tbuckley/cabot-search huggingface dataset:
Calculating the adenoma detection rate in screening colonoscopies only: Is it necessary? Can it be gamed?
Authors: Douglas Rex, Prasanna Ponugoti
Journal: Endoscopy (2017)

Background Current recommendations are to calculate the adenoma detection rate (ADR) in screening colonoscopies only. The need to confine the measure to screening has not been established. Methods We retrospectively assessed our quality database for whether calculating ADR from screening, surveillance, and diagnostic colonoscopies (overall ADR) would alter conclusions about the performance of colonoscopists, compared to using an ADR based only on screening colonoscopies. We also prospectively tested the extent to which one physician could corrupt the screening-only ADR by changing the procedure indication after reviewing the examination findings. Results For 15 physicians, screening ADRs differed from the overall ADR by a mean of 2.6 percentage points (range 0 - 6.9 percentage points). Using the overall ADR rather than screening ADR changed the ADR from just below to just above the recommended screening threshold for one physician. In the prospective assessment, a single expert colonoscopist utilized indication gaming in patients with both screening and diagnostic indications and was able to increase his apparent screening-only ADR from 48.4 % to 55.1 %. Conclusions Use of an overall ADR rather than screening-only ADR could simplify ADR measurement, increase the number of examinations available to measure ADR, seldom affect whether a doctor meets recommended ADR thresholds, and eliminate the potential for gaming the ADR by changing the colonoscopy indication.
Abstract 2130: Antitumor activity of marin natural product derived Psammaplin A analogs in human lung cancer cells
Authors: Woong sub Byun, Yoonho Shin, Sang Kook Lee, Hyeung-geun Park, Suckchang Hong
Journal: Cancer Research (2017)

Abstract Natural products are important sources for bioactive molecules, which have been developed to treat various human health-related symptoms. In our continuos efforts to search for anticancer agents from natural sources, Psammaplin A (PsA), isolated from marine natural products, was found to be a potential candidate in the growth inhibition of cancer cells. PsA, a unique symmetrical bromotyrosine contained in a number of marine sponges of the order Verongida, has exhibited a variety of bioactivities including antimicrobial activity, cytotoxicity against the leukemia cell line, and inhibitory activity of DNA gyrase and DNA topoisomerase. PsA is also known to be a potent inhibitor of DNA methyltransferase and histone deacetylase with growth-inhibitory activity of cancer cells. However, its underlying mechanism of action and the structure-activity relationship (SAR) with PsA analogs have not been elucidated yet. In the present study, twenty-eight synthetic analogs of PsA were newly synthesized and examined the potential of cytotoxicities against cancer cells. A SAR study revealed that the presence of free oxime and disulfide functional groups was responsible for high cytotoxicity. Furthermore, the bromotyrosine component in PsA was relatively tolerable and hydrophobic aromatic groups preserved the cytotoxicity. The aromatic groups were dependent on their size and spatial geometry. Among them, a β-naphthyl derivative of PsA showed a potential cytotoxicity and was comparable to that of PsA. The compound also exhibited a potential antitumor activity in a nude mouse xenograft model. These findings indicated that free oxime and disulfide linker in the chemical structure play an important role for cytotoxicity and PsA analogs might be provided as potential antitumor agents. This work was supported by the National Reseach Foundation of Korea (NRF) Grant funded by the Korean Government (MEST) (NRF-2016M3A9B6903499) and also supported by a National Research Foundation of Korea (NRF) grant funded by the Korean Government (MEST) (No.2009-0083533). Citation Format: Woong sub Byun, Yoonho Shin, Sang Kook Lee, Hyeung-geun Park, Suckchang Hong. Antitumor activity of marin natural product derived Psammaplin A analogs in human lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2130. doi:10.1158/1538-7445.AM2017-2130
Abstract 2128: PDGFR beta signaling is required for hypoxia induced mitophagy in glioblastoma survival
Authors: Jinkyu Jung, Mark R. Gilbert, Deric M. Park
Journal: Cancer Research (2017)

Abstract BACKGROUND: Platelet-derived growth factor (PDGF) signaling plays a key role in gliomagenesis. Glioblastomas express all PDGF ligands and both cell membrane receptors, PDGFRα and PDGFRβ, that are involved in pro-survival autocrine and paracrine loops. Our previous work demonstrated that expression of PDGFRβ is enriched in hypoxic glioblastoma tumor tissues. Also, induction of mitophagy is a well-known critical coping response to tissue hypoxia. We therefore investigated the role of PDGFRβ signaling cascade in regulating hypoxia-induced mitophagy of glioblastoma. METHODS: Protein detection was performed by immunoblotting and immunofluorescence to determine changes in levels of target proteins upon RNA interference, treatment with PDGFRβ inhibitor, and ectopic gene transfection. MitoSox assay was used to measure mitochondrial reactive oxygen species (ROS). Tumor growth assays were performed in vitro and in vivo using subcutaneous tumor implantation model. RESULTS: PDGFRβ signaling was essential for induction of hypoxia-mediated mitophagy in glioblastoma cells. Nix, a hypoxic responsive protein and regulator of mitophagy, was necessary for PDGFRβ-mediated glioblastoma survival. Inhibition of PDGFRβ signaling pathway killed glioblastoma cells by suppressing mitophagy and leading to subsequent elevation of mitochondrial ROS. Furthermore, interference of mitophagic response by blocking PDGFRβ signaling enhanced cell death even in chemotherapy-resistant tumor cells. CONCLUSION: This work suggests a potential mechanism by which PDGFRβ inhibition could kill glioblastoma cells through suppression of NIX-mediated mitophagy. Manipulation of NIX and PDGFRβ pathway may provide novel therapeutic opportunities in chemoresistant tumor models. Citation Format: Jinkyu Jung, Mark R. Gilbert, Deric M. Park. PDGFR beta signaling is required for hypoxia induced mitophagy in glioblastoma survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2128. doi:10.1158/1538-7445.AM2017-2128
Abstract 551: Assessment of computational approaches for quantification of immune cell infiltration from gene expression profiles of complex biological samples
Authors: Brendan P. Hodkinson, Michael E. Schaffer, Michael Gormley
Journal: Cancer Research (2017)

Abstract Anticancer immunotherapies target immune cells to block immune suppression and/or promote immune activation in order to eliminate cancer cells. Ipilumumab and Nivolumab, targeting CTLA4 and PD1 respectively, have demonstrated dramatic responses in melanoma and lung cancer (Hodi et al. 2010; Risvi et al. 2015). However, poor response rates in other types of cancer underscore the need to better understand immunomodulatory mechanisms (Topalian et al. 2012). Examination of immune cell specific signals, in either the tumor microenvironment or the periphery, has proven to be a useful tool in developing prognostic biomarkers (Chi et al. 2014; Gentles et al. 2015), inferring mechanisms of action (Krejcik et al. 2016), and discerning immune-based predictors of drug response (Tumeh et al. 2014). In this study we evaluate various gene expression-based computational approaches for inferring immune cell identity in complex cellular mixtures in order to rank their relative utility for illuminating the details of the tumor microenvironment and potentially revealing new biomarkers for prognosis and response prediction. Immune cell identity has been inferred by previous researchers using a variety of mathematical approaches, including least squares (Abbas et al. 2009), quadratic programming (Gong et al. 2011; Zhong et al. 2013), maximum likelihood (Qiao et al. 2012; Liebner et al. 2013), machine learning (Newman et al. 2015), and enrichment type approaches (Angelova et al. 2015). We used publically-available gene expression microarray data from blood, normal tissue, and tumor samples to assess the effectiveness of these methods in sample types relevant to oncology research. The results from comparisons of these different methods demonstrate that certain approaches are significantly more robust to noise, and are therefore more suitable for complex cellular mixtures such as tumor samples. The discerning use of methods to infer immune cell type proportions from gene expression profiles may lead to improved prognosis, predictive biomarkers for immunotherapy to assist in patient stratification, and new immunoncology targets by indicating immunosuppressive mechanisms. Citation Format: Brendan P. Hodkinson, Michael E. Schaffer, Michael Gormley. Assessment of computational approaches for quantification of immune cell infiltration from gene expression profiles of complex biological samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 551. doi:10.1158/1538-7445.AM2017-551
Risque d'infection suivant une coloscopie ou une sigmoidoscopie chez les patients symptomatiques.
Journal: Endoscopy (2017)

Introduction: Les complications de la coloscopie ont fait l’objet de nombreuses études et sont bien connues (perforation, douleurs abdominales, saignement, hématome splénique…). Dans la littérature, le risque d’infection est considéré comme peu fréquent. L’infection peut avoir 2 mécanismes: mécanique par l’endoscope et par translocation bactérienne. Toutefois, il n’y a pas de publication de grande envergure pour cette complication.
Abstract 14369: Long-term Reduction in Coronary Artery Disease and Stroke With 7,8 Years of Intensified, Multifactorial Intervention in Patients With Type 2 Diabetes and Microalbuminuria in the Steno-2 Study
Authors: Jens Oellgaard, Peter Gæde, Peter Rossing, Henrik Lund-Andersen, Hans Henrik Parving, Oluf Pedersen
Journal: Circulation (2016)

Introduction: Intensified multifactorial intervention for 7.8 years in patients with type 2 diabetes mellitus and microalbuminuria increased life length and reduces complication rates. The present ...
Abstract 1691: USP7 inhibitors impair Foxp3+ T regulatory cell function and promote antitumor immunity against solid tumors
Authors: Suresh Kumar, Jian Wu, Liqing Wang, Feng Wang, Ivan Sokirniy, Hui Wang, David Sterner, Charles Grove, Joseph Weinstock, Michael Mattern, Wayne Hancock
Journal: Cancer Research (2017)

Abstract Tumor microenvironment (TME) plays critical role in suppressing the immune system’s ability to recognize and destroy cancer cells. Although T cell checkpoint blockers such as anti-PD1 antibodies unleash anti-tumor immune response against a variety of tumors, the complex immunosuppressive tumor milieu necessitates development of additional therapeutic agents to potentiate active drugs and expand the realm of the revolutionary cancer immunotherapy. The presence of highly immunosuppressive Foxp3+ T-regulatory cells (Tregs) in the TME has been correlated with poor prognosis. Thus, depletion of Tregs or impairment of Treg function is considered an attractive therapeutic approach. USP7, a deubiquitylase (DUB) implicated as a critical node in several cancer signaling pathways has emerged as an essential factor in maintaining Treg functions. Treg specific deletion of USP7 impairs Treg function leading to lethal autoimmunity. Using the UbiProTM discovery platform, Progenra has identified selective covalent USP7 inhibitors that were subjected to lead optimization and preclinical evaluation. Potent and selective candidate USP7 inhibitors have been shown to impair Treg functions ex vivo and in vivo as well as exhibit powerful anti-tumor activity against syngeneic lung tumor models in immunocompetent mice. Most importantly, Progenra’s USP7 inhibitors enhances the efficacy of anti-PD1 antibody and cancer vaccines. Along with the already established direct anti-tumor activities of USP7 inhibitors, these studies provide a strong rationale for combining USP7 inhibitors to suppress Treg functions and improve the efficacy of currently approved cancer immunotherapy agents. Citation Format: Suresh Kumar, Jian Wu, Liqing Wang, Feng Wang, Ivan Sokirniy, Hui Wang, David Sterner, Charles Grove, Joseph Weinstock, Michael Mattern, Wayne Hancock. USP7 inhibitors impair Foxp3+ T regulatory cell function and promote antitumor immunity against solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1691. doi:10.1158/1538-7445.AM2017-1691
Rock the Baby, Not the Boat: A Defense of Epidemiology-Based and Values-Based Shared Decision Making at the Margin of Gestational Viability
Authors: Stephanie Kukora, Naomi Laventhal
Journal: The American Journal of Bioethics (2017)

In his article “Saving or Creating: Which Are We Doing When We Resuscitate Extremely Preterm Infants?” Rieder (2017) challenges an approach to the resuscitation of infants delivered at the margin o...
Abstract 815: Using CRISPR/Cas9 to generate isogenic cell lines and reference standards for applications in cancer diagnostics
Authors: Huanyu Jin, Xin Cheng, Nga Nguyen, Qi Zheng, Mi Shi, Andrew Hilmer, Yuan Yuan, Ruby Yanru Chen-Tsai, Ling-Jie Kong
Journal: Cancer Research (2017)

Abstract We are entering an era of precision medicine, in which there are significant initiatives to employ companion diagnostics and molecular profiling to inform clinical decisions in therapeutic treatment. In order for these initiatives to work as effectively as possible, there is a need for molecular reference materials that can help facilitate precision assay development. Cell-line based reference standards are ideal for such applications because they represent a reproducible and renewable source of control materials that can be employed for assay development, quality control, or lead compound discovery. With this in mind, we have used the CRISPR/Cas9 platform to engineer series of isogenic cell lines that feature 51 recurrent mutations in the MAPK signaling pathway. These cell lines contain footprint-free, homozygous mutations in the kinase domains of the EGFR, KRAS, and BRAF genes in HCT116 and RKO cancer cell lines, with 32 mutations in EGFR, 12 mutations in KRAS, and 7 mutations in BRAF. The mutations include precise deletions, point mutations and small fragment insertions, and these engineered cell lines have been further employed for the development of derivative reference materials, including genomic DNA (gDNA) and FFPE cell line blocks. Such materials can be employed as positive and negative controls in diverse assay platforms, including next generation sequencing (NGS), quantitative PCR (qPCR), in situ hybridization (ISH), and others. We present quality control data for these reference materials, which demonstrate excellent consistency and uniformity, as well as examples of the application of these materials in molecular assay validation. We conclude that using CRISPR/Cas9 technology to generate molecular reference standards is a very efficient and precise method in generating footprint-free, biorelevant mutations for companion diagnostic assays. Citation Format: Huanyu Jin, Xin Cheng, Nga Nguyen, Qi Zheng, Mi Shi, Andrew Hilmer, Yuan Yuan, Ruby Yanru Chen-Tsai, Ling-Jie Kong. Using CRISPR/Cas9 to generate isogenic cell lines and reference standards for applications in cancer diagnostics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 815. doi:10.1158/1538-7445.AM2017-815
Alternations of SLPI/GEP in paclitaxel resistant ovarian cancer cells
Authors: Nabila Rasool, Joshua G. Cohen, Nick Devoogdt, Elise C. Kohn
Journal: Cancer Research (2006)

4678  Chemoresistance to paclitaxel in ovarian cancer patients is an important clinical problem. We have shown previously that secretory leukocyte protease inhibitor (SLPI) is a survival factor for ovarian cancer cells. We have also demonstrated granulin epithelin precursor (GEP), a cancer growth factor, is overproduced by ovarian cancer cells and interacts with SLPI. SLPI is a protease inhibitor and has been shown to prevent the degradation of GEP. Given the survival advantage that the GEP/SLPI interaction provides in ovarian cancer, these proteins could potentially serve as an explanation for the development of chemoresistance seen in patients treated with paclitaxel. Hey A8 ovarian cancer cells, the A2780 ovarian cancer cell subline 1A9, and its two paclitaxel resistant strains PTX10 and PTX22, were used to investigate this hypothesis. The paclitaxel IC50 of PTX10 and PTX22 are 47 nM and 48 nM, respectively. GEP and SLPI protein expression in the presence or absence of paclitaxel over the course of 24 to 72 hours was assessed by immunoblot in cell lysates and conditioned medium (CM). Both GEP and SLPI are secreted. Western blot analysis revealed that PTX10 and PTX 22 express a lower level of SLPI in their lysates compared to the parental 1A9 line. A reverse trend was noted for GEP expression in the conditioned medium. All cell lines responded to paclitaxel exposure with an upregulation of SLPI and down regulation of GEP, suggesting that SLPI expression may be increased as a survival mechanism. The SLPI plasmid as well as F/R SLPI mutants, which have diminished protease inhibitory activity, were transfected into the Hey A8 cell line to better evaluate overexpression of SLPI in relation to paclitaxel resistance. The XTT assay was used to determine cell viability in the parental and transfectants in response to paclitaxel treatment. These XTT assays revealed a survival advantage for the SLPI transfected cell lines, in comparison to the empty plasmid control. Further analysis of this survival advantage is pending. Initial studies show that expression of SLPI and GEP confers a survival advantage against treatment with paclitaxel. This may provide insight into potential therapeutic treatments that will make it possible to overcome chemoresistance seen in the treatment of ovarian cancer.
Abstract 1621: Adoptively transferred B cells directly kill tumor cells via the CXCR4/CXCL12 &amp; perforin pathways
Authors: Leiming Xia, Yang Xia, Quanning Chen, Yi Wang, Yangyi Bao, Steven K. Lundy Lundy, Fu Dai, Alfred E Chang, Qiao Li
Journal: Cancer Research (2017)

Abstract Over the years, the role of B cells in the host immune response to malignancy has been overshadowed by our focus on T cells. The role played by B cells in cancer immunology is complex and controversial. The observation made by our lab that activated B cells alone can mediate tumor regression in the adoptive immunotherapy of solid tumors is innovative (JI 2009; CCR 2011; JSO 2012; EJI 2015). One novel mechanism by which activated B cells mediate tumor regression is via direct tumor cell cytotoxicity in the absence of antibodies. We previously reported that antitumor B cells directly kill tumor cells via the Fas/FasL pathway and are regulated by IL-10. In this study, we defined additional mechanisms involved in B cell antitumor immunity. Administration of IL-2 significantly augmented the therapeutic efficacy of adoptively transferred tumor-draining lymph node (TDLN) B cells which express IL-2R. Culture supernatant of purified B splenocytes harvested from the mice that received adoptive transfer of 4T1 TDLN B cells plus IL-2 administration produced larger amounts of IgG which bound to 4T1, resulting in 4T1 lysis. Furthermore, we detected CXCR4 expression on 4T1 TDLN B cells, and 4T1 tumor cells produced its ligand CXCL12. Transwell experiments demonstrated the chemotraction of CXCR4-expressing 4T1 TDLN B cells towards CXCL12-producing 4T1 cells. Blockade of CXCR4 using a CXCR4-specific inhibitor, AMD3100, significantly reduced the killing of 4T1 tumor cells by 4T1 TDLN B cells. Blockade of FasL and CXCR4 concurrently inhibited B cell-mediated direct killing of tumor cells in an additive manner, indicating that both Fas/FasL and CXCL12/CXCR4 pathways are involved in the direct killing of 4T1 cells by 4T1 TDLN B cells. TDLN B cells produced perforin. Additional transwell experiments showed that effector B cells could directly kill tumor cells in cell-cell contact via the Fas/FasL and CXCR4/CXCL12 pathways as well as perforin, while without cell contact, perforin secreted by B cells led to tumor cell cytotoxicity. These findings underscore the diversity of function by which B cells can play an important role in the host immune response to tumor, and clearly indicated that transferred effector B cells can act independently of T cells in causing tumor destruction in adoptive immunotherapy. Citation Format: Leiming Xia, Yang Xia, Quanning Chen, Yi Wang, Yangyi Bao, Steven K. Lundy Lundy, Fu Dai, Alfred E Chang, Qiao Li. Adoptively transferred B cells directly kill tumor cells via the CXCR4/CXCL12 &amp; perforin pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1621. doi:10.1158/1538-7445.AM2017-1621
Development of a Novel Patient-Reported Outcome Measure in Haematological Malignancy for Use in Routine Clinical Practice: Item Generation
Authors: Pushpendra Goswami, Sam Salek, Adele K. Fielding, Jonathan Kell, Saad Al-Ismail, Esther Oliva, Tatyana Ionova, Roger Else, Marina Karakantza, Daniel Jennings, Anita Waldmann
Journal: Blood (2016)
Abstract 2372: Xkr5 negatively regulates KIT/D816V signaling
Authors: Jianmin Sun, Tine Thingholm, Tianfeng Li, Julhash U. Kazi, Hui Zhao, Lars Rönnstrand
Journal: Cancer Research (2017)

Abstract D816V is the most often occurred mutation of type III receptor tyrosine kinase KIT in mastocytosis and CBF-AML. In attempting to identify specific downstream signaling pathways of KIT/D816V, we found that KIT/D816V but not wild-type KIT can bind to Xkr5 that was not studied previously. In addition to the association with KIT/D816V, Xkr5 is phosphorylated at Tyr 369, Tyr487 and Tyr 543 by KIT/D816V, and the phosphorylation is mediated by only mutations of Asp 816 in KIT but not by other KIT mutations that occurred in gastrointestinal stromal tumors and melanoma. Furthermore, the tyrosine phosphorylation of Xkr5 is not dependent on Src family kinases that play a crucial role in the activation of wild-type KIT. In KIT/D816V expressing mast cells, phosphorylation of Xkr5 inhibits KIT/D816V downstream signaling molecules Akt, Erk and p38. As a consequence, cell proliferation and colony formation are inhibited by the tyrosine phosphorylation of Xkr5 as well, indicating that Xkr5 is a negative regulator of KIT/D816V signaling. Citation Format: Jianmin Sun, Tine Thingholm, Tianfeng Li, Julhash U. Kazi, Hui Zhao, Lars Rönnstrand. Xkr5 negatively regulates KIT/D816V signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2372. doi:10.1158/1538-7445.AM2017-2372