tbuckley/cabot-search huggingface dataset:
Abstract 2727: LOX is a novel mitotic spindle-associated protein essential for mitosis
Authors: Myriem Boufraqech, Darmood Wei, Urbain Weyemi, Lisa Zhang, Martha Quezado, Petr Kalab, Electron Kebebew
Journal: Cancer Research (2016)

Abstract Lysyl oxidase (LOX) is a copper-dependent amine oxidase that plays a critical role in the biogenesis of connective tissue matrices. LOX is highly expressed in aggressive cancers; has been associated with a shorter survival and regulates cancer progression in a variety of human malignancies. Here, we report a new function of LOX in mitosis in anaplastic thyroid cancer cell line (THJ-16T), breast cancer cell line (MDA-MB231) and HeLa cells. We show that LOX co-localizes to mitotic spindles from metaphase to telophase, and p-H3(Ser10)-positive cells harbor strong LOX staining. Further, purification of mitotic spindles from synchronized cells show that LOX fails to bind to microtubules in the presence of nocodazole, whereas paclitaxel treated samples showed enrichment in LOX expression suggesting that LOX binds to stabilized microtubules only. Functional studies of LOX depletion resulted in decreased cellular proliferation, G2/M cell cycle arrest, and formation of gigantic nuclei. Further, LOX knockdown led to reduced p-H3(Ser10), cyclin B1, CDK1, and Aurora B expression. Lastly, LOX knockdown significantly increased sensitivity of cancer cells to chemotherapeutic agents that target microtubules and this effect was synergistic. Our results show identify a novel function of LOX in cancer cell mitosis, and that loss of LOX expression in cancer cells can enhanced effects of anti-microtubules agents used in cancer therapy. Citation Format: Myriem Boufraqech, Darmood Wei, Urbain Weyemi, Lisa Zhang, Martha Quezado, Petr Kalab, Electron Kebebew. LOX is a novel mitotic spindle-associated protein essential for mitosis. [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 2727.
Abstract 440: Quantification of somatic chromosomal rearrangements in circulating cell-free DNA from ovarian cancers
Authors: Faye R. Harris, Irina Kovtun, James Smadbeck, Francesco Multinu, Aminah Jatoi, Kimberly R. Kalli, Stephen J. Murphy, Geoffrey C. Halling, Farhad Kosari, Sarah H. Johnson, Andrea Mariani, George Vasmatzis
Journal: Cancer Research (2016)

Abstract Circulating tumor DNA (ctDNA) provides great potential for the non-invasive clinical assessment of tumor burden. We developed a monitoring protocol using next generation mate-pair sequencing to identify chromosomal rearrangement signatures in primary tumors to follow ctDNA in blood. Primary tumors of 10 patients with ovarian cancer were sequenced, and individualized tumor-specific panels were designed to detect the junctions in ctDNA. A novel algorithm was developed and applied to data generated by quantitative PCR to calculate the percent of ctDNA. Selected junctions, some with potential as therapeutic targets, were detected in pre-surgically drawn blood in eight out of ten patients. Of these eight, three demonstrated the continued presence of circulating tumor DNA post-surgery, and five had undetectable levels, consistent with their documented presence or absence of disease. The detection of somatic junctions derived from ctDNA could be an effective way to monitor ovarian cancer patients for relapse and therapy response. Citation Format: Faye R. Harris, Irina Kovtun, James Smadbeck, Francesco Multinu, Aminah Jatoi, Kimberly R. Kalli, Stephen J. Murphy, Geoffrey C. Halling, Farhad Kosari, Sarah H. Johnson, Andrea Mariani, George Vasmatzis. Quantification of somatic chromosomal rearrangements in circulating cell-free DNA from ovarian cancers. [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 440.
Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells
Authors: Partow Kebriaei, Harjeet Singh, M. Helen Huls, Matthew J. Figliola, Roland Bassett, Simon Olivares, Bipulendu Jena, Margaret J. Dawson, Pappanaicken R. Kumaresan, Shihuang Su, Sourindra Maiti, Jianliang Dai, Branden Moriarity, Marie-Andrée Forget, Vladimir Senyukov, Aaron Orozco, Tingting Liu, Jessica McCarty, Rineka N. Jackson, Judy S. Moyes, Gabriela Rondon, Muzaffar Qazilbash, Stefan Ciurea, Amin Alousi, Yago Nieto, Katy Rezvani, David Marin, Uday Popat, Chitra Hosing, Elizabeth J. Shpall, Hagop Kantarjian, Michael Keating, William Wierda, Kim Anh Do, David A. Largaespada, Dean A. Lee, Perry B. Hackett, Richard E. Champlin, Laurence J.N. Cooper
Journal: Journal of Clinical Investigation (2016)

T cells expressing antigen-specific chimeric antigen receptors (CARs) improve outcomes for CD19-expressing B cell malignancies. We evaluated a human application of T cells that were genetically modified using the Sleeping Beauty (SB) transposon/transposase system to express a CD19-specific CAR.T cells were genetically modified using DNA plasmids from the SB platform to stably express a second-generation CD19-specific CAR and selectively propagated ex vivo with activating and propagating cells (AaPCs) and cytokines. Twenty-six patients with advanced non-Hodgkin lymphoma and acute lymphoblastic leukemia safely underwent hematopoietic stem cell transplantation (HSCT) and infusion of CAR T cells as adjuvant therapy in the autologous (n = 7) or allogeneic settings (n = 19).SB-mediated genetic transposition and stimulation resulted in 2,200- to 2,500-fold ex vivo expansion of genetically modified T cells, with 84% CAR expression, and without integration hotspots. Following autologous HSCT, the 30-month progression-free and overall survivals were 83% and 100%, respectively. After allogeneic HSCT, the respective 12-month rates were 53% and 63%. No acute or late toxicities and no exacerbation of graft-versus-host disease were observed. Despite a low antigen burden and unsupportive recipient cytokine environment, CAR T cells persisted for an average of 201 days for autologous recipients and 51 days for allogeneic recipients.CD19-specific CAR T cells generated with SB and AaPC platforms were safe, and may provide additional cancer control as planned infusions after HSCT. These results support further clinical development of this nonviral gene therapy approach.Autologous, NCT00968760; allogeneic, NCT01497184; long-term follow-up, NCT01492036.National Cancer Institute, private foundations, and institutional funds. Please see Acknowledgments for details.
Abstract 1239: NVP-HDM201: Biochemical and biophysical profile of a novel highly potent and selective PPI inhibitor of p53-Mdm2
Authors: Thérèse Stachyra-Valat, Frédéric Baysang, Anne-Cécile D’Alessandro, Erdmann Dirk, Pascal Furet, Vito Guagnano, Joerg Kallen, Lukas Leder, Robert Mah, Keiichi Masuya, Stefan Stutz, Andrea Vaupel, Francesco Hofmann, Patrick Chène, Sébastien Jeay, Philipp Holzer
Journal: Cancer Research (2016)

Abstract An effective strategy to restore p53 activity in cancer cells containing wild type p53 is to inhibit the Mdm2-p53 protein-protein interaction (PPI). NVP-HDM201 is a novel PPI inhibitor currently under evaluation in a Phase I clinical trial. It binds to the p53 binding-site of the Mdm2 protein, disrupting the interaction of the two proteins and leading to the activation of the p53 pathway. NVP-HDM201 belongs to a novel chemical series with a distinct biophysical and biochemical profile. Affinity constant of NVP-HDM201 for Mdm2 is in the picomolar range, with a selectivity ratio greater than a 10000-fold vs. Mdm4. Analysis of its binding mode provides evidence for a distinct set of critical interactions between the small molecule and its target, as compared with our other Mdm2 inhibitor NVP-CGM097, and explains as to why NVP-HDM201 binds equally to human, mouse, rat and dog Mdm2. Characterization of its binding kinetics indicates that the optimized interactions of NVP-HDM201 with Mdm2 protein are responsible for the increased stabilization of the complex resulting in high potency against Mdm2. This feature, together with favorable physicochemical and drug-like properties, supported the selection of NVP-HDM201 for clinical development. Citation Format: Thérèse Stachyra-Valat, Frédéric Baysang, Anne-Cécile D’Alessandro, Erdmann Dirk, Pascal Furet, Vito Guagnano, Joerg Kallen, Lukas Leder, Robert Mah, Keiichi Masuya, Stefan Stutz, Andrea Vaupel, Francesco Hofmann, Patrick Chène, Sébastien Jeay, Philipp Holzer. NVP-HDM201: Biochemical and biophysical profile of a novel highly potent and selective PPI inhibitor of p53-Mdm2. [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 1239.
Transplantation of placenta-derived mesenchymal stem cells reduces hypoxic-ischemic brain damage in rats by ameliorating the inflammatory response
Authors: Hongfang Ding, Hui Zhang, Huifang Ding, Dong Li, Xinhao Yi, Xiaoxu Ma, Ruijuan Li, Mei Huang, Xiuli Ju
Journal: Cellular and Molecular Immunology (2015)
Abstract 3950: Optimization of a method for FACS analysis of checkpoint receptor expression on tumor infiltrating lymphocytes in clinical tumor samples
Authors: Norman Zhang, Qiyao Zhang, Yan Liu, Juntao Yu, Jingjing Wang, Jie Xu, Qunsheng Ji, Keith Wilcoxen, Jonathan Graves
Journal: Cancer Research (2016)

Abstract While immune checkpoint therapies against CTLA-4, PD-1 and PD-L1 have achieved promising clinical outcome recently, the dynamic therapeutic responses spanning individual patients and different cancer types warrant exploration and validation of additional therapeutic strategies. Since the expression of immune checkpoints in tumor infiltrating lymphocytes (TIL) has been of interest to the field, we attempted to analyze the expression of several checkpoint receptors on TILs in clinical tumor samples. Unexpectedly, a number of markers were subject to time-dependent degradation during the tissue disaggregation process. This degradation could be due to the proteolytic activity of a proteinase, which has been used commonly in various tissue disaggregation protocols. Analysis of the protein sequences verified the presence of the proteinase recognition sequences in the affected receptors. Using PHA-stimulated hPBMCs, we found and demonstrated that a specific protease was responsible for either partial or total degradation of these markers. To overcome this issue, we developed a protease-free tissue disaggregation method, which showed no adverse effect on protease affected cell membrane receptors, thus allowing for more reliable flow cytometric analysis of various TIL subpopulations. With this method, we analyzed these checkpoint receptors positivity of both CD4+ and CD8+ TILs and revealed a high degree of heterogeneity of these immune checkpoints in a number of tumor types, including lung, breast and gastric cancers. Analysis of the magnitude of lymphocyte infiltration to the tumor and expression of prominent immune checkpoints on CD4+ or CD8+ TILs will help understand the subtle interaction between tumor and the immune system in the tumor microenvironment and may provide guidance for clinical trials of novel combinatorial immuno-therapeutic strategies. Citation Format: Norman Zhang, Qiyao Zhang, Yan Liu, Juntao Yu, Jingjing Wang, Jie Xu, Qunsheng Ji, Keith Wilcoxen, Jonathan Graves. Optimization of a method for FACS analysis of checkpoint receptor expression on tumor infiltrating lymphocytes in clinical tumor samples. [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 3950.
Brexit will hamper introduction of seven day hospital services, expert warns
Authors: Abi Rimmer
Journal: BMJ (2016)

The United Kingdom’s exit from the European Union would make it more difficult to bring in seven day services in hospitals, an expert has warned.

Julian Bion, chief investigator of a research project looking at the provision of emergency, specialist led care at weekends, said it could take 20 years before seven day services were successfully introduced.1 Speaking at a Science Media Centre briefing in London on Monday 18 July, he said that seven day services were “unachievable with current funding, and post-Brexit it’s going to be even more …
Long-term antibiotics after ceftriaxone did not improve quality of life in persistent Lyme disease
Authors: John Meyerhoff
Journal: Annals of Internal Medicine (2016)

ACP Journal Club19 July 2016Long-term antibiotics after ceftriaxone did not improve quality of life in persistent Lyme diseaseJohn Meyerhoff, MDJohn Meyerhoff, MDSinai Hospital of Baltimore, Baltimore, Maryland, USA (J.M.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-2016-165-2-005 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationBerende A, ter Hofstede HJM, Vos FJ, et al. Randomized trial of longer-term therapy for symptoms attributed to Lyme disease. N Engl J Med. 2016;374:1209-20. https://pubmed.ncbi.nlm.nih.gov/27028911Clinical Impact RatingsGIM/FP/GP: Infectious Disease: Rheumatology: References1 Shapiro ED. Clinical practice. Lyme disease. N Engl J Med. 2014;370:1724-31. [PMID: 24785207] Google Scholar2 Coumou J, Herkes EA, Brouwer MC, et al. Ticking the right boxes: classification of patients suspected of Lyme borreliosis at an academic referral center in the Netherlands. Clin Microbiol Infect. 2015;21:368.e11-20. [PMID: 25658524] Google Scholar3 Shadick NA, Phillips CB, Sangha O, et al. Musculoskeletal and neurologic outcomes in patients with previously treated Lyme disease. Ann Intern Med. 1999;131:919-26. [PMID: 10610642] Google Scholar Author, Article, and Disclosure InformationAffiliations: Sinai Hospital of Baltimore, Baltimore, Maryland, USA (J.M.)This article was published at Annals.org on 5 July 2016. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 19 July 2016Volume 165, Issue 2Page: JC5Keywords36 item short form health surveyAdverse eventsAntibioticsDoxycyclineFatigueLyme diseasePharmacistsQuality of lifeRashes ePublished: 19 July 2016 Issue Published: 19 July 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Abstract 4237: Decreased hypoxia in a HER2+ breast cancer model following trastuzumab therapy
Authors: Anna G. Sorace, C. Chad Quarles, Violeta Sanchez, Thomas E. Yankeelov
Journal: Cancer Research (2016)

Abstract Introduction: Hypoxic tumors demonstrate treatment resistance with an increased risk of metastasis. Therefore, alleviating hypoxia has potential to improve efficiency of combination therapies. The primary goal of this study is to quantify alterations in hypoxia in response to trastuzumab in a murine model of HER2+ breast cancer through imaging and histology. Experimental Design: Mice were implanted subcutaneously with BT474 breast cancer cells (107) and randomly assigned into treated (10 mg/kg trastuzumab) or control (saline) groups. After tumors reached ∼250 mm3, animals (n = 32) were utilized to identify longitudinal changes in functional vascular through an intravenous injection of Hoechst 33342 nuclear stain (immediately prior to sacrifice) and hypoxia through pimonidazole intravenous injection (one hour prior to sacrifice). Tumors were extracted for immunofluorescence between days 0 through 7. Tumor sections were flash frozen and stained with anti-pimonidazole and propidium iodide (nuclear counterstain). Additionally, a set of tumors (n = 36) were sacrificed for immunohistochemistry (days 0 through 7), formalin fixed and stained for CA-IX. All stained sections were scanned in high resolution (20×) and quantitatively analyzed with Leica SCN400 software. Another cohort of animals (n = 10) were imaged with 18F-FMISO (fluoromisonidazole) PET between days 0 through 7 and quantified via mean tracer concentration (%ID/g). Results: Immunohistochemistry revealed significantly increased hypoxia in the control group compared to treated on days 3 (p = 0.03) and 7 (p = 0.002), as measured through CA-IX staining. Additionally, on day 4, functional vascular delivery was increased while hypoxia (pimonidazole) decreased in treated tumors compared to control. 18F-FMISO PET imaging corroborated histology findings with significantly decreased hypoxia in treated tumors compared to control tumors on day 7 (-47%; p&amp;lt;0.0001). Conclusion: Trastuzumab has been shown to decrease hypoxia, as measured through gold-standard immunofluorescence. Additionally, this trastuzumab-induced improvement in tumor hypoxia can be measured via clinically relevant, noninvasive imaging (18F-FMISO PET). Temporarily improving the tumor's functional vasculature and decreasing hypoxia during trastuzumab treatment has potential to enhance the effectiveness of combination therapies. Identifying windows of improved vascular and cellular normalization with noninvasive medical imaging provide opportunity to decrease resistance to standard-of-care treatments and optimize therapeutic timing and regimens. Citation Format: Anna G. Sorace, C. Chad Quarles, Violeta Sanchez, Thomas E. Yankeelov. Decreased hypoxia in a HER2+ breast cancer model following trastuzumab therapy. [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 4237.
Abstract 1521: Transcriptional networks of the normal human kidney
Authors: David Lindgren, Jennifer Hansson, Helen Nilsson, Krzysztof Krawczyk, Martin Johansson, Håkan Axelson
Journal: Cancer Research (2016)

Abstract The kidney is a complex but highly structured organ composed of more than 20 different cell types. Disturbances among these cell types leads to a plethora of diseases of acute or chronic type, some of which are life threatening. In addition, kidney cancer represents about 3 percent of all malignancies. Considerable efforts have been made to profile the different cell types of the kidney. However, these are mainly based on studies in rodents. In the current study we present a method, called composition based cellular stratification that define gene signatures specific to different cell types and regions of the kidney. The method uses correlation-based analyses of gene expression microarrays of needle core biopsies obtained from histologically normal kidney tissues. For example, a HNF-driven gene expression signatures of proximal tubuli cells could be defined. This signature was validated in publically available data at the gene expression as well as at the protein level. We employ these gene expression signatures as a framework to study expressional changes observed in renal cell carcinoma, thus increasing the possibility to pin-point cell specific alterations associated with the transformation of renal epithelial cells. Citation Format: David Lindgren, Jennifer Hansson, Helen Nilsson, Krzysztof Krawczyk, Martin Johansson, Håkan Axelson. Transcriptional networks of the normal human kidney. [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 1521.
Abstract 3376: Molecular drivers of endothelial hypoxic adaption during angiogenesis deciphered using the Berg Interrogative Biology® platform
Authors: Tony E. Walshe, Justin Bourdelais, Viatcheslav R. Akmaev, Leonardo O. Rodrigues, Socheata Lao, Stephane Gesta, Michael A. Kiebish, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain
Journal: Cancer Research (2016)

Abstract Angiogenesis is a key feature of tumor progression providing oxygen and nutrients required for tumor cell growth, hypoxia being a major driver of this phenomenon. A systems biology approach using the Berg Interrogative Biology® platform was implemented to identify drivers of the endothelial cell (EC) angiogenic response to hypoxia. To determine the proteomic profile of proliferating ECs and non-proliferating confluent ECs exposed to normoxia or hypoxia, a functional proteomic approach employing activity-based probes and phosphorylation analysis was utilized. Kinases and ATPases were labeled with ATP-binding domain enrichment probes and titanium dioxide enrichment of phosphopeptides was employed for capture of protein phosphorylation events. Phenotypic assays including proliferation rates, apoptosis, mitochondrial superoxide and ROS/NO signaling were included as a measure of EC phenotype. Comparative proteomics, kinase activity, phosphoproteomics and assay data were integrated using an AI based Bayesian Network Inference approach to investigate causal signaling networks in order to elucidate the complexity and dynamics of angiogenesis and more specifically, the role of hypoxia in driving intracellular signaling in response to changes in oxygen tension. High confidence causal networks identified novel proteins that modulate the EC hypoxic response, validation of which are in process. Previously characterized proteins that are responsive to hypoxia were also identified in the hypoxic, but not normoxic signaling networks, namely Aldoc, Rac1, mTor, Cav-1 and Bax. Endothelial proliferation rate is closely related to both hydrogen peroxide and nitric oxide signaling, as has previously been reported. Novel regulatory networks that determine these interactions were identified. Using the Berg Interrogative Biology® platform, we are deciphering both the effects of the hypoxic microenvironment, and the unique characteristics of proliferating ECs by applying integrated functional proteomic assays and a systems approach to determine global changes in intracellular signaling in response to hypoxia. Citation Format: Tony E. Walshe, Justin Bourdelais, Viatcheslav R. Akmaev, Leonardo O. Rodrigues, Socheata Lao, Stephane Gesta, Michael A. Kiebish, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain. Molecular drivers of endothelial hypoxic adaption during angiogenesis deciphered using the Berg Interrogative Biology® platform. [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 3376.