bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adherence to oral anticoagulants in patients with atrial fibrillation—a population-based retrospective cohort study linking health information systems in the Valencia region, Spain: a study protocol
Authors: Sanfélix-Gimeno G , Rodríguez-Bernal C L , Hurtado I , Baixáuli-Pérez C , Librero J , Peiró S 
Published: October 2015

IntroductionAdherence to oral anticoagulation (OAC) treatment, vitamin K antagonists or new oral anticoagulants, is an essential element for effectiveness. Information on adherence to OAC in atrial fibrillation (AF) and the impact of adherence on clinical outcomes using real-world data barely exists. We aim to describe the patterns of adherence to OAC over time in patients with AF, estimate the associated factors and their impact on clinical events, and assess the same issues with conventional measures of primary and secondary adherence—proportion of days covered (PDC) and persistence—in routine clinical practice.Methods and analysisThis is a population-based retrospective cohort study including all patients with AF treated with OAC from 2010 to date in Valencia, Spain; data will be obtained from diverse electronic records of the Valencia Health Agency. Primary outcome measure: adherence trajectories. Secondary outcomes: (1) primary non-adherence; (2) secondary adherence: (a) PDC, (b) persistence. Clinical outcomes: hospitalisation for haemorrhagic or thromboembolic events and death during follow-up. Analysis: (1) description of baseline characteristics, adherence patterns (trajectory models or latent class growth analysis models) and conventional adherence measures; (2) logistic or Cox multivariate regression models, to assess the associations between adherence measures and the covariates, and logistic multinomial regression models, to identify characteristics associated with each trajectory; (3) Cox proportional hazard models, to assess the relationship between adherence and clinical outcomes, with propensity score adjustment applied to further control for potential confounders; (4) to estimate the importance of different healthcare levels in the variations of adherence, logistic or Cox multilevel regression models.Ethics and disseminationThis study has been approved by the corresponding Clinical Research Ethics Committee. We plan to disseminate the project's findings through peer-reviewed publications and presentations at relevant health conferences. Policy reports will also be prepared in order to promote the translation of our findings into policy and clinical practice.
TNF Receptor-2 Facilitates an Immunosuppressive Microenvironment in the Liver to Promote the Colonization and Growth of Hepatic Metastases
Authors: Ham Boram , Wang Ni , D'Costa Zarina , Fernandez Maria Celia , Bourdeau France , Auguste Patrick , Illemann Martin , Eefsen Rikke Loevendahl , Høyer-Hansen Gunilla , Vainer Ben , Evrard Maximilien , Gao Zu-Hua , Brodt Pnina 
Published: October 2015

AbstractSuccessful colonization by a cancer cell of a distant metastatic site requires immune escape in the new microenvironment. TNF signaling has been implicated broadly in the suppression of immune surveillance that prevents colonization at the metastatic site and therefore must be blocked. In this study, we explored how TNF signaling influences the efficiency of liver metastasis by colon and lung carcinoma in mice that are genetically deficient for the TNF receptor TNFR2. We found a marked reduction in liver metastases that correlated with a greatly reduced accumulation at metastatic sites of CD11b+GR-1+ myeloid cells with enhanced arginase activity, identified as myeloid-derived suppressor cells (MDSC). Reduced infiltration of MDSC coincided with a reduction in the number of CD4+FoxP3+ T regulatory cells in the tumors. Reconstitution of TNFR2-deficient mice with normal bone marrow, or adoptive transfer of TNFR2-expressing MDSC into these mice, was sufficient to restore liver metastasis to levels in wild-type mice. Conversely, treatment with TNFR2 antisense oligodeoxynucleotides reduced liver metastasis in wild-type mice. Clinically, immunohistochemical analysis of liver metastases from chemotherapy-naïve colon cancer patients confirmed the presence of CD33+HLA-DR−TNFR2+ myeloid cells in the periphery of hepatic metastases. Overall, our findings implicate TNFR2 in supporting MDSC-mediated immune suppression and metastasis in the liver, suggesting the use of TNFR2 inhibitors as a strategy to prevent metastatic progression to liver in colon, lung, and various other types of cancer. Cancer Res; 75(24); 5235–47. ©2015 AACR.
Abstract A17: Identification and characterization of small molecules targeting MYC-cofactor interactions
Authors: Castell Alina , Yan Qinzi , Ridderstråle Karin , Larsson. Lars-Gunnar 
Published: October 2015

Abstract
Our aim is to develop specific inhibitors targeting the interaction between the oncoprotein/transcription factor MYC and its cofactors. MYC-family genes (MYC, MYCN, MYCL) are involved in over half of all cancers, including many childhood cancers such as neuroblastoma, medulloblastoma, leukemia and lymphoma, and is often strongly associated with poor prognosis. This emphasizes the need to identify clinically relevant MYC inhibitors. It regulates numerous genes involved in cell growth, metabolism, apoptosis, senescence and other processes. MYC is functionally dependent on interaction with the dimerization partner MAX and with several cofactors involved in different aspects of transcription regulation. Targeting such interactions with low Mw compounds is a plausible way to inhibit the transcriptional function of MYC. We have established several techniques to visualize MYC-cofactor interactions in living (BiFC, split Gaussia Luc) or fixed (isPLA) cells to screen small Mw compound libraries for MYC/cofactor-interaction inhibitors. In MYC/MAX BiFC and Gaussia Luc screens, 15 compounds were identified that directly or indirectly inhibit MYC/MAX interactions in cells. Several of these compounds including analogues are potent inhibitors of MYC/MYCN-dependent proliferation and transformation in neuroblastoma, leukemia/lymphoma and other cancer cells by inducing apoptosis or senescence. One of these, #2, and analogues completely inhibit MYC/MAX interactions in vitro by binding MYC. Another compound, 2XU, inhibit MYC/MAX interactions in sub-nanomolar concentration. We are evaluating the biological activities of these molecules further in different MYC-driven cell culture systems, and are elucidating their mechanisms of action by X-ray crystallography, FRET and SPR. In vivo studies with some of these molecules in mouse tumor models is ongoing. Furthermore, extended screens for finding molecules targeting MYC and other cofactor interactions, such as E3-ligases, are ongoing. The MYC inhibitors identified here have the potential to become important tools in the studies of MYC function in cells and in vivo as well as lead molecules for drug development for treatment of MYC-driven tumors.
Citation Format: Alina Castell, Qinzi Yan, Karin Ridderstråle, Lars-Gunnar Larsson. Identification and characterization of small molecules targeting MYC-cofactor interactions. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A17.
Abstract A23: Identification of KJ-Pyr-9 as a potent MYC inhibitor
Authors: Hart Jonathan R. , Bister Klaus , Janda Kim D. , Vogt Peter K. 
Published: October 2015

Abstract
We have identified a novel small-molecule inhibitor of MYC, KJ-Pyr-9, from a Kröhnke pyridine library. KJ-Pyr-9 functions as an inhibitor of MYC in biochemical assays, in cells and in xenograft experiments. In vitro, KJ-Pyr-9 binds to MYC as well as MYC-MAX dimers and can disrupt binding of MYC-MAX dimers with E-box DNA. In cells, MYC-MAX dimerization can be disrupted in cells as demonstrated by protein fragment complementation assays. KJ-Pyr-9 disrupts the transcriptional targets of MYC. The P493-6 cell line has tetracycline regulatable MYC expression. For this cell line, the transcriptional targets of MYC can be readily observed upon the addition of 0.1 ug/mL doxycycline. Both doxycycline and KJ-Pyr-9 negatively regulate MYC transcriptional signatures as determined by GSEA. The growth of a variety of different MYC-dependent cell lines is inhibited, including MYC-translocated Burkitt's lymphoma cell lines expressing high levels of MYC as well as solid tumor cell lines expressing moderate amounts of MYC. In vivo, KJ-Pyr-9 effectively blocks the growth of a xenotransplant of MYC-amplified human cancer cells.
Acknowledgements: This work was supported by the National Cancer Institute under award number R01 CA078230 (PKV), The Skaggs Institute for Chemical Biology (KDJ) and by the Austrian Science Fund (FWF) grant P23652 (KB). This is manuscript 25089 of The Scripps Research Institute.
Citation Format: Jonathan R. Hart, Klaus Bister, Kim D. Janda, Peter K. Vogt. Identification of KJ-Pyr-9 as a potent MYC inhibitor. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A23.
Abstract A27: Epigenomic and transcriptional analyses in a Tet-Myc driven mouse model of liver cancer
Authors: Kress Theresia , Bianchi Valerio , D'Artista Luana , Nicoli Paola , Doni Mirko , Radaelli Enrico , Amati Bruno 
Published: October 2015

Abstract
The c-myc proto-oncogene is frequently overexpressed in human hepatoblastoma due to gene amplification or constitutively active Wnt signaling. High Myc levels characterize an aggressive hepatoblastoma subtype, reproduced in mice with a liver-specific tetracyclin-regulated c-myc transgene (1, 2). Here, we used an analogous mouse model (tetO-MYC/Lap-tTA; ref. 3) to study the epigenomic and transcriptional mechanisms underlying tumor progression and maintenance. Tet-Myc induction in utero resulted in rapid and fully penetrant tumorigenesis by the age of six weeks. Pre-tumoral changes were detectable already at a late embryonic stage (E18.5) with increased liver size and hepatoblast fraction. As previously described (2), tumors remained dependent on the constitutive expression of the transgene. To study transcriptional changes during tumor progression and regression, we established RNA-seq profiles in control hepatoblasts, pre-tumoral Tet-Myc hepatoblasts and tumor nodules, in the latter before and after short-term inactivation of Tet-Myc. In parallel, we used ChIP-seq to profile the genome-wide distribution of Myc, RNAPII and several histone marks (H3K4me1, H3K4me3, H3K27ac), yielding comprehensive maps of Myc binding to regulatory elements (promoters and enhancers). This unique dataset is providing the basis for mechanistic studies addressing how Myc deregulates its target genes during liver tumorigenesis: comparison of differentially expressed mRNAs and Myc-binding profiles enables us to discriminate between directly and potentially indirectly regulated genes, for which we are currently investigating the underlying molecular basis. Furthermore, our genome-wide data are allowing us to unravel potentially druggable genes and pathways regulated by Myc during hepatoblastoma progression and maintenance. Our progress in characterizing this model will be presented at the meeting.
References:
1. Cairo S et al. 2008, Cancer Cell, 14:471-84
2. Shachaf CM et al. 2004, Nature, 431:1112-7
3. van Riggelen J et al. 2010, Genes Dev, 24:1281-94
Citation Format: Theresia Kress, Valerio Bianchi, Luana D'Artista, Paola Nicoli, Mirko Doni, Enrico Radaelli, Bruno Amati. Epigenomic and transcriptional analyses in a Tet-Myc driven mouse model of liver cancer. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A27.
Abstract A35: MAX inactivation in small cell lung cancer disrupts the MYC-SWI/SNF programs and is synthetic lethal with BRG1
Authors: Torres-Diz Manuel , Romero Octavio A. , Pros Eva , Savola Suvi , Gomez Antonio , Moran Sebastian , Montuenga Luis M. , Yokota Jun , Sanchez-Cespedes Montse 
Published: October 2015

Abstract
Our knowledge of small cell lung cancer (SCLC) genetics is still very limited, amplification of L-MYC , N-MYC , and C-MYC being some of the well-established genealterations. Here, we report our discovery of tumor-specifi c inactivation of the MYC-associated factorX gene, MAX , in SCLC. MAX inactivation is mutually exclusive with alterations of MYC and BRG1 , thelatter coding for an ATPase of the switch/sucrose nonfermentable (SWI/SNF) complex. We demonstratethat BRG1 regulates the expression of MAX through direct recruitment to the MAX promoter, and thatdepletion of BRG1 strongly hinders cell growth, specifi cally in MAX-defi cient cells, heralding a syntheticlethal interaction. Furthermore, MAX requires BRG1 to activate neuroendocrine transcriptional programsand to upregulate MYC targets, such as glycolysis-related genes. Finally, inactivation of the MAXdimerization protein, MGA, was also observed in both non–small cell lung cancer and SCLC. Our resultsprovide evidence that an aberrant SWI/SNF–MYC network is essential for lung cancer development.
SIGNIFICANCE: We discovered that the MYC-associated factor X gene, MAX , is inactivated in SCLCs.Furthermore, we revealed a preferential toxicity of the inactivation of the chromatin remodeler BRG1in MAX-defi cient lung cancer cells, which opens novel therapeutic possibilities for the treatment ofpatients with SCLC with MAX-defi cient tumors.
Citation Format: Manuel Torres-Diz, Octavio A. Romero, Eva Pros, Suvi Savola, Antonio Gomez, Sebastian Moran, Luis M. Montuenga, Jun Yokota, Montse Sanchez-Cespedes. MAX inactivation in small cell lung cancer disrupts the MYC-SWI/SNF programs and is synthetic lethal with BRG1. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A35.
Abstract A39: The mitochondrial translation machinery is a critical effector of Myc in lymphomagenesis
Authors: D'Andrea Aleco , Bianchi Valerio , Nicoli Paola , Amati Bruno 
Published: October 2015

Abstract
The Myc protein, encoded by the c-myc proto-oncogene, is a transcription factor that binds thousands of genomic loci. Based on genome-wide binding and expression profiles, we recently provided an exhaustive list of genes that are up- or down-regulated by Myc during B-cell lymphomagenesis in Eµ-myc transgenic mice (Sabò et al. 2014 Nature 511, 488-492). Which among those Myc-regulated genes are critical effectors in tumor progression and maintenance remained largely unknown. Here, we show that concerted activation by Myc of the mitochondrial translation machinery is critical for the maintenance of Myc-induced lymphomas. A majority of genes encoding for Mitochondrial Ribosomal Proteins (MRPs) and other associated polypeptides were directly up-regulated by Myc in Eµ-myc lymphomas. Among those was the gene encoding PTCD3, a Pentatricopeptide repeat protein involved in mitochondrial translation (Davies et al. 2009 FEBS Lett. 583, 1853-1858). RNAi-based knockdown of PTCD3 or several MRPs conferred a selective disadvantage in lymphoma cells, owing to impaired cell proliferation. As expected PTCD3 knockdown in lymphomas was also accompanied by a reduction in the levels of mitochondrial-encoded protein COX-I. Chemical inhibition of mitochondrial translation with Tigecycline led to rapid death of Eµ-myc lymphoma cells in vitro. We are currently testing the effect of Tigecycline on lymphoma growth in vivo.
Citation Format: Aleco D'Andrea, Valerio Bianchi, Paola Nicoli, Bruno Amati. The mitochondrial translation machinery is a critical effector of Myc in lymphomagenesis. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A39.
Abstract A41: Shaping Myc-dependent transcriptional amplification
Authors: Lin Charles , Bradner James E. 
Published: October 2015

Abstract
Myc deregulation, resulting in the elevated and constitutive expression of the protein, is a common oncogenic event that gives rise to numerous tumorigenic phenotypes in multiple tumor types. When, elevated, Myc acts as a general transcriptional regulator, non-linearly amplifying the expression of most transcriptionally active genes in the tumor cell. However the gene specific contexts that shape this non-linear response are poorly understood. Here we report that in B-cells, transcriptional response at active genes is largely a function of the change in Myc occupancy at promoter regions, consistent with Myc dependent transcriptional amplification. To explore determinants of Myc binding affinity, changes in Myc promoter occupancy were compared to sequence, transcription, and chromatin features in cells prior to Myc elevation. Changes in Myc occupancy correlate most strongly with promoter GC content rather than with the density of Myc E-box binding motifs or any other analyzed promoter feature. The ability of GC rich promoters to garner increased Myc occupancy levels suggest that general structural sequence and regulatory features of the promoter play a role in shaping Myc binding affinity. Importantly, Myc binding affinity, although generally correlating with transcriptional response, fails to articulate much of the observed gene expression variance suggesting that additional regulatory layers, including Myc interacting co-regulators such as MIZ1, likely contribute to shaping Myc dependent transcriptional responses.
Citation Format: Charles Lin, James E. Bradner. Shaping Myc-dependent transcriptional amplification. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A41.
Abstract B02: The role of the immune system in sustained tumor regression following oncogene inactivation
Authors: Casey Stephanie C. , Do Rachel K. , Felsher Dean W. 
Published: October 2015

Abstract
The MYC oncogene has been implicated in the pathogenesis of many types of human cancer. The Felsher laboratory uses a conditional Tet-off MYC mouse model to study the formation of tumors in multiple tissue types, such as lymphoma, and has demonstrated that MYC-induced tumorigenesis is reversible. We have found that many cancers are “oncogene addicted” to MYC. Our laboratory has shown that an adaptive T cell-mediated immune response is essential for sustained tumor regression upon MYC inactivation (Rakhra et al, Cancer Cell, 2010). Now, we have found evidence suggesting that upon MYC inactivation in tumors, B cells are activated and are critical to tumor regression. MYC inactivation in a tumor was associated with the induction of an antibody-mediated response against tumor cells. This humoral response could mediate the killing of tumor cells in an Antibody-Dependent Cellular Cytotoxicity (ADCC) assay. Our work suggests that MYC inactivation results in a B cell-mediated immune response and that ADCC may contribute to tumor regression.
Citation Format: Stephanie C. Casey, Rachel K. Do, Dean W. Felsher. The role of the immune system in sustained tumor regression following oncogene inactivation. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B02.
Abstract B30: Regulation of the core pre-mRNA splicing machinery by MYC and PRMT5 is essential to sustain lymphomagenesis
Authors: Koh Cheryl , Bezzi Marco , Low Diana , Ang WeiXia , Teo ShunXie , Gay Florence , Haddawi Muthafar Al , Tan SooYong , Osato Motomi , Sabo' Arianna , Wee KengBoon , Amati Bruno , Guccione Ernesto 
Published: October 2015

Abstract
Deregulated expression of the MYC transcription factor occurs in a majority of human cancers and correlates with high proliferation, reprogrammed cellular metabolism and poor prognosis. Over-expressed MYC binds to virtually all active promoters within a cell, although with different binding affinities, and modulates the expression of distinct subsets of genes. However, the critical effectors of MYC in tumorigenesis remain largely unknown.
Here, we show that during lymphomagenesis in Eµ-myc transgenic mice, MYC directly up-regulates the transcription of the core snRNP assembly genes, including Prmt5, an arginine methyltransferase that methylates Sm proteins. This coordinated regulatory effect is critical for snRNP biogenesis, effective mRNA splicing, cell survival and proliferation. Indeed, Prmt5 haplo-insufficiency significantly delays lymphoma onset in Eµ-myc transgenic mice and the acute deletion of PRMT5 in established lymphomas enhances the survival of tumor-bearing animals. In human lymphomas and leukemias, the expression of core snRNP genes also correlates with that of MYC, and PRMT5 knockdown results in aberrant pre-mRNA splicing and loss of viability. In both human or mouse lymphomas cells, MYC knockdown also reduces the expression of core snRNP components, causing aberrant pre-mRNA splicing.
Finally, we identify pre-mRNAs that are particularly sensitive to perturbation of the MYC-PRMT5 axis, resulting in either intron retention or exon skipping. Using antisense oligonucleotides (ASOs), we mimic these splicing defects and demonstrate their individual contribution to the anti-proliferative/apoptotic phenotype observed in Eµ-myc B-cells.
Thus, coordinate regulation of the core snRNP assembly machinery and PRMT5 is critical for the maintenance of normal pre-mRNA splicing and cell survival upon oncogenic activation of c-myc, pointing to PRMT5 methyl-transferase activity as a potential therapeutic target in MYC-driven tumors.
Citation Format: Cheryl Koh, Marco Bezzi, Diana Low, WeiXia Ang, ShunXie Teo, Florence Gay, Muthafar Al Haddawi, SooYong Tan, Motomi Osato, Arianna Sabo', KengBoon Wee, Bruno Amati, Ernesto Guccione. Regulation of the core pre-mRNA splicing machinery by MYC and PRMT5 is essential to sustain lymphomagenesis. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B30.