tbuckley/cabot-search huggingface dataset:
Abstract 5405: Immuno-phenotyping reveals cell types present in circulation of breast cancer patients and elucidates their funstional potential
Authors: Oscar Ramirez
Journal: Cancer Research (2012)

Abstract Myeloid derived suppressor cells (MDSC) have an identified role in suppressing anti-tumor immunity through Jak/Stat pathway activation and the generation of reactive oxygen species and arginase -1, thus promoting cancer progression. There is robust data on the identification of functionally suppressive MDSCs in preclinical models. However, such knowledge is underdeveloped in human cancers. Specifically, the clear identification of the true MDSC and their role in tumor immunoevasion, cancer progression and metastasis is undefined. Therefore, comprehensive identification of MDSCs and their ability to augment tumor-induced immune suppression in newly diagnosed early stage breast cancer is warranted to define their potential as a novel immunotherapeutic target. To delineate the role of MDSCs in newly diagnosed, untreated breast cancer and their tumor immunosuppressive effects in comparison to normal hosts, we conducted a prospective trial of stage I-IV breast cancer patients enrolled prior to initiation of systemic therapy and their age-matched normal donors. The following immune cell subsets were analyzed: regulatory T cells (CD3+/CD4+/CD25+/Foxp3+), MDSCs (Linlo/HLA-DR-/CD33+/CD11b+), and DCs (Lin-/CD14-CD4+/CD303+/CD1c+/CD141+). Functional assays of T cell activation and MDSCs mediated-T cell suppression were performed. We identified no significant differences in the percentage of regulatory T cells or mDC2 between breast cancer subjects and normal controls. In contrast, the percent of MDSC, pDCs and conventional DCs detected were suprisingly significantly higher in the healthy donor population as compared to breast cancer subjects. Breast cancer T cells showed reduced capability to respond to external stimulus as measured by up-regulation of CD25 and CD69 as well as T cell proliferation, although not statistically significant relative to normal controls. Breast cancer MDSC were significantly more suppressive of T cell activation relative to normal controls. The granulocytic but not monocyte subset of MDSCs (distinguished by CD15 expression) were identified as the main responders to PMA stimulation. Our results demonstrate immune suppression in newly diagnosed invasive breast cancer is characterized by increased immune suppressive function of MDSCs in the absence of increased cellular levels. When we looked at our cases with the highest MDSC levels, no distinct trend towards advanced stage or poorer prognosis biologic subtype was identified. These data support the identification of MDSCs in breast cancer as a novel therapeutic target to improve treatment outcomes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5405. doi:1538-7445.AM2012-5405
MGMT methylation in glioblastoma: tale of the tail
Authors: Nameeta Shah, Brett Schroeder, Charles Cobbs
Journal: Neuro-Oncology (2014)

Promoter region methylation of O6-methylguanine DNA methyltransferase (MGMT) is a critical biomarker in neuro-oncology. Introduction of temozolomide (TMZ) and concomitant radiation as a standard of care (Stupp protocol) for glioblastoma multiforme (GBM) has improved survival for some patients. Hegi et al. suggested that methylation status might be predictive of benefit from TMZ,1 and multiple studies ever since have confirmed that MGMT methylation status is predictive of TMZ response.2 However, debate persists regarding the best method for its evaluation. Consequently, MGMT status in the clinic has been underutilized, and TMZ remains a staple in caring for GBM patients regardless of their MGMT methylation status.

The MGMT promoter consists of 97 cytosine-guanine (CpG) dinucleotide sites, which can be grouped into 3 regions: R1, R2 and R3, where R1 is the most distal to the transcription start site and R3 is adjacent to the transcription start site. In our previous study,3 we comprehensively characterized methylation across the entire MGMT promoter and showed that all 3 regions correlate to mRNA expression, protein expression, and progression-free survival. The most widely used test that measures MGMT methylation is the qMSP test.4 The qMSP test measures methylation in region R3, which is the most strongly correlated to patient outcome. However, the success of the test depends upon the co-methylation of at least 4 out of the 7 CpG sites in R3. Another test, the MS-MLPA, can measure methylation of 3 individual CpG sites, one in each of the aforementioned regions.5 Hence, both tests are complementary in nature.

It has been suggested that GBM patients with and without MGMT methylation benefit from TMZ.1 The tail in the unmethylated group (>3-year survival, Fig. 1A and B) seemingly indicated that even patients with unmethylated MGMT benefit from TMZ treatment. This survival tail in our cohort is consistent with other large-scale studies.2 However, when we performed both qMSP and MS-MLPA tests together on 65 GBM samples, we observed increased detection sensitivity, and the tail in the unmethylated group disappeared (Fig. 1C and D). All 5 patients comprising the tail, when using just one of the tests, were indeed methylated by the other test. These data suggest that accurate MGMT characterization is grounds for questioning the alleged benefit of TMZ for all GBM patients and strengthen the case for needing new treatment regimens because the current standard of care does not provide benefit for MGMT-unmethylated patients. 



Fig. 1.

Kaplan–Meier survival curves for MGMT methylated versus unmethylated patients. (A) MGMT methylation tested using qMSP (log-rank P = .006). (B) MGMT methylation tested using MS-MLPA (log-rank P < .001). (C) MGMT methylation determined using ...
Abstract 4947: Analysis of structural mutations in cancer genomes
Authors: Xing Yi Woo, Francesca Menghi, Koichiro Inaki, Min Gong, Axel Hillmer, Faranak Sherbaf, Edison Liu
Journal: Cancer Research (2012)

Abstract In our group, we have extensively sequenced various cancer genomes (breast cancer, ovarian cancer and melanoma) using a range of genome-wide sequencing approaches, including DNA-PET, RNA-SEQ and exome-capture sequencing. Taking each tumor as a system of its own, we aim to integrate the different outputs of these technologies to explore the composite of hard-wired changes that drive tumorgenesis in different cancers. One type of hard-wired changes is copy number alterations, where the cancer genome tends to gain oncogenes and lose tumor suppressors by DNA amplifications and deletions respectively. While copy number variation data are now a standard output of the DNA-PET pipeline, the accurate prediction of copy number gains and losses is further complicated by several issues, including normal tissue contamination, tumor heterogeneity and aneuploidy. I will present my current work to deconvolute the contribution of these factors to the copy number profile. I will also discuss the classification of our sequenced cancer genomes into various chromotypes based on their unique copy number signatures. I will show how different chromotypes are enriched in specific types of structural variations, which may underlay alternative mechanisms of genomic instability promoting cancer evolution. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4947. doi:1538-7445.AM2012-4947
OP0007 Development of eular recommendations for the reporting of clinical trial extension studies
Authors: M.H. Buch, L. Carmona, L. Silva, M. Boers
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Randomised controlled trials (RCT) provide data on short-term, clinically measurable outcomes (safety and efficacy). Longer-term data requires extended follow-up. Post-RCT extension clinical data reporting holds challenges with no guidelines on optimal reporting<sup>1</sup>. <h3>Objectives</h3> To produce evidence- and consensus-based recommendations on key aspects of reporting of trial extension studies (TES), applying EULAR standard operating procedures; and thereby, develop a standardised format for future TES data reporting. <h3>Methods</h3> A taskforce of 21 (experts in RCTs, epidemiologists and patient representation) was formed. An initial meeting agreed the objectives and key areas for evaluation and formed the basis for a first Delphi survey ("0-10" level of agreement scale for given definitions). A second Delphi was undertaken; cut-off for accepting consensus was a mean score of 7/10 and rejected if more than 4 responses under 5 recorded. <h3>Results</h3> 16/21 completed the first Delphi and 20/21 the second survey. Of a total of 26 domains, consensus has been reached on 23 domains. A flowchart detailing progress of patients from start of placebo/active comparator RCT to TES completion (including numbers withdrawing early, switching to experimental/standard of care and subsequent progress) has been designed. Eight key domains with strong consensus are summarised below. Final review and voting will be undertaken shortly. <h3>Conclusions</h3> Strong consensus on majority of core elements of TES reporting has been reached. The final document will provide much needed recommendations to ensure a transparent and standardised approach to the reporting of TES. <h3>References</h3> Buch MH, et al. Ann Rheum Dis 2011; 70(6):886-90 <h3>Disclosure of Interest</h3> None Declared
Treatment of Postmenopausal Osteoporosis
Authors: Richard Eastell
Journal: New England Journal of Medicine (1998)

Osteoporosis affects an estimated 75 million people in Europe, the United States, and Japan.1 It is a preventable and treatable condition, yet many people with osteoporosis remain unrecognized and untreated. The purpose of this review is to consider the evidence that treatments for postmenopausal osteoporosis are effective and safe.Definition of OsteoporosisDefinitions of osteoporosis have usually been conceptual and therefore difficult to apply to individual patients. For example, a Consensus Development Conference defined osteoporosis as “a systemic skeletal disease characterised by low bone mass and microarchitectural deterioration with a consequent increase in bone fragility and susceptibility to fracture.”1 A . . .
Abstract 3431: Regulation of integrins AlphaV Beta3 and focal adhesion kinase signaling by PTTG in induction of EMT
Authors: Parag P. Shah, Sham S. Kakar
Journal: Cancer Research (2011)

Abstract Pituitary tumor transforming gene (PTTG) is a well-studied oncogene for its role in tumorigenesis. PTTG expression levels correlate with the tumor development, growth and metastasis and serve as a marker of malignancy in several cancer types including lung. Epithelial to mesenchymal transition (EMT) is a crucial step in tumor progression and metastasis, during which epithelial cells lose their polarity and cell-cell adhesion. Integrins are transmembrane proteins which bind ligands found in the extracellular matrix. Interactions between the extracellular matrix and the actin cytoskeleton commonly take place at focal adhesions on the cell surface that contain localized concentrations of integrins, signaling molecules, and cytoskeletal elements. Talin forms a direct interaction with the integrin cytoplasmic domain, and interacts with cytoskeletal elements (actin) and signaling factors. The present study was focused to define the regulation of integrins and FAK pathway by PTTG in induction of EMT. For our studies, we used lung cancer cell lines A549 and H1299 and infected with adenovirus expressing PTTG cDNA or adenovirus expressing control GFP. Using Real Time PCR and immunohistochemistry and FACS analysis, we observed that overexpression of PTTG in cells resulted in a significant increase in the expression of integrins αv and β3 in both cell lines compared to uninfected cells or cells infected with adenovirus expressing GFP. These results were confirmed by the down-regulation of PTTG expression using adenovirus expressing PTTG-specific siRNA that showed a significant decrease in the expression of integrins αv and β3. Western blot analysis revealed increased phosphorylation of FAK on overexpression of PTTG. Analysis of downstream signaling genes such as Paxillin, Metavinculin and Rac 1 by quantitative real time PCR analysis showed positive correlation between levels of PTTG and these genes. Treatment of A549 and H1299 cells with the αvβ3 antagonist echistatin (RGD peptide) and siRNA specific for integrin αv resulted in a decreased in phosphorylation of FAK as well as expression of downstream signaling genes Paxillin, Metavinculin and Rac 1. The Vinculin and Phallodoin are responsible for the functional link of FAK to the actin cytoskeleton. Disruption of actin cytoskeleton was confirmed with immunostaining. Taken together our results suggest for the first time an important role of PTTG in regulation of integrins αv and β3 leading to change in Focal Adhesion Kinase (FAK) pathway resulting in induction of EMT. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3431. doi:10.1158/1538-7445.AM2011-3431
Abstract 12: Metastatic neuroblastoma cancer stem cells display a mixed phenotype of tumor and niche origin required for survival
Authors: Loen M. Hansford, Olena Morozova, Tatiana Lipman, Kim Blakely, Miki Ohira, Paula Marrano, Paola Angelini, Jason Moffat, Carol J. Thiele, Paul Thorner, John Dick, Akira Nakagawara, Meredith Irwin, Marco Marra, David R. Kaplan
Journal: Cancer Research (2010)

Abstract Neuroblastoma (NB) is a pediatric tumor of neural crest origin, and is the most common cancer of infancy. 50% of patients have metastases at diagnosis, of which 85% will die after multiple relapses from metastatic disease. We identified tumor-initiating cells (TICs) from bone marrow (BM) metastases of high-risk patients that are propagated as spheres and that have many properties of cancer stem cells, and form NB in mice with as few as 1 cell. To understand patient relapse and disease progression, we compared NB-TICs from BM with those from tumor and brain metastases and SKPs, a normal pediatric stem cell counterpart, by cDNA microarray, flow cytometry, and whole genome shotgun sequencing transcriptome analysis. BM-derived NB-TICs expressed primitive neural crest and neuronal markers as well as hematopoietic markers from primitive, myeloid, and B-cell lineages and contained VDJ gene rearrangements, which are normally associated with B-cell leukemias. Hematopoietic genes were not expressed or expressed at very low levels in tumor-derived sphere lines and a line from an NB brain metastasis, however brain metastasis-derived TICs expressed CD133, while BM-derived NB-TICs did not. Furthermore, we found that shRNA to CD74, which is upregulated in B-cell lymphoma and multiple myeloma and is a therapeutic target for those cancers, induced the rapid death of NB-TICs but not normal SKPs. Interestingly cells co-staining for the hematopoietic markers CD45 or CD74 and the neural neural progenitor marker nestin were found in BM smears of patients with relapsed NB in the bone marrow. We suggest that metastatic TICs from some tumors adopt resident niche-specific gene expression signatures, which may aid diagnosis and the development of novel treatments. We hypothesize that drugs used for leukemia may be efficacious therapeutics for metastatic NB, and are currently testing this hypothesis in mouse models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 12.
THE INTERDEPENDENCE OF PHYSIOLOGY AND MORPHOLOGY AND THEIR EDUCATIONAL IMPORTANCE.
Authors: JAMES WEIR
Journal: JAMA (1900)

Since the great epoch-making theory of Darwin has now ceased to be merely a theory, and is accepted as a doctrine that is as clearly demonstrable as is the heliocentric doctrine of Copernicus, an early and universal entrance, by the students of our medical schools, into the study of morphology seems to be demanded. In our public schools, in which the vast majority of our population gain their education, the scheme of life, with its multitudinous ramifications throughout the animal and vegetable kingdom, receives but scanty attention. In point of fact, beyond a slight and necessarily imperfect knowledge of the fundamental principles of physiology and anatomy, the public school graduate passes through life in absolute ignorance of his or her status in the scale of animate beings and in the economy of Nature. Not only is this true of the public school graduate, but also of the university or college
Abstract 2189: Efficacy of combination therapies in lung cancer
Authors: Martin L. Sos, Jonathan Weiss, Martin Peifer, Roman K. Thomas
Journal: Cancer Research (2010)

Abstract Genetically activated oncogenes induce dependency on the constitutively activated oncoprotein in cancer cells. Targeted therapeutics that shut down the oncogenic signaling, induce apoptosis and thus lead to tumor shrinkage in patients can exploit this dependency. However, efficacy of single-agent inhibition often is limited by release of negative feedback loops or incomplete suppression of its primary target at clinically relevant concentrations. The lack of preclinical models that capture the genomic diversity of human tumors impedes the transition from preclinical drug discovery to clinical trials lies in and this diversity. We sought to overcome these limitations and therefore we established a panel of 84 non-small cell lung cancer cell lines and characterized in depth in gene copy number, gene expression and mutation space. We applied a chemo-genomics approach in order to determine the efficacy of single-agent and combination treatment with PI3K-, MAPK- and receptor tyrosine kinase (RTK-) inhibitors in genotypically defined subsets of tumor cells. We found RTK-driven tumors to largely depend on PI3K and RAS-/ RAF-driven tumors to be addicted to the MAPK signaling pathways, respectively. However, release of negative feedback loops led to activation of the alternate pathway. Combined inhibition of PI3K- and MAPK-pathways potently suppressed release of negative feedback loops, thereby resulting in enhanced induction of apoptosis in tumor cells and tumor shrinkage in vivo. In the subset of EGFR mutated cells harboring the gatekeeper mutation T790M we found limited efficacy of single-agent treatment with irreversible EGFR inhibitors. This limited activity could be linked to decreased binding velocity to the mutant kinase. However combined treatment of T790M-mutant tumor cells with irreversible ERBB inhibitors, and PI3K/mTOR inhibitors led to induction of apoptosis. Recently we established a systematic screening pipeline for the study of combined inhibition of key nodules of oncogenic signaling pathways and preliminary results suggest a critical role of PI3K/mTOR-signaling for efficacy of combination therapies. Overall our approach builds a robust framework for the preclinical study of combination therapies and might help to direct future drug development and patient stratification in clinical trials. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2189.
Abstract 1006: A novel class I histone deacetylase (HDAC) inhibitor, paragazole, demonstrates antiproliferative and proapoptotic effects in triple-negative breast cancer models.
Authors: David P. Astling, John J. Tentler, Benjamin R. Cross, Timothy P. Newton, Todd M. Pitts, Eric Gunther, Xuedong Liu, S. Gail Eckhardt, Jennifer R. Diamond
Journal: Cancer Research (2013)

Abstract Introduction: Triple-negative breast cancer (TNBC) is a clinically aggressive breast cancer subtype which lacks estrogen receptor expression. Histone deacetylase (HDAC) inhibitors have previously been shown to induce estrogen receptor expression in TNBC models. Paragazole is a selective class I HDAC inhibitor (HDACs 1, 2, and 3) currently in preclinical development. In this project, we explored the antiproliferative and proapoptotic activity of paragazole and investigated the combination of paragazole and chemotherapy in a panel of breast cancer cell lines. Methods: Breast cancer cell lines were exposed to varying sub-micromolar concentrations of paragazole alone and in combination with carboplatin, paclitaxel, and gemcitabine. Proliferation was assessed using an SRB assay and analyzed using the Calcusyn program, whereby synergy was defined as a Combination Index of less than 1. Cell cycle analysis was performed using flow cytometry and apoptosis was analyzed using a caspase 3/7 assay. Baseline HDAC expression was measured by RT-PCR and RNA-Seq was used pre- and post-treatment in a subset of 2 sensitive and 2 resistant cell lines. Results: Exposure to paragazole resulted in a decrease in cell proliferation at submicromolar concentrations with more robust antiproliferative activity observed in the TNBC cell lines compared to the estrogen receptor positive cell lines. An increase in apoptosis that was maximal at 24-48 hours was observed with single agent paragazole in a subset of sensitive TNBC cell lines. The combinations of paragazole with either paclitaxel, gemcitabine, or carboplatin all resulted in additive or synergistic growth inhibition. Expression of HDAC 1 was higher in the sensitive TNBC cell lines than in the resistant lines. Exposure to paragazole led to an increase in CARM1 mediated estrogen receptor expression. Discussion: These in vitro results demonstrate that paragazole has antiproliferative and proapototic activity against TNBC cell lines and may potentiate the activity of chemotherapy. These data support confirmation of the findings using in vivo models and the investigation of paragazole in combination with anti-estrogen agents such as tamoxifen and fulvestrant. Citation Format: David P. Astling, John J. Tentler, Benjamin R. Cross, Timothy P. Newton, Todd M. Pitts, Eric Gunther, Xuedong Liu, S. Gail Eckhardt, Jennifer R. Diamond. A novel class I histone deacetylase (HDAC) inhibitor, paragazole, demonstrates antiproliferative and proapoptotic effects in triple-negative breast cancer models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1006. doi:10.1158/1538-7445.AM2013-1006