine signaling have only a weak, if any, impact. The strict association with the cell cycle rate, as opposed to wall clock time, suggests that environmental factors play no dominant role either. In other words, with few exceptions such as genetic syndromes or unusually strong environmental factors such as radiation in cancer treatment, the OS risk is dominated by pure chance.
We find that the OS incidence rate is strictly proportional to the age dependent cell cycle rate. This result implies that there is only a single rate limiting factor in the etiology of the disease. This result is a remarkable as it suggests that the disease is not necessarily initiated within a stem cell because the Hayflick limit set by telomere shortening can not suppress single-hit-malignancies.
Our results are not only important for a better understanding of the disease and the design of future sequencing efforts. But they also inform development of treatment strategies to reduce the mortality caused by this still deadly disease.
1. Nordling, C. O. C. A New Theory on the Cancer-inducing Mechanism. Br. J. Cancer 7, 68¨C72 (1953).
2. Armitage, P. & Doll, R. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br. J. Cancer VIII, 1¨C12 (1954).
3. CDC Height Data. at
4. Cancer incidence in five continents, vol. I to VIII. CancerBase No. 7. (Lyon: IARC). at
Citation Format: Sven Bilke, Paul Meltzer. A single catastrophic genomic event is required for the development of osteosarcoma. [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 LB-192. doi:10.1158/1538-7445.AM2015-LB-192
Abstract LB-195: Supporting cancer epidemiology research through cohort registration: NCI's cancer epidemiology cohort descriptive database
Authors: Lane Crystal , Kennedy Amy , Brotzman Michelle , Miller Amy , Lai Gabriel , Khoury Muin , Seminara Daniela 
Published: August 2015

Abstract
Carefully designed observational studies have recognized value and efficiency in determining associations between exposures and outcomes and thereby evaluating health care. In particular, longitudinal cohorts have served as an essential research infrastructure for studies producing a wealth of information on disease etiology and prevention. The onset of the ‘omics age has compelled many funding agencies to foster collaborations across existing large cohorts, to design studies large enough to address the dynamic and interactive nature of the factors underlying common diseases.
There is currently an ongoing discussion in the scientific community of whether or not observational studies should be registered, and if so what the scientific and practical benefits of the implementation would be. Cohorts are the backbone of observational studies, and making their descriptive data rapidly available to the scientific community through a centralized descriptive database is the first step necessary to increase transparency, scientific quality and collaboration.
We have created the Cancer Epidemiology Descriptive Cohort Database (CEDCD) to assist the research community in identifying and accessing population resources, with the intention of maximizing the efficiency and effectiveness of existing cohorts and targeting areas of needs when establishing new ones. This public database includes many details, including cohort profiles and investigator contact information, study design and eligibility criteria, enrollment numbers broken down by race/ethnicity/gender, number and types of biospecimens and cancer diagnoses, policies, protocols and questionnaires, publications and funded research projects, and links to the cohort websites and related resources. The initial phase of this database will include cohorts focusing on cancer as their primary outcome, specifically those funded by NCI's EGRP and members of NCI's Cohort Consortium that have more than 10,000 subjects enrolled (healthy individuals or cancer survivors).
The CEDCD is serving as a model for a parallel world-wide cohort registration project. The creation of a querable web-based tools for direct population of this descriptive database, which will provide a valuable resource for the scientific community in the planning and design of large, cooperative observational studies is in progress.
Citation Format: Crystal Lane, Amy Kennedy, Michelle Brotzman, Amy Miller, Gabriel Lai, Muin Khoury, Daniela Seminara. Supporting cancer epidemiology research through cohort registration: NCI's cancer epidemiology cohort descriptive database. [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 LB-195. doi:10.1158/1538-7445.AM2015-LB-195
Abstract LB-197: Circulating rare cells enable highly efficient cancer detection
Authors: Obermayr Eva , Maritschnegg Elisabeth , Speiser Paul , Singer Christian , Schuster Eva M. , Danzinger Sabine , Pecha Nina , Zeillinger Robert 
Published: August 2015

Abstract
Objectives of the study
We intended to develop a protocol combining a novel micro-fluidic enrichment technology and RT-qPCR for the molecular analysis of CTCs. Recently we identified CTC-specific mRNA markers allowing CTC detection in 29% of breast cancer patients and in 24.5% of ovarian cancer patients at diagnosis. However, the detection of cancer cells was hampered by the large number of contaminating leukocytes. The necessary use of cut-off values for positivity reduced the specificity of the down-stream PCR assay. By improving the purity of cancer cells and PCR analysis we sought to increase both sensitivity and specificity of the diagnostic procedure.
Methodology
For reducing the blood sample volume (up to 20ml) density gradient centrifugation was used when needed. The samples were passed through a micro-fluidic disposable cassette, which captures tumor cells based on their less deformable nature and larger size compared to blood cells. Lysis of the captured cells was done directly in the cassette and total RNA was extracted. After a cDNA pre-amplification step gene expression levels of leukocyte-specific and CTC-related markers were measured using RT-qPCR. The efficiency of the combined protocol was assessed in blood samples taken from patients with primary and recurrent malignant diseases.
Results
7 out of 13 pre-selected RNA markers were not detectable in blood samples from 11 healthy volunteers. In cancer patients we observed measurable gene expression of at least one out of these 7 RNA markers. 5 out of 5 breast cancer (primary disease: N = 1; metastatic: N = 4), 9 out of 10 primary and 4 out of 8 relapsed ovarian cancer patients were classified correctly by the test. The most striking finding is the detection rate of 90% for primary ovarian cancer at a specificity of 100%.
Conclusions
The enrichment of rare cells from blood samples using micro-fluidics results in a highly pure cell population. This enables the application of extremely sensitive methods, like RT-qPCR to specifically detect rare events. By combining a novel micro-fluidic cell enrichment and molecular analysis we have taken a major step forward, which allows the implementation of ′liquid biopsies′ in cancer detection studies and as a companion diagnostic in clinical trials.
Citation Format: Eva Obermayr, Elisabeth Maritschnegg, Paul Speiser, Christian Singer, Eva M. Schuster, Sabine Danzinger, Nina Pecha, Robert Zeillinger. Circulating rare cells enable highly efficient cancer detection. [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 LB-197. doi:10.1158/1538-7445.AM2015-LB-197
Abstract LB-220: Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma
Authors: Napolitano A. , Pellegrini L. , Dey A. , Larson D. , Tanji M. , Flores E. G. , Kendrick B. , Lapid D. , Powers A. , Kanodia S. , Pastorino S. , Pass H. I. , Dixit V , Yang H. , Carbone M. 
Published: August 2015

Abstract
Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma (MM). MM pathogenesis is generally associated to professional exposure to asbestos. However, to date we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after even minimal exposure.
In a set of short-term experiments, we intraperitoneally injected BAP1+/- and wild-type littermates with low doses of asbestos fibers and analyzed the inflammatory response both at a cellular and humoral level. In a long-term experiment following a similar protocol, we assessed the incidence of MM in mice with and without germline BAP1 mutations and their survival.
We found that, compared to their wild type littermates, BAP1+/- mice exposed to low doses of asbestos fibers showed significant alterations of the peritoneal inflammatory response. In particular, we observed significantly higher levels of pro-tumorigenic alternatively polarized M2 macrophages, and lower levels of several chemokines and cytokines. Consistent with these data, BAP1+/- mice had a significantly higher incidence of mesothelioma after exposure to very low doses of asbestos, and shorter survival.
Our findings suggest that minimal exposure to carcinogenic fibers may significantly increase the risk of malignant mesothelioma in genetically predisposed individuals carrying germline BAP1 mutations, possibly via alterations of the inflammatory response.
Citation Format: A. Napolitano, L. Pellegrini, A. Dey, D. Larson, M. Tanji, E. G. Flores, B. Kendrick, D. Lapid, A. Powers, S. Kanodia, S. Pastorino, H. I. Pass, V Dixit, H. Yang, M. Carbone. Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. [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 LB-220. doi:10.1158/1538-7445.AM2015-LB-220