bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3164: Molecular determination of the clonal relationship between multiple tumors in BRCA1/2-associated cancer patients has clinical relevance
Authors: Geurts-Giele Willemina R.R. , van Verschuer Victorien M.T. , van Deurzen Carolien H.M. , van Diest Paul J. , Pedrosa Rute M. , Collee J. Margriet , Koppert Linetta B. , Seynaeve Caroline , Dinjens Winand N.M. 
Published: July 2016

Abstract
PURPOSE
Female BRCA1/2 mutation carriers commonly develop breast cancer and ovarian cancer. It is of utmost importance to know the clonal relationship between multiple tumor localizations, (multiple primaries or metastasized disease), since prognosis and treatment differ between these tumors and their metastases. We evaluated the value of targeted Next Generation Sequencing (NGS) in the diagnostic workup of BRCA1/2 mutation carriers with ≥2 tumor localizations and uncertain tumor origins.
METHODS
Forty-two female BRCA1/2 mutation carriers with ≥2 tumor locations with tumor material available for pathologic revision were selected. Median age at first cancer diagnosis was 48.0 years (range 30-68). Four patients with inconclusive tumor origin after histological and immunohistochemical analyses were ‘cases’; 10 patients with certain tumor origin of ≥3 tumors served as ‘controls’. Tumors of cases and controls were analyzed by targeted NGS using a panel including CDKN2A, PTEN and TP53, hotspot mutation sites for 27 different genes and 143 single nucleotide polymorphisms for detection of loss of heterozygosity (LOH). Based on prevalence of identical or different mutations and/or LOH patterns, tumors were classified as ‘multiple primaries’ or ‘one entity’.
RESULTS
In 44 tumors, 48 mutations were found; 39 (81%) concerned TP53 mutations. In all 10 controls and all 4 cases, the intrapatient clonal relationships between the tumors could be unequivocally identified by molecular analysis. In all controls, tumor origins based on molecular outcomes matched the conventional histopathological diagnosis.
CONCLUSION
In 90% of BRCA1/2 mutation carriers with multiple tumors routine pathology work-up is sufficient to determine tumor origins and relatedness. In case of inconclusive conventional pathology results, molecular analyses using NGS can reliably determine clonal relationships between tumors, enabling optimal treatment of individual patients.
Citation Format: Willemina R.R. Geurts-Giele, Victorien M.T. van Verschuer, Carolien H.M. van Deurzen, Paul J. van Diest, Rute M. Pedrosa, J. Margriet Collee, Linetta B. Koppert, Caroline Seynaeve, Winand N.M. Dinjens. Molecular determination of the clonal relationship between multiple tumors in BRCA1/2-associated cancer patients has clinical relevance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3164.
Abstract 3180: Deletions of 18q characterizes a subset of aggressive prostate cancers with metastatic potential
Authors: Hube-Magg Claudia , Kluth Martina , Graunke Maximilian , Koop Christina , Thomas Steuber , Graefen Markus , Steurer Stefan , Schlomm Thorsten , Sauter Guido , Simon Ronald 
Published: July 2016

Abstract
Large chromosomal deletions and rearrangements of the TMPRSS:ERG locus are hallmarks of prostate cancer. Deletion of 18q is recurrently found in prostate cancer, but the prevalence and clinical significance of this alteration have not been studied in detail as to yet. We took advantage of our large prostate cancer prognosis tissue microarray (TMA) containing more than 12,000 prostate cancers with clinical follow-up data and performed fluorescence in situ hybridization (FISH) analysis using an 18q21 probe. A total of 6,881 prostate cancers were interpretable by FISH. Deletion of 18q was found in 7.5% of cancers, and was linked to advanced tumor stage (p&lt;0.0001), high Gleason grade (p = 0.0013) and biochemical recurrence (BCR, p&lt;0.0001). Comparison with data from TMPRSS:ERG fusion and ERG protein expression revealed that deletions of 18q were only marginally related to an ERG-fusion negative phenotype (p = 0.0063). Multivariate analysis showed that the prognostic value of 18q deletion was independent from the established prognostic factors in all cancers (p = 0.0004) as well as in the subsets of ERG-fusion negative (p = 0.0148) and ERG-fusion positive cancers (p = 0.0264). From the clinical data attached to our TMA, we defined additional clinical endpoints beyond BCR, which represent the four hallmarks (local, local invasive, occult systemic and metastatic) of tumor growth and dissemination in prostate cancer. Deletion of 18q was linked to unfavorable outcome also according to these alternative clinical endpoints. For example, the fraction of cancers with occult systemic or metastatic dissemination increased from 33.6% in patients whose tumors lacked 18q deletion to 41.8% in patients with tumors harboring 18q deletion (p = 0.0458). In summary, the results of our study demonstrate a pivotal role of 18q deletions for prognosis in prostate cancer independent of the established prognosticators.
Citation Format: Claudia Hube-Magg, Martina Kluth, Maximilian Graunke, Christina Koop, Steuber Thomas, Markus Graefen, Stefan Steurer, Thorsten Schlomm, Guido Sauter, Ronald Simon. Deletions of 18q characterizes a subset of aggressive prostate cancers with metastatic potential. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3180.
Abstract 3200: New epigenetic mechanism of disulfiram targeting chromatin remodeling in neuroblastoma
Authors: Jacques-Ricard Simon , Raynal Noel , Armaos Gregory , Da Costa Elodie , Beaudry Annie 
Published: July 2016

Abstract
Pediatric neuroblastoma is one of the most common extra cranial cancers in children. Despite an improvement in survival with the currently available therapies, neuroblastoma with an amplification of the transcription factor MYCN have a very poor prognosis. New therapeutic approaches must be developed to increase the survival of patients. One such approach is epigenetic drug therapy. Neuroblastoma, like many other pediatric cancers, contains several epigenetic alterations at the level of DNA methylation and histone modifications. In a screening of FDA approved drugs, we discovered some molecules having characteristics of epigenetic drugs that were unknown until now. Our study seeks to demonstrate the efficacy of these molecules in the treatment of neuroblastoma cell lines. Following preliminary tests, one of the molecules approved by the FDA stood out: disulfiram, a medication approved for the treatment of chronic alcoholism. We treated neuroblastoma cell lines (MYCN amplified: IMR-32, N91 and SK-N-DZ; MYCN non-amplified: SK-N-AS and SK-N-SH) for 48 hours with disulfiram at clinically relevant concentrations (from 10 nM to 50 μM). Our results demonstrate a 50% growth inhibition (IC50) of 50nM for the cell lines tested. In addition, after analysis by flow cytometry, we found a cell cycle block in G2/M. We also observed a decrease in the transcription factor MYCN and a reduction in acetylation of several histone marks by Western blots analysis. Further studies are underway to determine the mechanism of action of disulfiram and we also plan on doing RNA sequencing and ChIP sequencing. This study will evaluate the efficacy of disulfiram alone as well as in combination with other epigenetic drugs, such as DNA methyltransferase inhibitor decitabine, for the treatment of neuroblastoma.
Citation Format: Simon Jacques-Ricard, Noel Raynal, Gregory Armaos, Elodie Da Costa, Annie Beaudry. New epigenetic mechanism of disulfiram targeting chromatin remodeling in neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3200.
Abstract 3218: Disruption of the CD39 immune checkpoint pathway increases the efficacy of various anticancer therapies in syngeneic mouse models
Authors: Lapierre Marion , Dejou Cécile , Paturel Carine , Michaud Henri-Alexandre , Gros Laurent , Bensussan Armand , Eliaou Jean-François , Bastid Jeremy , Bonnefoy Nathalie 
Published: July 2016

Abstract
The CD39-CD73-adenosine pathway is an emerging regulator of the immune antitumor response. CD39 is expressed within tumors and the tumor microenvironment by several cell population including immune and cancer cells. In tumor tissues, the pathway leads to the accumulation of immunosuppressive adenosine together with decreased levels of immunoactivating peritumoral ATP. We reported previously that CD39 blockade increased T cell and NK cell-mediated cytotoxic activity in vitro and disclose, during this meeting, the development of the first human-CD39-blocking humanized antibody (S. Augier et al., Preclinical development of a humanized blocking antibody targeting the CD39 immune checkpoint for cancer immunotherapy). Here we demonstrated that this pathway is involved in tumor-induced resistance to various cancer therapies in syngeneic mouse melanoma, colon cancer and fibrosarcoma models. We used therapy-resistant mouse models or inefficacious treatment regimens in the CD39 knockout mice to assess the capacity of CD39 to affect the response to chemotherapies, tumor associated antigen (TAA)-targeting antibodies and immunomodulators such as anti-PD1 antibodies. We achieved increased response rates, increased response duration and some complete and long lasting tumor regressions in the CD39 deficient context. These preclinical proof-of-concept studies highlight the role of the CD39 immune checkpoint pathway in limiting the efficacy of various anticancer therapies in syngeneic mouse models and thereby support the potential clinical value of the humanized CD39-neutralizing antibody under development.
Citation Format: Marion Lapierre, Cécile Dejou, Carine Paturel, Henri-Alexandre Michaud, Laurent Gros, Armand Bensussan, Jean-François Eliaou, Jeremy Bastid, Nathalie Bonnefoy. Disruption of the CD39 immune checkpoint pathway increases the efficacy of various anticancer therapies in syngeneic mouse models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3218.
Abstract 3229: Microglia/macrophages activation status in diffuse gliomas
Authors: Galatro Thais F. , Sola Paula , Oba-Shinjo Sueli M. , Eggen Bart J. , Marie Suely K. 
Published: July 2016

Abstract
Diffuse gliomas are primary brain tumors characterized by infiltrative growth and high heterogeneity, which renders the disease mostly incurable. Advances in genetic analysis have characterized molecular and epigenetic alterations leading to impact on patients’ overall survival and clinical outcome, particularly in glioblastoma (GBM). However, glioma tumorigenicity is not controlled uniquely by its genetic alterations. The crosstalk between tumor cells and the surrounding microenvironment plays a crucial role in modulating glioma growth and aggressiveness. The most abundant non-neoplastic cells in this microenvironment belong to the myeloid lineage, comprising resident microglia, with central nervous system (CNS)-tailored functions, and infiltrating monocytes/macrophages from the bone marrow. Understanding the dynamics between tumor and myeloid cells and the correlation between oncogenic molecular alterations in the tumor and the inflammatory activation status of innate immunity cells would elucidate potential treatment alternatives. Our large cohort of human glioma consisted of both astrocytoma and oligodendroglioma tumors, ranging from grades II to IV. Using high-throughput DNA sequencing and immunohistochemistry, we have classified GBM samples in proneural, classical and mesenchymal. Next, we evaluated the activation status of microglia/macrophages within these samples. Despite the great heterogeneity, we observed higher levels of myeloid markers (IBA1, CD11b and CD68) in astrocytic tumors compared to oligodendrocytic ones and to non-neoplastic (NN) tissue. Anti-inflammation markers, such as CD163, are also more abundant in astrocytomas, as well as in the mesenchymal and classical GBM subtypes, while pro-inflammation markers, such as IL1-beta, show a more widespread expression throughout samples. Our preliminary data suggests an immune-suppressive and growth supportive characteristic for tumors with worse clinical outcome, linked to an activation profile of myeloid cells. Further exploring the characteristics and dynamics of innate immune cells within the microenvironment of different grades and subtypes of glioma is crucial for the better understanding of the disease progression.
Citation Format: Thais F. Galatro, Paula Sola, Sueli M. Oba-Shinjo, Bart J. Eggen, Suely K. Marie. Microglia/macrophages activation status in diffuse gliomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3229.
Abstract 3231: Identification of CD245 as myosin 18A, a receptor for surfactant A: A novel pathway for activating human NK lymphocytes effector function
Authors: Giustiniani Jérôme , de Masson Adèle , Marie-Cardine Anne , Bouaziz Jean-David , Garbar Christian , Bagot Martine , Merrouche Yacine , Bensussan Armand 
Published: July 2016

Abstract
Natural Killer (NK) cells were identified over 40 years ago as a subset of lymphocytes able to spontaneously kill tumor cells in the absence of pre-stimulation. Present in most mammalian and avian species, NK cells play a critical role in the anti-tumor and anti-infectious immunity and in reproduction. NK cell cytotoxicity is tightly controlled by a balance between signals delivered through the engagement of activating and inhibitory receptors. Beside these receptors, costimulatory molecules co-exist at the surface of activated NK cells to potentiate NK cells functions. 4-1BB (CD137) is a costimulatory receptor expressed on T, B and NK cells whose expression is triggered by engagement of the Fc receptors on the NK cell surface, as during antibody-dependent cell cytotoxicity (ADCC). Consequently the engagement of CD137 increases cetuximab-, rituximab-, and trastuzumab-dependent NK cell cytotoxic function in different cancer models. We previously described CD245 as an unidentified structure on the surface of human peripheral blood lymphocytes that was recognized by the monoclonal antibodies DY12 and DY35. We also reported that CD245 on NK lymphocytes was associated with tyrosine phosphatase activities. We found that CD245 is the unconventional myosin 18A, which is a receptor for the surfactant protein A (SP-A). We characterized the molecular and functional properties of CD245 and identified a novel co-activation pathway that potentiates the NK cell cytotoxicity. Stimulation by specific antibodies or its physiological ligand SP-A is able to increase NK cell degranulation and lymphokine-activated killer activity towards tumor B cells and EBV-infected B cells, respectively. We also found that myosin 18A stimulation is able to induce CD137 expression at the NK cell surface and that the myosin 18A-induced NK cell cytotoxicity toward CD137L-expressing tumor cells is dependent on the CD137/CD137L interaction. Thus, CD245 could represent a novel and promising target in cancer immunotherapy.
Citation Format: Jérôme Giustiniani, Adèle de Masson, Anne Marie-Cardine, Jean-David Bouaziz, Christian Garbar, Martine Bagot, Yacine Merrouche, Armand Bensussan. Identification of CD245 as myosin 18A, a receptor for surfactant A: A novel pathway for activating human NK lymphocytes effector function. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3231.
Abstract 327: Anti-tumor effect and destabilization of R175H-mutant p53 by CB002, a p53-pathway restoring small molecule that stimulates autophagy
Authors: Hernandez Borrero Liz J. , Zhang Shengliang , Dicker David , El-Deiry Wafik 
Published: July 2016

Abstract
Tumor suppressor p53 is a master regulator of genotoxic and cellular stress signals, controlling cell fate by transcriptionally activating genes involved in DNA repair, cell cycle arrest, and apoptosis. p53 is mutated in over half of human cancers and this is associated with tumor development and chemotherapy resistance. TP53 gene mutations can result in the abolishment of p53 contact with DNA and disruption of p53 structural conformation. These mutations not only prevent p53 to exert its normal tumor suppressive functions but can result in gain-of-function activity, acquiring oncogenic characteristics. Therefore, altering the stability of mutant p53 protein is an attractive therapeutic strategy in cancer cells. We investigated small molecules that modulate mutant p53 stability and restore the p53-signaling pathway. We identified a small molecule, CB002, as a candidate for restoration of the p53 pathway in mutant p53-bearing cancer cells. Three colorectal cancer cell lines: SW480, DLD-1, HCT116-R175H and the RXF393 renal cancer cell line, were treated with different concentrations of CB002 at various time points. Cell lines exposed to CB002 showed an increase in apoptotic and cell death markers, such as NOXA/DR5 induction, cleaved caspases and PARP, as early as 16 hrs. CB002 decreased mutant p53 stability in structural conformation-mutant bearing cells (HCT116 R175H and RXF393). Our data suggests that CB002 stimulates an increase of p53 target genes and promotes expression of pro-apoptotic proteins. R175H p53 mutant protein expression was largely rescued by the co-treatment with MG132, a proteasomal inhibitor, implicating a role for the ubiquitin proteasome system. Furthermore, we observed significant autophagy induction upon CB002 treatment, as indicated by LC3 conversion and p62 levels. Autophagy inhibition decreased levels of cell death markers and increased the stability of the R175H-mutant p53, suggesting that autophagy might be required for CB002-induced cell death and mutant p53 turnover. Therefore, we hypothesize that CB002 is capable of degrading mutant p53 and restoring the p53 pathway through p53 family members in colorectal cancer cells. Currently we are investigating p53 degradation mechanism by CB002, the role of p53 family members in the restoration of the pathway and autophagy on mutant p53 stability. Hence, our results provide an insight on effective p53 pathway activation through the use of small molecules.
Citation Format: Liz J. Hernandez Borrero, Shengliang Zhang, David Dicker, Wafik El-Deiry. Anti-tumor effect and destabilization of R175H-mutant p53 by CB002, a p53-pathway restoring small molecule that stimulates autophagy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 327.
Abstract 3294: Treponema denticola, a periodontal pathogen, promotes stemness and migration in oral squamous cell carcinoma
Authors: Kamarajan Pachiyappan , Ateia Islam , Shin Jae M. , Fenno J Christopher , Kapila Yvonne L. 
Published: July 2016

Abstract
Periodontitis is a chronic infectious disease characterized by inflammation and destruction of periodontal tissues including the periodontal ligament fibers and alveolar bone. Recent epidemiological studies have revealed a significant association between periodontitis and oral cancer. While the precise mechanisms that mediate these associations are not well understood, periodontal pathogens, including Treponema denticola (T. denticola), which are believed to initiate the destructive inflammatory responses and dysbiosis or dysregulation of tissue homeostasis that characterize periodontal disease may contribute to oral cancer. However, knowledge about T. denticola's contribution to oral cancer is limited. Previously, we showed that nisin ZP, a bacteriocin and commonly used food preservative, reduced tumorigenesis in vivo and long term treatment with nisin ZP extended survival. In a separate study, we further showed that nisin ZP exhibits antimicrobial and antibiofilm effects, limiting T. denticola viability. The antimicrobial doses of nisin ZP are two orders of magnitude lower than the antitumor doses. The present study investigated the impact of T. denticola on the stemness, migration, and tumorigenesis of oral squamous cell carcinoma (OSCC), and nisin's potential modulatory effects on these processes. To investigate the role of T. denticola on OSCC tumorigenesis, OSCC cells were treated with T. denticola and with or without nisin ZP then assayed for stemness (orasphere) and migration. Treatment with T. denticola enhanced OSCC orasphere formation and migration without affecting cell viability or inducing apoptosis. Addition of nisin ZP inhibited these T. denticola-mediated processes. These data indicate that the periodontal pathogen T. denticola promotes stemness and migration of OSCC cells, and thereby may contribute to oral cancer tumorigenesis.
Citation Format: Pachiyappan Kamarajan, Islam Ateia, Jae M. Shin, J Christopher Fenno, Yvonne L. Kapila. Treponema denticola, a periodontal pathogen, promotes stemness and migration in oral squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3294.
Abstract 3296: Breast mammographic density and the fecal microbiota
Authors: Jones Gieira S. , Feigelson Heather S. , Ravel Jacques , Goedert James J. 
Published: July 2016

Abstract
The microbial population (microbiota) of the distal human gut has multiple functions that modulate cancer risk including digestion of nutrients, deconjugation and enterohepatic circulation of hormones and other bile acids, and regulation of immunity and inflammation. We have previously reported that postmenopausal breast cancer cases, compared to controls, have lower fecal microbiota alpha diversity, independent of age, body mass index, and estrogen levels, and that the cases’ microbiota is compositionally altered. For deeper understanding of these associations with breast cancer, we compared microbiota metrics to a strong cancer risk factor, breast density, among 48 cancer-free, postmenopausal controls in the Breast and Colon Health study (86% non-Hispanic White, mean age 62 years). In routine screening mammograms, they had the following Breast Imaging Reporting and Data System (BI-RADS, 5th ed.) composition: a) almost entirely fatty (N = 4); b) scattered areas of fibroglandular density (N = 14); c) heterogeneously dense (N = 26); and d) extremely dense (N = 4).
As shown in the Table, simple linear regression across these four ordered BI-RADS categories revealed that there was no significant association with fecal microbiota alpha diversity (PD_tree β -0.08, P = 0.56). Breast density in these women also was not associated with microbiota beta diversity (composition) by MiRKAT analysis of un-weighted and weighted UniFrac metrics (P = 0.25 and 0.08, respectively).
We conclude that breast density is unlikely to mediate the association of the gut microbiota with breast cancer in postmenopausal women. Fecal alpha diversity by mammographic density categoryBI-RADS DensityNo.Mean (SD) PD_Whole_TreeAlmost Entirely Fatty436.06 (4.22)Scattered Fibroglandular1438.18 (8.25)Heterogeneously Dense2637.19 (4.88)Extremely Dense438.33 (7.99)
Citation Format: Gieira S. Jones, Heather S. Feigelson, Jacques Ravel, James J. Goedert. Breast mammographic density and the fecal microbiota. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3296.