tbuckley/cabot-search huggingface dataset:
Abstract 881: Dissecting chromatin dynamics in malignant progression
Authors: Hanseul Yang, Daniel Schramek, Rene Adam, John Levorse, Brice Keyes, Ping Wang, Deyou Zheng, Elaine Fuchs
Journal: Cancer Research (2016)

Abstract Tumor-initiating cells within a cancer exhibit distinct patterns of transcription factors and gene expression compared to stem cells within their healthy tissue. Little is known about the key transcription factors that dictate chromatin remodeling and the accompanying transcriptional changes that ultimately hardwire the malignant behavior of tumor-initiating stem cells. Here, by in vivo chromatin and transcription profiling, we show that dramatic shifts in large open-chromatin (super-enhancer) landscapes underlie these differences. Focusing on one of the most common and life-threatening cancers world-wide, squamous cell carcinoma (SCC), we show that super-enhancers of SCC-stem cells contain the binding sites for a distinct set of putative master transcription factors. Many of their genes, including Ets2 and Elk3, are themselves regulated by SCC super-enhancers, suggesting a cooperative feed-forward loop. Malignant progression requires these genes, whose knockdown severely impairs tumor growth and prohibits progression from benign papillomas to SCCs. Interestingly, ETS2 is known to be phosphorylated and activated by RAS/MAPK signaling, and knockdown of ETS2 results in loss of expression of SCC super-enhancer-associated genes. Conversely, in vivo forced expression of an active ETS2 version harboring a phosphomimetic substitution at the MAPK-activation residue is sufficient to trigger cellular transformation without oncogenic RAS. Moreover, ETS2-overactivation in epidermal progenitors rewires the super-enhancer landscape and induces SCC super-enhancer associated genes including Fos, Junb, Klf5 and Elk3. Finally, we identify dramatic remodeling of the Cxcl1/2 locus from an H3K27me3-repressed to an ETS-regulated, super-enhancer-activated state, and provide evidence for their autocrine oncogenic role in SCCs through a cognate receptor Cxcr2. Together, our findings unearth an essential regulatory network required for the SCC chromatin landscape and unveil its importance in malignant progression. This work was funded by grants from the National Institutes of Health (R01-AR31737) and NYSTEM #CO29559. Citation Format: Hanseul Yang, Daniel Schramek, Rene Adam, John Levorse, Brice Keyes, Ping Wang, Deyou Zheng, Elaine Fuchs. Dissecting chromatin dynamics in malignant progression. [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 881.
Translational Pkpd of Dnib0600A, an Anti-Napi2B-Vc-Mmae Adc in Ovarian and Nsclc Cancers
Authors: K. Lin, S. Sukumaran, J. Xu, C. Zhang, Y. Choi, S. Yu, P. Polakis, D. Maslyar
Journal: Annals of Oncology (2014)
Abstract LB-124: Preliminary anti-proliferative effect of ethanolic extracts of Xylopia aethiopica on prostate and breast cancer cell lines
Authors: Emeka E.J Iweala, Eunice W. Bankole
Journal: Cancer Research (2016)

Abstract Xylopia aethiopica (African Pepper), a plant found throughout West Africa, has both nutritional and medicinal uses. The aim of this research was to study the preliminary anti-proliferative effects of ethanolic extracts of Xylopia aethiopica on prostate and breast cancer cell lines. Dried X. aethiopica fruits were extracted with 70% ethanol and tested against prostate(LNCaP) and breast cancer (MCF7 and MDA-MB231) cells’ viability in vitro using the MTT ((3-(4,5-Dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide) assay. The IC50 values for the extract were determined through linear regression using GraphPad Prism 6 software. The data obtained were expressed as mean ± SEM. Statistical analysis was carried out by one-way ANOVA followed by Dunnet's test (α = 0.05) to compare experimental means with controls. The data generated indicates that X. aethiopica fruits extract showed a dose-dependent anti-proliferative activity against LNCaP, MDA-MB231and MCF7 cancer cell lines after treatment for 48 and 72 hours. The extract induced a 16.96% and 93.5% inhibition on MDA-MB231 cells, 29.76% and 94.03% on the MCF7 cells and a 9.15% and 94.61% inhibition on the LNCaP cells at the lowest (1μg/ml) and highest (100μg/ml) dose respectively after 48 hours. The extract induced a 12.26% and 91.8% cell growth inhibition on the MDA-MB231 cells, 3.35% and 87.36% growth inhibition on the MCF7 cells and 2.28% and 92.42% cell growth inhibition on the LNCaP cells at the lowest (1μg/ml) and highest (100μg/ml) dose respectively after 72 hours. The IC50 was estimated to be 3.408μg/ml, 2.064μg/ml, 3.371μg/ml for MDA-MB231, MCF7 and LNCaP cells respectively. The data generated from this research indicates the anti-proliferative effects of ethanolic extract of X. aethiopica fruits on breast and prostate cancer cells. This can be seen from the inhibition of cell growth by this extract thus highlighting its potential as a therapy against breast and prostate cancer. Citation Format: Emeka E.J Iweala, Eunice W. Bankole. Preliminary anti-proliferative effect of ethanolic extracts of Xylopia aethiopica on prostate and breast cancer cell lines. [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 LB-124.
Thinner thread is better for cervical stitch procedure, say researchers
Authors: Jacqui Wise
Journal: BMJ (2016)

Switching to a thinner thread for cervical cerclage could reduce the numbers of premature births and intrauterine baby deaths, say researchers in the journal Science Translational Medicine . Their study found that the thicker thread most commonly used in cervical stitches could encourage the growth of dangerous bacteria.1

If women are at high risk of late miscarriage or premature birth, surgeons place a stitch in the cervix to hold it closed to delay labour. In around 80% of cases surgeons use multifilament: a 5 mm thread comprising several small threads woven together. It is believed to be stronger and more efficient at holding the cervix closed than the alternative monofilament nylon thread, which is around 1 mm thick.

The study assessed birth outcomes in a retrospective …
Frequency of KRAS mutations in female colorectal cancer (CRC) patients: Findings of a Brazilian cohort of 8,234 cases.
Authors: Carlos G. M. Ferreira, Mariano Zalis, Ilana Zalcberg-Renault, Martin H Bonamino, Marcos Barcelos de Pinho, Rafaela Cordeiro Helal, Jonas Hauben Salem, Ana Paula Ornelas Victorino, Fernando Meton Vieira
Journal: Journal of Clinical Oncology (2012)

e14101 Background: Although major advances in the last decades, there are still important gaps in our understanding of CRC carcinogenesis, particularly whether sex-linked factors play any role. Some groups, including ours, observed that KRAS mutation may be more frequent in female than male (Ferreira C.G. et al. J Clin Oncol 28: 2010 suppl abstr 3614; Uetake H. et al. J Clin Oncol 29: 2011 suppl abstr 3605). Methods: Between July 2008 and July 2011, we analyzed 8,234 consecutive patient samples sent to a reference laboratory for KRAS genotyping as a screening for cetuximab use. DNA was extracted from paraffin-embedded tissue, exon 1 was amplified by PCR and submitted to direct sequencing. Codons 12 and 13 were analyzed. Results: The median age was 59 years and well balanced according to gender with 51.9% of male and 48.1% female patients. The percentage of wild-type and mutated KRAS was 66.4 and 33.6%, respectively. Corroborating previous findings a significant difference in the percentage of mutated KRAS patients was observed between female and male (34.8% versus 32.5%, p = 0.03). However there were no differences in the distribution of any specific KRAS mutation according to gender. Among the 2,626 mutated cases, 83% were in codon 12 versus 17% in codon 13. Mutation Gly12Asp was the most common being detected in 36% of the mutated cases. Conclusions: This is one of the largest cohorts of KRAS genotyping in CRC patients. In line with previous data our present findings indicate that KRAS-mutations are more frequent in female than male. Further research is required to better address the impact of gender differences and/or hormones as potential drivers of CRC carcinogenesis.
Abstract 2804: Disrupted integrity in IκB kinase alpha promotes lung adenocarcinoma progression via an oxidative stress-inflammation circuitry
Authors: Na-Young Song, Jami Willette-Brown, Mahesh Dalta, Yinling Hu
Journal: Cancer Research (2016)

Abstract Recent advanced research has highlighted that multiple drivers and somatic aberrations drive intratumor heterogeneity. Multiple hits in different nucleotides of a single critical gene and diverse deregulatory mechanisms in one tumor have challenged to understand how these various forms of a single gene cooperate with other drivers in cancer development. IκB kinase alpha (IKKα) down-or-up-regulation and mutations have been detected in many human cancers; however, the function of IKKα in lung adenocarcinoma (ADC), a major type of human lung cancers, has not been explored. To study how the different mutant forms of IKKα regulate KrasG12D-induced lung ADC development, we crossed KrasG12D mice with Ikkα floxed mice and two Ikkα knock-in mice and found that a lung specific IKKα deletion (IkkαΔLung) and two different IKKα point mutants (IkkαKA/KA: K→A at amino acid 44 and IkkαAA/AA: S→A at amino acids 176 and 180) promote the progression of KrasG12D-induced lung ADCs. The IKKα mutants integrate into the KrasG12D-mediated diverse oncogenic pathways; additionally the mutants increase levels of pulmonary macrophage infiltration, ROS, and DNA damage compared to KrasG12D-induced lung ADCs. IKKα deficiency results in decreased levels of Nrf2, a transcription factor that regulates expression of genes encoding many anti-oxidants, and increased levels of NADPH oxidase 2 (Nox2), which form an oxidative stress-inflammation circuitry partially regulated by a new identified pathway of IKKα, aryl hydrocarbon receptor and Nox2. Treatment with a Nox inhibitor (apocynin) or a ROS scavenger (N-acetyl cysteine), and/or Nox2 null bone marrow transplant inhibits the pathogenesis of ADCs. Also, we observed various aberrations of IKKα in human lung ADCs. The study not only demonstrates that IKKα serves as a gatekeeper to suppress oncogenic oxidative stress in lung ADC development, but also provides an advanced model that explains how the different mutant forms of a signal gene integrate into distinct signalings to enhance the crucial driver KrasG12D-induced lung cancer development. Citation Format: Na-Young Song, Jami Willette-Brown, Mahesh Dalta, Yinling Hu. Disrupted integrity in IκB kinase alpha promotes lung adenocarcinoma progression via an oxidative stress-inflammation circuitry. [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 2804.
Abstract 597: Defining the role of macrophage mediated trogocytosis in the clearance of antibody-opsonized tumor cells
Authors: Ramraj Velmurugan, Dilip Challa, Sripad Ram, Raimund J. Ober, E. Sally Ward
Journal: Cancer Research (2016)

Abstract Understanding the complex behavior of effector cells such as monocytes or macrophages in regulating cancerous growth is of central importance for cancer immunotherapy. Earlier studies using CD20-specific antibodies have demonstrated that the Fcγ receptor (FcγR)-mediated transfer of the targeted receptors from tumor cells to these effector cells through trogocytosis can enable escape from antibody therapy, leading to the viewpoint that this process is pro-tumorigenic. However, there is limited information concerning the role of trogocytosis in antibody-based treatment of solid tumors such as breast cancer. We have used advanced microscopy methods and quantitative flow cytometric assays to study the effect of antibody-mediated trogocytosis on breast cancer cells and whether they can lead to tumor cell death. Our results show that long-term coculture with macrophages can reduce cancer cell numbers in an antibody-dependent manner even at low effector:target ratios. Quantitation from simultaneous long-term imaging of macrophage:cancer cell interactions reveals that this cell death is caused by both macrophage-mediated phagocytosis and trogocytosis, with the contribution of each process differing by the phenotype of the effector macrophages. Together, our results add to our understanding of the numerous interactions macrophages can have with cancer cells, and how therapeutic antibodies modulate their effects. Our recent observations in this area will be presented. Citation Format: Ramraj Velmurugan, Dilip Challa, Sripad Ram, Raimund J. Ober, E. Sally Ward. Defining the role of macrophage mediated trogocytosis in the clearance of antibody-opsonized tumor cells. [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 597.
Abstract 2734: Click colorimetric EdU proliferation and TUNEL assay: Conversion of click chemistry from fluorescent to colorimetric for use with bright field microscopy
Authors: Scott T. Clarke, Carmen Finnessy, Fernada M. Bosada, Ben Armstrong, Michael O’Grady
Journal: Cancer Research (2016)

Abstract We present here the conversion of click chemistry fluorescence-based EdU proliferation assay and TUNEL apoptosis assay to use with bright field microscopy. Advantages of having a colorimetric signal are the retention of the click chemistry work flow while allowing for compatibility with standard H&amp;E staining and protocols. Proliferation using copper-catalyzed labeling of the thymidine analog EdU (ethynyl deoxyuridine) was introduced in 2007. This click-based assay has advantages over the traditional antibody based BrdU assay. The small molecule detection is simple, rapid and gives a bright signal useful for multiplexing. Additionally, recent improvements to the chemistry allow for GFP and R-PE compatibly with the EdU and TUNEL assays. Several approaches for creating a colorimetric signal for EdU proliferation were attempted. The method presented here had the shortest protocol and uses a biotin-based click reaction followed by streptavidin -horseradish peroxidase (HRP) step. This two-step reaction creates an essentially covalent link between the EdU incorporated in the DNA and the enzyme reporter. Then standard HRP chromogens such as DAB were used to produce a signal marking the proliferating cells. Examples of proliferation using colorimetric EdU labeling in adult Zebrafish caudal fin, mouse cardiac, and rat intestine, mammary and uterine FFPE treated tissue are presented. Multiplexing with alkaline phosphatase for two color detection are also presented. Two color detection of EdU with BrdU or EdU with progesterone receptor (PR) are shown. Most HIER protocols are compatible with EdU detection. For EdU alone no HCl treatment is required. For EdU/BrdU double labeling the BrdU protocol for DNA revelation is used. Anti-BrdU mouse antibody clone MoBU-1 is used because of its lack of cross-reactivity with EdU. Additionally, we present the click chemistry-based apoptotic TUNEL assay colorimetric detection using the same approach. Clickable biotin adapters are used to couple HRP to the ethynyl tails created by TdT enzyme extension at 3′ end of double stranded breaks. We provide examples of this late stage indicator of apoptosis visualized with DAB substrate and stained with standard H&amp;E and other histological stains. Citation Format: Scott T. Clarke, Carmen Finnessy, Fernada M. Bosada, Ben Armstrong, Michael O’Grady. Click colorimetric EdU proliferation and TUNEL assay: Conversion of click chemistry from fluorescent to colorimetric for use with bright field microscopy. [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 2734.
Abstract 2726: WWP2 is required for normal cell cycle progression
Authors: Byeong Hyeok Choi, Xun Che, Changyan Chen, Luo Lu, Wei Dai
Journal: Cancer Research (2016)

Abstract WWP2 is a ubiquitin E3 ligase belonging to the Nedd4-like family. Given that WWP2 target proteins including PTEN that are crucial for regulating cell proliferation or suppressing tumorigenesis, we have asked whether WWP2 plays a role in controlling cell cycle progression. Here we report that WWP2 is necessary for normal cell cycle progression as its silencing significantly reduces the cell proliferation rate. We have identified that an isoform of WWP2 (WWP2-V4) is highly expressed in the M phase of the cell cycle. Silencing of WWP2 accelerates the turnover of cyclin E, which is accompanied by increased levels of phospho-histone H3 (p-H3) and cyclin B. Moreover, silencing of WWP2 results in compromised phosphorylation of AktS473, a residue whose phosphorylation is tightly associated with the activation of the kinase. Combined, these results strongly suggest that WWP2 is an important component in regulating the Akt signaling cascade, as well as cell cycle progression. Citation Format: Byeong Hyeok Choi, Xun Che, Changyan Chen, Luo Lu, Wei Dai. WWP2 is required for normal cell cycle progression. [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 2726.
Abstract 1446: Discovery of a distinct human lung tissue microbiome and its epidemiologic and clinical features
Authors: Guoqin Yu
Journal: Cancer Research (2016)

Abstract The human lung tissue microbiota remains largely uncharacterized although a number of studies based on airway samples suggest the existence of a viable human lung microbiota. Here we characterized the microbiota taxonomic and derived functional profiles in 165 non-malignant lung tissue samples from cancer patients. We show that the lung microbiota is unique, differing from the microbiota of oral, nasal, stool, skin, and vagina samples. Microbiota diversity increases with environmental exposures, such as air particulates, residence in low to high population density areas, and pack-years of tobacco smoking. Moreover, the non-malignant lung tissue microbiota is altered in subjects with chronic bronchitis or advanced stage of lung cancer, and differs significantly from the microbiota in lung tumor samples. These findings provide insights on the human lung microbiota composition and function, and their link to human life style and clinical outcomes. Citation Format: Guoqin Yu. Discovery of a distinct human lung tissue microbiome and its epidemiologic and clinical features. [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 1446.
Abstract 4389: Therapeutic opportunities of RANK pathway in breast cancer
Authors: Hector Perez Montoyo, Jorge Gomez Miragaya, Eva M. Trinidad, Antonio Martinez-Aranda, Maria Teresa Soler Monso, Anna Petit, Angels Sierra, Eva Gonzalez Suarez
Journal: Cancer Research (2016)

Abstract RANK pathway, key in bone remodeling and metastasis, is essential for mammary gland development. Using genetic mouse models we have previously shown that RANKL is the main mediator of the protumorigenic role of progesterone in the mouse mammary gland. RANK overexpression in non-transformed human mammary cell lines induces epithelial to mesenchymal transition and stemness, and promotes tumorigenesis and metastasis in breast cancer lines. RANK is expressed in a subset of basal and luminal human adenocarcinomas. Our goal is to determine a putative association of RANK and RANKL expression in breast adenocarcinomas with clinical parameters and to evaluate the functional role of RANK signaling using patient derived orthoxenografts of breast cancer. We have analyzed RANK and RANKL expression levels in an extensive collection of human breast adenocarcinomas collected from multiple centers, enriched in metastatic tumor samples. From the 318 patients with breast adenocarcinomas 138 developed metastasis. RANK expression is found on tumor cells but also on stromal cells, including tumor associated macrophages. RANKL is strongly expressed in some tumors, although the frequency is low. Analyses of RANK and RANKL mRNA and protein expression has been performed in multiple models of patient derived breast orthoxenografts. Several models with variable levels of RANK as well as RANKL expression have been identified and established in the laboratory. Functionality of the pathway was corroborated analyzing NF-kB activation upon in vitro and in vivo treatments with RANKL, in order to activate RANK signaling, or with RANK-Fc to inhibit it. We found that RANKL treatment induced NF-kB activation even in tumor cells with low levels of RANK expression. Citation Format: Hector Perez Montoyo, Jorge Gomez Miragaya, Eva M. Trinidad, Antonio Martinez-Aranda, Maria Teresa Soler Monso, Anna Petit, Angels Sierra, Eva Gonzalez Suarez. Therapeutic opportunities of RANK pathway in breast 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 4389.
Mechanistic and Pharmacodynamic Studies of Adct-301, a Pyrrolobenzodiazepine (PBD) Dimer-Containing Antibody Drug Conjugate (ADC) Targeting CD25-Expressing Hematological Malignancies
Authors: Michael J. Flynn, Patrick H. van Berkel, Francesca Zammarchi, Peter C. Tyrer, Ayse U. Akarca, Narinder Janghra, Vishvesh Shende, Joseph Linares, Teresa Marafioti, David G. Williams, Philip W. Howard, John A. Hartley
Journal: Blood (2015)
Patterns of Care of Aged Chronic Lymphocytic Leukemia Patients in the United States: Systematic Analysis of 457 Patients in the Connect CLL Registry
Authors: Chadi Nabhan, Natalie Galanina, Neil E. Kay, Anthony R. Mato, David L. Grinblatt, Thomas J. Kipps, Nicole Lamanna, Mark Weiss, Ian Flinn, Arlene S. Swern, Thomas Street, Sullivan Kristen, Christopher R. Flowers
Journal: Blood (2014)