bluuebunny/crossref_metadata_2025_split huggingface dataset:
Null Association between Tamoxifen Use and Dementia in Danish Breast Cancer Patients
Authors: Ording Anne Gulbech , Jensen Anders Bonde , Cronin-Fenton Deirdre , Pedersen Lars , Sørensen Henrik Toft , Lash Timothy L. 
Published: April 2013

Abstract
Background: Concerns have been raised about the risk of dementia associated with antiestrogen adjuvant therapy in breast cancer, but study results have been inconsistent. We examined whether tamoxifen or other endocrine therapy was associated with dementia risk in a large population of patients with breast cancer.
Methods: We used Danish nationwide medical registries to identify patients with breast cancer diagnosed between 1990 and 2004, use of endocrine therapy, and subsequent diagnoses of dementia. We used Cox regression to estimate the risk of dementia among patients who received five years of tamoxifen or other endocrine therapies.
Results: The study included 16,419 patients with breast cancer. In this cohort, 37% were unexposed to endocrine therapy, 9% had five years of tamoxifen therapy, and 54% had other endocrine regimens, some of them containing tamoxifen for less than five years with subsequent aromatase inhibitor therapy. Tamoxifen therapy was associated with a near-null risk of dementia [HR, 1.4; 95% confidence interval (CI), 1.0–1.9], and a null association was observed after death was taken into account as a competing risk (sub-HR, 1.0; 95% CI, 0.76–1.4).
Conclusions: No clinically relevant association between use of tamoxifen or other endocrine therapy and risk of dementia was observed.
Impact: Our result contradicts earlier research findings suggesting tamoxifen and other endocrine therapies increase the risk of dementia in breast cancer patients. Cancer Epidemiol Biomarkers Prev; 22(5); 993–6. ©2013 AACR.
Molecular Pathways: The Complex Roles of Inflammation Pathways in the Development and Treatment of Liver Cancer
Authors: Nikolaou Kostas , Sarris Michalis , Talianidis Iannis 
Published: April 2013

Abstract
Inflammatory signals from the surrounding microenvironment play important roles in tumor promotion. Key inflammatory mediators and pathways that induce and sustain tumorigenesis have recently been identified in many different cancers. Hepatocellular carcinoma is a paradigm for inflammation-induced cancer, as it most frequently develops in the setting of chronic hepatitis, consecutive cellular damage, and compensatory regeneration. Recent studies revealed that liver damage–mediated inflammation and carcinogenesis are triggered by a complex cross-talk between NF-κB, c-jun-NH2-kinase, and STAT3 signaling pathways. Molecular dissection of the mechanisms involved in the interplay between these pathways identified promising new targets for therapeutic intervention. Targeting different components of the signaling cascades may provide efficient means for blocking the apparently irreversible sequence of events initiated by chronic liver inflammation and culminating in liver cancer. Clin Cancer Res; 19(11); 2810–6. ©2013 AACR.
Altered DNA Methylation Landscapes of Polycomb-Repressed Loci Are Associated with Prostate Cancer Progression and ERG Oncogene Expression in Prostate Cancer
Authors: Kron Ken , Trudel Dominique , Pethe Vaijayanti , Briollais Laurent , Fleshner Neil , van der Kwast Theodorus , Bapat Bharati 
Published: April 2013

Abstract
Purpose: To assess differentially methylated “landscapes” according to prostate cancer Gleason score (GS) and ERG oncogene expression status, and to determine the extent of polycomb group (PcG) target gene involvement, we sought to assess the genome-wide DNA methylation profile of prostate cancer according to Gleason score and ERG expression.
Experimental Design: Genomic DNA from 39 prostate cancer specimens was hybridized to CpG island microarrays through differential methylation hybridization. We compared methylation profiles between Gleason score and ERG expression status as well as Gleason score stratified by ERG expression status. In addition, we compared results from our dataset to publicly available datasets of histone modifications in benign prostate cells.
Results: We discovered hundreds of distinct differentially methylated regions (DMR) associated with increasing Gleason score and ERG. Furthermore, the number of DMRs associated with Gleason score was greatly expanded by stratifying samples into ERG-positive versus ERG-negative, with ERG-positive/GS–associated DMRs being primarily hypermethylated as opposed to hypomethylated. Finally, we found that there was a significant overlap between either Gleason score–related or ERG-hypermethylated DMRs and distinct regions in benign epithelial cells that have PcG signatures (H3K27me3, SUZ12) and lack active gene expression signatures (H3K4me3, RNA pol II).
Conclusions: This work defines methylation landscapes of prostate cancer according to Gleason score, and suggests that initiating genetic events may influence the prostate cancer epigenome, which is further perturbed as prostate cancer progresses. Moreover, CpG islands with silent chromatin signatures in benign cells are particularly susceptible to prostate cancer–related hypermethylation. Clin Cancer Res; 19(13); 3450–61. ©2013 AACR.
Predictive Biomarkers for Bevacizumab: Are We There Yet?
Authors: Maru Dipen , Venook Alan P. , Ellis Lee M. 
Published: April 2013

Abstract
Therapy targeting VEGF has become the standard of care in several solid malignancies. Early investigations attempting to identify predictive markers for the efficacy of therapy failed to identify any predictive markers that could help oncologists decide who should—and, more importantly, who should not—receive VEGF-targeted therapies. However, interest has been renewed in predictive biomarkers for VEGF-targeted therapies, especially in light of the fact that the U.S. Food and Drug Administration withdrew approval for use of bevacizumab, an antibody to VEGF, in patients with metastatic breast cancer. In a recent publication in the Journal of Clinical Oncology, investigators identified circulating VEGF and tumor neuropilin-1 expression as potential predictive biomarkers for bevacizumab. From this perspective, we provide a critical evaluation of the use of these markers and the need for validation in prospective clinical trials. Clin Cancer Res; 19(11); 2824–7. ©2013 AACR.
Molecular Pathways: Environmental Estrogens Activate Nongenomic Signaling to Developmentally Reprogram the Epigenome
Authors: Wong Rebecca Lee Yean , Walker Cheryl Lyn 
Published: April 2013

Abstract
Exposure to environmental xenoestrogens is a major health concern because of the ability of these compounds to perturb estrogen receptor (ER) signaling and act as endocrine disrupting compounds (EDC). Inappropriate exposure to EDCs during development, even at low doses, can predispose individuals to an increased lifetime risk of disease, including cancer. Recent data indicate that perinatal exposure to EDCs increases cancer risk by (re)programming the epigenome via alterations in DNA and histone methylation. We and others have begun to dissect the mechanisms by which xenoestrogens disrupt the epigenetic machinery to reprogram the epigenome and induce developmental reprogramming. Our studies revealed that xenoestrogens induce nongenomic ER signaling to activate PI3K/AKT, resulting in AKT phosphorylation and inactivation of the histone methyltransferase EZH2, thus providing a direct link to disruption of the epigenome. Other epigenetic “readers, writers, and erasers” may also be targeted by nongenomic signaling, suggesting this is a central mechanism by which xenoestrogens and other EDCs disrupt the epigenome to induce developmental reprogramming. Elucidating mechanisms of developmental reprogramming of the epigenome is important for understanding how environmental exposures increase cancer risk, and provides a rationale for developing epigenetic interventions that can reverse the effects of environmental exposures to reduce cancer risk. Clin Cancer Res; 19(14); 3732–7. ©2013 AACR.
Abstract A29: Notch-dependent modulation of microRNAs in rhabdomyosarcoma
Authors: Rota Rossella , Ciarapica Roberta , Da Sacco Letizia , De Salvo Maria , Masotti Andrea , Miele Lucio , Locatelli Franco 
Published: April 2013

Abstract
Rhabdomyosarcoma (RMS) is a pediatric tumor that originates from skeletal muscle precursors. Therapeutic strategies aimed at restoring the differentiation potential of RMS tumor cells are accepted as anti-cancer approaches. Therefore, pathways involved in skeletal muscle determination are good potential targets. We have recently demonstrated that Notch3 signaling is over-activated in RMS cell lines of both embryonal and alveolar subtype. Down-regulation of Notch3 expression resulted in cell cycle inhibition of RMS alveolar and embryonal cell lines that showed the appearance of multinucleated structures indicative of skeletal muscle-like myotubes in vitro. Moreover, Notch3 knockdown impaired tumor growth in vivo. Here we expand this study evaluating, through microarrays profiling, the expression of microRNAs 48 hours after Notch3 siRNA treatment compared to that of control siRNA. Several up- or down-regulated microRNAs were detected in both RH30 alveolar and RD embryonal cells. The up-regulation of muscle-specific microRNAs such as miR-1, miR-133 and miR-206 was confirmed 24 and 48 hours post-Notch3 depletion by RT-qPCR. Moreover, non-muscle-specific microRNAs such as miR-26a and miR-214 that cooperate to myogenesis were up-regulated as well. Altogether, these preliminary results indicate that Notch3 prevents the differentiation of RMS cells also through down-regulation of pro-myogenic microRNAs. More deep studies are in course to dissect the Notch3-dependent modulation of these small non-coding RNAs in this soft tissue sarcoma.
Citation Format: Rossella Rota, Sr., Roberta Ciarapica, Jr., Letizia Da Sacco, Jr., Maria De Salvo, Jr., Andrea Masotti, Sr., Lucio Miele, Sr., Franco Locatelli, Sr. Notch-dependent modulation of microRNAs in rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr A29.
Abstract A31: Differential processing of let-7a precursors influences gemcitabine chemosensitivity in pancreatic cancer: Role of ribonucleotide reductase subunit M2
Authors: Govindarajan Rajgopal 
Published: April 2013

Abstract
Ribonucleotide reductase subunit M2 (RRM2) involved in deoxyribonucleotide synthesis acts as a key determinant of chemoresistance to nucleoside drugs (e.g., gemcitabine) used in treating pancreatic cancer. While silencing RRM2 expression by synthetic means (e.g., siRNA) improves the chemosensitivity of pancreatic cancer cells to gemcitabine, targeting endogenous molecules to advance gemcitabine chemotherapeutic responses has never been explored. Based on existing evidence and computational predictions, we hypothesized that the let-7 tumor suppressor microRNAs will inhibit RRM2-mediated gemcitabine chemoresistance in pancreatic cancer. Reduced expression of the majority of let-7 miRNAs with an inverse relationship to RRM2 expression was identified in inherently gemcitabine-resistant pancreatic cancer cells. Direct binding of let-7 miRNA to the 3′-UTR of RRM2 transcripts identified post-transcriptional repression of RRM2 as a novel phenomenon influencing gemcitabine chemosensitivity. Intriguingly, overexpression of human precursor-let-7 miRNAs led to differential RRM2 expression and gemcitabine chemosensitization in a poorly differentiated gemcitabine-resistant pancreatic cancer cell line MIA PaCa-2. Defective processing of the let-7a precursors to mature forms explained, in part, the discrepancies observed with let-7a expressional outcomes. Screening putative regulators of let-7a biogenesis in MIA PaCa-2 cells identified LIN-28 and SET oncoprotein to differentially modulate let-7 biogenesis and chemosensitivity in gemcitabine-sensitive versus-resistant pancreatic cancer cells. Additionally, acquired gemcitabine chemoresistance was found to be independent of let-7 alterations. These data demonstrate an intricate post-transcriptional regulation of RRM2 expression by let-7 and that the manipulation of let-7 processing machinery may provide a mechanism for improving gemcitabine chemosensitivity in innately-resistant pancreatic cancer cells.
Citation Format: Rajgopal Govindarajan. Differential processing of let-7a precursors influences gemcitabine chemosensitivity in pancreatic cancer: Role of ribonucleotide reductase subunit M2 [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr A31.
Abstract B15: Repression of PDGFRA-targeting miR-34a promotes tumorigenesis in proneural malignant gliomas
Authors: Silber Joachim , Jacobsen Anders , Ozawa Tatsuya , Harinath Girish , Holland Eric C. , Sander Chris , Huse Jason T. 
Published: April 2013

Abstract
Malignant gliomas - particularly glioblastoma (GBM) - continue to cause a disproportionate degree of morbidity and mortality within human oncology. Recent integrated genomics has demonstrated biologically distinct subclasses within malignant glioma that transcend conventional histopathological boundaries. Perhaps the broadest of these subclassess has been termed “proneural” and includes both a large fraction of GBMs along with most of their lower-grade astrocytic and oligodendroglial counterparts. The pathogenesis of proneural gliomas has been strongly linked to dysregulated PDGF signaling; but although genomic amplification or activating mutations involving the PDGF receptor (PDGFRA) characterize a significant subset of proneural GBMs, the mechanisms driving dysregulated PDGF signaling and downstream oncogenic networks in non-amplified/mutated tumors remain unclear. MicroRNAs (miRNAs) are a class of small, noncoding RNAs that regulate gene expression on a pre-translational level by binding loosely to complimentary sequences in target mRNAs. The role of miRNA biology in numerous cancer variants is well established. In an analysis of miRNA involvement in the phenotypic expression and regulation of oncogenic PDGF signaling, we found that expression of miR-34a is responsive to PDGF pathway activation in vitro. Similarly, analysis of data from the Cancer Genome Atlas (TCGA) revealed that expression of miR-34a is highly negatively correlated in proneural gliomas and in gliomas harboring amplified PDGFRA compared to other tumor subtypes. Using primary GBM cells maintained under neurosphere conditions, we then demonstrated that miR-34a specifically affects growth of proneural GBM cells in vitro and in vivo. Using data from TCGA, we identified PDGFRA as a direct target of miR-34a and validated this interaction experimentally. Finally, we provided evidence for a p53-independent mechanism mediated by PDGF signaling for negative regulation of miR-34a in proneural tumors. Taken together, our data suggest reciprocal negative feedback regulation of miR-34 and PDGFRA expression in proneural gliomas and, as such, identify a subtype specific therapeutic potential for miR-34a.
Citation Format: Joachim Silber, Anders Jacobsen, Tatsuya Ozawa, Girish Harinath, Eric C. Holland, Chris Sander, Jason T. Huse. Repression of PDGFRA-targeting miR-34a promotes tumorigenesis in proneural malignant gliomas [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr B15.
Abstract B30: Exogenous miR-128 Enforced HNSCC Inhibits Proliferation
Authors: Hauser Belinda , Hao Yubin , Califano Joseph , Gu Xinbin 
Published: April 2013

Abstract
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with complex molecular abnormalities. There are more than 65,000 Americans diagnosed with head and neck cancer and 25,000 die from this disease. microRNAs are 22~nucleotide-long endogenously expressed, highly conserved noncoding RNAs with important regulatory functions in proliferation, apoptosis, and metastasis. miR-128 a brain-enriched microRNA most commonly in gliomas that have shown to function as a tumor suppressor which decreases cell proliferation and cell invasiveness in prostate cancer. miR-128 has been shown to target BMI-1 in squamous cell carcinoma; however we believe miR-128 functions by targeting multiple targets in HNSCC.
Methods: We established HNSCC cell lines that stably expressed individual members of the miR-128 using a lentiviral delivery system. The levels of miR-128 and their targeted proteins were analyzed by qRT-PCR and Western blot. miR-128 affinity was elucidated by MTT, colony formation, flow cytometry, and a tumor xenograft model.
Results: Enforced transfection of miR-128 in HNSCC (JHU-22) expression was stable in vitro and in vivo. We identified five specific targets of miR-128 (BMI-1, BAG2, BAX, H3f3b, and Paip2). BMI-1 and H3f3b were shown to be a more dominant targeted of miR-128. Overexpression of miR-128, lead to the down regulation of these targets including decrease cell viability (30%), decrease of proliferation (55%), and significantly reduced solid tumor formation in tumor xenografts models.
Conclusions: miR-128 exhibits anti-proliferative effects and phenotypic alteration in HNSCC by targeting multiple predicted conserved targets activity function in apoptosis, cell cycle, transcription, and translation. Therefore, screening for differentially expressed targets of miR-128 help elucidate the possible mechanisms underlining the function of miR-128.Our results indicate that miR-128 has the potential to serve as a therapeutic approach.
Citation Format: Belinda Hauser, Yubin Hao, Joseph Califano, Xinbin Gu. Exogenous miR-128 Enforced HNSCC Inhibits Proliferation [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr B30.
Abstract B7: microRNA regulation of cell viability and drug sensitivity in lung cancer
Authors: Du Liqin , DeSevo Christopher , Robert Borkowski , Michael Baker , Gazdar Adi F. , Minna John D. , Pertsemlidis Alexander 
Published: April 2013

Abstract
Introduction: Lung cancer is the leading cause of cancer-related deaths, with the majority of deaths due to failed therapy from tumor drug resistance. Third-generation chemotherapeutic agents represent the standard first-line treatment for advanced small cell (SCLC) and non-small cell (NSCLC) lung cancer patients. Response rates are poor (20–40%) with a median survival of 8–10 months.
Methods: In an unbiased and comprehensive approach, we have combined a high-throughput screening platform with a library of chemically synthesized microRNA mimics and inhibitors. We have used this platform to identify mimics and inhibitors that reduce cell viability in general, and those that specifically sensitize cells to taxanes.
Results: We have identified several miRNAs for which over-expression or inhibition has a dramatic and selective effect on cell viability or drug response. We have demonstrated that miR-337-3p mimic sensitizes NSCLC cells to taxanes. By combining in vitro and in silico approaches, we identified STAT3 and RAP1A as direct targets that mediate the effect of miR-337-3p by enhancing taxane-induced arrest in the G2 phase of the cell cycle. We have also identified an inhibitor of miR-139-5p as a potent and selective regulator of SCLC cell viability. Inhibiting miR-139-5p decreases SCLC cell viability by over 80%, but has a minimal cytotoxic effect on that of NSCLCs or immortalized human bronchial epithelial cells. We are currently investigating the targets of miR-139-5p that mediate its effect on SCLC cell viability.
Conclusion: We have identified miR-337-3p as a regulator of taxane sensitivity in NSCLC, and miR-139-5p as a modulator of viability in SCLC. Increasing levels of miR-337-3p and inhibiting miR-139-5p may therefore provide novel therapeutic tools for the treatment of NSCLC and SCLC lung tumors, respectively.
Citation Format: Liqin Du, Christopher DeSevo, Borkowski Robert, Baker Michael, Adi F. Gazdar, John D. Minna, Alexander Pertsemlidis. microRNA regulation of cell viability and drug sensitivity in lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr B7.
Abstract IA15: MicroRNA reprogramming in cancer: mechanisms and consequences
Authors: Mendell Joshua T. 
Published: April 2013

Abstract
miRNA gain- and loss-of-function can potently influence cellular behavior in normal physiologic states and in diseases such as cancer. The regulation of miRNA expression and activity by cellular signaling cascades can therefore result in dramatic phenotypic outputs. We previously demonstrated extensive control of miRNA expression by well-characterized oncogenic and tumor suppressor networks including the Myc, Kras, and p53 pathways. We are now employing novel mouse models with gain and loss of miRNA function to investigate the roles of the miRNAs embedded within these signaling pathways and the pathologic consequences when their functions are disrupted. Insights gained from these functional studies have led to the development of novel therapeutic strategies for cancer and other pathologic states based on miRNA delivery. I will present our latest findings related to miRNA regulation in cancer and exploitation of these findings for the development of novel therapeutic approaches.
Citation Format: Joshua T. Mendell. MicroRNA reprogramming in cancer: mechanisms and consequences [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr IA15.