tbuckley/cabot-search huggingface dataset:
Abstract 3949: Rapid 5-marker multiplex phenotyping of breast cancer subtypes &amp; tumor-infiltrating leukocytes “in situ” in FFPE sections
Authors: Matt Levin, Stephen J. Kron, David Schwartz, Helen Snyder
Journal: Cancer Research (2016)

Abstract Breast cancer can be divided into four subgroups HER2+, Luminal A, Luminal B and triple negative using multiple clinically validated monoclonal antibodies. Each subtype presents a different prognosis and treatment option. It is also increasingly clear that immune subsets within the tumor microenvironment may also have a bearing on prognosis, with certain subsets being associated with increased patient survival. Determining the tumor and immunologic phenotype of initial tumor biopsies both in the composition of cells and their relative spatial distribution is becoming key in selecting optimal treatment. The aim of our research has been to develop a multiplex immunofluorescence technology that can rapidly and simultaneously detect 5+ markers on a single section, allowing multiparametric quantitative analysis of cell phenotype and tissue composition as well as providing important spatial information of cells relative to each other. Our multiplex immunofluorescence (mxIF), modified-hapten based technology allows the simultaneous detection of multiple biomarkers using a standard two-step procedure. The technology is antibody species independent and produces signals 3-4X stronger than direct fluor-labeled secondary antibodies. It can detect multiple co-localized markers and while it has been engineered to detect four biomarkers and DAPI, it has the potential for significantly higher multiplexing. In addition it is modular and can be readily modified for any multiplex panel. The data generated from a staining experiment can be readily exported into any image analysis program. In comparison to existing technologies from GE and PerkinElmer, our technology allows multiple targets to be interrogated rapidly and simultaneously without the need for multiple rounds of stripping and imaging. The breast cancer phenotyping panel (BC-1) provides rapid phenotyping information allowing identification of Luminal A, Luminal B, HER2+ or triple negative cancer. Our immuno-oncology panel (IO-1) identifies CD4 and CD8 T cells, CD20+ B cells and CD68+ macrophages. Application of each panel to one of two sequential sections and then image overlay allows both tumor and immunophenotyping. The modular and non-species specific nature of this technology means that panels can be modified and expanded to characterize multiple different tumors and immune cell subpopulations in a rapid, sensitive and quantitative manner. Citation Format: Matt Levin, Stephen J. Kron, David Schwartz, Helen Snyder. Rapid 5-marker multiplex phenotyping of breast cancer subtypes &amp; tumor-infiltrating leukocytes “in situ” in FFPE sections. [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 3949.
Abstract 3383: Tumor vasculature normalization by recoupling nitric oxide synthase with a tetrahydrobiopterin precursor
Authors: Christopher Rabender, Ninu Bruno, Ross B. Mikkelsen
Journal: Cancer Research (2016)

Abstract The abnormal, irregular nature of tumor vasculature has been well documented. The aberrant nature of the vasculature results in uneven, heterogeneous blood flow and leaky, hemorrhagic blood vessels. Due to the unusual nature of tumor vessels, areas of hypoxia tend to develop that contribute to radioresistance and inefficiency of therapeutic drug delivery. Our current studies examine the role of nitric oxide synthase (NOS) in tumor vasculature. NOS has been demonstrated to be “uncoupled” in tumor cells due to reduced levels of tetrahydrobiopterin (BH4), a necessary cofactor, resulting in peroxynitrite (ONOO-) formation in lieu of nitric oxide (NO). NO signaling is critical for vascular function and thus uncoupling of eNOS in the endothelial cells may partly explain the poor vasculature structure found within solid tumors. Having previously demonstrated that NOS can be “recoupled” and NO production restored through treatment of tumor cells with Sepiapterin (SP), a BH4 precursor, we examined whether SP could normalize tumor vasculature, promoting radiosensitivity and improving drug uptake. Multispectral optoacoustic tomography analysis of both flank tumor xenografts and a spontaneous breast tumor model (MMTV) demonstrate that SP given orally significantly enhances the percent of oxyhemoglobin in the tumor. Immunohistochemical analysis of tumors treated with SP showed a significant reduction in CD31 staining and a significant increase in smooth muscle actin (SMA), both hallmarks of vascular normalization. Ex vivo analysis of tumors revealed that the enhanced tumor oxygenation resulted in over a two-fold increase in radiation induced cell killing. These preliminary data demonstrate great potential for SP as an adjuvant in the treatment of cancer, especially when we take into consideration that SP has been demonstrated to be cytotoxic to both breast and colon tumors. Future studies will examine drug uptake in tumors as well as the mechanism behind the vascular normalization. Citation Format: Christopher Rabender, Ninu Bruno, Ross B. Mikkelsen. Tumor vasculature normalization by recoupling nitric oxide synthase with a tetrahydrobiopterin precursor. [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 3383.
Abstract 2589: Dissecting extrinsic and intrinsic cancer risk
Authors: Song Wu, Scott Powers, Wei Zhu, Yusuf Hannun
Journal: Cancer Research (2016)

Abstract Cancers were once thought to originate from mature tissue cells that underwent dedifferentiation in response to cancer progression. Today, cancers are proposed to originate from the malignant transformation of normal tissue progenitor and stem cells, although this is not uniformly accepted. Nevertheless, recent research has highlighted a strong correlation between tissue-specific cancer risk and the lifetime population size and cumulative number of cell divisions of tissue-specific stem cells. However, there has been extensive controversy regarding the conclusion that this correlation implies that there is a very high unavoidable risk for many specific cancers that are due solely to the intrinsic baseline population size of tissue-specific stem cells. This issue has become a key public health debate with dissemination of the ‘bad luck’ hypothesis. Here we provide strong evidence that unavoidable intrinsic risk factors contribute only modestly (&amp;lt;10-30%) to the development of many common cancer types. In an initial approach, we demonstrate that the correlation between stem-cell division and cancer risk does not distinguish between the effects of intrinsic and extrinsic factors. We then develop a novel data-driven approach to estimate intrinsic risk by considering the lower bound risk value for most cancers as a limiting condition for contribution of intrinsic processes. Furthermore, we present an independent mathematical model that capitalizes on the accumulation of endogenous mutations in stem cells. Using mutation rates as a starting point, we found that rates of intrinsic mutations are not sufficient to account for the observed lifetime cancer risk, even in the conservative estimate that all these mutations are due to intrinsic processes alone. Our results are consistent with vast epidemiological data at population level and also mutational signature data at molecular level. The consensus suggests that cancer risk is likely to be heavily influenced by extrinsic factors, and therefore is possibly modifiable and preventable. These results carry immense consequences for strategizing cancer prevention, research, and public health. [Note: this work is in press in Nature.] Citation Format: Song Wu, Scott Powers, Wei Zhu, Yusuf Hannun. Dissecting extrinsic and intrinsic cancer risk. [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 2589.
Decoding Intratumoral Heterogeneity of Breast Cancer by Multiparametric <i>In Vivo</i> Imaging: A Translational Study
Authors: Jennifer Schmitz, Julian Schwab, Johannes Schwenck, Qian Chen, Leticia Quintanilla-Martinez, Markus Hahn, Beate Wietek, Nina Schwenzer, Annette Staebler, Ursula Kohlhofer, Olulanu H. Aina, Neil E. Hubbard, Gerald Reischl, Alexander D. Borowsky, Sara Brucker, Konstantin Nikolaou, Christian la Fougère, Robert D. Cardiff, Bernd J. Pichler, Andreas M. Schmid
Journal: Cancer Research (2016)

Abstract Differential diagnosis and therapy of heterogeneous breast tumors poses a major clinical challenge. To address the need for a comprehensive, noninvasive strategy to define the molecular and functional profiles of tumors in vivo, we investigated a novel combination of metabolic PET and diffusion-weighted (DW)-MRI in the polyoma virus middle T antigen transgenic mouse model of breast cancer. The implementation of a voxelwise analysis for the clustering of intra- and intertumoral heterogeneity in this model resulted in a multiparametric profile based on [18F]Fluorodeoxyglucose ([18F]FDG)-PET and DW-MRI, which identified three distinct tumor phenotypes in vivo, including solid acinar, and solid nodular malignancies as well as cystic hyperplasia. To evaluate the feasibility of this approach for clinical use, we examined estrogen receptor-positive and progesterone receptor-positive breast tumors from five patient cases using DW-MRI and [18F]FDG-PET in a simultaneous PET/MRI system. The postsurgical in vivo PET/MRI data were correlated to whole-slide histology using the latter traditional diagnostic standard to define phenotype. By this approach, we showed how molecular, structural (microscopic, anatomic), and functional information could be simultaneously obtained noninvasively to identify precancerous and malignant subtypes within heterogeneous tumors. Combined with an automatized analysis, our results suggest that multiparametric molecular and functional imaging may be capable of providing comprehensive tumor profiling for noninvasive cancer diagnostics. Cancer Res; 76(18); 5512–22. ©2016 AACR.
In adults &lt; 65 years of age, antidepressant drugs were not linked to increased risk for CV outcomes
Authors: Hem Raj Pal
Journal: Annals of Internal Medicine (2016)

Source Citation Coupland C, Hill T, Morriss R, et al. Antidepressant use and risk of cardiovascular outcomes in people aged 20 to 64: cohort study using primary care database. BMJ. 2016;352:i1350. 27005565
Abstract 2884: Role of Kaiso in intestinal tumorigenesis
Authors: Manish K. Tripathi, Albert B. Reynolds
Journal: Cancer Research (2016)

Abstract p120-catenin is a master regulator of classical cadherin stability and essential for epithelial homeostasis. p120 physically interacts with transcription factor Kaiso (ZBTB33) suggesting a direct or indirect role in transcription, but its precise function with respect to Kaiso is largely unknown. Kaiso belongs to the ZBTB family of transcription factors, most of which have important roles in development and/or cancer. Interestingly, Kaiso is strongly expressed in the intestinal crypt and abruptly downregulated as the cells move up onto the villus and terminally differentiate. Kaiso is constitutively upregulated in nascent adenomas initiated by loss of the tumor suppressor APC, suggesting a link between canonical Wnt signaling, Kaiso upregulation and intestinal tumorigenesis. Here, using ChipSeq and proteomics we describe several candidate Kaiso interactions with a group of proteins that include the tumor suppressor BRCA1, CHD2 (a chromatin remodifier) and the Ets1 oncoprotein, along with preliminary evidence for functional significance relevant to intestinal tumorigenesis. Citation Format: Manish K. Tripathi, Albert B. Reynolds. Role of Kaiso in intestinal tumorigenesis. [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 2884.
<i>Notes from the Field</i>:<i>Rickettsia parkeri</i>Rickettsiosis — Georgia, 2012–2014
Authors: Anne Straily, Amanda Feldpausch, Carl Ulbrich, Kiersten Schell, Shannon Casillas, Sherif R. Zaki, Amy M. Denison, Marah Condit, Julie Gabel, Christopher D. Paddock
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

During 2012-2014, five cases of Rickettsia parkeri rickettsiosis were identified by a single urgent care practice in Georgia, located approximately 40 miles southwest of Atlanta. Symptom onset occurred during June-October, and all patients had a known tick bite. Patients ranged in age from 27 to 72 years (median = 53 years), and all were male. The most commonly reported initial signs were erythema (n = 3) and swelling (n = 2) at the site of the bite. Two patients reported fever and a third patient reported a rash and lymphadenopathy without fever. Other symptoms included myalgia (n = 3), chills (n = 3), fatigue (n = 2), arthralgia (n = 2), and headache (n = 2). Eschar biopsy specimens were collected from each patient using a 4-mm or 5-mm punch and placed in 10% neutral buffered formalin or sterile saline. These specimens were tested by immunohistochemical (IHC) stains, quantitative polymerase chain reaction (qPCR) assays, or cell culture isolation to determine if there was evidence of infection with a Rickettsia species (1). IHC evidence of spotted fever group rickettsiae was found in the eschar biopsy specimens in all five cases. In four cases, the biopsy specimens were also positive for R. parkeri by qPCR. The fifth case (specimen positive only by IHC testing) was considered a probable R. parkeri case based on clinical signs and symptoms. R. parkeri was grown in cell culture from one specimen from which isolation was attempted. All patients were treated with oral doxycycline (100 mg twice daily) for a minimum of 10 days, and all recovered.
Abstract 5018: Immunohistochemical expression of lysyl oxidase in prostate cancer
Authors: Virgilia Macias, Santiago Delgado, Andre A. Kajdacsy-Balla
Journal: Cancer Research (2016)

Abstract Background: Lysyl oxydase (LOX) is a family of enzymes involved in catalyzing the cross-linking of collagen and elastin in the extracellular matrix, playing a crucial role in the building, strengthening and maintenance of tissues. Changes in its expression have been associated with many diseases. In oncology, these changes have been implicated in every step of tumor progression in different organs, with currently little existing data on prostate. The aim of this study is to analyze the nuclear expression of LOX in prostate tumor epithelial cells using a prostate cancer tissue array cohort. Design: PCa tumor samples were obtained from an outcome-based TMA set (5 tissue microarray blocks with 200 paired recurrence (R) and non-recurrence (NR) cases, 400 subjects total, each with quadruplicate 0.6 mm in diameter cores) from the Cooperative Prostate Cancer Tissue Resource (CPCTR). Each case was obtained from a PSA-recurrence subject matched to a non-recurrence subject based on age; race; interval since prostatectomy; Gleason sum-score and pTNM stage. All had at least 5 years follow up, and cases with known metastases were excluded. TMA sections were incubated with rabbit polyclonal anti-human LOX antibody (1:800, NB100-2527, Novus Biologicals) using the Bond™ polymer refine detection HRP (Leica Biosystems, DS9800). Nuclear LOX staining was scored semi-quantitatively as follows: 0, negative; 1+, weak; 2+, moderate; and 3+, strong. Percentage of positively stained cells at each intensity level was recorded to obtain a final h-score The Wilcoxon signed-rank test was used for the statistical analysis of the pair-matched dataset to assess the 2 groups (R vs. NR) for differences in LOX expression. Results: Data generated was available in 168 complete pairs. The Wilcoxon signed rank test showed no statistically significant differences for the h-score between the two groups (R vs. NR) (median = 2.15625 [range 0-3] vs. median = 2.2583333335 [range 0-3], p = 0.24604). Conclusions: The role of LOX in prostate cancer has not been fully established, and inhibitory and stimulatory effects have been reported. This is the first study in a case-control cohort evaluating the expression of LOX in prostate cancer. Based on our results we are now completing the analysis comparing expression of LOX in normal epithelium and cancer associated stroma. Citation Format: Virgilia Macias, Santiago Delgado, Andre A. Kajdacsy-Balla. Immunohistochemical expression of lysyl oxidase in prostate cancer. [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 5018.
Pre-operative flow mediated dilatation in patients undergoing coronary artery bypass surgery: Prediction of NO-bioavailability and vascular superoxide production in arterial and vein grafts
Authors: C A Antoniades, S Mussa, C Shirodaria, J Lee, T Van-Assche, J Diesch, D Taggart, K M Channon, P Leeson
Journal: Journal of the American College of Cardiology (2008)
Abstract 1992: Exploring target genes of eukaryotic initiation factor 5A in cancer using RNA sequence analysis
Authors: Tomoki Muramatsu, Kousuke Tanimoto, Johji Inazawa
Journal: Cancer Research (2016)

Abstract Protein synthesis has a key role of maintaining cellular homeostasis such as growth and metabolism. However, dysregulation of translational process is a frequent feature of cancer and contributes to cancer progression. Since oncogenes and tumor suppressor genes are regulated by the translation machinery, therapeutic drugs which target the translation machinery have the possibility for overcoming cancer. We then focused on the hypusine cascade which is related to translational process. In our previous study, we showed that overexpression of the deoxyhypusine synthase (DHPS), an enzyme contained in the hypusine cascade, promoted cancer progression such as migration and invasion ability through RhoA signaling pathway. A DHPS inhibitor, GC7, showed significant decrease in the tumor formation in vivo. In particular, eukaryoutec initiation factor 5A (eIF5A) which is activated by hypusination has important roles of the translational regulation such as initiation and elongation of protein synthesis and nucleocytoplasmic transport of mRNA. We tried to identify the target genes of eIF5A by combining RNA-ChIP method with RNA sequencing analysis. As a result, candidate genes which bound to eIF5A were extracted by bioinformatics analysis, and redundant binding motifs for eIF5A in mRNAs emerged. These findings and future analyses would reveal the regulation of translational machinery by eIF5A which could be an important target for cancer therapy. Citation Format: Tomoki Muramatsu, Kousuke Tanimoto, Johji Inazawa. Exploring target genes of eukaryotic initiation factor 5A in cancer using RNA sequence analysis. [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 1992.
Abstract 3957: Optimized plasma collection procedures for liquid biopsy analyses in cancer
Authors: Sonya T. Parpart-Li, Bjarne Bartlett, Maria Popoli, Vilmos Adleff, Julie Brahmer, Nilo Azad, Sarah Bonerigo, Ilene Browner, Amy Ryan, Victor Velculescu, Mark Sausen, Luis A. Diaz
Journal: Cancer Research (2016)

Abstract Analyses of genomic alterations in cell-free DNA (cfDNA) shed from tumors into the blood stream is rapidly advancing as a method to detect and genotype cancer. Liquid biopsy analyses are a favorable alternative to invasive tissue approaches, particularly for cancers in organs where tissue is difficult to obtain. As these methods become a clinical standard, the method for blood collection and plasma isolation will be an important consideration to ensure optimal assay performance with limited degradation of circulating tumor DNA (ctDNA). We compared blood collection and plasma isolation using both K2EDTA and cell-free DNA Streck™ BCT tubes to determine the stability of cfDNA and ctDNA in blood at room temperature or at 4°C. Blood was collected from nine cancer patients with KRAS mutations using K2EDTA and Streck™ BCT tubes. Over the course of seven days, cell lysis occurred in K2EDTA tubes at room temperature, releasing germline DNA into the blood (1300% increase over seven days), which significantly increased the number of total genomic equivalents. Additionally, we found that the volume of plasma collected from both tube types during blood fractionation decreased over time when tubes were at room temperature (an average of 3.5 mL vs. 1.0 mL, respectively). To evaluate the effect of storage conditions on performance of each tube type, blood was also collected from six cancer patients with KRAS or EGFR mutations and either maintained at room temperature or stored at 4°C for up to three days. Taken together, K2EDTA tubes stored at 4°C prevented cell lysis and preserved the ctDNA in a manner equivalent to Streck™ BCT tubes. These data demonstrate that liquid biopsies can be collected using either tube type with similar performance and appropriate consideration of storage conditions. Citation Format: Sonya T. Parpart-Li, Bjarne Bartlett, Maria Popoli, Vilmos Adleff, Julie Brahmer, Nilo Azad, Sarah Bonerigo, Ilene Browner, Amy Ryan, Victor Velculescu, Mark Sausen, Luis A. Diaz. Optimized plasma collection procedures for liquid biopsy analyses in cancer. [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 3957.